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Sample records for enantioselective mannich-type aza

  1. A chiral Brønsted acid-catalyzed highly enantioselective Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines.

    Science.gov (United States)

    Unhale, Rajshekhar A; Sadhu, Milon M; Ray, Sumit K; Biswas, Rayhan G; Singh, Vinod K

    2018-04-03

    A chiral phosphoric acid-catalyzed asymmetric Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines, derived from 3-hydroxyisoindolinones has been demonstrated in this communication. A variety of isoindolinone-based α-amino diazo esters bearing a quaternary stereogenic center were afforded in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). Furthermore, the synthetic utility of the products has been depicted by the hydrogenation of the diazo moiety of adducts.

  2. Enantioselective catalytic fluorinative aza-semipinacol rearrangement.

    Science.gov (United States)

    Romanov-Michailidis, Fedor; Pupier, Marion; Besnard, Céline; Bürgi, Thomas; Alexakis, Alexandre

    2014-10-03

    An efficient and highly stereoselective fluorinative aza-semipinacol rearrangement is described. The catalytic reaction requires use of Selectfluor in combination with the chiral, enantiopure phosphate anion derived from acid L3. Under optimized conditions, cyclopropylamines A were transformed into β-fluoro cyclobutylimines B in good yields and high levels of diastereo- and enantiocontrol. Furthermore, the optically active cyclobutylimines were reduced diastereoselectively with L-Selectride in the corresponding fluorinated amines C, compounds of significant interest in the pharmacological industry.

  3. L-Threonine-derived novel bifunctional phosphine-sulfonamide catalyst-promoted enantioselective aza-morita-Baylis-Hillman reaction

    KAUST Repository

    Zhong, Fangrui

    2011-03-18

    A series of novel bifunctional phosphine-sulfonamide organic catalysts were designed and readily prepared from natural amino acids, and they were utilized to promote enantioselective aza-Morita-Baylis-Hillman (MBH) reactions. l-Threonine-derived phosphine-sulfonamide 9b was found to be the most efficient catalyst, affording the desired aza-MBH adducts in high yields and with excellent enantioselectivities. © 2011 American Chemical Society.

  4. Asymmetric NHC-catalyzed aza-Diels-Alder reactions: Highly enantioselective route to α-amino acid derivatives and DFT calculations

    KAUST Repository

    Yang, Limin; Wang, Fei; Lee, Richmond; Lv, Yunbo; Huang, Kuo-Wei; Zhong, Guofu

    2014-01-01

    A facile N-heterocyclic carbene catalytic enantioselective aza-Diels-Alder reaction of oxodiazenes with α-chloroaldehydes as dienophile precursors is reported, with excellent enantioselectivity (ee > 99%) and excellent yield (up to 93%). DFT study

  5. The origin of enantioselectivity in the l-threonine-derived phosphine-sulfonamide catalyzed aza-Morita-Baylis-Hillman reaction: Effects of the intramolecular hydrogen bonding

    KAUST Repository

    Lee, Richmond

    2013-01-01

    l-Threonine-derived phosphine-sulfonamide 4 was identified as the most efficient catalyst to promote enantioselective aza-Morita-Baylis-Hillman (MBH) reactions, affording the desired aza-MBH adducts with excellent enantioselectivities. Density functional theory (DFT) studies were carried out to elucidate the origin of the observed enantioselectivity. The importance of the intramolecular N-H⋯O hydrogen-bonding interaction between the sulfonamide and enolate groups was identified to be crucial in inducing a high degree of stereochemical control in both the enolate addition to imine and the subsequent proton transfer step, affording aza-MBH reactions with excellent enantioselectivity. © 2013 The Royal Society of Chemistry.

  6. The origin of enantioselectivity in the l-threonine-derived phosphine-sulfonamide catalyzed aza-Morita-Baylis-Hillman reaction: Effects of the intramolecular hydrogen bonding

    KAUST Repository

    Lee, Richmond; Zhong, Fangrui; Zheng, Bin; Meng, Yuezhong; Lu, Yixin; Huang, Kuo-Wei

    2013-01-01

    in inducing a high degree of stereochemical control in both the enolate addition to imine and the subsequent proton transfer step, affording aza-MBH reactions with excellent enantioselectivity. © 2013 The Royal Society of Chemistry.

  7. Asymmetric NHC-catalyzed aza-Diels-Alder reactions: Highly enantioselective route to α-amino acid derivatives and DFT calculations

    KAUST Repository

    Yang, Limin

    2014-08-01

    A facile N-heterocyclic carbene catalytic enantioselective aza-Diels-Alder reaction of oxodiazenes with α-chloroaldehydes as dienophile precursors is reported, with excellent enantioselectivity (ee > 99%) and excellent yield (up to 93%). DFT study showed that cis-TSa, formed from a top face approach of oxodiazene to cis-IIa, is the most favorable transition state and is consistent with the experimental observations. © 2014 American Chemical Society.

  8. Choline-based biodegradable ionic liquid catalyst for Mannich-type

    Indian Academy of Sciences (India)

    Choline-based biodegradable ionic liquid catalyst for Mannich-type reaction ... Abstract. A three-component Mannich-type reaction of aromatic aldehydes, ketones, and amines was catalyzed by a novel ... Journal of Chemical Sciences | News.

  9. The Brønsted Acid-Catalyzed, Enantioselective Aza-Diels-Alder Reaction for the Direct Synthesis of Chiral Piperidones.

    Science.gov (United States)

    Weilbeer, Claudia; Sickert, Marcel; Naumov, Sergei; Schneider, Christoph

    2017-01-12

    We disclose herein the first enantioselective aza-Diels-Alder reaction of β-alkyl-substituted vinylketene silyl-O,O-acetals and imines furnishing a broad range of optically highly enriched 4-alkyl-substituted 2-piperidones. As a catalyst for this one-pot reaction we employed a chiral phosphoric acid which effects a vinylogous Mannich reaction directly followed by ring-closure to the lactam. Subsequent fully diastereoselective transformations including hydrogenation, enolate alkylation, and lactam alkylation/reduction processes converted the cycloadducts into various highly substituted piperidines of great utility for the synthesis of natural products and medicinally active compounds. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. ALDOL- AND MANNICH-TYPE REACTIONS VIA IN SITU OLEFIN MIGRATION IN IONIC LIQUID

    Science.gov (United States)

    An aldol-type and a Mannich-type reaction via the cross-coupling of aldehydes and imines with allylic alcohols catalyzed by RuCl2(PPh3)3 was developed with ionic liquid as the solvent. The solvent/catalyst system could be reused for at least five times with no loss of reactiv...

  11. Asymmetric Brønsted acid-catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene

    Directory of Open Access Journals (Sweden)

    Magnus Rueping

    2012-10-01

    Full Text Available A new chiral Brønsted acid-catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene has been developed. The reaction provides optically active aza-tetracycles in good yields with high diastereo- and enantioselectivities under mild reaction conditions.

  12. Application of the aza-Diels-Alder reaction in the synthesis of natural products.

    Science.gov (United States)

    Cao, Min-Hui; Green, Nicholas J; Xu, Sheng-Zhen

    2017-04-11

    The Diels-Alder reaction that involves a nitrogen atom in the diene or dienophile is termed the aza-Diels-Alder reaction. As well as the powerful all-carbon Diels-Alder reaction, the aza-Diels-Alder reaction has also played an important role in the total synthesis of natural products. Herein, we review various natural products using an aza-Diels-Alder reaction as a key step to their total synthesis, and divide the syntheses into inter- and intra-molecular aza-Diels-Alder reactions and a retro-aza-Diels-Alder reaction. Inter- and intra-molecular aza-Diels-Alder reactions involve an imine as an electron deficient dienophile and an imine as an electron deficient azadiene. The significance of the aza-Diels-Alder reaction for the construction of a six-membered ring containing nitrogen is tremendous, but the development of asymmetric, in particular catalytic enantioselective intramolecular aza-Diels-Alder reaction in the total synthesis of natural products remains highly challenging, and will no doubt see enormous advances in the future.

  13. Highly efficient and generalized asymmetric synthesis of quaternary stereogenic carbon-containing β-amino indanones/indanoles via Mannich-type additions between 1-indanones and N-tert-butanesulfinylketimines.

    Science.gov (United States)

    Wu, Lingmin; Xie, Chen; Mei, Haibo; Soloshonok, Vadim A; Han, Jianlin; Pan, Yi

    2014-07-14

    Here we report that, unlike other ketones, 1-indanone and acetophenone derived enolates undergo Mannich-type addition reactions with N-tert-butanesulfinyl ketimines with excellent yields (up to 98%) and diastereoselectivity (>99/1). The resulting compounds represent a new type of biologically relevant β-aminoketone derivative bearing quaternary stereogenic carbon, which could be further converted into the corresponding β-amino ketones and β-amino alcohols, possessing three consecutive stereogenic centres.

  14. Organocatalytic aza-Michael/retro-aza-Michael reaction: pronounced chirality amplification in aza-Michael reaction and racemization via retro-aza-Michael reaction.

    Science.gov (United States)

    Cai, Yong-Feng; Li, Li; Luo, Meng-Xian; Yang, Ke-Fang; Lai, Guo-Qiao; Jiang, Jian-Xiong; Xu, Li-Wen

    2011-05-01

    A detailed experimental investigation of an aza-Michael reaction of aniline and chalcone is presented. A series of Cinchona alkaloid-derived organocatalysts with different functional groups were prepared and used in the aza-Michael and retro-aza-Michael reaction. There was an interesting finding that a complete reversal of stereoselectivity when a benzoyl group was introduced to the cinchonine and cinchonidine. The chirality amplification vs. time proceeds in the quinine-derived organocatalyst containing silicon-based bulky group, QN-TBS, -catalyzed aza-Michael reaction under solvent-free conditions. In addition, we have demonstrated for the first time that racemization was occurred in suitable solvents under mild conditions due to retro-aza-Michael reaction of the Michael adduct of aniline with chalcone. These indicate the equilibrium of retro-aza-Michael reaction and aza-Michael reaction produce the happening of chirality amplification in aza-Michael reaction and racemization via retro-aza-Michael reaction under different conditions, which would be beneficial to the development of novel chiral catalysts for the aza-Michael reactions. Copyright © 2011 Wiley-Liss, Inc.

  15. [Manuel Azaña and psychology].

    Science.gov (United States)

    Bandrés, Javier; Llavona, Rafael

    2010-08-01

    Manuel Azaña (1880-1940) was President of the II Spanish Republic and one of the most influential intellectuals of the Republican culture. His doctoral thesis addressed some of the social psychology problems of his time regarding the issue of the legal responsibility of the masses. Azaña also showed interest in psychology during his time as a grantee in Paris and he became a close friend of two of the most influential Spanish psychologists: Luis Simarro y Gonzalo Rodríguez Lafora. Azaña's biography reflects the rise of Spanish psychologists of the early 20th century and their tragic dispersion at the end of the Spanish Civil War.

  16. Application of 7-azaisatins in enantioselective Morita–Baylis–Hillman reaction

    Directory of Open Access Journals (Sweden)

    Qing He

    2016-02-01

    Full Text Available 7-Azaisatin and 7-azaoxindole skeletons are valuable building blocks in diverse biologically active substances. Here 7-azaisatins turned out to be more efficient electrophiles than the analogous isatins in the enantioselective Morita–Baylis–Hillman (MBH reactions with maleimides using a bifunctional tertiary amine, β-isocupreidine (β-ICD, as the catalyst. This route allows a convenient approach to access multifunctional 3-hydroxy-7-aza-2-oxindoles with high enantiopurity (up to 94% ee. Other types of activated alkenes, such as acrylates and acrolein, could also be efficiently utilized.

  17. A Tunable and Enantioselective Hetero-Diels-Alder Reaction Provides Access to Distinct Piperidinoyl Spirooxindoles.

    Science.gov (United States)

    Jayakumar, Samydurai; Louven, Kathrin; Strohmann, Carsten; Kumar, Kamal

    2017-12-11

    The active complexes of chiral N,N'-dioxide ligands with dysprosium and magnesium salts catalyze the hetero-Diels-Alder reaction between 2-aza-3-silyloxy-butadienes and alkylidene oxindoles to selectively form 3,3'- and 3,4'-piperidinoyl spirooxindoles, respectively, in very high yields and with excellent enantioselectivities. The exo-selective asymmetric cycloaddition successfully regaled the construction of sp 3 -rich and highly substituted natural-product-based spirooxindoles supporting many chiral centers, including contiguous all-carbon quaternary centers. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Catalytic Wittig and aza-Wittig reactions

    Directory of Open Access Journals (Sweden)

    Zhiqi Lao

    2016-11-01

    Full Text Available This review surveys the literature regarding the development of catalytic versions of the Wittig and aza-Wittig reactions. The first section summarizes how arsenic and tellurium-based catalytic Wittig-type reaction systems were developed first due to the relatively easy reduction of the oxides involved. This is followed by a presentation of the current state of the art regarding phosphine-catalyzed Wittig reactions. The second section covers the field of related catalytic aza-Wittig reactions that are catalyzed by both phosphine oxides and phosphines.

  19. Aza-Michael reaction: achievements and prospects

    International Nuclear Information System (INIS)

    Rulev, Alexander Yu

    2011-01-01

    Data published in the last 10 years on the use of the aza-Michael reaction in organic synthesis are described systematically. The attention is focused on environmentally friendly processes following green chemistry principles and on methods for the synthesis of compounds that are difficult to access by other routes.

  20. Cross-conjugated Trienamine Catalysis with α'-Alkylidene 2-Cyclohexenones: Application in β,γ-Regioselective Aza-Diels-Alder Reaction.

    Science.gov (United States)

    Zhou, Zhi; Wang, Zhou-Xiang; Ouyang, Qin; Xiao, Wei; Du, Wei; Chen, Ying-Chun

    2017-02-24

    Endo-type cross-conjugated trienamines between highly congested α'-alkylidene 2-cyclohexenones and a chiral primary amine catalyst serve as HOMO-raised dienophiles in inverse-electron-demand aza-Diels-Alder cycloadditions with a number of 1-azadiene substrates. The reactions exhibit exclusive β,γ-regioselectivity, and multifunctional products with high molecular complexity are efficiently constructed in excellent diastereo- and enantioselectivity (>19:1 d.r., up to 99 % ee). © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Exo selective enantioselective nitrone cycloadditions.

    Science.gov (United States)

    Sibi, Mukund P; Ma, Zhihua; Jasperse, Craig P

    2004-01-28

    We have developed a novel method for accessing exo adducts with high enantioselectivity in nitrone cycloadditions to enoates. Pyrazolidinones proved to be effective achiral templates in the cycloadditions, providing exo adducts typically in >15:1 selectivity and 90-98% ee. The use of Lewis acids that form square planar complexes, such as copper triflate, was important for obtaining high exo selectivity.

  2. Cyclopalladated complexes in enantioselective catalysis

    Energy Technology Data Exchange (ETDEWEB)

    Dunina, Valeria V; Gorunova, Olga N; Zykov, P A; Kochetkov, Konstantin A

    2011-01-31

    The results of the use of optically active palladacycles in enantioselective catalysis of [3,3]-sigmatropic rearrangements, aldol condensation, the Michael reaction and cross-coupling are analyzed. Reactions with allylic substrates or reagents and some other transformations are considered.

  3. Catalytic enantioselective Reformatsky reaction with ketones

    NARCIS (Netherlands)

    Fernandez-Ibanez, M. Angeles; Macia, Beatriz; Minnaard, Adriaan J.; Feringa, Ben L.

    2008-01-01

    Chiral tertiary alcohols were obtained with good yields and enantioselectivities via a catalytic Reformatsky reaction with ketones, including the challenging diaryl ketones, using chiral BINOL derivatives.

  4. The enantioselective total synthesis of (+)-clusianone.

    Science.gov (United States)

    Horeischi, Fiene; Guttroff, Claudia; Plietker, Bernd

    2015-02-11

    (+)-Clusianone, an exo-type B PPAP with reported anti-HIV and chemoprotective activities, was synthesized in eleven steps with 97% ee starting from acetylacetone. An enantioselective decarboxylative Tsuji-Trost-allylation and a Ru-catalyzed ring-closing metathesis-decarboxylative allylation were used to control both diastereo- and enantioselectivity.

  5. Copper(I)-Catalyzed Asymmetric Desymmetrization through Inverse-Electron-Demand aza-Diels-Alder Reaction: Efficient Access to Tetrahydropyridazines Bearing a Unique α-Chiral Silane Moiety.

    Science.gov (United States)

    Wei, Liang; Zhou, Yu; Song, Zhi-Min; Tao, Hai-Yan; Lin, Zhenyang; Wang, Chun-Jiang

    2017-04-11

    An unprecedented copper(I)-catalyzed asymmetric desymmetrization of 5-silylcyclopentadienes with in situ formed azoalkene was realized through an inverse-electron-demand aza-Diels-Alder reaction (IEDDA) pathway, in which 5-silylcyclopentadienes served as efficient enophiles. This new protocol provides a facile access to the biologically important heterocyclic tetrahydropyridazines containing a unique α-chiral silane motif and three adjoining stereogenic centers in generally good yield (up to 92 %) with exclusive regioselectivity, high diastereoselectivity (>20:1 diastereomeric ratio), and excellent enantioselectivity (up to 98 % enantiomeric excess). DFT calculations and control experiments further confirmed the proposed reaction mechanism. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Enantioselective synthesis of tetrafluorinated ribose and fructose.

    Science.gov (United States)

    Linclau, Bruno; Boydell, A James; Timofte, Roxana S; Brown, Kylie J; Vinader, Victoria; Weymouth-Wilson, Alexander C

    2009-02-21

    A perfluoroalkylidene lithium mediated cyclisation approach for the enantioselective synthesis of a tetrafluorinated aldose (ribose) and of a tetrafluorinated ketose (fructose), both in the furanose and in the pyranose form, is described.

  7. Kinetic investigation on enantioselective hydrolytic resolution of ...

    African Journals Online (AJOL)

    Kinetic investigation on enantioselective hydrolytic resolution of epichlorohydrin by crude epoxide hydrolase from domestic duck liver. X Ling, D Lu, J Wang, J Chen, L Ding, J Chen, H Chai, P Ouyang ...

  8. Enantioselective addition of nitrones to activated cyclopropanes.

    Science.gov (United States)

    Sibi, Mukund P; Ma, Zhihua; Jasperse, Craig P

    2005-04-27

    In this paper, we demonstrate the first examples of chiral Lewis acid catalysis in the formation of tetrahydro-1,2-oxazines with very high enantioselectivity starting with diactivated cyclopropanes and nitrones (>90% yields and ee). Reactions with racemic substituted cyclopropanes provide approximately 1:1 diastereomeric tetrahydro-1,2-oxazine products with high enantioselectivity. Mechanistic information for the formation of the tetrahydro-1,2-oxazines is also detailed.

  9. 5-AZA-2'-DEOXYCYTIDINE INDUCED CYTOTOXICITY AND LONG BONE REDUCTION DEFECTS IN THE MURINE LIMB

    Science.gov (United States)

    The antineoplastic drug 5-aza-2'-deoxycytidine (dAZA) is a DNA hypomethylating agent that can be used to induce hind limb phocomelia in the offspring of CD-1 Swiss Webster mice. Previously, our laboratory investigated the possibility that dAZA induced alterations in gene express...

  10. The Catalytic Enantioselective Total Synthesis of (+)‐Liphagal

    DEFF Research Database (Denmark)

    Day, Joshua J.; McFadden, Ryan M.; Virgil, Scott C.

    2011-01-01

    Ring a ding: The first catalytic enantioselective total synthesis of the meroterpenoid natural product (+)-liphagal is disclosed. The approach showcases a variety of technology including enantioselective enolate alkylation, a photochemical alkyne-alkene [2+2] reaction, microwaveassisted metal...

  11. Aza-Michael Reaction for an Undergraduate Organic Chemistry Laboratory

    Science.gov (United States)

    Nigam, Manisha; Rush, Brittney; Patel, Jay; Castillo, Raul; Dhar, Preeti

    2016-01-01

    A green, aza-Michael reaction is described that can be used to teach undergraduate students conjugate addition of nitrogen nucleophile to an a,ß-unsaturated ester. Students analyze spectral data of the product obtained from the assigned reaction to determine product structure and propose the mechanism of its formation. The experiment requires…

  12. Enantioselective Biotransformation of Chiral Persistent Organic Pollutants.

    Science.gov (United States)

    Zhang, Ying; Ye, Jing; Liu, Min

    2017-01-01

    Enantiomers of chiral compounds commonly undergo enantioselective transformation in most biologically mediated processes. As chiral persistent organic pollutants (POPs) are extensively distributed in the environment, differences between enantiomers in biotransformation should be carefully considered to obtain exact enrichment and specific health risks. This review provides an overview of in vivo biotransformation of chiral POPs currently indicated in the Stockholm Convention and their chiral metabolites. Peer-reviewed journal articles focused on the research question were thoroughly searched. A set of inclusion and exclusion criteria were developed to identify relevant studies. We mainly compared the results from different animal models under controlled laboratory conditions to show the difference between enantiomers in terms of distinct transformation potential. Interactions with enzymes involved in enantioselective biotransformation, especially cytochrome P450 (CYP), were discussed. Further research areas regarding this issue were proposed. Limited evidence for a few POPs has been found in 30 studies. Enantioselective biotransformation of α-hexachlorocyclohexane (α-HCH), chlordane, dichlorodiphenyltrichloroethane (DDT), heptachlor, hexabromocyclododecane (HBCD), polychlorinated biphenyls (PCBs), and toxaphene, has been investigated using laboratory mammal, fish, bird, and worm models. Tissue and excreta distributions, as well as bioaccumulation and elimination kinetics after administration of racemate and pure enantiomers, have been analyzed in these studies. Changes in enantiomeric fractions have been considered as an indicator of enantioselective biotransformation of chiral POPs in most studies. Results of different laboratory animal models revealed that chiral POP biotransformation is seriously affected by chirality. Pronounced results of species-, tissue-, gender-, and individual-dependent differences are observed in in vivo biotransformation of chiral POPs

  13. The Development of an Aza-C-Glycoside Library Based on a Tandem Staudinger/Aza-Wittig/Ugi Three-Component Reaction

    NARCIS (Netherlands)

    Wennekes, T.; Bonger, K.M.; Vogel, K.; Berg, van den S.A.; Strijland, A.; Donker-Koopman, W.E.; Aerts, J.; Marel, van der A.; Overkleeft, H.S.

    2012-01-01

    We report the tandem Staudinger/aza-Wittig/Ugi three-component reaction mediated synthesis of a 64-member compound library of aza-C-glycosides. The library is composed of four pyrrolidine and three piperidine scaffolds, onto which a number of functional groups is grafted to form seven sublibraries.

  14. 5-Aza-2'-deoxycytidine synergistic action with thymidine on leukemic cells and interaction of 5-aza-dCMP with dCMP deaminase

    International Nuclear Information System (INIS)

    Momparler, R.L.; Bartolucci, S.; Bouchard, J.; Momparler, L.F.; Raia, C.A.; Rossi, M.

    1986-01-01

    The authors observe a synergistic antineoplastic effect between 5-AZA-dCR and dTR on leukemia cells in culture. In order to understand the mechanism behind this interaction the authors investigate the effects of dTTP on the deamination of 5-aza-2'-deoxycytidine-5'-monophosphate (5-AZA-dCMP) by dCMP deaminase. The effects of 5-AZA-dCTP on this enzyme is also studied. The incorporation of tritium-5-AZA-Cdr into DNA of leukemic cells was performed. The amount of radioactivity incorproated into DNA was determined by trapping the cells on GF/C glass fiber filters and washing with cold TCA. It is shown that the modulation of the atieoplastic activity of deoxycytidine analogs by allosteric effectors such as dTTP may have the potential to increase the effectiveness of the chemotherapy for acute leukemia

  15. Reversal of the sense of enantioselectivity between 1-and 2-aza[6]helicenes used as chiral inducers of asymmetric autocatalysis

    Czech Academy of Sciences Publication Activity Database

    Matsumoto, A.; Yonemitsu, K.; Ozaki, H.; Míšek, Jiří; Starý, Ivo; Stará, Irena G.; Soai, K.

    2017-01-01

    Roč. 15, č. 6 (2017), s. 1321-1324 ISSN 1477-0520 R&D Projects: GA ČR(CZ) GA14-29667S Institutional support: RVO:61388963 Keywords : azahelicene * Soai reaction * asymmetric autocatalysis Subject RIV: CC - Organic Chemistry OBOR OECD: Organic chemistry Impact factor: 3.564, year: 2016 http://pubs.rsc.org/en/content/articlehtml/2013/ob/c6ob02745h

  16. CSA/AZA, in the absence of prednisone, improves linear growth in renal transplanted children.

    Science.gov (United States)

    David-Neto, E; Nahas, W; Sampaio, E C; Ianhez, L E; Sabbaga, E; Arap, S

    1992-01-01

    We compared the results of 44 renal transplants in children, of whom 24 were treated with CSA/AZA and 20 with prednisone in combination with AZA and/or CSA. There were no differences in age distribution or mean ages at transplant between the two treatment groups. The CSA/AZA group had a longer follow-up (29 +/- 33 vs 17 +/- 18 months). At the last follow-up, five children in the CSA/AZA and none in the prednisone group had lost their grafts. Serum creatinine increased in both groups from 0.7 +/- 0.1 mg/dl and 0.9 +/- 0.1 mg/dl at the end of the first month to 1.1 +/- 0.2 mg/dl in the 36th month (CSA/AZA group) (P renal transplant in children, but only 75% tolerated AZA/CSA without same damage to their grafts.

  17. The Catalytic Enantioselective Total Synthesis of (+)-Liphagal

    KAUST Repository

    Day, Joshua J.

    2011-06-10

    Ring a ding: The meroterpenoid natural product (+)-liphagal has been synthesized enantioselectively in 19 steps from commercially available materials. The trans-homodecalin system was achieved by ring expansion followed by stereoselective hydrogenation. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. The Catalytic Enantioselective Total Synthesis of (+)-Liphagal

    KAUST Repository

    Day, Joshua J.; McFadden, Ryan M.; Virgil, Scott C.; Kolding, Helene; Alleva, Jennifer L.; Stoltz, Brian M.

    2011-01-01

    Ring a ding: The meroterpenoid natural product (+)-liphagal has been synthesized enantioselectively in 19 steps from commercially available materials. The trans-homodecalin system was achieved by ring expansion followed by stereoselective hydrogenation. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Enantioselective properties of induced lipases from Geotrichum

    Czech Academy of Sciences Publication Activity Database

    Zarevúcka, Marie; Kejík, Z.; Šaman, David; Wimmer, Zdeněk; Demnerová, K.

    2005-01-01

    Roč. 37, - (2005), s. 481-486 ISSN 0141-0229 R&D Projects: GA MŠk(CZ) OC D30.001; GA MŠk(CZ) OC D13.10 Institutional research plan: CEZ:AV0Z40550506 Keywords : Geotrichum * lipase * enantioselectivity Subject RIV: CC - Organic Chemistry Impact factor: 1.705, year: 2005

  20. Enantioselective pharmacokinetics of sibutramine in rat.

    Science.gov (United States)

    Noh, Keumhan; Bae, Kyoungjin; Min, Bokyoung; Kim, Eunyoung; Kwon, Kwang-il; Jeong, Taecheon; Kang, Wonku

    2010-02-01

    Racemic sibutramine is widely used to treat obesity owing to its inhibition of serotonin and noradrenaline reuptake in synapses. Although the enantioselective effects of sibutramine and its two active desmethyl-metabolites, monodesmethylsibutramine (MDS) and didesmethylsibutramine (DDS), on anorexia and energy expenditure have been elucidated, the enantioselective pharmacokinetics of sibutramine are still unclear. Therefore, we aimed to characterize the enantioselective pharmacokinetics of sibutramine and its metabolites in plasma and urine following an intravenous and a single oral administration of sibutramine in rats. The absolute bioavailability of sibutramine was only about 7%. The pharmacologically less effective S-isomer of DDS was predominant in the plasma: the C ( max ) and the AUC ( inf ) were 28 and 30 times higher than those of the R-isomer, respectively (psibutramine metabolites MDS and DDS were present at lower concentrations, owing to their rapid biotransformation to hydroxylated and/or carbamoylglucuronized forms and their faster excretion in the urine. The present study is the first to elucidate the enantioselective pharmacokinetics of sibutramine in rats.

  1. Enantioselectivity in environmental risk assessment of modern chiral pesticides

    International Nuclear Information System (INIS)

    Ye Jing; Zhao Meirong; Liu Jing; Liu Weiping

    2010-01-01

    Chiral pesticides comprise a new and important class of environmental pollutants nowadays. With the development of industry, more and more chiral pesticides will be introduced into the market. But their enantioselective ecotoxicology is not clear. Currently used synthetic pyrethroids, organophosphates, acylanilides, phenoxypropanoic acids and imidazolinones often behave enantioselectively in agriculture use and they always pose unpredictable enantioselective ecological risks on non-target organisms or human. It is necessary to explore the enantioselective toxicology and ecological fate of these chiral pesticides in environmental risk assessment. The enantioselective toxicology and the fate of these currently widely used pesticides have been discussed in this review article. - Chiral pesticides could pose unpredictable enantioselective toxicity on non-target organisms.

  2. A general enantioselective route to the chamigrene natural product family

    KAUST Repository

    White, David E.

    2010-06-01

    Described in this report is an enantioselective route toward the chamigrene natural product family. The key disconnections in our synthetic approach include sequential enantioselective decarboxylative allylation and ring-closing olefin metathesis to form the all-carbon quaternary stereocenter and spirocyclic core present in all members of this class of compounds. The generality of this strategy is demonstrated by the first total syntheses of elatol and the proposed structure of laurencenone B, as well as the first enantioselective total syntheses of laurencenone C and α-chamigrene. A brief exploration of the substrate scope of the enantioselective decarboxylative allylation/ring-closing metathesis sequence with fully substituted vinyl chlorides is also presented.

  3. A general enantioselective route to the chamigrene natural product family

    KAUST Repository

    White, David E.; Stewart, Ian C.; Seashore-Ludlow, Brinton A.; Grubbs, Robert H.; Stoltz, Brian M.

    2010-01-01

    Described in this report is an enantioselective route toward the chamigrene natural product family. The key disconnections in our synthetic approach include sequential enantioselective decarboxylative allylation and ring-closing olefin metathesis to form the all-carbon quaternary stereocenter and spirocyclic core present in all members of this class of compounds. The generality of this strategy is demonstrated by the first total syntheses of elatol and the proposed structure of laurencenone B, as well as the first enantioselective total syntheses of laurencenone C and α-chamigrene. A brief exploration of the substrate scope of the enantioselective decarboxylative allylation/ring-closing metathesis sequence with fully substituted vinyl chlorides is also presented.

  4. Vancomycin Molecular Interactions: Antibiotic and Enantioselective Mechanisms

    Science.gov (United States)

    Ward, Timothy J.; Gilmore, Aprile; Ward, Karen; Vowell, Courtney

    Medical studies established that vancomycin and other related macrocyclic antibiotics have an enhanced antimicrobial activity when they are associated as dimers. The carbohydrate units attached to the vancomycin basket have an essential role in the dimerization reaction. Covalently synthesized dimers were found active against vancomycin-resistant bacterial strains. A great similarity between antibiotic potential and enantioselectivity was established. A covalent vancomycin dimer was studied in capillary electrophoresis producing excellent chiral separation of dansyl amino acids. Balhimycin is a macrocyclic glycopeptide structurally similar to vancomycin. The small differences are, however, responsible for drastic differences in enantioselectivity in the same experimental conditions. Contributions from studies examining vancomycin's mechanism for antimicrobial activity have substantially aided our understanding of its mechanism in chiral recognition.

  5. A Divergent Mechanistic Course of Pd(0)-Catalyzed Aza-Claisen Rearrangement and Aza-Rautenstrauch-Type Cyclization of N-Allyl-Ynamides

    Science.gov (United States)

    DeKorver, Kyle A.; Hsung, Richard P.; Lohse, Andrew G.; Zhang, Yu

    2010-01-01

    A fascinating mechanistic study of ynamido-palladium-π-allyl complexes is described that features isolation of a unique silyl-ketenimine via aza-Claisen rearrangement, which can be accompanied by an unusual thermal N-to-C 1,3-Ts shift in the formation of tertiary nitriles, and a novel cyclopentenimine formation via a palladium catalyzed aza-Rautenstrauch-type cyclization pathway. PMID:20337418

  6. Fluxional additives: a second generation control in enantioselective catalysis.

    Science.gov (United States)

    Sibi, Mukund P; Manyem, Shankar; Palencia, Hector

    2006-10-25

    The concept of "fluxional additives", additives that can adopt enantiomeric conformations depending on the chiral information in the ligand, is demonstrated in enantioselective Diels-Alder and nitrone cycloaddition reactions. The additive design is modular, and diverse structures are accessible in three steps. Chiral Lewis acids from main group and transition metals show enhancements in enantioselectivity in the presence of these additives.

  7. Tin-free enantioselective radical reactions using silanes.

    Science.gov (United States)

    Sibi, Mukund P; Yang, Yong-Hua; Lee, Sunggi

    2008-12-04

    Readily available hexyl silane is an excellent choice as a H-atom donor and a chain carrier in Lewis acid mediated enantioselective radical reactions. Conjugate radical additions to alpha,beta-unsaturated imides at room temperature proceed in good yields and excellent enantioselectivities.

  8. Chiral amides via copper-catalysed enantioselective conjugate addition

    NARCIS (Netherlands)

    Schoonen, Anne K.; Fernández-Ibáñez, M. Ángeles; Fañanás-Mastral, Martín; Teichert, Johannes F.; Feringa, Bernard

    2014-01-01

    A highly enantioselective one pot procedure for the synthesis of beta-substituted amides was developed starting from the corresponding alpha,beta-unsaturated esters. This new methodology is based on the copper-catalysed enantioselective conjugate addition of Grignard reagents to

  9. Kinetic mechanism and enantioselectivity of halohydrin dehalogenase from Agrobacterium radiobacter

    NARCIS (Netherlands)

    Tang, Lixia; Lutje Spelberg, Jeffrey H.; Fraaije, Marco W.; Janssen, DB

    2003-01-01

    Halohydrin dehalogenase (HheC) from Agrobacterium radiobacter AD1 catalyzes the reversible intramolecular nucleophilic displacement of a halogen by a hydroxyl group in vicinal haloalcohols, producing the corresponding epoxides. The enzyme displays high enantioselectivity toward some aromatic

  10. Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals

    Science.gov (United States)

    Kern, Nicolas; Plesniak, Mateusz P.; McDouall, Joseph J. W.; Procter, David J.

    2017-12-01

    The rapid generation of molecular complexity from simple starting materials is a key challenge in synthesis. Enantioselective radical cyclization cascades have the potential to deliver complex, densely packed, polycyclic architectures, with control of three-dimensional shape, in one step. Unfortunately, carrying out reactions with radicals in an enantiocontrolled fashion remains challenging due to their high reactivity. This is particularly the case for reactions of radicals generated using the classical reagent, SmI2. Here, we demonstrate that enantioselective SmI2-mediated radical cyclizations and cascades that exploit a simple, recyclable chiral ligand can convert symmetrical ketoesters to complex carbocyclic products bearing multiple stereocentres with high enantio- and diastereocontrol. A computational study has been used to probe the origin of the enantioselectivity. Our studies suggest that many processes that rely on SmI2 can be rendered enantioselective by the design of suitable ligands.

  11. Calcium(ii)-catalyzed enantioselective conjugate additions of amines.

    Science.gov (United States)

    Uno, Brice E; Dicken, Rachel D; Redfern, Louis R; Stern, Charlotte M; Krzywicki, Greg G; Scheidt, Karl A

    2018-02-14

    The direct enantioselective chiral calcium(ii)·phosphate complex (Ca[CPA] 2 )-catalyzed conjugate addition of unprotected alkyl amines to maleimides was developed. This mild catalytic system represents a significant advance towards the general convergent asymmetric amination of α,β-unsaturated electrophiles, providing medicinally relevant chiral aminosuccinimide products in high yields and enantioselectivities. Furthermore, the catalyst can be reused directly from a previously chromatographed reaction and still maintain both high yield and selectivity.

  12. Rhodium(II)-catalyzed enantioselective synthesis of troponoids.

    Science.gov (United States)

    Murarka, Sandip; Jia, Zhi-Jun; Merten, Christian; Daniliuc, Constantin-G; Antonchick, Andrey P; Waldmann, Herbert

    2015-06-22

    We report a rhodium(II)-catalyzed highly enantioselective 1,3-dipolar cycloaddition reaction between the carbonyl moiety of tropone and carbonyl ylides to afford troponoids in good to high yields with excellent enantioselectivity. We demonstrate that α-diazoketone-derived carbonyl ylides, in contrast to carbonyl ylides derived from diazodiketoesters, undergo [6+3] cycloaddition reactions with tropone to yield the corresponding bridged heterocycles with excellent stereoselectivity. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Enantioselective biotransformations of nitriles in organic synthesis.

    Science.gov (United States)

    Wang, Mei-Xiang

    2015-03-17

    The hydration and hydrolysis of nitriles are valuable synthetic methods used to prepare carboxamides and carboxylic acids. However, chemical hydration and hydrolysis of nitriles involve harsh reaction conditions, have low selectivity, and generate large amounts of waste. Therefore, researchers have confined the scope of these reactions to simple nitrile substrates. However, biological transformations of nitriles are highly efficient, chemoselective, and environmentally benign, which has led synthetic organic chemists and biotechologists to study these reactions in detail over the last two decades. In nature, biological systems degrade nitriles via two distinct pathways: nitrilases catalyze the direct hydrolysis of nitriles to afford carboxylic acids with release of ammonia, and nitrile hydratases catalyze the conversion of nitriles into carboxamides, which then furnish carboxylic acids via hydrolysis in the presence of amidases. Researchers have subsequently developed biocatalytic methods into useful industrial processes for the manufacture of commodity chemicals, including acrylamide. Since the late 1990s, research by my group and others has led to enormous progress in the understanding and application of enantioselective biotransformations of nitriles in organic synthesis. In this Account, I summarize the important advances in enantioselective biotransformations of nitriles and amides, with a primary focus on research from my laboratory. I describe microbial whole-cell-catalyzed kinetic resolution of various functionalized nitriles, amino- and hydroxynitriles, and nitriles that contain small rings and the desymmetrization of prochiral and meso dinitriles and diamides. I also demonstrate how we can apply the biocatalytic protocol to synthesize natural products and bioactive compounds. These nitrile biotransformations offer an attractive and unique protocol for the enantioselective synthesis of polyfunctionalized organic compounds that are not readily obtainable by

  14. Evaluation of achiral templates with fluxional Brønsted basic substituents in enantioselective conjugate additions.

    Science.gov (United States)

    Adachi, Shinya; Takeda, Norihiko; Sibi, Mukund P

    2014-12-19

    Enantioselective conjugate addition of malononitrile to pyrazolidinone-derived enoates proceeds in excellent yields and high enantioselectivities. A comparison of fluxional substituents with and without a Brønsted basic site and their impact on selectivity is detailed. Molecular sieves as an additive were found to be essential to achieve high enantioselectivity.

  15. Examination of the Potential for Adaptive Chirality of the Nitrogen Chiral Center in Aza-Aspartame

    Directory of Open Access Journals (Sweden)

    Samir H. Bouayad-Gervais

    2013-11-01

    Full Text Available The potential for dynamic chirality of an azapeptide nitrogen was examined by substitution of nitrogen for the α-carbon of the aspartate residue in the sweetener S,S-aspartame. Considering that S,S- and R,S-aspartame possess sweet and bitter tastes, respectively, a bitter-sweet taste of aza-aspartame 9 could be indicative of a low isomerization barrier for nitrogen chirality inter-conversion. Aza-aspartame 9 was synthesized by a combination of hydrazine and peptide chemistry. Crystallization of 9 indicated a R,S-configuration in the solid state; however, the aza-residue chiral center was considerably flattened relative to its natural amino acid counterpart. On tasting, the authors considered aza-aspartame 9 to be slightly bitter or tasteless. The lack of bitter sweet taste of aza-aspartame 9 may be due to flattening from sp2 hybridization in the urea as well as a high barrier for sp3 nitrogen inter-conversion, both of which may interfere with recognition by taste receptors.

  16. Examination of the potential for adaptive chirality of the nitrogen chiral center in aza-aspartame.

    Science.gov (United States)

    Bouayad-Gervais, Samir H; Lubell, William D

    2013-11-28

    The potential for dynamic chirality of an azapeptide nitrogen was examined by substitution of nitrogen for the α-carbon of the aspartate residue in the sweetener S,S-aspartame. Considering that S,S- and R,S-aspartame possess sweet and bitter tastes, respectively, a bitter-sweet taste of aza-aspartame 9 could be indicative of a low isomerization barrier for nitrogen chirality inter-conversion. Aza-aspartame 9 was synthesized by a combination of hydrazine and peptide chemistry. Crystallization of 9 indicated a R,S-configuration in the solid state; however, the aza-residue chiral center was considerably flattened relative to its natural amino acid counterpart. On tasting, the authors considered aza-aspartame 9 to be slightly bitter or tasteless. The lack of bitter sweet taste of aza-aspartame 9 may be due to flattening from sp2 hybridization in the urea as well as a high barrier for sp3 nitrogen inter-conversion, both of which may interfere with recognition by taste receptors.

  17. An Efficient Synthesis of de novo Imidates via Aza-Claisen Rearrangements of N-Allyl Ynamides

    Science.gov (United States)

    DeKorver, Kyle A.; North, Troy D.; Hsung, Richard P.

    2010-01-01

    A novel thermal 3-aza-Claisen rearrangement of N-allyl ynamides for the synthesis of α-allyl imidates is described. Also, a sequential aza-Claisen, Pd-catalyzed Overman rearrangement is described for the synthesis of azapine-2-ones. PMID:21278848

  18. AzaSite® inhibits Staphylococcus aureus and coagulase-negative Staphylococcus biofilm formation in vitro.

    Science.gov (United States)

    Wu, Eric C; Kowalski, Regis P; Romanowski, Eric G; Mah, Francis S; Gordon, Y Jerold; Shanks, Robert M Q

    2010-12-01

    The aim of this study was to analyze the effect of azithromycin (AZM) 1% ophthalmic solution in DuraSite® (AzaSite®) on biofilm formation by Staphylococcus aureus and coagulase-negative staphylococci in vitro. Susceptible and resistant clinical strains (n = 8) of S. aureus and coagulase-negative staphylococci were challenged with serial dilutions of AzaSite® and its components: AZM, benzalkonium chloride (BAK), and the DuraSite drug delivery vehicle. After 20 h of incubation, bacterial growth was quantified using a spectrophotometer (A = 600 nm). Plates were stained with crystal violet and biofilm formation was quantified spectrophotometrically at A = 590 nm. AzaSite® and AZM inhibited bacterial growth (P reduction in biofilm formation (P reduction in biofilm formation at concentrations from 1.25 to 10 mg/mL in most strains. DuraSite® inhibited biofilm formation at concentrations between 10% and 2.5% in all studied strains (P < 0.05), without affecting bacterial growth. BAK inhibited bacterial growth and biofilm formation in all strains between concentrations of 0.042 and 0.375 mg/mL (P < 0.05). AzaSite®, AZM, or BAK prevented biofilm formation by inhibiting growth of AZM-susceptible strains. AzaSite®, AZM, and DuraSite® also reduced biofilm formation at subinhibitory concentrations for growth. Our data indicate that AZM has a moderate inhibitory effect on biofilm formation, whereas DuraSite® appears to play a greater role in the inhibition of staphylococcal biofilm formation by AzaSite®.

  19. Asymmetric Catalytic Aza-Diels-Alder/Ring-Closing Cascade Reaction Forming Bicyclic Azaheterocycles by Trienamine Catalysis.

    Science.gov (United States)

    Li, Yang; Barløse, Casper; Jørgensen, Julie; Carlsen, Bjørn Dreiø; Jørgensen, Karl Anker

    2017-01-01

    An asymmetric catalytic aza-Diels-Alder/ring-closing cascade reaction between acylhydrazones and in situ formed trienamines is presented. The reaction proceeds through a formal aza-Diels-Alder cycloaddition, followed by a ring-closing reaction forming the hemiaminal ring leading to chiral bicyclic azaheterocycles in moderate to good yield (up to 71 %), good enantio- (up to 92 % ee) and diastereoselectivity (up to >20:1 d.r.). Furthermore, transformations are presented to show the potential application of the formed product. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Asymmetric Formal Aza-Diels-Alder Reaction of Trifluoromethyl Hemiaminals with Enones Catalyzed by Primary Amines.

    Science.gov (United States)

    Zhang, Sheng; Cha, Lide; Li, Lijun; Hu, Yanbin; Li, Yanan; Zha, Zhenggen; Wang, Zhiyong

    2016-04-15

    A primary amine-catalyzed asymmetric formal aza-Diels-Alder reaction of trifluoromethyl hemiaminals with enones was developed via a chiral gem-diamine intermediate. This novel protocol allowed facile access to structurally diverse trifluoromethyl-substituted piperidine scaffolds with high stereoselectivity. The utility of this method was further demonstrated through a concise approach to biologically active 4-hydroxypiperidine. More importantly, a stepwise mechanism involving an asymmetric induction process was proposed to rationalize the positive correlation between the chirality of the gem-diamine intermediate and the formal aza-Diels-Alder product.

  1. Copper-Mediated Reactions of Nitriles with Nitromethanes: Aza-Henry Reactions and Nitrile Hydrations.

    Science.gov (United States)

    Kuwabara, Jun; Sawada, Yoshiharu; Yoshimatsu, Mitsuhiro

    2018-02-16

    In this study, the first aza-Henry reaction of nitriles with nitromethane in a CuI/Cs 2 CO 3 /DBU system is described. The process was conveniently and directly used for the synthesis of β-aminonitroalkenes 2a-x and tolerated aryl-, alkyl-, hetaryl-, alkenyl-, and alkynylnitriles. The resulting aminonitroalkenes 2 could be successfully transformed to the corresponding 2-nitroacetophenones, 2-amino-1-halonitroalkenes, 2-alkylaminonitroalkenes, or 3-nitropyridines. In the presence of H 2 O, the aza-Henry reaction turned the reaction path to the nitrile hydration to exclusively yield the amides 3a-s.

  2. Enantioselective Copper-Catalyzed Oxy-Alkynylation of Diazo Compounds.

    Science.gov (United States)

    Hari, Durga Prasad; Waser, Jerome

    2017-06-28

    Enantioselective catalytic methods allowing the addition of both a nucleophile and an electrophile onto diazo compounds give a fast access into important building blocks. Herein, we report the highly enantioselective oxyalkynylation of diazo compounds using ethynylbenziodoxol-(on)e reagents and a simple copper bisoxazoline catalyst. The obtained α-benzoyloxy propargylic esters are useful building blocks, which are difficult to synthesize in enantiopure form using other methods. The obtained products could be efficiently transformed into vicinal diols and α-hydroxy propargylic esters without loss in enantiopurity.

  3. Pentanidium-catalyzed enantioselective phase-transfer conjugate addition reactions

    KAUST Repository

    Ma, Ting

    2011-03-09

    A new chiral entity, pentanidium, has been shown to be an excellent chiral phase-transfer catalyst. The enantioselective Michael addition reactions of tert-butyl glycinate-benzophenone Schiff base with various α,β- unsaturated acceptors provide adducts with high enantioselectivities. A successful gram-scale experiment at a low catalyst loading of 0.05 mol % indicates the potential for practical applications of this methodology. Phosphoglycine ester analogues can also be utilized as the Michael donor, affording enantioenriched α-aminophosphonic acid derivatives and phosphonic analogues of (S)-proline. © 2011 American Chemical Society.

  4. Asymmetric aza-Diels-Alder reaction of Danishefsky's diene with imines in a chiral reaction medium

    Directory of Open Access Journals (Sweden)

    Pégot Bruce

    2006-09-01

    Full Text Available Abstract The asymmetric aza-Diels-Alder reaction of chiral imines with Danishefsky's diene in chiral ionic liquids provides the corresponding cycloadduct with moderate to high diastereoselectivity. The reaction has proved to perform better at room temperature in ionic liquids without either Lewis acid catalyst or organic solvent. Chiral ionic liquids are recycled while their efficiency is preserved.

  5. Assessing Process Mass Intensity and Waste via an "aza"-Baylis-Hillman Reaction

    Science.gov (United States)

    Go´mez-Biagi, Rodolfo F.; Dicks, Andrew P.

    2015-01-01

    A synthetic procedure is outlined where upper-level undergraduate organic chemistry students perform a two-week, semimicroscale "aza"-Baylis-Hillman reaction to generate an allylic sulfonamide product. Students evaluate several green chemistry reaction metrics of industrial importance (process mass intensity (PMI), E factor, and reaction…

  6. Preparation of alpha-5-aza-2'-deoxy-[6-3H]cytidine

    Czech Academy of Sciences Publication Activity Database

    Elbert, Tomáš; Černý, B.

    2008-01-01

    Roč. 73, č. 5 (2008), s. 701-704 ISSN 0010-0765 Institutional research plan: CEZ:AV0Z40550506 Keywords : alfa-5aza-2'-deoxy-cytidine Subject RIV: CC - Organic Chemistry Impact factor: 0.784, year: 2008

  7. Enantioselective cycloadditions with alpha,beta-disubstituted acrylimides.

    Science.gov (United States)

    Sibi, Mukund P; Ma, Zhihua; Itoh, Kennosuke; Prabagaran, Narayanasamy; Jasperse, Craig P

    2005-06-09

    [reaction: see text] The use of N-H imide templates provides a solution to the problem of rotamer control in Lewis acid catalyzed reactions of alpha,beta-disubstituted acryloyl imides. Reactions proceed through the s-cis rotamer and with improved reactivity because A(1,3) strain is avoided. Enantioselective nitrone, nitrile oxide, and Diels-Alder cycloadditions demonstrate the principle.

  8. Pyrones to pyrans: enantioselective radical additions to acyloxy pyrones.

    Science.gov (United States)

    Sibi, Mukund P; Zimmerman, Jake

    2006-10-18

    This paper describes a highly site-, diastereo-, and enantioselective intermolecular radical addition/hydrogen atom transfer to hydroxypyrone pyromeconic and kojic acids. The methodology can be extended to the formation of chiral quaternary centers. The products obtained are densely functionalized pyran moieties. The products contain structural features amenable for the introduction of additional substituents.

  9. Lanthanide Lewis acid-mediated enantioselective conjugate radical additions.

    Science.gov (United States)

    Sibi, Mukund P; Manyem, Shankar

    2002-08-22

    [reaction: see text] Lanthanide triflates along with proline-derived ligands have been found to be efficient catalysts for enantioselective conjugate addition of nucleophilic radicals to enoates. N-Acyl oxazolidinones, when used as achiral additives, gave meaningful enhancements in the ees for the product.

  10. Guanidine-catalyzed enantioselective desymmetrization of meso-aziridines

    KAUST Repository

    Zhang, Yan

    2011-01-01

    An amino-indanol derived chiral guanidine was developed as an efficient Brønsted base catalyst for the desymmetrization of meso-aziridines with both thiols and carbamodithioic acids as nucleophiles, which provided 1,2-difunctionalized ring-opened products in high yields and enantioselectivities. © The Royal Society of Chemistry.

  11. Graphene-based hybrid for enantioselective sensing applications.

    Science.gov (United States)

    Zor, Erhan; Morales-Narváez, Eden; Alpaydin, Sabri; Bingol, Haluk; Ersoz, Mustafa; Merkoçi, Arben

    2017-01-15

    Chirality is a major field of research of chemical biology and is essential in pharmacology. Accordingly, approaches for distinguishing between different chiral forms of a compound are of great interest. We report on an efficient and generic enantioselective sensor that is achieved by coupling reduced graphene oxide with γ-cyclodextrin (rGO/γ-CD). The enantioselective sensing capability of the resulting structure was operated in both electrical and optical mode for of tryptophan enantiomers (D-/L-Trp). In this sense, voltammetric and photoluminescence measurements were conducted and the experimental results were compared to molecular docking method. We gain insight into the occurring recognition mechanism with selectivity toward D- and L-Trp as shown in voltammetric, photoluminescence and molecular docking responses. As an enantioselective solid phase on an electrochemical transducer, thanks to the different dimensional interaction of enantiomers with hybrid material, a discrepancy occurs in the Gibbs free energy leading to a difference in oxidation peak potential as observed in electrochemical measurements. The optical sensing principle is based on the energy transfer phenomenon that occurs between photoexcited D-/L-Trp enantiomers and rGO/γ-CD giving rise to an enantioselective photoluminescence quenching due to the tendency of chiral enantiomers to form complexes with γ-CD in different molecular orientations as demonstrated by molecular docking studies. The approach, which is the first demonstration of applicability of molecular docking to show both enantioselective electrochemical and photoluminescence quenching capabilities of a graphene-related hybrid material, is truly new and may have broad interest in combination of experimental and computational methods for enantiosensing of chiral molecules. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. A stereoselective synthesis of (+)-physoperuvine using a tandem aza-Claisen rearrangement and ring closing metathesis reaction.

    Science.gov (United States)

    Zaed, Ahmed M; Swift, Michael D; Sutherland, Andrew

    2009-07-07

    A stereoselective synthesis of (+)-physoperuvine, a tropane alkaloid from Physalis peruviana Linne has been developed using a one-pot tandem aza-Claisen rearrangement and ring closing metathesis reaction to form the key amino-substituted cycloheptene ring.

  13. Equitoxic doses of 5-azacytidine and 5-aza-2'deoxycytidine induce diverse immediate and overlapping heritable changes in the transcriptome.

    Directory of Open Access Journals (Sweden)

    Xiangning Qiu

    2010-09-01

    Full Text Available The hypomethylating agent 5-Azacytidine (5-Aza-CR is the first drug to prolong overall survival in patients with myelodysplastic syndrome (MDS. Surprisingly, the deoxyribonucleoside analog 5-Aza-2'deoxycytidine (5-Aza-CdR did not have a similar effect on survival in a large clinical trial. Both drugs are thought to exert their effects after incorporation into DNA by covalent binding of DNA methyltransferase (DNMT. While 5-Aza-CdR is incorporated into only DNA, 5-Aza-CR is also incorporated into RNA. Here, we have analyzed whether this difference in nucleic acid incorporation may influence the capacities of these drugs to regulate the expression of mRNA and microRNAs (miRNA, which may potentially affect the activities of the drugs in patients.A hematopoietic (HL-60; acute myeloid leukemia and a solid (T24; transitional cell carcinoma cancer cell line were treated with equitoxic doses of 5-Aza-CR and 5-Aza-CdR for 24 hrs, and the immediate (day 2 and lasting (day 8 effects on RNA expression examined. There was considerable overlap between the RNAs heritably upregulated by both drugs on day 8 but more RNAs were stably induced by the deoxy analog. Both drugs strongly induced expression of cancer testis antigens. On day 2 more RNAs were downregulated by 5-Aza-CR, particularly at higher doses. A remarkable downregulation of miRNAs and a significant upregulation of tRNA synthetases and other genes involved in amino acid metabolism was observed in T24 cells.Overall, this suggests that significant differences exist in the immediate action of the two drugs, however the dominant pattern of the lasting, and possible heritable changes, is overlapping.

  14. Enantioselective conjugate addition of diethylzinc to chalcone catalyzed by Co(acac)2 and chiral amino alcohols

    NARCIS (Netherlands)

    Vries, André H.M. de; Feringa, Bernard

    1997-01-01

    Co(acac)2 in the presence of chiral ligands has been employed as catalyst for the enantioselective conjugate addition of diethylzinc to chalcone. With chiral amino alcohols derived from (+)-camphor, enantioselectivities up to 83% were achieved.

  15. The Aza Lineage. Origin, Evolution and Impact of an Aristocratic Family in South-Eastern Castile

    Directory of Open Access Journals (Sweden)

    Iván GARCÍA IZQUIERDO

    2017-07-01

    Full Text Available This article analyzes the trajectory of the Aza aristocratic lineage and its impact on a sector of the eastern Castilian Extremadura between the 12th and mid-13th Centuries. Its originality resides in the focus on the role of an external aristocratic lineage, when previous studies of such areas have tended to focus on the dynamics of local concejil government. Whilst recent studies highlight the importance of local elites in the process of territory building prior to royal intervention, the projection of some of those groups was relatively limited at a national scale and was circumscribed in many cases to areas controlled by the local councils. This was the case with the Riaza Valley, similarly split into small territorial enclaves, in which the influence of an external aristocratic lineage, the Azas, became stronger with the passage of time.

  16. Aza-crown ether complex cation ionic liquids: preparation and applications in organic reactions.

    Science.gov (United States)

    Song, Yingying; Cheng, Chen; Jing, Huanwang

    2014-09-26

    Aza-crown ether complex cation ionic liquids (aCECILs) were devised, fabricated, and characterized by using NMR spectroscopy, MS, thermogravimetric differential thermal analysis (TG-DTA), elemental analysis and physical properties. These new and room-temperature ILs were utilized as catalysts in various organic reactions, such as the cycloaddition reaction of CO2 to epoxides, esterification of acetic acid and alcohols, the condensation reaction of aniline and propylene carbonate, and Friedel-Crafts alkylation of indole with aldehydes were investigated carefully. In these reactions, the ionic liquid exhibited cooperative catalytic activity between the anion and cation. In addition, the aza-[18-C-6HK][HSO4]2 was the best acidic catalyst in the reactions of esterification and Friedel-Crafts alkylation under mild reaction conditions. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Manuel Azaña : biografía y obras completas

    Directory of Open Access Journals (Sweden)

    Santos Juliá

    2012-03-01

    Full Text Available La primera vez que oí hablar en serio de Manuel Azaña fue a don Ramón Carande, en alguno de nuestros largos paseos por calles y plazas de Sevilla, hacia mediados de los años sesenta, cuando todavía era costumbre conversar mientras se caminaba. Me decía don Ramón que nosotros, los jóvenes, debíamos conocer a don Manuel Azaña y leer sus obras. Y como yo acostumbraba a seguir las indicaciones de lectura recibidas de don Ramón, me animé a comprar en una librería que que él mismo me recomendó, sit...

  18. Hydrogen-Bonding Catalysis of Tetraalkylammonium Salts in an Aza-Diels-Alder Reaction.

    Science.gov (United States)

    Kumatabara, Yusuke; Kaneko, Shiho; Nakata, Satoshi; Shirakawa, Seiji; Maruoka, Keiji

    2016-08-05

    A piperidine-derived tetraalkylammonium salt with a non-coordinating counteranion worked as an effective hydrogen-bonding catalyst in an aza-Diels-Alder reaction of imines and a Danishefsky diene. The hydrogen-bonding interaction between the ammonium salt and an imine was observed as part of a (1) H NMR titration study. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Methods for the synthesis of aza(deaza)xanthines as a basis of biologically active compounds

    International Nuclear Information System (INIS)

    Babkov, D A; Geisman, A N; Novikov, M S; Khandazhinskaya, A L

    2016-01-01

    The review covers methods for the synthesis of aza(deaza)xanthines, i.e., fused pyrrolo-, pyrazolo- and triazolopyrimidine heterocyclic systems, which are common core structures of various biologically active compounds. The extensive range of modern synthetic approaches is organized according to target structures and starting building blocks. The presented material is intended to benefit broad audience of specialists in the fields of organic, medicinal and pharmaceutical chemistry. The bibliography includes 195 references

  20. Enantioselective Epoxide Polymerization Using a Bimetallic Cobalt Catalyst

    KAUST Repository

    Thomas, Renee M.

    2010-11-24

    A highly active enantiopure bimetallic cobalt complex was explored for the enantioselective polymerization of a variety of monosubstituted epoxides. The polymerizations were optimized for high rates and stereoselectivity, with s-factors (kfast/kslow) for most epoxides exceeding 50 and some exceeding 300, well above the threshold for preparative utility of enantiopure epoxides and isotactic polyethers. Values for mm triads of the resulting polymers are typically greater than 95%, with some even surpassing 98%. In addition, the use of a racemic catalyst allowed the preparation of isotactic polyethers in quantitative yields. The thermal properties of these isotactic polyethers are presented, with many polymers exhibiting high T m values. This is the first report of the rapid synthesis of a broad range of highly isotactic polyethers via the enantioselective polymerization of racemic epoxides. © 2010 American Chemical Society.

  1. Enantioselective Epoxide Polymerization Using a Bimetallic Cobalt Catalyst

    KAUST Repository

    Thomas, Renee M.; Widger, Peter C. B.; Ahmed, Syud M.; Jeske, Ryan C.; Hirahata, Wataru; Lobkovsky, Emil B.; Coates, Geoffrey W.

    2010-01-01

    A highly active enantiopure bimetallic cobalt complex was explored for the enantioselective polymerization of a variety of monosubstituted epoxides. The polymerizations were optimized for high rates and stereoselectivity, with s-factors (kfast/kslow) for most epoxides exceeding 50 and some exceeding 300, well above the threshold for preparative utility of enantiopure epoxides and isotactic polyethers. Values for mm triads of the resulting polymers are typically greater than 95%, with some even surpassing 98%. In addition, the use of a racemic catalyst allowed the preparation of isotactic polyethers in quantitative yields. The thermal properties of these isotactic polyethers are presented, with many polymers exhibiting high T m values. This is the first report of the rapid synthesis of a broad range of highly isotactic polyethers via the enantioselective polymerization of racemic epoxides. © 2010 American Chemical Society.

  2. Enhancing the potential of enantioselective organocatalysis with light

    Science.gov (United States)

    Silvi, Mattia; Melchiorre, Paolo

    2018-02-01

    Organocatalysis—catalysis mediated by small chiral organic molecules—is a powerful technology for enantioselective synthesis, and has extensive applications in traditional ionic, two-electron-pair reactivity domains. Recently, organocatalysis has been successfully combined with photochemical reactivity to unlock previously inaccessible reaction pathways, thereby creating new synthetic opportunities. Here we describe the historical context, scientific reasoning and landmark discoveries that were essential in expanding the functions of organocatalysis to include one-electron-mediated chemistry and excited-state reactivity.

  3. Enantioselective synthesis of alpha,beta-disubstituted-beta-amino acids.

    Science.gov (United States)

    Sibi, Mukund P; Prabagaran, Narayanasamy; Ghorpade, Sandeep G; Jasperse, Craig P

    2003-10-01

    Highly diastereoselective and enantioselective addition of N-benzylhydroxylamine to imides 17 and 20-30 produces alpha,beta-trans-disubstituted N-benzylisoxazolidinones 19 and 31-41. These reactions proceed in 60-96% ee with 93-99% de's using 5 mol % of Mg(NTf2)2 and ligand 18. The product isoxazolidinones can be hydrogenolyzed directly to provide alpha,beta-disubstituted-beta-amino acids.

  4. Enantioselective conjugate radical addition to alpha'-hydroxy enones.

    Science.gov (United States)

    Lee, Sunggi; Lim, Chae Jo; Kim, Sunggak; Subramaniam, Rajesh; Zimmerman, Jake; Sibi, Mukund P

    2006-09-14

    Enantioselective conjugate radical addition to alpha'-hydroxy alpha,beta-unsaturated ketones, compounds containing bidentate donors, has been investigated. It has been found that radical additions to alpha'-hydroxy alpha,beta-unsaturated ketones in the presence of Mg(NTf2)2 and bisoxazoline ligand 5a proceeded cleanly, yielding the addition products in high chemical yields and good enantiomeric excesses.

  5. Catalytic enantioselective alkene aminohalogenation/cyclization involving atom transfer.

    Science.gov (United States)

    Bovino, Michael T; Chemler, Sherry R

    2012-04-16

    Problem solved: the title reaction was used for the synthesis of chiral 2-bromo, chloro, and iodomethyl indolines and 2-iodomethyl pyrrolidines. Stereocenter formation is believed to occur by enantioselective cis aminocupration and C-X bond formation is believed to occur by atom transfer. The ultility of the products as versatile synthetic intermediates was demonstrated, as was a radical cascade cyclization sequence. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Additive effects of 5-Aza-2'-deoxycytidine and irradiation on clonogenic survival of human medulloblastoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Patties, Ina; Jahns, Jutta; Kortmann, Rolf-Dieter; Glasow, Annegret [Dept. of Radiotherapy and Radiooncology, Universitaetsklinikum Leipzig AoeR (Germany); Hildebrandt, Guido [Dept. of Radiotherapy and Radiooncology, Universitaetsklinikum Leipzig AoeR (Germany); Dept. of Radiotherapy, Univ. of Rostock (Germany)

    2009-05-15

    Background and purpose: in recent years, epigenetic modulators were introduced into tumor therapy. Here, the authors investigated the antitumor effect of 5-aza-2'-deoxycytidine-(5-aza-dC-)induced demethylation combined with irradiation on human medulloblastoma (MB) cells, which form the most common malignant brain tumor in children. Material and methods: three MB cell lines were treated with 5-aza-dC in a low-dose (0.1 {mu}M, 6 days) or high-dose (3/5 {mu}M, 3 days) setting and irradiated with 2, 4, 6, or 8 Gy single dose on an X-ray unit. Methylation status and mRNA expression of three candidate genes were analyzed by methylation-specific PCR (polymerase chain reaction) and quantitative real-time RT-PCR. Cell survival and mortality were determined by trypan blue exclusion test. Proliferation was analyzed by BrdU incorporation assay, and long-term cell survival was assessed by clonogenic assay. Results: 5-aza-dC treatment resulted in partial promoter demethylation and increased expression of hypermethylated candidate genes. A significant decrease of vital cell count, proliferation inhibition and increase of mortality was observed in 5-aza-dC-treated as well as in irradiated MB cells, whereby combination of both treatments led to additive effects. Although high-dose 5-aza-dC treatment was more effective in terms of demethylation, clonogenic assay revealed no differences between high- and low-dose settings indicating no relevance of 5-aza-dC-induced demethylation for decreased cell survival. MB cells pretreated with 5-aza-dC showed significantly lower plating efficiencies than untreated cells at all irradiation doses investigated. Analysis of surviving curves in irradiated MB cells, however, revealed no significant differences of {alpha}-, {beta}-values and 2-Gy surviving fraction with or without 5-aza-dC treatment. Conclusion: 5-aza-dC did not enhance radiation sensitivity of MB cells but significantly reduced the clonogenicity versus irradiation alone, which

  7. Enantiomerization and enantioselective bioaccumulation of metalaxyl in Tenebrio molitor larvae.

    Science.gov (United States)

    Gao, Yongxin; Wang, Huili; Qin, Fang; Xu, Peng; Lv, Xiaotian; Li, Jianzhong; Guo, Baoyuan

    2014-02-01

    The enantiomerization and enantioselective bioaccumulation of metalaxyl by a single dose of exposure to Tenebrio molitor larvae under laboratory condition were studied by high-performance liquid chromatography tandem mass spectroscopy (HPLC-MS/MS) based on a ChiralcelOD-3R [cellulosetris-tris-(3, 5-dichlorophenyl-carbamate)] column. Exposure of enantiopure R-metalaxyl and S-metalaxyl in Tenebrio molitor larvae exhibited significant enantiomerization, with formation of the R enantiomers from the S enantiomers, and vice versa, which might be attributed to the chiral pesticide catalyzed by a certain enzyme in Tenebrio molitor larvae. Enantiomerization was not observed in wheat bran during the period of 21 d. In addition, bioaccumulation of rac-metalaxyl in Tenebrio molitor larvae was enantioselective with a preferential accumulation of S-metalaxyl. These results showed that enantioselectivity was caused not only by actual degradation and metabolism but also by enantiomerization, which was an important process in the environmental fate and behavior of metalaxyl enantiomers. Copyright © 2013 Wiley Periodicals, Inc.

  8. Global demethylation of rat chondrosarcoma cells after treatment with 5-aza-2'-deoxycytidine results in increased tumorigenicity.

    Directory of Open Access Journals (Sweden)

    Christopher A Hamm

    Full Text Available Abnormal patterns of DNA methylation are observed in several types of human cancer. While localized DNA methylation of CpG islands has been associated with gene silencing, the effect that genome-wide loss of methylation has on tumorigenesis is not completely known. To examine its effect on tumorigenesis, we induced DNA demethylation in a rat model of human chondrosarcoma using 5-aza-2-deoxycytidine. Rat specific pyrosequencing assays were utilized to assess the methylation levels in both LINEs and satellite DNA sequences following 5-aza-2-deoxycytidine treatment. Loss of DNA methylation was accompanied by an increase in invasiveness of the rat chondrosarcoma cells, in vitro, as well as by an increase in tumor growth in vivo. Subsequent microarray analysis provided insight into the gene expression changes that result from 5-aza-2-deoxycytidine induced DNA demethylation. In particular, two genes that may function in tumorigenesis, sox-2 and midkine, were expressed at low levels in control cells but upon 5-aza-2-deoxycytidine treatment these genes became overexpressed. Promoter region DNA analysis revealed that these genes were methylated in control cells but became demethylated following 5-aza-2-deoxycytidine treatment. Following withdrawal of 5-aza-2-deoxycytidine, the rat chondrosarcoma cells reestablished global DNA methylation levels that were comparable to that of control cells. Concurrently, invasiveness of the rat chondrosarcoma cells, in vitro, decreased to a level indistinguishable to that of control cells. Taken together these experiments demonstrate that global DNA hypomethylation induced by 5-aza-2-deoxycytidine may promote specific aspects of tumorigenesis in rat chondrosarcoma cells.

  9. Exciplex emission and photoinduced energy transfer as a function of cavity dimension in naphthalene-linked aza-crown ethers

    International Nuclear Information System (INIS)

    Roy, Mailrayee Basu; Samanta, Subhodip; Chattopadhyay, Gautam; Ghosh, Sanjib

    2004-01-01

    We report here the photophysical properties of two derivatives of N-(β-methylnaphthalene) aza-crown systems having different cavity dimensions. The aza-crown moiety is attached to β-position of naphthalene moiety by one >CH 2 unit in both the derivatives. The cavity size is found to have a pronounced effect on exciplex formation as well as energy transfer in the systems at room temperature and low temperature, respectively. Both the systems exhibit photoinduced electron transfer (PET) which is evident from their weaker fluorescence emission and their quenched singlet lifetimes as compared to that of free naphthalene. The systems also show a solvent sensitive red shifted broad structureless emission which is assigned to exciplex formation. The ratio of quantum yields of exciplex to monomer emission (phi (cursive,open) Greek Exp /phi (cursive,open) Greek M ) is lower in the smaller aza-crown (L1) as compared to that in the larger aza-crown (L2) implying a different geometry of the two systems in the excited state. Semi-emperical calculations performed on the systems also corroborate the different geometry of the two systems. Complexation of alkali metals, rare earth ions and protons by the aza-crown moiety results in enhancement of fluorescence emission due to blocking of PET. In the presence of protons, L1 exhibits a new emission due to excimer formation which has not been observed in L2 under similar conditions. The rare earth ion complexes of L1 and L2 at low temperature exhibit energy transfer from the lowest triplet state of naphthalene to the rare earth ion states, the extent of energy transfer being greater in the larger aza-crown (L2) as compared to that in smaller aza-crown system (L1)

  10. Enantioselective carbenoid insertion into C(sp3–H bonds

    Directory of Open Access Journals (Sweden)

    J. V. Santiago

    2016-05-01

    Full Text Available The enantioselective carbenoid insertion into C(sp3–H bonds is an important tool for the synthesis of complex molecules due to the high control of enantioselectivity in the formation of stereogenic centers. This paper presents a brief review of the early issues, related mechanistic studies and recent applications on this chemistry area.

  11. Application of enantioselective radical reactions: synthesis of (+)-ricciocarpins A and B.

    Science.gov (United States)

    Sibi, Mukund P; He, Liwen

    2004-05-27

    Enantioselective synthesis of (+)-ricciocarpins A and B has been achieved in 41 and 45% overall yields, respectively, starting from a beta-substituted oxazolidinone. The key steps in the strategy are an enantioselective conjugate radical addition and the addition of a furyl organometallic to a key aldehyde intermediate. [reaction--see text

  12. Copper(II)-catalyzed exo and enantioselective cycloadditions of azomethine imines.

    Science.gov (United States)

    Sibi, Mukund P; Rane, Digamber; Stanley, Levi M; Soeta, Takahiro

    2008-07-17

    A strategy for exo and enantioselective 1,3-dipolar cycloaddition of azomethine imines to 2-acryloyl-3-pyrazolidinone is described. The corresponding cycloadducts are isolated with high diastereoselectivities (up to >96:4 exo/endo) and enantioselectivities (up to 98% ee).

  13. Enantioselective rhodium enolate protonations. A new methodology for the synthesis of beta2-amino acids.

    Science.gov (United States)

    Sibi, Mukund P; Tatamidani, Hiroto; Patil, Kalyani

    2005-06-23

    [reaction: see text] Rhodium-catalyzed conjugate addition of an aryl boronic acid to alpha-methylamino acrylates followed by enantioselective protonation of the oxa-pi-allylrhodium intermediate provides access to aryl-substituted beta(2)-amino acids. The impact of the different variables of the reaction on the levels of enantioselectivity has been assessed.

  14. Enantioselective H-atom transfer reaction: a strategy to synthesize formaldehyde aldol products.

    Science.gov (United States)

    Sibi, Mukund P; Patil, Kalyani

    2005-04-14

    [reaction: see text] Enantioselective radical alkylation of Baylis-Hillman adducts furnished aldol products in good yield and selectivity. The results illustrate that the selectivity in the hydrogen atom transfer is dependent on the size of the ester substituent, with smaller substituents providing better enantioselectivity.

  15. Enantioselective Rhodium Enolate Protonations. A New Methodology for the Synthesis of β2-Amino Acids

    Science.gov (United States)

    Sibi, Mukund P.; Tatamidani, Hiroto; Patil, Kalyani

    2008-01-01

    Rhodium catalyzed conjugate addition of an aryl boronic acid to α-methylamino acrylates followed by enantioselective protonation of the oxa-π-allylrhodium intermediate provides access to aryl substituted β2-amino acids. The impact of the different variables of the reaction on the levels of enantioselectivity has been assessed. PMID:15957893

  16. DNA-based catalytic enantioselective intermolecular oxa-Michael addition reactions

    NARCIS (Netherlands)

    Megens, Rik P.; Roelfes, Gerard

    2012-01-01

    Using the DNA-based catalysis concept, a novel Cu(II) catalyzed enantioselective oxa-Michael addition of alcohols to enones is reported. Enantioselectivities of up to 86% were obtained. The presence of water is important for the reactivity, possibly by reverting unwanted side reactions such as

  17. Antineoplastic activity of the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine in anaplastic large cell lymphoma

    Science.gov (United States)

    Hassler, Melanie R.; Klisaroska, Aleksandra; Kollmann, Karoline; Steiner, Irene; Bilban, Martin; Schiefer, Ana-Iris; Sexl, Veronika; Egger, Gerda

    2012-01-01

    DNA methylation is an epigenetic mechanism establishing long-term gene silencing during development and cell commitment, which is maintained in subsequent cell generations. Aberrant DNA methylation is found at gene promoters in most cancers and can lead to silencing of tumor suppressor genes. The DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-CdR) is able to reactivate genes silenced by DNA methylation and has been shown to be a very potent epigenetic drug in several hematological malignancies. In this report, we demonstrate that 5-aza-CdR exhibits high antineoplastic activity against anaplastic large cell lymphoma (ALCL), a rare CD30 positive non-Hodgkin lymphoma of T-cell origin. Low dose treatment of ALCL cell lines and xenografted tumors causes apoptosis and cell cycle arrest in vitro and in vivo. This is also reflected in genome-wide expression analyses, where genes related to apoptosis and cell death are amongst the most affected targets of 5-aza-CdR. Furthermore, we observed demethylation and re-expression of p16INK4A after drug administration and senescence associated β-galactosidase activity. Thus, our data provide evidence that 5-aza-CdR is highly efficient against ALCL and warrants further clinical evaluation for future therapeutic use. PMID:22687603

  18. [The Role of 5-Aza-CdR on Methylation of Promoter in RASSF1A Gene in Endometrial Carcinoma].

    Science.gov (United States)

    Huang, Li-ping; Chen, Chen; Wang, Xue-ping; Liu, Hui

    2015-05-01

    To explore the effect of demethylating drug 5-Aza-2'-deoxycytidine (5-Aza-CdR) on methtylation status of the Ras-association domain familylA gene (RASSF1A) in human endometrial carcinoma. Randomly'assign the human endometrial carcinoma cell line HEC-1-B into groups and use demethylating drug 5-Aza-CdR of different concentration to treat them. Then Methylation-specific polymerase chain reaction (MSP), real-time PCR, Western blot, TUNEL technology were used to analyze methylation status of RASSF1A promoter CpG islands, RASSF1A mRNA expression, RASSF1A protein expression and apoptosis of HEC-1-B cell. High DNA methylation in RASSF1A gene promoter region, low RASSF1A mRNA level and protein expression and out of control of human endometrial carcinoma cell HEC-1-B apoptosis were observed. 5-Aza-CdR of different concentration could reverse RASSF1A gene's methylation status, recover the expression of mRNA and protein, and control the growth of HEC-1-B by inducing apoptosis. Aberrant methylation of RASSF1A in endometrial cancer as a therapeutic target, demethylating agent 5-Aza-CdR could be an effective way of gene therapy.

  19. Effects of 5-aza-2′deoxycytidine on RECK gene expression and tumor invasion in salivary adenoid cystic carcinoma

    International Nuclear Information System (INIS)

    Zhou, X.Q.; Huang, S.Y.; Zhang, D.S.; Zhang, S.Z.; Li, W.G.; Chen, Z.W.; Wu, H.W.

    2014-01-01

    Reversion-inducing cysteine-rich protein with kazal motifs (RECK), a novel tumor suppressor gene that negatively regulates matrix metalloproteinases (MMPs), is expressed in various normal human tissues but downregulated in several types of human tumors. The molecular mechanism for this downregulation and its biological significance in salivary adenoid cystic carcinoma (SACC) are unclear. In the present study, we investigated the effects of a DNA methyltransferase (DNMT) inhibitor, 5-aza-2′deoxycytidine (5-aza-dC), on the methylation status of the RECK gene and tumor invasion in SACC cell lines. Methylation-specific PCR (MSP), Western blot analysis, and quantitative real-time PCR were used to investigate the methylation status of the RECK gene and expression of RECK mRNA and protein in SACC cell lines. The invasive ability of SACC cells was examined by the Transwell migration assay. Promoter methylation was only found in the ACC-M cell line. Treatment of ACC-M cells with 5-aza-dC partially reversed the hypermethylation status of the RECK gene and significantly enhanced the expression of mRNA and protein, and 5-aza-dC significantly suppressed ACC-M cell invasive ability. Our findings showed that 5-aza-dC inhibited cancer cell invasion through the reversal of RECK gene hypermethylation, which might be a promising chemotherapy approach in SACC treatment

  20. Effects of 5-aza-2′deoxycytidine on RECK gene expression and tumor invasion in salivary adenoid cystic carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, X.Q. [Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, Jinan (China); Department of Oral and Maxillofacial Surgery, The First People' s Hospital of Jining, Shandong (China); Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan (China); Huang, S.Y. [Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan (China); Zhang, D.S. [Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, Jinan (China); Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan (China); Zhang, S.Z.; Li, W.G.; Chen, Z.W.; Wu, H.W. [Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan (China)

    2014-12-12

    Reversion-inducing cysteine-rich protein with kazal motifs (RECK), a novel tumor suppressor gene that negatively regulates matrix metalloproteinases (MMPs), is expressed in various normal human tissues but downregulated in several types of human tumors. The molecular mechanism for this downregulation and its biological significance in salivary adenoid cystic carcinoma (SACC) are unclear. In the present study, we investigated the effects of a DNA methyltransferase (DNMT) inhibitor, 5-aza-2′deoxycytidine (5-aza-dC), on the methylation status of the RECK gene and tumor invasion in SACC cell lines. Methylation-specific PCR (MSP), Western blot analysis, and quantitative real-time PCR were used to investigate the methylation status of the RECK gene and expression of RECK mRNA and protein in SACC cell lines. The invasive ability of SACC cells was examined by the Transwell migration assay. Promoter methylation was only found in the ACC-M cell line. Treatment of ACC-M cells with 5-aza-dC partially reversed the hypermethylation status of the RECK gene and significantly enhanced the expression of mRNA and protein, and 5-aza-dC significantly suppressed ACC-M cell invasive ability. Our findings showed that 5-aza-dC inhibited cancer cell invasion through the reversal of RECK gene hypermethylation, which might be a promising chemotherapy approach in SACC treatment.

  1. Molecular Rearrangement of an Aza-Scorpiand Macrocycle Induced by pH: A Computational Study

    Directory of Open Access Journals (Sweden)

    Jesus Vicente De Julián-Ortiz

    2016-07-01

    Full Text Available Rearrangements and their control are a hot topic in supramolecular chemistry due to the possibilities that these phenomena open in the design of synthetic receptors and molecular machines. Macrocycle aza-scorpiands constitute an interesting system that can reorganize their spatial structure depending on pH variations or the presence of metal cations. In this study, the relative stabilities of these conformations were predicted computationally by semi-empirical and density functional theory approximations, and the reorganization from closed to open conformations was simulated by using the Monte Carlo multiple minimum method.

  2. Nitrogen-Containing Coronenes: Theoretical Evaluation of the Influence of Aza-substitution on their Aromaticity

    Science.gov (United States)

    Pop, Raluca; van Staden, Jacobus; Diudea, Mircea

    2015-03-01

    The aromaticity of coronene derivatives where two C atoms of each outer six-membered ring are replaced by N have been investigated. Three types of substitution, namely 1,2-, 1,3-, and 1,4- are proposed. Computations of the geometric (HOMA index), energetic (HOMO-LUMO gap), and magnetic indices (NICS(0) and NICS(1)) were performed, and the results compared to the ones obtained for the all-carbon species. The results outline that the aza-derivatives have aromatic character comparable to the all-carbon species and an enlarged HOMO-LUMO gap.

  3. Dansyl - Substituted Aza Crown Ethers: Complexation with Alkali, Alkaline Earth Metal Ions and Ammonium

    Science.gov (United States)

    Deiab, Shihab; Archibong, Edikan; Tasheva, Donka; Mochona, Bereket; Gangapuram, Madhavi; Redda, Kinfe

    2011-01-01

    The present study investigates the binding properties of four dansyl substituted aza-crown ethers with alkali, alkaline earth metal ions and ammonium. The influence of the solvent polarity and protonation on the photophysical properties of the compounds was studied by UV/Vis and fluorescence methods. The host species caused only slight changes on the absorption spectra of the ligands. The fluorescence changes were more pronounced and concentration dependent thus allowing to calculate the binding constants of the process. The most stable complex under our working conditions was the one between Ba2+ and DNS18C6. PMID:21738561

  4. Protecting-Group-Free Synthesis of 2-Deoxy-Aza-Sugars

    Directory of Open Access Journals (Sweden)

    Mattie Simon Maria Timmer

    2009-12-01

    Full Text Available The protecting-group-free asymmetric synthesis of 1,2,4-trideoxy-1,4-imino-L-xylitol is readily achieved in five steps from 2-deoxy-D-ribose and with an overall yield of 48%. Key in this synthesis is the application of our recently developed Vasella-reductive amination and carbamate annulation methodologies to the synthesis of 2-deoxy-aza-sugars. The carbamate annulation occurred with excellent yield and diastereoselectively (>20:1 d.r., in favour of the 3,4-cis isomer.

  5. Aza-Michael Mono-addition Using Acidic Alumina under Solventless Conditions

    Directory of Open Access Journals (Sweden)

    Giovanna Bosica

    2016-06-01

    Full Text Available Aza-Michael reactions between primary aliphatic and aromatic amines and various Michael acceptors have been performed under environmentally-friendly solventless conditions using acidic alumina as a heterogeneous catalyst to selectively obtain the corresponding mono-adducts in high yields. Ethyl acrylate was the main acceptor used, although others such as acrylonitrile, methyl acrylate and acrylamide were also utilized successfully. Bi-functional amines also gave the mono-adducts in good to excellent yields. Such compounds can serve as intermediates for the synthesis of anti-cancer and antibiotic drugs.

  6. Highly Efficient Synthesis of Allopurinol Locked Nucleic Acid Monomer by C6 Deamination of 8-Aza-7-bromo-7-deazaadenine Locked Nucleic Acid Monomer

    DEFF Research Database (Denmark)

    Kosbar, Tamer Reda El-Saeed; Sofan, M.; Abou-Zeid, L.

    2013-01-01

    An allopurinol locked nucleic acid (LNA) monomer was prepared by a novel strategy through C6 deamination of the corresponding 8-aza-7-bromo-7-deazaadenine LNA monomer with aqueous sodium hydroxide. An 8-aza-7-deazaadenine LNA monomer was also synthesized by a modification of the new synthetic...... the required LNA monomers....

  7. Enantioselective Copper-Catalyzed Carboetherification of Unactivated Alkenes**

    Science.gov (United States)

    Bovino, Michael T.; Liwosz, Timothy W.; Kendel, Nicole E.; Miller, Yan; Tyminska, Nina

    2014-01-01

    Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein is reported a highly efficient copper-catalyzed cyclization of γ-unsaturated pentenols that terminates in C-C bond formation, a net alkene carboetherification. Both intra- and intermolecular C-C bond formations are demonstrated, yielding functionalized chiral tetrahydrofurans as well as fused-ring and bridged-ring oxabicyclic products. Transition state calculations support a cis-oxycupration stereochemistry-determining step. PMID:24798697

  8. A Perspective on the Comparative Antileukemic Activity of 5-Aza-2′-deoxycytidine (Decitabine and 5-Azacytidine (Vidaza

    Directory of Open Access Journals (Sweden)

    Richard L. Momparler

    2012-08-01

    Full Text Available 5-Aza-2′-deoxycytidine (5-AZA-CdR, decitabine, Dacogen® and 5-azacytidine (5-AC, Vidaza® are epigenetic agents that have been approved for the clinical treatment of the hematological malignancy myelodysplastic syndrome (MDS and are currently under clinical evaluation for the treatment of acute myeloid leukemia (AML. Most investigators currently classify 5-AZA-CdR and 5-AC as inhibitors of DNA methylation, which can reactivate tumor suppressor genes silenced by this epigenetic event. Examination of the pharmacology of these analogues reveals important differences with respect to their molecular mechanism of action. The action of 5-AZA-CdR is due to its incorporation into DNA. 5-AC is a riboside analogue that is incorporated primarily into RNA. A small fraction of 5-AC is converted to its deoxyribose form by ribonucleotide reductase and subsequently incorporated into DNA. The incorporation of 5-AC into RNA can interfere with the biological function of RNA and result in an inhibition protein synthesis. Microarray analysis revealed that both these analogues target the expression of different cohorts of genes. Preclinical studies show that 5-AZA-CdR is a more effective antileukemic agent than 5-AC. One explanation for this observation is that 5-AC blocks the progression of some leukemic cells from G1 into S phase, and this protects these cells from the chemotherapeutic action of this riboside analogue related to its incorporation into DNA. However, differences in chemotherapeutic efficacy of these related analogues have not been clearly demonstrated in clinical trials in patients with hematological malignancies. These observations should be taken into consideration in the design of new clinical trials using 5-AZA-CdR or 5-AC in patients with MDS and AML.

  9. Development of Environment-Friendly Insecticides Based on Enantioselectivity: Bifenthrin as a Case.

    Science.gov (United States)

    Qian, Yi; Zhou, Peixue; Zhang, Quan

    2017-01-01

    Chiral insecticides significantly contribute to the environmental pollutions recently. As the development of industry and agriculture, increasing number of chiral insecticides are to be introduced into the market. However, their enantioselective toxicology to ecosystem still remains uncertain. In this review, we embarked on a structured search of bibliographic databases for peer-reviewed articles regarding the enantioselective effects of bifenthrin, a typical chiral insecticide, on both target and non-target species. With this enantioselective property of chiral insecticides, they often exhibit adverse effects on non-target species enantioselectively. Specifically, the enantioselective effects of bifenthrin on target and non-target organisms were discussed. In target species, R-bifenthrin exerts more significant activities in deinsectization, compared with S-bifenthrin. On the other hand, Sbifenthrin is more toxic to non-target species than R-bifenthrin, which suggests that the application of sole enantiomer is more efficient and environment-friendly than that of racemate. This review confirms the choice of environment-friendly insecticides from the perspective of the enantioselectivity of chiral insecticides. To make insecticides more efficient to target species and less toxic to non-target species, further research should be done to investigated the potential effects of targetactive enantiomers on non-target organisms as well as the enantioselective fate of enantiomers in multiple environmental matrix.

  10. ALDOL- AND MANNICH-TYPE REACTIONS VIA IN SITU OLEFIN MIGRATION IN IONIC LIQUID. (R828129)

    Science.gov (United States)

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  11. RUTHENIUM-CATALYZED TANDEM OLEFIN MIGRATION-ALDOL AND MANNICH-TYPE REACTIONS IN IONIC LIQUID.

    Science.gov (United States)

    In the presence of a catalytic amount of RuCl2(PPh3)3, a cross-coupling of 3-buten-2-ol with aldehydes and imines was developed via a tandem olefin migration--aldol--Mannich reaction in bmim[PF6]. With In(OAc)3 as a co-catalyst, a-vinylbenzyl alcohol and aldehydes underwent sim...

  12. Choline-based biodegradable ionic liquid catalyst for Mannich-type ...

    Indian Academy of Sciences (India)

    MS received 2 February 2016; revised 20 October 2016; accepted 21 October 2016. Abstract. ... secondary amine or ammonia.1 The products of Man- nich reaction ... rate test was supplied by Nanjing Sewage Treatment. Plant, China.

  13. Enantioselective synthesis of α-oxy amides via Umpolung amide synthesis.

    Science.gov (United States)

    Leighty, Matthew W; Shen, Bo; Johnston, Jeffrey N

    2012-09-19

    α-Oxy amides are prepared through enantioselective synthesis using a sequence beginning with a Henry addition of bromonitromethane to aldehydes and finishing with Umpolung Amide Synthesis (UmAS). Key to high enantioselection is the finding that ortho-iodo benzoic acid salts of the chiral copper(II) bis(oxazoline) catalyst deliver both diastereomers of the Henry adduct with high enantiomeric excess, homochiral at the oxygen-bearing carbon. Overall, this approach to α-oxy amides provides an innovative complement to alternatives that focus almost entirely on the enantioselective synthesis of α-oxy carboxylic acids.

  14. Highly Enantioselective Rhodium-Catalyzed Addition of Arylboroxines to Simple Aryl Ketones: Efficient Synthesis of Escitalopram.

    Science.gov (United States)

    Huang, Linwei; Zhu, Jinbin; Jiao, Guangjun; Wang, Zheng; Yu, Xingxin; Deng, Wei-Ping; Tang, Wenjun

    2016-03-24

    Highly enantioselective additions of arylboroxines to simple aryl ketones have been achieved for the first time with a Rh/(R,R,R,R)-WingPhos catalyst, thus providing a range of chiral diaryl alkyl carbinols with excellent ee values and yields. (R,R,R,R)-WingPhos has been proven to be crucial for the high reactivity and enantioselectivity. The method has enabled a new, concise, and enantioselective synthesis of the antidepressant drug escitalopram. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Nickel-catalyzed regio- and enantioselective aminolysis of 3,4-epoxy alcohols.

    Science.gov (United States)

    Wang, Chuan; Yamamoto, Hisashi

    2015-04-08

    The first catalytic regio- and enantioselective aminolysis of 3,4-epoxy alcohols has been accomplished. Under the catalysis of Ni(ClO4)2·6H2O, the C4 selective ring opening of various 3,4-epoxy alcohols proceeded in a stereospecific manner with high regioselectivities. Furthermore, with the Ni-BINAM catalytic system the enantioselective ring opening of 3,4-epoxy alcohols furnished various γ-hydroxy-δ-amino alcohols as products with complete regiocontrol and high enantioselectivities (up to 94% ee).

  16. Infrared-thermographic screening of the activity and enantioselectivity of enzymes.

    Science.gov (United States)

    Reetz, M T; Hermes, M; Becker, M H

    2001-05-01

    The infrared radiation caused by the heat of reaction of an enantioselective enzyme-catalyzed transformation can be detected by modern photovoltaic infrared (IR)-thermographic cameras equipped with focal-plane array detectors. Specifically, in the lipase-catalyzed enantioselective acylation of racemic 1-phenylethanol, the (R)- and (S)-substrates are allowed to react separately in the wells of microtiter plates, the (R)-alcohol showing hot spots in the IR-thermographic images. Thus, highly enantioselective enzymes can be identified at kinetic resolution.

  17. Dual Enantioselective Control using D-phenylglycine-L-proline-derived Catalysts for the Enantioselective Addition of Diethylzinc to Aldehyde

    International Nuclear Information System (INIS)

    Kang, Seock Yong; Park, Yong Sun

    2016-01-01

    Dipeptide-derived catalysts are of great interest in various asymmetric transformations because of their short and simple preparation and easy modification of their modular structure by using different α-amino acids. We recently reported the first example of dipeptide-catalyzed enantioselective addition of dialkylzinc to aldehydes. We have developed a novel D-Phg-L-Pro dipeptide-derived catalyst for the addition of diethylzinc to aromatic aldehydes. We also disclosed an effective chiral switching by simply modifying nonchiral part of D-Phg-L-Pro dipeptide.

  18. Diastereoselective and enantioselective reduction of tetralin-1,4-dione

    Directory of Open Access Journals (Sweden)

    2008-10-01

    Full Text Available BackgroundThe chemistry of tetralin-1,4-dione, the stable tautomer of 1,4-dihydroxynaphthalene, has not been explored previously. It is readily accessible and offers interesting opportunities for synthesis.ResultsThe title reactions were explored. L-Selectride reduced the diketone to give preferentially the cis-diol (d.r. 84 : 16. Red-Al gave preferentially the trans-diol (d.r. 13 : 87. NaBH4, LiAlH4, and BH3 gave lower diastereoselectivities (yields: 76–98%. Fractional crystallization allowed isolation of the cis-diol and the trans-diol (55% and 66% yield, respectively. Borane was used to cleanly give the mono-reduction product. Highly enantioselective CBS reductions afforded the trans-diol (72% yield, 99% ee and the mono-reduction product (81%, 95% ee.ConclusionDiastereoselective and enantioselective reductions of the unexplored tetralin-1,4-dione provides a very convenient entry into a number of synthetically highly attractive 1,4-tetralindiols and 4-hydroxy-1-tetralone.

  19. Diastereoselective and enantioselective reduction of tetralin-1,4-dione.

    Science.gov (United States)

    Kündig, E Peter; Enriquez-Garcia, Alvaro

    2008-01-01

    The chemistry of tetralin-1,4-dione, the stable tautomer of 1,4-dihydroxynaphthalene, has not been explored previously. It is readily accessible and offers interesting opportunities for synthesis. The title reactions were explored. L-Selectride reduced the diketone to give preferentially the cis-diol (d.r. 84 : 16). Red-Al gave preferentially the trans-diol (d.r. 13 : 87). NaBH(4), LiAlH(4), and BH(3) gave lower diastereoselectivities (yields: 76-98%). Fractional crystallization allowed isolation of the cis-diol and the trans-diol (55% and 66% yield, respectively). Borane was used to cleanly give the mono-reduction product. Highly enantioselective CBS reductions afforded the trans-diol (72% yield, 99% ee) and the mono-reduction product (81%, 95% ee). Diastereoselective and enantioselective reductions of the unexplored tetralin-1,4-dione provides a very convenient entry into a number of synthetically highly attractive 1,4-tetralindiols and 4-hydroxy-1-tetralone.

  20. Enantioselective degradation and enantiomerization of indoxacarb in soil.

    Science.gov (United States)

    Sun, Dali; Pang, Junxiao; Qiu, Jing; Li, Li; Liu, Chenglan; Jiao, Bining

    2013-11-27

    In this study, the enantioselective degradation and enantiomerizaton of indoxacarb were investigated in two soils under nonsterilized and sterilized conditions using a chiral OD-RH column on a reversed-phase HPLC. Under nonsterilized conditions, the degradation of indoxacarb in two soils was enantioselective. In acidic soil, the half-lives of R-(-)- and S-(+)-indoxacarb were 10.43 and 14.00 days, respectively. Acidic soil was preferential to the degradation of R-(-)-indoxacarb. In alkaline soil, the half-lives of R-(-)- and S-(+)-indoxacarb were 12.14 and 4.88 days, respectively. S-(+)-Indoxacarb was preferentially degraded. Under sterilized conditions, approximately 5-10% of the initial concentration degraded after 75 days of incubation in acidic soil, whereas in alkaline soil, approximately half of the initial concentration degraded due to chemical hydrolysis under alkaline conditions. Enantiomerization was also discovered in acidic and alkaline soils. The results showed that mutual transformation existed between two enantiomers and that S-(+)-indoxacarb had a significantly higher inversion rate to R-(-)-indoxacarb than its antipode.

  1. Chiral separation and enantioselective degradation of vinclozolin in soils.

    Science.gov (United States)

    Liu, Hui; Liu, Donghui; Shen, Zhigang; Sun, Mingjing; Zhou, Zhiqiang; Wang, Peng

    2014-03-01

    Vinclozolin is a chiral fungicide with potential environmental problems. The chiral separation of the enantiomers and enantioselective degradation in soil were investigated in this work. The enantiomers were separated by high-performance liquid chromatography (HPLC) on Chiralpak IA, IB, and AZ-H chiral columns under normal phase and the influence of the mobile phase composition on the separation was also studied. Complete resolutions were obtained on all three chiral columns under optimized conditions with the same elution order of (+)/(-). The residual analysis of the enantiomers in soil was conducted using accelerate solvent extraction followed by HPLC determination. The recoveries of the enantiomers ranged from 85.7-105.7% with relative standard deviation (SD) of 0.12-3.83%, and the limit of detection (LOD) of the method was 0.013 µg/g. The results showed that the degradations of vinclozolin enantiomers in the soils followed first-order kinetics. Preferential degradation of the (-)-enantiomer was observed only in one soil with the largest |ES| value of 0.047, and no obvious enantioselective degradation was observed in other soils. It was found that the persistence of vinclozolin in soil was related to pH values based on the half-lives. The two enantiomers disappeared about 8 times faster in basic soils than that in neutral or acidic soils. © 2014 Wiley Periodicals, Inc.

  2. Rhodium-Catalyzed Enantioselective Cyclopropanation of Olefins with N-Sulfonyl 1,2,3-Triazoles

    Science.gov (United States)

    Chuprakov, Stepan; Kwok, Sen Wai; Zhang, Li; Lercher, Lukas; Fokin, Valery V.

    2009-01-01

    N-Sulfonyl 1,2,3-triazoles readily form rhodium(II) azavinyl carbenes, which react with olefins to produce cyclopropanes with excellent diastereo- and enantioselectivity and in high yield. PMID:19928917

  3. Optimisation of stabilised carboxylesterase NP for enantioselective hydrolysis of naproxen methyl ester

    CSIR Research Space (South Africa)

    Steenkamp, Lucia H

    2008-12-01

    Full Text Available Although the enantioselective kinetic resolution of ester racemates of the non-steroidal antiinflammatory drug naproxen ([2-(6-methoxy-2-naphthyl) propionic acid]) is a common demonstration for biocatalysis, the enantiomeric excess of the reactions...

  4. Asymmetric Synthesis of Optically Active Spirocyclic Indoline Scaffolds through an Enantioselective Reduction of Indoles

    KAUST Repository

    Borrmann, Ruediger; Knop, Nils; Rueping, Magnus

    2016-01-01

    An enantioselective synthesis of spirocyclic indoline scaffolds was achieved by applying an asymmetric iridium-catalyzed hydrogenation of 3H-indoles. Low catalyst loadings and mild reaction conditions provide a broad range of differently substituted

  5. BIOACCUMULATION AND ENANTIOSELECTIVE BIOTRANSFORMATION OF FIPRONIL BY RAINBOW TROUT (ONCORHYNCHUS MYKISS)

    Science.gov (United States)

    Dietary accumulation and enantioselective biotransformation was determined for rainbow trout (Oncorhynchus mykiss) exposed to fipronil, a widely used chiral pesticide. Measurement of the fish carcass tissue (whole fish minus GI tract and liver) showed a rapid accumulation of fip...

  6. Purification and characterisation of a novel enantioselective epoxide hydrolase from Aspergillus niger M200

    Czech Academy of Sciences Publication Activity Database

    Kotík, Michael; Kyslík, Pavel

    2006-01-01

    Roč. 1760, - (2006), s. 245-252 ISSN 0006-3002 Institutional research plan: CEZ:AV0Z50200510 Keywords : epoxide hydrolase * enantioselectivity * aspergillus niger Subject RIV: EE - Microbiology, Virology

  7. Enantioselective synthesis of almorexant via iridium-catalysed intramolecular allylic amidation

    NARCIS (Netherlands)

    Fananas Mastral, Martin; Teichert, Johannes F.; Fernandez-Salas, Jose Antonio; Heijnen, Dorus; Feringa, Ben L.

    2013-01-01

    An enantioselective synthesis of almorexant, a potent antagonist of human orexin receptors, is presented. The chiral tetrahydroisoquinoline core structure was prepared via iridium-catalysed asymmetric intramolecular allylic amidation. Further key catalytic steps of the synthesis include an oxidative

  8. Carbocyclization cascades of allyl ketenimines via aza-Claisen rearrangements of N-phosphoryl-N-allyl-ynamides.

    Science.gov (United States)

    DeKorver, Kyle A; Wang, Xiao-Na; Walton, Mary C; Hsung, Richard P

    2012-04-06

    A series of carbocyclization cascades of allyl ketenimines initiated through a thermal aza-Claisen rearrangement of N-phosphoryl-N-allyl ynamides is described. Interceptions of the cationic intermediate via Meerwein-Wagner rearrangements and polyene-type cyclizations en route to fused bi- and tricyclic frameworks are featured.

  9. Enzyme active site mimics based on TriAzaCyclophane (TAC)-scaffolded peptides and amino acid residues

    NARCIS (Netherlands)

    Albada, H.B.

    2009-01-01

    This thesis describes the scope and limitations of the application of TriAzaCyclophane (TAC)-scaffolded peptides or amino acid residues as enzyme active site mimics, as ligands in asymmetric catalysis and as hydrolysis catalysts attached to vancomycin. For the mimicry of functional group enzymes, of

  10. Solvent-free, catalyst-free aza-Michael addition of cyclohexylamine to diethyl maleate: reaction mechanism and kinetics

    Czech Academy of Sciences Publication Activity Database

    Bláha, Michal; Trhlíková, Olga; Podešva, Jiří; Abbrent, Sabina; Steinhart, Miloš; Dybal, Jiří; Dušková-Smrčková, Miroslava

    2018-01-01

    Roč. 74, č. 1 (2018), s. 58-67 ISSN 0040-4020 Institutional support: RVO:61389013 Keywords : Aza-Michael addition * solvent-free * catalyst-free Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 2.651, year: 2016

  11. Asymmetric Synthesis of Optically Active Spirocyclic Indoline Scaffolds through an Enantioselective Reduction of Indoles

    KAUST Repository

    Borrmann, Ruediger

    2016-11-30

    An enantioselective synthesis of spirocyclic indoline scaffolds was achieved by applying an asymmetric iridium-catalyzed hydrogenation of 3H-indoles. Low catalyst loadings and mild reaction conditions provide a broad range of differently substituted products with excellent yields and enantioselectivities. The developed methodology allows an efficient synthesis of this important spirocyclic structural motif, which is present in numerous biologically active molecules and privileged structures in medicinal chemistry.

  12. A New Mn–Salen Micellar Nanoreactor for Enantioselective Epoxidation of Alkenes in Water

    Directory of Open Access Journals (Sweden)

    Francesco P. Ballistreri

    2018-03-01

    Full Text Available A new chiral Mn–salen catalyst, functionalized with a long aliphatic chain and a choline group, able to act as surfactant catalyst for green epoxidation in water, is here described. This catalyst was employed with a commercial surfactant (CTABr leading to a nanoreactor for the enantioselective epoxidation of some selected alkenes in water, using NaClO as oxidant. This is the first example of a nanoreactor for enantioselective epoxidation of non-functionalized alkenes in water.

  13. Direct enantioselective conjugate addition of carboxylic acids with chiral lithium amides as traceless auxiliaries.

    Science.gov (United States)

    Lu, Ping; Jackson, Jeffrey J; Eickhoff, John A; Zakarian, Armen

    2015-01-21

    Michael addition is a premier synthetic method for carbon-carbon and carbon-heteroatom bond formation. Using chiral dilithium amides as traceless auxiliaries, we report the direct enantioselective Michael addition of carboxylic acids. A free carboxyl group in the product provides versatility for further functionalization, and the chiral reagent can be readily recovered by extraction with aqueous acid. The method has been applied in the enantioselective total synthesis of the purported structure of pulveraven B.

  14. Enantioselective 1,3-dipolar cycloadditions of diazoacetates with electron-deficient olefins.

    Science.gov (United States)

    Sibi, Mukund P; Stanley, Levi M; Soeta, Takahiro

    2007-04-12

    [reaction: see text] A general strategy for highly enantioselective 1,3-dipolar cycloaddition of diazoesters to beta-substituted, alpha-substituted, and alpha,beta-disubstituted alpha,beta-unsaturated pyrazolidinone imides is described. Cycloadditions utilizing less reactive alpha,beta-disubstituted dipolarophiles require elevated reaction temperatures, but still provide the corresponding pyrazolines with excellent enantioselectivities. Finally, an efficient synthesis of (-)-manzacidin A employing this cycloaddition methodology as a key step is illustrated.

  15. Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

    Directory of Open Access Journals (Sweden)

    Yiyang Liu

    2014-10-01

    Full Text Available Pd-catalyzed enantioselective alkylation in conjunction with further synthetic elaboration enables the formal total syntheses of a number of “classic” natural product target molecules. This publication highlights recent methods for setting quaternary and tetrasubstituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods will impact both academic and industrial settings, where the synthesis of stereogenic quaternary carbons is a continuing challenge.

  16. Enantioselective Addition of Allyltin Reagents to Amino Aldehydes Catalyzed with Bis(oxazolinylphenylrhodium(III Aqua Complexes

    Directory of Open Access Journals (Sweden)

    Hisao Nishiyama

    2011-06-01

    Full Text Available Bis(oxazolinylphenylrhodium(III aqua complexes, (PheboxRhX2(H2O [X = Cl, Br], were found to be efficient Lewis acid catalysts for the enantioselective addition of allyl- and methallyltributyltin reagents to amino aldehydes. The reactions proceed smoothly in the presence of 5–10 mol % of (PheboxRhX2(H2O complex at ambient temperature to give the corresponding amino alcohols with modest to good enantioselectivity (up to 94% ee.

  17. Direct Enantioselective Conjugate Addition of Carboxylic Acids with Chiral Lithium Amides as Traceless Auxiliaries

    Science.gov (United States)

    2016-01-01

    Michael addition is a premier synthetic method for carbon–carbon and carbon–heteroatom bond formation. Using chiral dilithium amides as traceless auxiliaries, we report the direct enantioselective Michael addition of carboxylic acids. A free carboxyl group in the product provides versatility for further functionalization, and the chiral reagent can be readily recovered by extraction with aqueous acid. The method has been applied in the enantioselective total synthesis of the purported structure of pulveraven B. PMID:25562717

  18. Determinants of orofacial clefting II: Effects of 5-Aza-2'-deoxycytidine on gene methylation during development of the first branchial arch.

    Science.gov (United States)

    Seelan, Ratnam S; Mukhopadhyay, Partha; Warner, Dennis R; Smolenkova, Irina A; Pisano, M Michele; Greene, Robert M

    2017-01-01

    Defects in development of the secondary palate, which arise from the embryonic first branchial arch (1-BA), can cause cleft palate (CP). Administration of 5-Aza-2'-deoxycytidine (AzaD), a demethylating agent, to pregnant mice on gestational day 9.5 resulted in complete penetrance of CP in fetuses. Several genes critical for normal palatogenesis were found to be upregulated in 1-BA, 12h after AzaD exposure. MethylCap-Seq (MCS) analysis identified several differentially methylated regions (DMRs) in DNA extracted from AzaD-exposed 1-BAs. Hypomethylated DMRs did not correlate with the upregulation of genes in AzaD-exposed 1-BAs. However, most DMRs were associated with endogenous retroviral elements. Expression analyses suggested that interferon signaling was activated in AzaD-exposed 1-BAs. Our data, thus, suggest that a 12-h in utero AzaD exposure demethylates and activates endogenous retroviral elements in the 1-BA, thereby triggering an interferon-mediated response. This may result in the dysregulation of key signaling pathways during palatogenesis, causing CP. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. 5-Aza-2'-deoxycytidine in the medial prefrontal cortex regulates alcohol-related behavior and Ntf3-TrkC expression in rats.

    Directory of Open Access Journals (Sweden)

    Xiaomeng Qiao

    Full Text Available Recent studies have indicated that DNA methylation plays an important role in the development of alcohol abuse. 5-Aza-2'-deoxycytidine (5-Aza-dc, an inhibitor of DNA methyltransferases, was FDA approved for myelodysplastic syndrome treatment. However, it is unclear whether 5-Aza-dc is involved in alcohol abuse. In this study, using a chronic alcohol exposure model in rats, 5-Aza-dc was injected into the medial prefrontal cortex (mPFC. Alcohol-drinking behavior and the anxiety related behavior were evaluated by two-bottle choice and open field test. We found that 5-Aza-dc injection into the mPFC significantly decreased alcohol consumption and alcohol preference in alcohol-exposure rats, corresponding to the reduced blood alcohol levels. Although 5-Aza-dc potentiated the anxiety-like behavior of alcohol-exposure rats, it had no effect on the locomotor activity. Moreover, both of the mRNA and protein levels of DNA Methyltransferase 3A (DNMT3A and DNMT3B in the mPFC were upregulated after 35 days of alcohol exposure and this upregulation could be reversed by 5-Aza-dc treatment. Additionally, 5-Aza-dc reversed the alcohol-induced downregulation of neurotrophin-3 (Ntf3, correspondingly the expression of its receptor-TrkC was reduced. These findings identified a functional role of 5-Aza-dc in alcohol-related behavioral phenotypes and one of the potential target genes, Ntf3. We also provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcohol abuse.

  20. Flexible Enantioselectivity of Tryptophanase Attributable to Benzene Ring in Heterocyclic Moiety of D-Tryptophan

    Directory of Open Access Journals (Sweden)

    Akihiko Shimada

    2012-05-01

    Full Text Available The invariance principle of enzyme enantioselectivity must be absolute because it is absolutely essential to the homochiral biological world. Most enzymes are strictly enantioselective, and tryptophanase is one of the enzymes with extreme absolute enantioselectivity for L-tryptophan. Contrary to conventional knowledge about the principle, tryptophanase becomes flexible to catalyze D-tryptophan in the presence of diammonium hydrogenphosphate. Since D-amino acids are ordinarily inert or function as inhibitors even though they are bound to the active site, the inhibition behavior of D-tryptophan and several inhibitors involved in this process was examined in terms of kinetics to explain the reason for this flexible enantioselectivity in the presence of diammonium hydrogenphosphate. Diammonium hydrogenphosphate gave tryptophanase a small conformational change so that D-tryptophan could work as a substrate. As opposed to other D-amino acids, D-tryptophan is a very bulky amino acid with a benzene ring in its heterocyclic moiety, and so we suggest that this structural feature makes the catalysis of D-tryptophan degradation possible, consequently leading to the flexible enantioselectivity. The present results not only help to understand the mechanism of enzyme enantioselectivity, but also shed light on the origin of homochirality.

  1. Integrative assessment of enantioselectivity in endocrine disruption and immunotoxicity of synthetic pyrethroids

    Energy Technology Data Exchange (ETDEWEB)

    Zhao Meirong [Research Center of Environmental Science, College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032 (China); Chen Fang [College of Environmental Science and Engineering, Zhejiang Gongshang University, Hangzhou 310018 (China); Wang Cui; Zhang Quan [Research Center of Environmental Science, College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032 (China); Gan Jianying [Department of Environmental Sciences, University of California, Riverside, CA 92521 (United States); Liu Weiping, E-mail: wliu@zjut.edu.c [Research Center of Environmental Science, College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032 (China)

    2010-05-15

    The increasing release of chiral chemicals into the environment dictates attention to a better understanding of enantioselectivity in their human and ecotoxicological effects. Although enantioselectivity has been considered in many recent studies, there is little effort for discerning the connection between different processes, and as such, our current knowledge about chiral contaminants is rather scattered and incoherent. In this study, we simultaneously evaluated enantioselectivity of two chiral pesticides, lambda-cyhalothrin (LCT) and (Z)-cis-bifenthrin (cis-BF), in immunotoxicity to macrophage cells (RAW264.7), and endocrine disruption activity in human breast carcinoma cell line MCF-7. Analysis of cell proliferation, cell viability, apoptosis, and receptor gene expression showed significant differences between the enantiomers of LCT or cis-BF in estrogenic potential and immunocytotoxicity. The selectivity in these effects consistently followed the same direction, with (-)-LCT or 1S-cis-BF displaying a greater activity than its counterpart. The consistency was attributed to interplaying mechanisms in the closely interacting immune and endocrine systems. The underlying interplays suggest that other chiral xenobiotics may also show a directional enantioselectivity in immunotoxicity and endocrine toxicity. Given that many biological processes are inter-related, enantioselectivity may follow specific patterns that can be revealed via integrative assessments as demonstrated in this study. - Chiral contaminants should consider multiple effects and relate directions of enantioselectivity to their interplaying processes.

  2. Integrative assessment of enantioselectivity in endocrine disruption and immunotoxicity of synthetic pyrethroids

    International Nuclear Information System (INIS)

    Zhao Meirong; Chen Fang; Wang Cui; Zhang Quan; Gan Jianying; Liu Weiping

    2010-01-01

    The increasing release of chiral chemicals into the environment dictates attention to a better understanding of enantioselectivity in their human and ecotoxicological effects. Although enantioselectivity has been considered in many recent studies, there is little effort for discerning the connection between different processes, and as such, our current knowledge about chiral contaminants is rather scattered and incoherent. In this study, we simultaneously evaluated enantioselectivity of two chiral pesticides, lambda-cyhalothrin (LCT) and (Z)-cis-bifenthrin (cis-BF), in immunotoxicity to macrophage cells (RAW264.7), and endocrine disruption activity in human breast carcinoma cell line MCF-7. Analysis of cell proliferation, cell viability, apoptosis, and receptor gene expression showed significant differences between the enantiomers of LCT or cis-BF in estrogenic potential and immunocytotoxicity. The selectivity in these effects consistently followed the same direction, with (-)-LCT or 1S-cis-BF displaying a greater activity than its counterpart. The consistency was attributed to interplaying mechanisms in the closely interacting immune and endocrine systems. The underlying interplays suggest that other chiral xenobiotics may also show a directional enantioselectivity in immunotoxicity and endocrine toxicity. Given that many biological processes are inter-related, enantioselectivity may follow specific patterns that can be revealed via integrative assessments as demonstrated in this study. - Chiral contaminants should consider multiple effects and relate directions of enantioselectivity to their interplaying processes.

  3. Impact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells.

    Science.gov (United States)

    Kehrmann, Jan; Tatura, Roman; Zeschnigk, Michael; Probst-Kepper, Michael; Geffers, Robert; Steinmann, Joerg; Buer, Jan

    2014-07-01

    The epigenetic regulation of transcription factor genes is critical for T-cell lineage specification. A specific methylation pattern within a conserved region of the lineage specifying transcription factor gene FOXP3, the Treg-specific demethylated region (TSDR), is restricted to regulatory T (Treg) cells and is required for stable expression of FOXP3 and suppressive function. We analysed the impact of hypomethylating agents 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate on human CD4(+)  CD25(-) T cells for generating demethylation within FOXP3-TSDR and inducing functional Treg cells. Gene expression, including lineage-specifying transcription factors of the major T-cell lineages and their leading cytokines, functional properties and global transcriptome changes were analysed. The FOXP3-TSDR methylation pattern was determined by using deep amplicon bisulphite sequencing. 5-aza-2'-deoxycytidine induced FOXP3-TSDR hypomethylation and expression of the Treg-cell-specific genes FOXP3 and LRRC32. Proliferation of 5-aza-2'-deoxycytidine-treated cells was reduced, but the cells did not show suppressive function. Hypomethylation was not restricted to FOXP3-TSDR and expression of master transcription factors and leading cytokines of T helper type 1 and type 17 cells were induced. Epigallocatechin-3-gallate induced global DNA hypomethylation to a lesser extent than 5-aza-2'-deoxycitidine, but no relevant hypomethylation within FOXP3-TSDR or expression of Treg-cell-specific genes. Neither of the DNA methyltransferase inhibitors induced fully functional human Treg cells. 5-aza-2'-deoxycitidine-treated cells resembled Treg cells, but they did not suppress proliferation of responder cells, which is an essential capability to be used for Treg cell transfer therapy. Using a recently developed targeted demethylation technology might be a more promising approach for the generation of functional Treg cells. © 2014 John Wiley & Sons Ltd.

  4. Catalytic Enantioselective Alkylation of β-Keto Esters with Xanthydrol in the Presence of Chiral Palladium Complex

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyu Yeon; Kim, Dae Young [Soonchunhyang Univ., Asan (Korea, Republic of)

    2016-01-15

    Our research interest has been directed toward the development of synthetic methods for the enantioselective construction of stereogenic carbon centers. Recently, we explored the catalytic enantioselective functionalization of active methines in the presence of chiral palladium(II) complexes. In conclusion, we have accomplished the efficient catalytic enantioselective alkylation of β-keto esters 1 with xanthydrol 2 with high yields and excellent enantioselectivity (up to 98% ee). It should be noted that this alkyaltion reaction proceeds well using air- and moisture-stable chiral palladium com- plexes with low loading (1 mol%)

  5. Aza Cope Rearrangement of Propargyl Enammonium Cations Catalyzed By a Self-Assembled `Nanozyme

    Energy Technology Data Exchange (ETDEWEB)

    Hastings, Courntey J.; Fiedler, Dorothea; Bergman, Robert G.; Raymond, Kenneth N.

    2008-02-27

    The tetrahedral [Ga{sub 4}L{sub 6}]{sup 12-} assembly (L = N,N-bis(2,3-dihydroxybenzoyl)-1,5-diaminonaphthalene) encapsulates a variety of cations, including propargyl enammonium cations capable of undergoing the aza Cope rearrangement. For propargyl enammonium substrates that are encapsulated in the [Ga{sub 4}L{sub 6}]{sup 12-} assembly, rate accelerations of up to 184 are observed when compared to the background reaction. After rearrangement, the product iminium ion is released into solution and hydrolyzed allowing for catalytic turnover. The activation parameters for the catalyzed and uncatalyzed reaction were determined, revealing that a lowered entropy of activation is responsible for the observed rate enhancements. The catalyzed reaction exhibits saturation kinetics; the rate data obey the Michaelis-Menten model of enzyme kinetics, and competitive inhibition using a non-reactive guest has been demonstrated.

  6. Mass analyzed threshold ionization spectroscopy of aza-aromatic bicyclic molecules: Benzimidazole and benzotriazole

    International Nuclear Information System (INIS)

    Lin, J.L.; Li, Y.C.; Tzeng, W.B.

    2007-01-01

    We report the vibrationally resolved cation spectra of benzimidazole and benzotriazole, which give the respective adiabatic ionization energies (IEs) to be 67552 ± 5 cm -1 and 70474 ± 5 cm -1 . Comparing these data with that of indole, one finds that the IE of these aza-aromatic bicyclic molecules increases with the number of the N atoms. Most of the active modes of the benzimidazole cation are related to the in-plane ring vibrations. In contrast, the observed spectral bands of the benzotriazole cation correspond to the out-of-plane N2-H and skeleton N1N2N3 bending vibrations. These experimental findings may be attributed to the nature and the N atoms in the five-membered ring

  7. Acceleration of Singlet Fission in an Aza-Derivative of TIPS-Pentacene.

    Science.gov (United States)

    Herz, Julia; Buckup, Tiago; Paulus, Fabian; Engelhart, Jens; Bunz, Uwe H F; Motzkus, Marcus

    2014-07-17

    The influence of the carbon to nitrogen substitution on the photoinduced dynamics of TIPS-pentacene was investigated by ultrafast transient absorption measurements on spin-coated thin films in the visible and in the near-infrared spectral region. A global target analysis was performed to provide a detailed picture of the excited-state dynamics. We found that the chemical modification has a high impact on the triplet formation and leads to shorter dynamics; hence it speeds up the singlet fission process. A faster relaxation from the singlet into the triplet manifold implies a higher efficiency because other relaxation channels are avoided. The air-stable aza-derivatives have the potential to exceed the energy conversion efficiency of TIPS-pentacene.

  8. Enantioselective behaviour of tetraconazole during strawberry wine-making process.

    Science.gov (United States)

    Liu, Na; Pan, Xinglu; Zhang, Shuang; Ji, Mingshan; Zhang, Zhihong

    2018-05-01

    The fate of tetraconazole enantiomers in strawberries during wine-making process was studied. The residues were determined by ultra-performance convergence chromatography tandem triple quadrupole mass spectrometry after each process steps. Results indicated that there was significant enantioselective dissipation of tetraconazole enantiomers during the fermentation process. And (-)-tetraconazole degraded faster than (+)-tetraconazole. The half-lives of (-)-tetraconazole and (+)-tetraconazole were 3.12, 3.76 days with washing procedure and 3.18, 4.05 days without washing procedure. The processing factors of strawberry wine samples after each step were generally less than 1. In particular, the processing factors of the fermentation process were the lowest. The results could help facilitate more accurate risk assessments of tetraconazole during wine-making process. © 2018 Wiley Periodicals, Inc.

  9. Enantioselective organo-photocatalysis mediated by atropisomeric thiourea derivatives.

    Science.gov (United States)

    Vallavoju, Nandini; Selvakumar, Sermadurai; Jockusch, Steffen; Sibi, Mukund P; Sivaguru, Jayaraman

    2014-05-26

    Can photocatalysis be performed without electron or energy transfer? To address this, organo-photocatalysts that are based on atropisomeric thioureas and display lower excited-state energies than the reactive substrates have been developed. These photocatalysts were found to be efficient in promoting the [2+2] photocycloaddition of 4-alkenyl-substituted coumarins, which led to the corresponding products with high enantioselectivity (77-96% ee) at low catalyst loading (1-10 mol%). The photocatalytic cycle proceeds by energy sharing via the formation of both static and dynamic complexes (exciplex formation), which is aided by hydrogen bonding. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Enantioselective copper-catalyzed carboetherification of unactivated alkenes.

    Science.gov (United States)

    Bovino, Michael T; Liwosz, Timothy W; Kendel, Nicole E; Miller, Yan; Tyminska, Nina; Zurek, Eva; Chemler, Sherry R

    2014-06-16

    Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein reported is a highly efficient copper-catalyzed cyclization of γ-unsaturated pentenols which terminates in C-C bond formation, a net alkene carboetherification. Both intra- and intermolecular C-C bond formations are demonstrated, thus yielding functionalized chiral tetrahydrofurans as well as fused-ring and bridged-ring oxabicyclic products. Transition-state calculations support a cis-oxycupration stereochemistry-determining step. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Chemo- and Enantioselective Intramolecular Silver-Catalyzed Aziridinations.

    Science.gov (United States)

    Ju, Minsoo; Weatherly, Cale D; Guzei, Ilia A; Schomaker, Jennifer M

    2017-08-07

    Asymmetric nitrene-transfer reactions are a powerful tool for the preparation of enantioenriched amine building blocks. Reported herein are chemo- and enantioselective silver-catalyzed aminations which transform di- and trisubstituted homoallylic carbamates into [4.1.0]-carbamate-tethered aziridines in good yields and with ee values of up to 92 %. The effects of the substrate, silver counteranion, ligand, solvent, and temperature on both the chemoselectivity and ee value were explored. Stereochemical models were proposed to rationalize the observed absolute stereochemistry of the aziridines, which undergo nucleophilic ring opening to yield enantioenriched amines with no erosion in stereochemical integrity. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Azañón's disease. A 19th century epidemic of neurolathyrism in Spain.

    Science.gov (United States)

    Giménez-Roldán, S; Spencer, P S

    2016-12-01

    The cultivation and consumption of grasspea (Lathyrus sativus) in Spain probably dates back centuries, especially during times of famine when the neurotoxic potential of this legume was expressed in the form of a spastic paraparesis known as neurolathyrism. Little known outside the country, the epidemic of neurolathyrism in the years following the Spanish Civil War (1936-1939) came to affect more than a thousand people. In late 1872, during the Six Years Revolutionary Term, young Alejandro San Martín Satrústegui (1847-1908), then editor of the popular weekly El Siglo Médico, travelled to Azañón, a remote village in the province of Guadalajara, to clarify a so-far unknown disease. We analysed the original article published in 1873 by San Martin, as well as communications sent by El Siglo Médico readers reporting similar cases in many other Castilian provinces. San Martín's neurological findings in seven personally examined cases were astonishingly accurate; he concluded the subjects' neurological deficits resulted from injury to the lateral columns in the lower portion of the spinal cord. Description of the clinical findings provided both by San Martín, and by the readers of El Siglo Médico, leave no doubt as to the diagnosis of neurolathyrism. However, none suspected the patient's staple food was the determinant cause of the disease. San Martín proposed the eponym Azañón's disease for lack of a better name the same year (1873) in which Cantani in Italy introduced the term lathyrism. The epidemic of neurolathyrism that affected many Castilian towns represents one of the best-documented in Europe during the last third of the 19th century. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  13. Enantioselective bioaccumulation of diniconazole in Tenebrio molitor larvae.

    Science.gov (United States)

    Liu, Chen; LV, Xiao Tian; Zhu, Wen Xue; QU, Hao Yang; Gao, Yong Xin; Guo, Bao Yuan; Wang, Hui Li

    2013-12-01

    The enantioselective bioaccumulation of diniconazole in Tenebrio molitor Linne larva was investigated with liquid chromatography tandem mass spectrometry based on the ChiralcelOD-3R[cellulose tri-(3,5-dimethylphenyl carbamate)] column. In this study we documented the effects of dietary supplementation with wheat bran contaminated by racemic diniconazole at two dose levels of 20 mg kg(-1) and 2 mg kg(-1) (dry weight) in Tenebrio molitor. The results showed that both doses of diniconazole were taken up by Tenebrio molitor rapidly in the first few days, the concentrations of R-enantiomer and S-enantiomer at high doses reached the highest level of 0.55 mg kg(-1) and 0.48 mg kg(-1) , respectively, on the 1(st) d, and the concentrations of them obtained a maxima of 0.129 mg kg(-1) and 0.128 mg kg(-1) at low dose, respectively, on the 3(rd) d, which means that the concentration of diniconazole was proportional to the time of achieving the highest accumulated level. It afterwards attained equilibrium after a sharp decline at both 20 mg kg(-1) and 2 mg kg(-1) of diniconazole. The determination results from the feces of Tenebrio molitor demonstrated that the extraction recovery (ER) values of the high dose group were higher than that of the low dose group and the values were all above 1; therefore, it could be inferred that enantiomerization existed in Tenebrio molitor. Additionally, the biota accumulation factor was used to evaluate the bioaccumulation of diniconazole enantiomers, showing that the bioaccumulation of diniconazole in Tenebrio molitor was enantioselective with preferential accumulation of S-enantiomer. © 2013 Wiley Periodicals, Inc.

  14. Enantioselective γ-Alkylation of α,β-Unsaturated Malonates and Ketoesters by a Sequential Ir-Catalyzed Asymmetric Allylic Alkylation/Cope Rearrangement

    OpenAIRE

    Liu, Wen-Bo; Okamoto, Noriko; Alexy, Eric J.; Hong, Allen Y.; Tran, Kristy; Stoltz, Brian M.

    2016-01-01

    A catalytic, enantioselective ? -alkylation of ?,?-unsaturated malonates and ketoesters is reported. This strategy entails a highly regio- and enantioselective iridium-catalyzed ?-alkylation of an extended enolate, and a subsequent translocation of chirality to the ?-position via a Cope rearrangement.

  15. RUNX3 is involved in caspase-3-dependent apoptosis induced by a combination of 5-aza-CdR and TSA in leukaemia cell lines.

    Science.gov (United States)

    Zhai, Feng-Xian; Liu, Xiang-Fu; Fan, Rui-Fang; Long, Zi-Jie; Fang, Zhi-Gang; Lu, Ying; Zheng, Yong-Jiang; Lin, Dong-Jun

    2012-03-01

    Epigenetic therapy has had a significant impact on the management of haematologic malignancies. The aim of this study was to assess whether 5-aza-CdR and TSA inhibit the growth of leukaemia cells and induce caspase-3-dependent apoptosis by upregulating RUNX3 expression. K562 and Reh cells were treated with 5-aza-CdR, TSA or both compounds. RT-PCR and Western blot analyses were used to examine the expression of RUNX3 at the mRNA and protein levels, respectively. Immunofluorescence microscopy was used to detect the cellular location of RUNX3. Additionally, after K562 cells were transfected with RUNX3, apoptosis and proliferation were studied using Annexin V staining and MTT assays. The expression of RUNX3 in leukaemia cell lines was markedly less than that in the controls. Demethylating drug 5-aza-CdR could induce RUNX3 expression, but the combination of TSA and 5-aza-CdR had a greater effect than did treatment with a single compound. The combination of 5-aza-CdR and TSA induced the translocation of RUNX3 from the cytoplasm into the nucleus. TSA enhanced apoptosis induced by 5-aza-CdR, and Annexin V and Hoechst 33258 staining showed that the combination induced apoptosis but not necrosis. Furthermore, apoptosis was dependent on the caspase-3 pathway. RUNX3 overexpression in K562 cells led to growth inhibition and apoptosis and potentiated the effects of 5-aza-CdR induction. RUNX3 plays an important role in leukaemia cellular functions, and the induction of RUNX3-mediated effects may contribute to the therapeutic value of combination TSA and 5-aza-CdR treatment.

  16. Determinants of orofacial clefting I: Effects of 5-Aza-2'-deoxycytidine on cellular processes and gene expression during development of the first branchial arch.

    Science.gov (United States)

    Mukhopadhyay, Partha; Seelan, Ratnam S; Rezzoug, Francine; Warner, Dennis R; Smolenkova, Irina A; Brock, Guy; Pisano, M Michele; Greene, Robert M

    2017-01-01

    In this study, we identify gene targets and cellular events mediating the teratogenic action(s) of 5-Aza-2'-deoxycytidine (AzaD), an inhibitor of DNA methylation, on secondary palate development. Exposure of pregnant mice (on gestation day (GD) 9.5) to AzaD for 12h resulted in the complete penetrance of cleft palate (CP) in fetuses. Analysis of cells of the embryonic first branchial arch (1-BA), in fetuses exposed to AzaD, revealed: 1) significant alteration in expression of genes encoding several morphogenetic factors, cell cycle inhibitors and regulators of apoptosis; 2) a decrease in cell proliferation; and, 3) an increase in apoptosis. Pyrosequencing of selected genes, displaying pronounced differential expression in AzaD-exposed 1-BAs, failed to reveal significant alterations in CpG methylation levels in their putative promoters or gene bodies. CpG methylation analysis suggested that the effects of AzaD on gene expression were likely indirect. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Enantioselective radical addition/trapping reactions with alpha,beta-disubstituted unsaturated imides. Synthesis of anti-propionate aldols.

    Science.gov (United States)

    Sibi, Mukund P; Petrovic, Goran; Zimmerman, Jake

    2005-03-02

    This manuscript describes a highly diastereo- and enantioselective intermolecular radical addition/hydrogen atom transfer to alpha,beta-disubstituted enoates. Additionally, we show that anti-propionate aldol-like products can be easily prepared from alpha-methyl-beta-acyloxyenoates in good yields and high diastereo- and enantioselectivities.

  18. Enantioselective conjugate addition of diethylzinc to chalcone catalyzed by Co(acac)(2) and chiral amino alcohols

    NARCIS (Netherlands)

    de Vries, A.H.M.; Feringa, B.L.

    1997-01-01

    Co(acac)(2) in the presence of chiral ligands has been employed as catalyst for the enantioselective conjugate addition of diethylzinc to chalcone. With chiral amino alcohols derived from (+)-camphor, enantioselectivities up to 83% were achieved. (C) 1997 Elsevier Science Ltd.

  19. Cu(I)-Catalyzed Enantioselective Friedel-Crafts Alkylation of Indoles with 2-Aryl-N-sulfonylaziridines as Alkylating Agents.

    Science.gov (United States)

    Ge, Chen; Liu, Ren-Rong; Gao, Jian-Rong; Jia, Yi-Xia

    2016-07-01

    A highly enantioselective Friedel-Crafts alkylation of indoles with N-sulfonylaziridines as alkylating agents has been developed by utilizing the complex of Cu(CH3CN)4BF4/(S)-Segphos as a catalyst. A range of optically active tryptamine derivatives are obtained in good to excellent yields and enantioselectivities (up to >99% ee) via a kinetic resolution process.

  20. Enantioselective Cytotoxicity Profile of o,p’-DDT in PC 12 Cells

    Science.gov (United States)

    Zhang, Chunlong; Wen, Yuezhong; Liu, Weiping

    2012-01-01

    Background The continued uses of dichlordiphenyltrichloroethane (DDT) for indoor vector control in some developing countries have recently fueled intensive debates toward the global ban of this persistent legacy contaminant. Current approaches for ecological and health risk assessment has ignored the chiral nature of DDT. In this study by employing an array of cytotoxicity related endpoints, we investigated the enantioselective cytotoxicity of o,p’-DDT. Principal Findings we demonstrated for the first time that R-(−)-o,p’-DDT caused more neuron cell death by inducing more severe oxidative stress, which selectively imbalanced the transcription of stress-related genes (SOD1, SOD2, HSP70) and enzyme (superoxide dismutase and lactate dehydrogenase) activities, and greater cellular apoptosis compared to its enantiomer S-(+)-o,p’-DDT at the level comparable to malaria area exposure (parts per million). We further elucidated enantioselective modes of action using microarray combined with enzyme-linked immunosorbent assay. The enantioselective apoptosis might involve three signaling pathways via caspase 3, tumor protein 53 (p53) and NFkB. Conclusions Based on DDT stereochemistry and results reported for other chiral pesticides, our results pointed to the same directional enantioselectivity of chiral DDT toward mammalian cells. We proposed that risk assessment on DDT should consider the enantiomer ratio and enantioselectivities. PMID:22937105

  1. 5-Aza-2'-deoxycytidine protects against emphysema in mice via suppressing p16Ink4a expression in lung tissue

    Directory of Open Access Journals (Sweden)

    He ZH

    2017-10-01

    Full Text Available Zhi-Hui He,1 Yan Chen,2 Ping Chen,2 Sheng-Dong He,2 Hui-Hui Zeng,2 Ji-Ru Ye,2 Da Liu,2 Jun Cao3 1Intensive Care Unit, 2Department of Respiratory Medicine, Second Xiangya Hospital, Central South University, Changsha, 3Department of Respiratory Medicine, Hunan Provincial People’s Hospital, Changsha, China Background: There is a growing realization that COPD, or at least emphysema, involves several processes presenting in aging and cellular senescence. Endothelial progenitor cells (EPCs contribute to neovascularization and play an important role in the development of COPD. The gene for p16Ink4a is a major dominant senescence one. The aim of the present study was to observe changes in lung function, histomorphology of lung tissue, and expression of p16Ink4a in lung tissue and bone marrow-derived EPCs in emphysematous mice induced by cigarette-smoke extract (CSE, and further to search for a potential candidate agent protecting against emphysema induced by CSE. Materials and methods: An animal emphysema model was induced by intraperitoneal injection of CSE. 5-Aza-2'-deoxycytidine (5-Aza-CdR was administered to the emphysematous mice. Lung function and histomorphology of lung tissue were measured. The p16Ink4a protein and mRNA in EPCs and lung tissues were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction, respectively. Results: CSE induced emphysema with increased p16Ink4a expression in lung tissue and bone marrow-derived EPCs. 5-Aza-CdR partly protected against emphysema, especially in the lung-morphology profile, and partly protest against the overexpression of p16Ink4a in EPCs and lung tissue induced by CSE. Conclusion: 5-Aza-CdR partly protected against emphysema in mice via suppressing p16Ink4a expression in EPCs and lung tissue. Keywords: 5-Aza-2'-deoxycytidine, cigarette smoke, emphysema, endothelial progenitor cells, p16Ink4a

  2. Enantioselective Effect of Flurbiprofen on Lithium Disposition in Rats.

    Science.gov (United States)

    Uwai, Yuichi; Matsumoto, Masashi; Kawasaki, Tatsuya; Nabekura, Tomohiro

    2017-01-01

    Lithium is administered for treating bipolar disorders and is mainly excreted into urine. Nonsteroidal anti-inflammatory drugs inhibit this process. In this study, we examined the enantioselective effect of flurbiprofen on the disposition of lithium in rats. Pharmacokinetic experiments with lithium were performed. Until 60 min after the intravenous administration of lithium chloride at 30 mg/kg as a bolus, 17.8% of lithium injected was recovered into the urine. Its renal clearance was calculated to be 1.62 mL/min/kg. Neither creatinine clearance (Ccr) nor pharmacokinetics of lithium was affected by the simultaneous injection of (R)-flurbiprofen at 20 mg/kg. (S)-flurbiprofen impaired the renal function and interfered with the urinary excretion of lithium. The ratio of renal clearance of lithium to Ccr was decreased by the (S)-enantiomer. This study clarified that the (S)-flurbiprofen but not (R)-flurbiprofen inhibited the renal excretion of lithium in rats. © 2017 S. Karger AG, Basel.

  3. Direct, enantioselective α-alkylation of aldehydes using simple olefins.

    Science.gov (United States)

    Capacci, Andrew G; Malinowski, Justin T; McAlpine, Neil J; Kuhne, Jerome; MacMillan, David W C

    2017-11-01

    Although the α-alkylation of ketones has already been established, the analogous reaction using aldehyde substrates has proven surprisingly elusive. Despite the structural similarities between the two classes of compounds, the sensitivity and unique reactivity of the aldehyde functionality has typically required activated substrates or specialized additives. Here, we show that the synergistic merger of three catalytic processes-photoredox, enamine and hydrogen-atom transfer (HAT) catalysis-enables an enantioselective α-aldehyde alkylation reaction that employs simple olefins as coupling partners. Chiral imidazolidinones or prolinols, in combination with a thiophenol, iridium photoredox catalyst and visible light, have been successfully used in a triple catalytic process that is temporally sequenced to deliver a new hydrogen and electron-borrowing mechanism. This multicatalytic process enables both intra- and intermolecular aldehyde α-methylene coupling with olefins to construct both cyclic and acyclic products, respectively. With respect to atom and step-economy ideals, this stereoselective process allows the production of high-value molecules from feedstock chemicals in one step while consuming only photons.

  4. Silica-Supported Catalyst for Enantioselective Arylation of Aldehydes under Batch and Continuous-Flow Conditions.

    Science.gov (United States)

    Watanabe, Satoshi; Nakaya, Naoyuki; Akai, Junichiro; Kanaori, Kenji; Harada, Toshiro

    2018-05-04

    A silica-supported 3-aryl H 8 -BINOL-derived titanium catalyst exhibited high performance in the enantioselective arylation of aromatic aldehydes using Grignard and organolithium reagents not only under batch conditions but also under continuous-flow conditions. Even with a simple pipet reactor packed with the heterogeneous catalyst, the enantioselective production of chiral diarylmethanols could be achieved through a continuous introduction of aldehydes and mixed titanium reagents generated from the organometallic precursors. The pipet reactor could be used repeatedly in different reactions without appreciable deterioration of the activity.

  5. Asymmetric Hydrogenation of Seven-Membered C=N-containing Heterocycles and Rationalization of the Enantioselectivity.

    Science.gov (United States)

    Balakrishna, Bugga; Bauzá, Antonio; Frontera, Antonio; Vidal-Ferran, Anton

    2016-07-18

    Iridium(I) complexes with phosphine-phosphite ligands efficiently catalyze the enantioselective hydrogenation of diverse seven-membered C=N-containing heterocyclic compounds (eleven examples; up to 97 % ee). The P-OP ligand L3, which incorporates an ortho-diphenyl substituted octahydrobinol phosphite fragment, provided the highest enantioselectivities in the hydrogenation of most of the heterocyclic compounds studied. The observed stereoselection was rationalized by means of DFT calculations. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Application of Phosphine-Phosphite Ligands in the Iridium Catalyzed Enantioselective Hydrogenation of 2-Methylquinoline

    Directory of Open Access Journals (Sweden)

    Miguel Rubio

    2010-10-01

    Full Text Available The hydrogenation of 2-methylquinoline with Ir catalysts based on chiral phosphine-phosphites has been investigated. It has been observed that the reaction is very sensitive to the nature of the ligand. Optimization of the catalyst, allowed by the highly modular structure of these phosphine-phosphites, has improved the enantioselectivity of the reaction up to 73% ee. The influence of additives in this reaction has also been investigated. Contrary to the beneficial influence observed in related catalytic systems, iodine has a deleterious effect in the present case. Otherwise, aryl phosphoric acids produce a positive impact on catalyst activity without a decrease on enantioselectivity.

  7. Influence of biochar on the enantioselective behavior of the chiral fungicide metalaxyl in soil

    Science.gov (United States)

    Gámiz, Beatriz; Pignatello, Joseph J.; Hermosín, María Carmen; Cox, Lucía; Celis, Rafael

    2015-04-01

    Chiral pesticides comprise an emerging and important class of organic pollutants currently, accounting for more than a quarter of used pesticides. Consequently, the contamination problems caused by chiral pesticides are concern matter and factors affecting enantioselective processes of chiral pesticides in soil need to be understood. For example, certain soil management practices, such as the use of organic amendments, can affect the enantioselective behavior of chiral pesticides in soils. Recently, biochar (BC), i.e. organic matter subjected to pyrolysis, has been proposed as organic amendment due to beneficial properties such as its high stability against decay in soil environments and its apparent ability to influence the availability of nutrients. BC is considered to be more biologically inert as compared to otherforms of organic carbon. However, its side-effects on the enantioselectivity of processes affecting the fate of chiral pesticides is unknown. The aim of this study was to assess the effect of biochar (BC) on the enantioselectivity of sorption, degradation, and leaching of the chiral fungicide metalaxyl in an agricultural soil. Amending the soil with BC (2% w/w) resulted in 3 times higher sorption of metalaxyl enantiomers compared to unamended soil, but no enantioselectivity in the process was observed. Moreover, both enantiomers showed some resistance to be desorbed in BC-amended soil compared to unamended soil. Dissipation studies revealed that the degradation of metalaxylwas more enantioselective in the unamended soil than in BC-amended soil. In unamended soil, R-metalaxyl(biologically active) and S- metalaxyl had half-lives (t1/2) of 3 and 34 days, respectively. BC enhanced the persistence of both enantiomers in the soil, with R-metalaxyl being degraded faster (t1/2=43 days) than S-metalaxyl (t1/2= 100 days). The leaching of both S-and R-metalaxyl was almost suppressed after amending the soil with BC; less than 10% of the fungicide applied to soil

  8. Effect of DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine on radiosensitivity of the human lung cancer cells in three-dimensional culture

    International Nuclear Information System (INIS)

    Pan Dong; Xue Gang; Li Xiaoman; Chen Yaxiong; Ren Zhenxin; Du Yarong; Hu Burong

    2014-01-01

    5-Aza-CdR is a specific inhibitor of DNMTs which could suppress tumor growth by demethylation of genomic DNA. There have only few studies thus far concerning it as radiosensitizers in three-dimensional (3D) cells. The principal aim of this study is to evaluate the effects of 5-Aza-CdR on the radiosensitivity of A549 cells in monolayer (2D) and 3D cultures in an attempt to find out a new combination treatments with radiotherapy. The cell proliferation was detected by MTT assay after pretreated with different doses of 5-Aza-CdR for 72 h. A549 cells were treated with or without 5-Aza-CdR (2, 5 μmol/L) for 72 h before be exposed to X-rays of 1, 2, 4, 6 Gy, respectively. The DNA damage was evaluated by micronucleus assay and clonogenic assays. Pretreatment with 5-Aza-CdR inhibited the A549 cell proliferation significantly. More micronucleus were observed after irradiation in 3D cells pretreated with 2 and 5 μmol/L concentration of drug than those without treatment. The survival fractions of cells pretreated by both 2 and 5 μmol/L drug reduced significantly in 3D cultures after irradiation. These significances, however, were found in 2D cells pretreated by only 5 μmol/L drug. Our results suggest that 5-Aza-CdR can inhibit the A549 cells proliferation and apparently enhance the radiosensitivity of cells in 3D cultures. Using of the low dose 5-Aza-CdR in clinical radiotherapy may reduce side effects and enhance effectively the cancer target therapy. (authors)

  9. The combination effect of sodium butyrate and 5-Aza-2'-deoxycytidine on radiosensitivity in RKO colorectal cancer and MCF-7 breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Oh Seong

    2009-05-01

    Full Text Available Abstract Background The overall level of chromatin compaction is an important mechanism of radiosensitivity, and modification of DNA methylation and histone deacetylation may increase radiosensitivity by altering chromatin compaction. In this study, we investigated the effect of a demethylating agent, a histone deacetylase(HDAC inhibitor, and the two agents combined on radiosensitivity in human colon and breast cancer cell lines. Methods In this study, we used RKO colorectal cancer cell line and MCF-7 breast cancer cell lines and normal colon cell lines. On each of the cell lines, we used three different agents: the HDAC inhibitor sodium butyrate(SB, the demethylating agent 5-Aza-2'-deoxycytidine(5-aza-DC, and radiation. We then estimated the percentage of the cell survival using the XTT method and experimented to determine if there was an augmentation in the therapeutic effect by using different combinations of the two or three of the treatment methods. Results After treatment of each cell lines with 5-aza-DC, SB and 6 grays of radiation, we observed that the survival fraction was lower after the treatment with 5-aza-DC or SB than with radiation alone in RKO and MCF-7 cell lines(p Conclusion In conclusion, 5-aza-DC and SB can enhance radiosensitivity in both MCF-7 and RKO cell lines. The combination effect of a demethylating agent and an HDAC inhibitor is more effective than that of single agent treatment in both breast and colon cancer cell lines.

  10. Quinine-Promoted, Enantioselective Boron-Tethered Diels-Alder Reaction by Anomeric Control of Transition State Conformation.

    Science.gov (United States)

    Scholl, Katie; Dillashaw, John; Timpy, Evan; Lam, Yu-Hong; DeRatt, Lindsey; Benton, Tyler R; Powell, Jacqueline P; Houk, Kendall N; Morgan, Jeremy B

    2018-05-01

    Diels-Alder reactions of tethered vinyl-metal species offer the opportunity to fashion highly functionalized diol intermediates for synthesis. We have developed the first enantioselective boron-tethered Diels-Alder reaction using quinine as a chiral promoter. Quinine recovery, enantioselectivity enhancement, and manipulation of the cyclohexene core are also investigated. DFT modeling calculations confirm the role of quinine as a bidentate ligand enhancing reaction rates. The enantioselectivity of the cycloaddition is proposed to originate from a boron-centered anomeric effect.

  11. Enantioselective Alkylation of 2-Oxindoles Catalyzed by a Bifunctional Phase-Transfer Catalyst: Synthesis of (-)-Debromoflustramine B.

    Science.gov (United States)

    Craig, Ryan; Sorrentino, Emiliano; Connon, Stephen J

    2018-03-26

    A new bifunctional phase-transfer catalyst that employs hydrogen bonding as a control element was developed to promote efficient enantioselective S N 2 reactions for the construction all-carbon quaternary stereocenters in high yield and excellent enantioselectivity (up to 97 % ee) utilizing the alkylation of a malleable oxindole substrate. The utility of the methodology was demonstrated through a concise and highly enantioselective synthesis of (-)-debromoflustramine B. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Palladium-Catalyzed Enantioselective C-H Olefination of Diaryl Sulfoxides through Parallel Kinetic Resolution and Desymmetrization.

    Science.gov (United States)

    Zhu, Yu-Chao; Li, Yan; Zhang, Bo-Chao; Zhang, Feng-Xu; Yang, Yi-Nuo; Wang, Xi-Sheng

    2018-03-07

    The first example of Pd II -catalyzed enantioselective C-H olefination with non-chiral or racemic sulfoxides as directing groups was developed. A variety of chiral diaryl sulfoxides were synthesized with high enantioselectivity (up to 99 %) through both desymmetrization and parallel kinetic resolution (PKR). This is the first report of Pd II -catalyzed enantioselective C(sp 2 )-H functionalization through PKR, and it represents a novel strategy to construct sulfur chiral centers. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Photobiological behavior of bacteria and phages supplemented with aza-analogues of nucleic acid bases

    Energy Technology Data Exchange (ETDEWEB)

    Kittler, L; Hradecna, Z; Jacob, H E; Loeber, G

    1975-01-01

    The photochemical stability of anomalous nucleic acid bases of the azatype, 5-azacytosine (1), 5-azacytidine (II), 6-azacytosine (III), 6-azacytidine (IV), 6-azathymine (V), 6-azauracil (VI), and 8-aza-adenine (VII) to uv light of the wavelength 254 nm differs from the uv stability of the normal constituents. Changes of the uv inactivation of Escherichia coli K12 C600, E. coli B, Bacillus cereus, as well as E. coli phages lambda cb/sub 2/ and lambda b/sub 2/b/sub 5/ supplemented with azaderivatives prior to irradiation were investigated. It was found that I, II, III, IV, and VII are more, V and VI less sensitive to uv light compared with corresponding natural nucleic acid bases. Their changed uv sensitivities are reflected in the survival curves after uv irradiation in as far as azabases are incorporated into the nucleic acids in vivo. This explains the increase in uv sensitivity of E. coli K 12 C600, E. coli B, and B. cereus supplemented with I, II, III, IV, and VII and the decrease in uv sensitivity of Streptococcus faecalis supplemented with V (the latter information was taken from Gunther and Prusoff 1967). The lack of any significant influence of inactivation curves of E. coli K 12 C600 by V and VI, and on E. coli phages lambda cb/sub 2/ and lambda c/sub 2/b/sub 5/ by II, is discussed in terms of too small incorporation rates. No discrimination was put forward with respect to DNA and RNA incorporation.

  14. Enantioselective Synthesis of (-)-Vallesine: Late-Stage C17-Oxidation via Complex Indole Boronation.

    Science.gov (United States)

    Antropow, Alyssa H; Garcia, Nicholas R; White, Kolby L; Movassaghi, Mohammad

    2018-06-04

    The first enantioselective total synthesis of (-)-vallesine via a strategy that features a late-stage regioselective C17-oxidation followed by a highly stereoselective transannular cyclization is reported. The versatility of this approach is highlighted by the divergent synthesis of the archetypal alkaloid of this family, (+)-aspidospermidine, and an A-ring-oxygenated derivative, (+)-deacetylaspidospermine, the precursor to (-)-vallesine, from a common intermediate.

  15. In-silico driven engineering of enantioselectivity of a penicillin G acylase towards active pharmaceutical ingredients

    Czech Academy of Sciences Publication Activity Database

    Grulich, Michal; Brezovský, J.; Štěpánek, Václav; Palyzová, Andrea; Marešová, Helena; Zahradník, Jiří; Kyslíková, Eva; Kyslík, Pavel

    2016-01-01

    Roč. 133, Supplement 1 (2016), s. 53-59 ISSN 1381-1177 Institutional support: RVO:61388971 Keywords : Docking experiments * Enantioselectivity * Penicillin G acylase Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 2.269, year: 2016

  16. Enantioselective polymerization of epoxides using biaryl-linked bimetallic cobalt catalysts: A mechanistic study

    KAUST Repository

    Ahmed, Syud M.; Poater, Albert; Childers, M. Ian; Widger, Peter C B; Lapointe, Anne M.; Lobkovsky, Emil B.; Coates, Geoffrey W.; Cavallo, Luigi

    2013-01-01

    The enantioselective polymerization of propylene oxide (PO) using biaryl-linked bimetallic salen Co catalysts was investigated experimentally and theoretically. Five key aspects of this catalytic system were examined: (1) the structural features of the catalyst, (2) the regio- and stereoselectivity of the chain-growth step, (3) the probable oxidation and electronic state of Co during the polymerization, (4) the role of the cocatalyst, and (5) the mechanism of monomer enchainment. Several important insights were revealed. First, density functional theory (DFT) calculations provided detailed structural information regarding the regio- and stereoselective chain-growth step. Specifically, the absolute stereochemistry of the binaphthol linker determines the enantiomer preference in the polymerization, and the interaction between the salen ligand and the growing polymer chain is a fundamental aspect of enantioselectivity. Second, a new bimetallic catalyst with a conformationally flexible biphenol linker was synthesized and found to enantioselectively polymerize PO, though with lower enantioselectivity than the binaphthol linked catalysts. Third, DFT calculations revealed that the active form of the catalyst has two active exo anionic ligands (chloride or carboxylate) and an endo polymer alkoxide which can ring-open an adjacent cobalt-coordinated epoxide. Fourth, calculations showed that initiation is favored by an endo chloride ligand, while propagation is favored by the presence of two exo carboxylate ligands. © 2013 American Chemical Society.

  17. Enantioselective functionalization of allylic C-H bonds following a strategy of functionalization and diversification.

    Science.gov (United States)

    Sharma, Ankit; Hartwig, John F

    2013-11-27

    We report the enantioselective functionalization of allylic C-H bonds in terminal alkenes by a strategy involving the installation of a temporary functional group at the terminal carbon atom by C-H bond functionalization, followed by the catalytic diversification of this intermediate with a broad scope of reagents. The method consists of a one-pot sequence of palladium-catalyzed allylic C-H bond oxidation under neutral conditions to form linear allyl benzoates, followed by iridium-catalyzed allylic substitution. This overall transformation forms a variety of chiral products containing a new C-N, C-O, C-S, or C-C bond at the allylic position in good yield with a high branched-to-linear selectivity and excellent enantioselectivity (ee ≤97%). The broad scope of the overall process results from separating the oxidation and functionalization steps; by doing so, the scope of nucleophile encompasses those sensitive to direct oxidative functionalization. The high enantioselectivity of the overall process is achieved by developing an allylic oxidation that occurs without acid to form the linear isomer with high selectivity. These allylic functionalization processes are amenable to an iterative sequence leading to (1,n)-functionalized products with catalyst-controlled diastereo- and enantioselectivity. The utility of the method in the synthesis of biologically active molecules has been demonstrated.

  18. Aziridino Alcohols as Catalysts for the Enantioselective Addition of Diethylzinc to Aldehydes

    DEFF Research Database (Denmark)

    Tanner, David Ackland; Kornø, Hanne Tøfting; Guijarro, David

    1998-01-01

    The chiral aziridino alcohols 1 -3 have been prepared either from amino acids (1a from serine; 1b - 1i and 3 from threonine; 2a - 2e from allo-threonine) or via asymmetric synthesis (1j, 1k, 1l and 2f from methyl cinnamate). These easily available ligands act as catalysts for the enantioselective...

  19. Enantioselective radical reactions. Evaluation of nitrogen protecting groups in the synthesis of β2-amino acids

    Science.gov (United States)

    Sibi, Mukund P.; Patil, Kalyani

    2006-01-01

    We have investigated the effect of nitrogen protecting groups in radical addition trapping experiments leading to β2-amino acids. Of the three N-protecting groups examined, the phthalimido group was optimal with respect to both yields and enantioselectivity. Additionally, radical additions to more complex acrylates were also investigated, which provided access to functionalized β2-amino acids in modest selectivity. PMID:16799704

  20. Enantioselective radical reactions. Evaluation of nitrogen protecting groups in the synthesis of beta-amino acids.

    Science.gov (United States)

    Sibi, Mukund P; Patil, Kalyani

    2006-02-20

    We have investigated the effect of nitrogen protecting groups in radical addition trapping experiments leading to beta(2)-amino acids. Of the three N-protecting groups examined, the phthalimido group was optimal with respect to both yields and enantioselectivity. Additionally, radical additions to more complex acrylates were also investigated, which provided access to functionalized beta(2)-amino acids in modest selectivity.

  1. An entry to a chiral dihydropyrazole scaffold: enantioselective [3 + 2] cycloaddition of nitrile imines.

    Science.gov (United States)

    Sibi, Mukund P; Stanley, Levi M; Jasperse, Craig P

    2005-06-15

    We have developed a versatile strategy to access dihydropyrazoles in highly enantioenriched form. Dipolar cycloaddition of electron-deficient acceptors and in situ-generated nitrile imines proceeds with high regio- and enantioselectivity using 10 mol % chiral Lewis acid catalyst. A variety of dihydropyrazoles that incorporate functionality for further manipulation have been prepared.

  2. Exploiting the enantioselectivity of Baeyer-Villiger monooxygenases via boron oxidation

    NARCIS (Netherlands)

    Brondani, Patricia B.; Dudek, Hanna; Reis, Joel S.; Fraaije, Marco W.; Andrade, Leandro H.

    2012-01-01

    The enantioselective carbon-boron bond oxidation of several chiral boron-containing compounds by Baeyer-Villiger monooxygenases was evaluated. PAMO and M446G PAMO conveniently oxidized 1-phenylethyl boronate into the corresponding 1-(phenyl)ethanol (ee = 82-91%). Cyclopropyl boronic esters were also

  3. Stereospecific nickel-catalyzed cross-coupling reactions of alkyl ethers: enantioselective synthesis of diarylethanes.

    Science.gov (United States)

    Taylor, Buck L H; Swift, Elizabeth C; Waetzig, Joshua D; Jarvo, Elizabeth R

    2011-01-26

    Secondary benzylic ethers undergo stereospecific substitution reactions with Grignard reagents in the presence of nickel catalysts. Reactions proceed with inversion of configuration and high stereochemical fidelity. This reaction allows for facile enantioselective synthesis of biologically active diarylethanes from readily available optically enriched carbinols.

  4. Enantioselective polymerization of epoxides using biaryl-linked bimetallic cobalt catalysts: A mechanistic study

    KAUST Repository

    Ahmed, Syud M.

    2013-12-18

    The enantioselective polymerization of propylene oxide (PO) using biaryl-linked bimetallic salen Co catalysts was investigated experimentally and theoretically. Five key aspects of this catalytic system were examined: (1) the structural features of the catalyst, (2) the regio- and stereoselectivity of the chain-growth step, (3) the probable oxidation and electronic state of Co during the polymerization, (4) the role of the cocatalyst, and (5) the mechanism of monomer enchainment. Several important insights were revealed. First, density functional theory (DFT) calculations provided detailed structural information regarding the regio- and stereoselective chain-growth step. Specifically, the absolute stereochemistry of the binaphthol linker determines the enantiomer preference in the polymerization, and the interaction between the salen ligand and the growing polymer chain is a fundamental aspect of enantioselectivity. Second, a new bimetallic catalyst with a conformationally flexible biphenol linker was synthesized and found to enantioselectively polymerize PO, though with lower enantioselectivity than the binaphthol linked catalysts. Third, DFT calculations revealed that the active form of the catalyst has two active exo anionic ligands (chloride or carboxylate) and an endo polymer alkoxide which can ring-open an adjacent cobalt-coordinated epoxide. Fourth, calculations showed that initiation is favored by an endo chloride ligand, while propagation is favored by the presence of two exo carboxylate ligands. © 2013 American Chemical Society.

  5. Optimisation of the enantioselective biocatalytic hydrolysis of naproxen ethyl ester using ChiroCLEC-CR

    CSIR Research Space (South Africa)

    Brady, D

    2004-03-04

    Full Text Available In a biocatalytic reaction the immobilized lipase ChiroCLEC-CR enantioselectively hydrolysed a naproxen ethyl ester racemate, yielding (S)-naproxen with an enantiomeric excess of more than 98%, an enantiomeric ratio (E) of more than 100...

  6. DNA-based asymmetric catalysis : Sequence-dependent rate acceleration and enantioselectivity

    NARCIS (Netherlands)

    Boersma, Arnold J.; Klijn, Jaap E.; Feringa, Ben L.; Roelfes, Gerard

    2008-01-01

    This study shows that the role of DNA in the DNA-based enantioselective Diels-Alder reaction of azachalcone with cyclopentadiene is not limited to that of a chiral scaffold. DNA in combination with the copper complex of 4,4'-dimethyl-2,2'-bipyridine (Cu-L1) gives rise to a rate acceleration of up to

  7. Equilibrium Studies on Enantioselective Liquid-Liquid Amino Acid Extraction Using a Cinchona Alkaloid Extractant

    NARCIS (Netherlands)

    Schuur, Boelo; Winkelman, Jozef G. M.; Heeres, Hero J.

    2008-01-01

    The enantioselective extraction of aqueous 3,5-dinitrobenzoyl-R,S-leucine (A(R,S)) by a cinchona alkaloid extractant (C) in 1,2-dichloroethane was studied at room temperature (294 K) in a batch system for a range of intake concentrations (10(-4)-10(-3) mol/L) and pH values (3.8-6.6). The

  8. Iridium-Catalyzed Asymmetric Intramolecular Allylic Amidation : Enantioselective Synthesis of Chiral Tetrahydroisoquinolines and Saturated Nitrogen Heterocycles

    NARCIS (Netherlands)

    Teichert, Johannes F.; Fañanás-Mastral, Martín; Feringa, Bernard

    2011-01-01

    For the first time iridium catalysis has been used for the synthesis of chiral tetrahydroisoquinolines with excellent yields and high enantioselectivities (see scheme; cod=1,5-cyclooctadiene, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene). These products are important chiral building blocks for the

  9. Improvement of enantioselectivity by immobilized imprinting of epoxide hydrolase from Rhodotorula glutinis

    NARCIS (Netherlands)

    Kronenburg, N.A.E.; Bont, de J.A.M.; Fischer, L.

    2001-01-01

    The yeast Rhodotorula glutinis contains an enantioselective, membrane-associated epoxide hydrolase (EH). Partially purified EH was immobilized in a two-step procedure. In the first step, the proteins were derivatized with itaconic anhydride. In the second step, the derivatized proteins were

  10. A DFT exploration of the enantioselective rearrangement of cyclohexene oxide to cyclohexenol

    DEFF Research Database (Denmark)

    Brandt, Peter; Norrby, Per-Ola; Andersson, Pher G.

    2003-01-01

    In this paper, we present computational results for the (1S,3R,4R)-3-(pyrrolidinyl)-methyl-2-azabicyclo[2.2.1]heptane mediated rearrangement of cyclohexene oxide. The results nicely explain the differences in enantioselectivities between catalytic and stoichiometric mode between different ligands...

  11. Efficient and highly enantioselective formation of the all-carbon quaternary stereocentre of lyngbyatoxin A

    DEFF Research Database (Denmark)

    Vital, Paulo J.V.; Tanner, David

    2006-01-01

    Indole 25, an advanced intermediate in a projected enantioselective total synthesis of lyngbyatoxin A 1, was prepared from allylic alcohol 11 in 9 steps and >95% ee, key transformations being the enantiospecific rearrangement of vinyl epoxide 14 and the Hemetsberger-Knittel reaction of azide 24....

  12. Uncovering Key Structural Features of an Enantioselective Peptide-Catalyzed Acylation Utilizing Advanced NMR Techniques

    Czech Academy of Sciences Publication Activity Database

    Procházková, Eliška; Kolmer, A.; Ilgen, J.; Schwab, M.; Kaltschnee, L.; Fredersdorf, M.; Schmidts, V.; Wende, R. C.; Schreiner, P. R.; Thiele, C. M.

    2016-01-01

    Roč. 55, č. 51 (2016), s. 15754-15759 ISSN 1433-7851 Institutional support: RVO:61388963 Keywords : conformational analysis * enantioselective acylations * NMR spectroscopy * pure shift NMR * RDCs Subject RIV: CC - Organic Chemistry Impact factor: 11.994, year: 2016

  13. Resolution of alpha/beta-amino acids by enantioselective penicillin G acylase from Achromobacter sp

    Czech Academy of Sciences Publication Activity Database

    Grulich, Michal; Brezovský, J.; Štěpánek, Václav; Palyzová, Andrea; Kyslíková, Eva; Kyslík, Pavel

    2015-01-01

    Roč. 122, DEC 2015 (2015), s. 240-247 ISSN 1381-1177 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61388971 Keywords : Penicillin G acylase * Enantioselectivity * Homologous model Subject RIV: CE - Biochemistry Impact factor: 2.189, year: 2015

  14. Enantioselective analysis of proteinogenic amino acids in cerebrospinal fluid by capillary electrophoresis–mass spectrometry

    NARCIS (Netherlands)

    Prior, Amir; Sánchez-Hernández, Laura; Sastre-Toraño, Javier; Marina, Maria Luisa; de Jong, Gerhardus J.; Somsen, Govert W.

    2016-01-01

    d-Amino acids (AAs) are increasingly being recognized as essential molecules in biological systems. Enantioselective analysis of proteinogenic AAs in biological samples was accomplished by CE–MS employing β-CD as chiral selector and ESI via sheath-liquid (SL) interfacing. Prior to analysis, AAs were

  15. Enantioselective [3+3] atroposelective annulation catalyzed by N-heterocyclic carbenes

    KAUST Repository

    Zhao, Changgui; Guo, Donghui; Munkerup, Kristin; Huang, Kuo-Wei; Li, Fangyi; Wang, Jian

    2018-01-01

    on the transition-metal-catalyzed transformations. Here, we report the enantioselective NHC-catalyzed (NHC: N-heterocyclic carbenes) atroposelective annulation of cyclic 1,3-diones with ynals. In the presence of NHC precatalyst, base, Lewis acid and oxidant, a

  16. Combining silver- and organocatalysis: an enantioselective sequential catalytic approach towards pyrano-annulated pyrazoles.

    Science.gov (United States)

    Hack, Daniel; Chauhan, Pankaj; Deckers, Kristina; Mizutani, Yusuke; Raabe, Gerhard; Enders, Dieter

    2015-02-11

    A one-pot asymmetric Michael addition/hydroalkoxylation sequence, catalyzed by a sequential catalytic system consisting of a squaramide and a silver salt, provides a new series of chiral pyrano-annulated pyrazole derivatives in excellent yields (up to 95%) and high enantioselectivities (up to 97% ee).

  17. The Enantioselectivity of Odor Sensation: Some Examples for Undergraduate Chemistry Courses

    Science.gov (United States)

    Kraft, Philip; Mannschreck, Albrecht

    2010-01-01

    This article discusses seven chiral odorants that demonstrate the enantioselectivity of odor sensation: carvone, Celery Ketone, camphor, Florhydral, 3-methyl-3-sulfanylhexan-1-ol, muscone, and methyl jasmonate. After a general introduction of the odorant-receptor interaction and the combinatorial code of olfaction, the olfactory properties of the…

  18. Simple Aziridino Alcohols as Chiral Ligands. Enantioselective Additions of Diethylzinc to N-Diphenylphosphinoylimines

    DEFF Research Database (Denmark)

    Tanner, David Ackland; Andersson, Pher G.; Guijarro, David

    1996-01-01

    Simple chiral aziridino alcohols 2-5, easily available from L-serine, L-threonine or L-allo-threonine, have been used as ligands to promote the addition of Et(2)Zn to the diphenylphosphinoylimine 1 (Ar=Ph). Enantioselectivities of up to 94% could be obtained by proper choice of the substituents...

  19. Pd(II)-Catalyzed Enantioselective C-H Olefination of Diphenylacetic Acids

    Science.gov (United States)

    Shi, Bing-Feng; Zhang, Yang-Hui; Lam, Jonathan K.; Wang, Dong-Hui; Yu, Jin-Quan

    2009-01-01

    Pd(II)-catalyzed enantioselective C-H olefination of diphenylacetic acid substrates has been achieved through the use of mono-protected chiral amino acid ligands. The absolute configuration of the resulting olefinated products is consistent with that of a proposed C-H insertion intermediate. PMID:20017549

  20. A Green, Enantioselective Synthesis of Warfarin for the Undergraduate Organic Laboratory

    Science.gov (United States)

    Wong, Terence C.; Sultana, Camille M.; Vosburg, David A.

    2010-01-01

    The enantioselective synthesis of drugs is of fundamental importance in the pharmaceutical industry. In this experiment, students synthesize either enantiomer of warfarin, a widely used anticoagulant, in a single step from inexpensive starting materials. Stereoselectivity is induced by a commercial organocatalyst, ("R","R")- or…

  1. Metabolism of styrene in the human liver in vitro: interindividual variation and enantioselectivity

    NARCIS (Netherlands)

    Wenker, M. A.; Kezić, S.; Monster, A. C.; de Wolff, F. A.

    2001-01-01

    1. The interindividual variation and enantioselectivity of the in vitro styrene oxidation by cytochrome P450 have been investigated in 20 human microsomal liver samples. Liver samples were genotyped for the CYP2E1*6 and CYP2E1*5B alleles. 2. Kinetic analysis indicated the presence of at least two

  2. Enantioselective Evans-Tishchenko Reduction of b-Hydroxyketone Catalyzed by Lithium Binaphtholate

    Directory of Open Access Journals (Sweden)

    Makoto Nakajima

    2011-06-01

    Full Text Available Lithium diphenylbinaphtholate catalyzed the enantioselective Evans-Tishchenko reduction of achiral b-hydroxyketones to afford monoacyl-protected 1,3-diols with high stereoselectivities. In the reaction of racemic b-hydroxyketones, kinetic optical resolution occurred in a highly stereoselective manner.

  3. New eco-friendly animal bone meal catalysts for preparation of chalcones and aza-Michael adducts

    Directory of Open Access Journals (Sweden)

    Riadi Yassine

    2012-06-01

    Full Text Available Abstract Two efficient reactions were successfully carried out using Animal Bone Meal (ABM and potassium fluoride or sodium nitrate doped ABMs as new heterogeneous catalysts under very mild conditions. After preparation and characterization of the catalysts, we first report their use in a simple and convenient synthesis of various chalcones by Claisen–Schmidt condensation and then in an aza-Michael addition involving several synthesized chalcones with aromatic amines. All the reactions were carried out at room temperature in methanol; the chalcone synthesis was also achieved in water environment under microwave irradiation. Doping ABM enhances the rate and yield at each reaction. Catalytic activities are discussed and the ability to re-use the ABM is demonstrated. Results For Claisen–Schmidt the use of ABM alone, yields never exceeded 17%. In each entry, KF/ABM and NaNO3/ABM (79-97% gave higher yields than using ABM alone under thermic condition. Also the reaction proceeded under microwave irradiation in good yields (72-94% for KF/ABM and 81-97% for NaNO3/ABM and high purity. For aza-Michael addition the use of ABM doped with KF or NaNO3 increased the catalytic activity remarkably. The very high yields could be noted (84-95% for KF/ABM and 81-94% for NaNO3/ABM. Conclusion The present method is an efficient and selective procedure for the synthesis of chalcones an aza-Michael adducts. The ABM and doped ABMs are a new, inexpensive and attractive solid supports which can contribute to the development of catalytic processes and reduced environmental problems.

  4. A Catalyst-Enabled Diastereodivergent Aza-Diels-Alder Reaction: Complementarity of N-Heterocyclic Carbenes and Chiral Amines.

    Science.gov (United States)

    Rong, Zi-Qiang; Wang, Min; Chow, Chi Hao Eugene; Zhao, Yu

    2016-07-04

    Highly efficient and diastereodivergent aza-Diels-Alder reactions have been developed to access either diastereomeric series of benzofuran-fused δ-lactams and dihydropyridines in nearly perfect stereoselectivity (d.r. >20:1, >99 % ee for all examples). The complementarity of N-heterocyclic carbene and chiral amine as the catalyst was demonstrated for the first time, together with an excellent level of catalytic efficiency (1 mol % loading). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Electrochemical Synthesis, Structure Elucidation and Antibacterial Evaluation of 9a-aza-9a-chloro-9a-homoerythromycin A

    Directory of Open Access Journals (Sweden)

    Zoran Mandic

    2014-09-01

    Full Text Available Electrochemical synthesis, structure elucidation and antibacterial evaluation of 9a-aza-9a-chloro-9a-homoerythromycin A were carried out. It was found that the anodic oxidation of 9a-aza-9a-homoerythromycin A via electrogenerated reactive chlorine species leads to the chlorination of lactam nitrogen in high yield provided the pH of the reaction mixture is maintained above 3. NOESY spectra reveal the existence of the mixture of two conformational families in the solution, the "folding-out" conformer being slightly more abundant comparing to 9a-Aza-9a-homoerythromycin A. The chlorine substitution of lactam hydrogen resulted in improved antimicrobial potency against Sreptococcus pyogenes PSCB0542, Moraxella catarrhalis ATCC 25238, Haemophilus  influenzae ATCC 49247 and Enteroccocus faecalis ATCC 29212.

  6. Comparison of the anti-cancer effect of Disulfiram and 5-Aza-CdR on pancreatic cancer cell line PANC-1.

    Science.gov (United States)

    Dastjerdi, Mehdi Nikbakht; Babazadeh, Zahra; Salehi, Mansour; Hashemibeni, Batool; Kazemi, Mohammad

    2014-01-01

    Pancreatic cancer has poor prognosis by surgical and chemotherapy when it is diagnosed, so other anti-cancerous assistant therapeutic drugs are suggested e.g. epigenetic reversal of tumor-suppressor genes on promoter hypermethylation. 5-Aza-CdR is a nucleoside analog of DNMTi but it has long-term cytotoxicity effects. This study compares the anticancer effect of 5-Aza-CdR and Disulfiram potencies on PANC-1 cell line and up-regulation of p21. PANC-1 cell line was cultured in DMEM high glucose and treated by 5-Aza-CdR with 5 and 10 μM concentration for four days and 13 μM DSF (Diulfiram) for 24 hours. MS-PCR and RT-PCR were carried out to detect the methylation pattern and estimate the mRNA expression of RASSF1A and p21 in PANC-1. MS-PCR demonstrated partial unmethylation after treatment with 5-Aza-CdR while there was no unmethylated band after DSF treatment. RT-PCR showed significant differences between re-expression of RASSF1A before and after treatment with 10 μM 5-Aza-CdR (P 0.05). The significant correlation was observed between RASSF1A re-expression and p21 up-regulation before and after treatment with 10 μM 5-Aza-CdR (P 0.05), while p21 up-regulation was significantly higher after DSF treatment (P PANC-1. DSF showed no epigenetic reversion while it affected p21 up-regulation.

  7. DNA demethylation by 5-aza-2-deoxycytidine treatment abrogates 17 beta-estradiol-induced cell growth and restores expression of DNA repair genes in human breast cancer cells.

    Science.gov (United States)

    Singh, Kamaleshwar P; Treas, Justin; Tyagi, Tulika; Gao, Weimin

    2012-03-01

    Prolonged exposure to elevated levels of estrogen is a risk factor for breast cancer. Though increased cell growth and loss of DNA repair capacity is one of the proposed mechanisms for estrogen-induced cancers, the mechanism through which estrogen induces cell growth and decreases DNA repair capacity is not clear. DNA hypermethylation is known to inactivate DNA repair genes and apoptotic response in cancer cells. Therefore, the objective of this study was to determine the role of DNA hypermethylation in estrogen-induced cell growth and regulation of DNA repair genes expression in breast cancer cells. To achieve this objective, the estrogen-responsive MCF-7 cells either pretreated with 5-aza-2-deoxycytidine (5-aza-dC) or untreated (as control) were exposed to 17 beta-estradiol (E2), and its effect on cell growth and expression of DNA repair genes were measured. The result revealed that 5-aza-dC abrogates the E2-induced growth in MCF-7 cells. An increased expression of OGG1, MSH4, and MLH1 by 5-aza-dC treatment alone, suggest the DNA hypermethylation as a potential cause for decreased expression of these genes in MCF-7 cells. The decreased expression of ERCC1, XPC, OGG1, and MLH1 by E2 alone and its restoration by co-treatment with 5-aza-dC further suggest that E2 reduces the expression of these DNA repair genes potentially through promoter hypermethylation. Reactivation of mismatch repair (MMR) gene MLH1 and abrogation of E2-induced cell growth by 5-aza-dC treatment suggest that estrogen causes increased growth in breast cancer cells potentially through the inhibition of MMR-mediated apoptotic response. In summary, this study suggests that estrogen increases cell growth and decreases the DNA repair capacity in breast cancer cells, at least in part, through epigenetic mechanism. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  8. Crystallization and preliminary X-ray analysis of an enantioselective halohydrin dehalogenase from Agrobacterium radiobacter AD1

    NARCIS (Netherlands)

    Jong, René M. de; Rozeboom, Henriëtte J.; Kalk, Kor H.; Tang, Lixia; Janssen, Dick B.; Dijkstra, Bauke W.

    2002-01-01

    Halohydrin dehalogenases are key enzymes in the bacterial degradation of vicinal halopropanols and structurally related nematocides. Crystals of the enantioselective halohydrin dehalogenase HheC from Agrobacterium radiobacter AD1 have been obtained at room temperature from hanging-drop

  9. Crystallization and preliminary X-ray analysis of an enantioselective halohydrin dehalogenase from Agrobacterium radiobacter AD1

    NARCIS (Netherlands)

    de Jong, RM; Rozeboom, HJ; Kalk, KH; Tang, Lixia; Janssen, DB; Dijkstra, BW

    Halohydrin dehalogenases are key enzymes in the bacterial degradation of vicinal halopropanols and structurally related nematocides. Crystals of the enantioselective halohydrin dehalogenase HheC from Agrobacterium radiobacter AD1 have been obtained at room temperature from hanging-drop

  10. Total syntheses of mitragynine, paynantheine and speciogynine via an enantioselective thiourea-catalysed Pictet-Spengler reaction

    NARCIS (Netherlands)

    Kerschgens, I. P.; Claveau, E.; Wanner, M.J.; Ingemann, S.; van Maarseveen, J.H.; Hiemstra, H.

    2012-01-01

    The pharmacologically interesting indole alkaloids (-)-mitragynine, (+)-paynantheine and (+)-speciogynine were synthesised in nine steps from 4-methoxytryptamine by a route featuring (i) an enantioselective thiourea-catalysed Pictet-Spengler reaction, providing the tetrahydro-β-carboline ring and

  11. One pot 'click' reactions : tandem enantioselective biocatalytic epoxide ring opening and [3+2] azide alkyne cycloaddition

    NARCIS (Netherlands)

    Campbell-Verduyn, Lachlan S.; Szymanski, Wiktor; Postema, Christiaan P.; Dierckx, Rudi A.; Elsinga, Philip H.; Janssen, Dick B.; Feringa, Ben L.

    2010-01-01

    Halohydrin dehalogenase (HheC) can perform enantioselective azidolysis of aromatic epoxides to 1,2-azido alcohols which are subsequently ligated to alkynes producing chiral hydroxy triazoles in a one-pot procedure with excellent enantiomeric excess.

  12. Tuning and Switching Enantioselectivity of Asymmetric Carboligation in an Enzyme through Mutational Analysis of a Single Hot Spot.

    Science.gov (United States)

    Wechsler, Cindy; Meyer, Danilo; Loschonsky, Sabrina; Funk, Lisa-Marie; Neumann, Piotr; Ficner, Ralf; Brodhun, Florian; Müller, Michael; Tittmann, Kai

    2015-12-01

    Enantioselective bond making and breaking is a hallmark of enzyme action, yet switching the enantioselectivity of the reaction is a difficult undertaking, and typically requires extensive screening of mutant libraries and multiple mutations. Here, we demonstrate that mutational diversification of a single catalytic hot spot in the enzyme pyruvate decarboxylase gives access to both enantiomers of acyloins acetoin and phenylacetylcarbinol, important pharmaceutical precursors, in the case of acetoin even starting from the unselective wild-type protein. Protein crystallography was used to rationalize these findings and to propose a mechanistic model of how enantioselectivity is controlled. In a broader context, our studies highlight the efficiency of mechanism-inspired and structure-guided rational protein design for enhancing and switching enantioselectivity of enzymatic reactions, by systematically exploring the biocatalytic potential of a single hot spot. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. NYESO-1/LAGE-1s and PRAME are targets for antigen specific T cells in chondrosarcoma following treatment with 5-Aza-2-deoxycitabine.

    Directory of Open Access Journals (Sweden)

    Seth M Pollack

    Full Text Available Chondrosarcoma has no proven systemic option in the metastatic setting. The development of a non-cross-resistant strategy, such as cellular immunotherapy using antigen-specific T cells would be highly desirable. NY-ESO-1 and PRAME are members of the Cancer Testis Antigen (CTA family that have been identified as promising targets for T cell therapy. LAGE-1 is a cancer testis antigen 90% homologous to NY-ESO-1, sharing the 157-165 A*0201 NY-ESO-1 epitope with its transcript variant, LAGE-1s. A number of CTA's have been induced using 5-Aza-2-Deoxycitabine (5-Aza-dC in other cancers. We sought to evaluate the feasibility of targeting chondrosarcoma tumors using NY-ESO-1/LAGE-1s and PRAME specific T cells using 5-Aza-dC to induce antigen expression.We used 11 flash frozen tumors from the University of Washington tumor bank to test for the expression of NY-ESO-1, PRAME, LAGE-1s and LAGE-1L in chondrosarcoma tumors. Using four chondrosarcoma cell lines we tested the expression of these CTA's with and without 5-Aza-dC treatments. Finally, using NY-ESO-1/LAGE-1s and PRAME specific effectors that we generated from sarcoma patients, we evaluated the ability of these T cells to lyse A*0201 expressing chondrosarcoma cell lines in vitro both with and without 5-Aza-dC treatment.A minority (36% of chondrosarcoma tumors expressed either NY-ESO-1 or LAGE-1s at >10% of our reference value and none expressed PRAME at that level. However, in all four of the chondrosarcoma cell lines tested, NY-ESO-1 and PRAME expression could be induced following treatment with 5-Aza-dC including in cell lines where expression was absent or barely detectable. Furthermore, NY-ESO-1/LAGE-1s and PRAME specific CD8+ effector T cells were able to specifically recognize and lyse A*0201 expressing chondrosarcoma cell lines following 5-Aza-dC treatment.These data suggest that adoptive immunotherapy in combination with 5-Aza-dC may be a potential strategy to treat unresectable or metastatic

  14. Demethylation by 5-aza-2'-deoxycytidine in colorectal cancer cells targets genomic DNA whilst promoter CpG island methylation persists

    International Nuclear Information System (INIS)

    Mossman, David; Kim, Kyu-Tae; Scott, Rodney J

    2010-01-01

    DNA methylation and histone acetylation are epigenetic modifications that act as regulators of gene expression. Aberrant epigenetic gene silencing in tumours is a frequent event, yet the factors which dictate which genes are targeted for inactivation are unknown. DNA methylation and histone acetylation can be modified with the chemical agents 5-aza-2'-deoxycytidine (5-aza-dC) and Trichostatin A (TSA) respectively. The aim of this study was to analyse de-methylation and re-methylation and its affect on gene expression in colorectal cancer cell lines treated with 5-aza-dC alone and in combination with TSA. We also sought to identify methylation patterns associated with long term reactivation of previously silenced genes. Colorectal cancer cell lines were treated with 5-aza-dC, with and without TSA, to analyse global methylation decreases by High Performance Liquid Chromatography (HPLC). Re-methylation was observed with removal of drug treatments. Expression arrays identified silenced genes with differing patterns of expression after treatment, such as short term reactivation or long term reactivation. Sodium bisulfite sequencing was performed on the CpG island associated with these genes and expression was verified with real time PCR. Treatment with 5-aza-dC was found to affect genomic methylation and to a lesser extent gene specific methylation. Reactivated genes which remained expressed 10 days post 5-aza-dC treatment featured hypomethylated CpG sites adjacent to the transcription start site (TSS). In contrast, genes with uniformly hypermethylated CpG islands were only temporarily reactivated. These results imply that 5-aza-dC induces strong de-methylation of the genome and initiates reactivation of transcriptionally inactive genes, but this does not require gene associated CpG island de-methylation to occur. In addition, for three of our selected genes, hypomethylation at the TSS of an epigenetically silenced gene is associated with the long term reversion of

  15. Enantioselective synthesis of chiral 3-aryl-1-indanones through rhodium-catalyzed asymmetric intramolecular 1,4-addition.

    Science.gov (United States)

    Yu, Yue-Na; Xu, Ming-Hua

    2013-03-15

    Enantioselective synthesis of potentially useful chiral 3-aryl-1-indanones was achieved through a rhodium-catalyzed asymmetric intramolecular 1,4-addition of pinacolborane chalcone derivatives using extraordinary simple MonoPhos as chiral ligand under relatively mild conditions. This novel protocol offers an easy access to a wide variety of enantioenriched 3-aryl-1-indanone derivatives in high yields (up to 95%) with excellent enantioselectivities (up to 95% ee).

  16. Enantioselective Construction of 3-Hydroxypiperidine Scaffolds by Sequential Action of Light and Rhodium upon N-Allylglyoxylamides.

    Science.gov (United States)

    Ishida, Naoki; Nečas, David; Masuda, Yusuke; Murakami, Masahiro

    2015-06-15

    3-Hydroxypiperidine scaffolds were enantioselectively constructed in an atom-economical way by sequential action of light and rhodium upon N-allylglyoxylamides. In a formal sense, the allylic C-H bond was selectively cleaved and enantioselectively added across the ketonic carbonyl group with migration of the double bond (carbonyl-ene-type reaction). © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Catalytic Enantioselective Synthesis of 3,4-Unsubstituted Thiochromenes through Sulfa-Michael/Julia-Kocienski Olefination Cascade Reaction.

    Science.gov (United States)

    Simlandy, Amit Kumar; Mukherjee, Santanu

    2017-05-05

    A highly enantioselective cascade sulfa-Michael/Julia-Kocienski olefination reaction between 2-mercaptobenzaldehydes and β-substituted vinyl PT-sulfones has been realized for the synthesis of 3,4-unsubstituted 2H-thiochromenes. This reaction, catalyzed by diphenylprolinol TMS ether, proceeds through an aromatic iminium intermediate and furnishes a wide range of 2-substiuted 2H-thiochromenes with excellent enantioselectivities (up to 99:1 er).

  18. Enantioselective silver nanoclusters: Preparation, characterization and photoluminescence spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Farrag, Mostafa, E-mail: mostafafarrag@aun.edu.eg

    2016-09-01

    prepared silver nanoclusters were investigated using nitrogen adsorption-desorption at −196 °C. Specific surface area S{sub BET}, pore volume and average pore diameter were calculated. - Highlights: • New wet chemistry method to prepare mirror image small silver clusters protected by penicillamine. • Preparation enantioselective catalysts by easy wet chemistry method. • The synthesized silver clusters have photoluminescence properties. • The synthesized silver clusters show high Anisotropy factors up to 3 × 10{sup −4}. • The adsorption isotherms of all synthesized clusters are mainly of type II of Brunaue’s classification.

  19. Cyclic aldimines as superior electrophiles for Cu-catalyzed decarboxylative Mannich reaction of β-ketoacids with a broad scope and high enantioselectivity.

    Science.gov (United States)

    Zhang, Heng-Xia; Nie, Jing; Cai, Hua; Ma, Jun-An

    2014-05-02

    A novel Cu-catalyzed enantioselective decarboxylative Mannich reaction of cyclic aldimines with β-ketoacids is described. The cyclic structure of these aldimines, in which the C═N bond is constrained in the Z geometry, appears to be important, allowing Mannich condensation to proceed in high yields with excellent enantioselectivities. A chiral chroman-4-amine was synthesized from the decarboxylative Mannich product in several steps without loss of enantioselectivity.

  20. Enantioselective Analysis in instruments onboard ROSETTA/PHILAE and ExoMars

    Science.gov (United States)

    Hendrik Bredehöft, Jan; Thiemann, Wolfram; Meierhenrich, Uwe; Goesmann, Fred

    It has been suggested a number of times in the past, to look for chirality as a biomarker. So far, for lack of appropriate instrumentation, space missions have never included enantioselective analysis. The distinction between enantiomers is of crucial importance to the question of the origin of the very first (pre)biotic molecules. If molecules detected in situ on another celestial body were found to exhibit a chiral bias, this would mean that at least partial asymmetric synthesis could take place abiotically. If this chiral bias should be found to be near 100For the currently flying ESA mission ROSETTA an enantioselective instrument was built, to try for the first time to detect and separate chiral molecules in situ. This instrument is COSAC, the Cometary Sampling and Acquisition Experiment, an enantioselective GCMS device[1,2], which is included in the lander PHLIAE that will eventually in 2014 land on the nucleus of comet 67P/Churyumov-Gerasimenko. A similar but even more powerful type of enantioselective GC-MS is in preparation for ESA's ExoMars mission. This instrument is part of MOMA, the Mars Organic Molecules Analyser. It has the objective of identifying and quantifying chiral organic molecules in surface and subsurface samples of Mars. Currently ExoMars is scheduled for 2018. The newly developed enantioselective technique utilized by both COSAC and MOMA will be described, including sample acquisition, derivatization, and separation in space-resistant chiral stationary capillary columns with time-of-flight mass spectrometric detection. Results of enantioselective analyses of representative test samples with special emphasis on amino acids[3], the building blocks of protein polymers, will be presented and we will discuss potential results of space missions Rosetta and ExoMars. [1] Thiemann W.H.-P., Meierhenrich U.: ESA Mission ROSETTA Will Probe for Chirality of Cometary Amino Acids. Origins of Life and Evolution of Biospheres 31 (2001), 199-210. [2

  1. Evaluation of reversible interconversion in comprehensive two-dimensional gas chromatography using enantioselective columns in first and second dimensions.

    Science.gov (United States)

    Kröger, Sabrina; Wong, Yong Foo; Chin, Sung-Tong; Grant, Jacob; Lupton, David; Marriott, Philip J

    2015-07-24

    The reversible molecular interconversion behaviour of a synthesised oxime (2-phenylpropanaldehyde oxime; (C6H5)CH(CH3)CHN(OH)) was investigated by both, single dimensional gas chromatography (1D GC) and comprehensive two-dimensional gas chromatography (GC×GC). Previous studies on small molecular weight oximes were extended to this larger aromatic oxime (molar mass 149.19gmol(-1)) with interest in the extent of interconversion, enantioselective resolution, and retention time. On a polyethylene glycol (PEG; wax-type) column, a characteristic interconversion zone between two antipodes of E and Z isomers was formed by molecules which have undergone isomerisation on the column (E⇌Z). The extent of interconversion was investigated by varying chromatographic conditions (oven temperature and carrier flow rate) to understand the nature of the behaviour observed. The extent of interconversion was negligible in both enantioselective and methyl-phenylpolysiloxane phase-columns, correlating with the low polarity of the stationary phase. In order to obtain isomerisation along with enantio-resolution, a wax-type and an enantioselective column were coupled in either enantioselective-wax or wax-enantioselective order. The most appropriate column arrangement was selected for study by using a GC×GC experiment with either a wax-phase or phenyl-methylpolysiloxane phase as (2)D column. In addition to evaluation of these fast elution columns, a long narrow-bore enantioselective column (10m) was introduced as (2)D, providing an enantioselective-PEG (coupled-column ensemble: (1)D1+(1)D2)×enantioselective ((2)D) column combination. In this instance, the (1)D1 enantioselective column provides enantiomeric separation of the corresponding enantiomers ((R) and (S)) of (E)- and (Z)-2-phenylpropanaldehyde oxime, followed by E/Z isomerisation in the coupled (1)D2 PEG (reactor) column. The resulting chromatographic interconversion region was modulated and separated into either E/Z isomers

  2. Domino Aza-Michael-ih-Diels-Alder Reaction to Various 3-Vinyl-1,2,4-triazines: Access to Polysubstituted Tetrahydro-1,6-naphthyridines.

    Science.gov (United States)

    Jouha, Jabrane; Buttard, Floris; Lorion, Magali; Berthonneau, Clément; Khouili, Mostafa; Hiebel, Marie-Aude; Guillaumet, Gérald; Brière, Jean-François; Suzenet, Franck

    2017-09-15

    A straightforward domino aza-Michael-inverse-electron-demand-hetero-Diels-Alder/retro-Diels-Alder reaction between primary and secondary propargylamine derivatives and 3-vinyl-1,2,4-triazines is developed highlighting not only the uniqueness of this dual-heterocyclic platform but also a novel and unprecedented path to polysubstituted tetrahydro-1,6-naphthyridine scaffolds.

  3. One-pot synthesis of spiropyrroloquinoline-isoindolinone and their aza-analogs via the Ugi-4CR/metal-free intramolecular bis-annulation process.

    Science.gov (United States)

    Ghandi, Mehdi; Zarezadeh, Nahid; Abbasi, Alireza

    2015-08-14

    This presentation discloses a one-pot synthesis of a series of spiropyrroloquinoline isoindolinone and spiropyrroloquinoline aza-isoindolinone scaffolds. The reaction proceeds by the combination of a Ugi four-component reaction (4CR) and two intramolecular cyclizations under metal-free conditions. The proof of the structures relies on analytical investigation and X-ray crystallography.

  4. IBX-mediated oxidation of unactivated cyclic amines: application in highly diastereoselective oxidative Ugi-type and aza-Friedel-Crafts reactions.

    Science.gov (United States)

    de Graaff, C; Bensch, L; van Lint, Matthijs J; Ruijter, E; Orru, R V A

    2015-10-28

    The first o-iodoxybenzoic acid (IBX) mediated oxidation of unactivated amines to imines is described. A range of meso-pyrrolidines were shown to be suitable substrates. The chemical space was further explored with one-pot oxidative Ugi-type and aza-Friedel-Crafts reactions, which proved to be highly diastereoselective.

  5. Asymmetric Domino Aza-Michael Addition/[3+2] Cycloaddition Reactions as a Versatile Approach to alpha,beta,gamma,-Triamino Acid Derivatives

    Czech Academy of Sciences Publication Activity Database

    Kapras, Vojtěch; Pohl, Radek; Císařová, I.; Jahn, Ullrich

    2014-01-01

    Roč. 16, č. 4 (2014), s. 1088-1091 ISSN 1523-7060 Institutional support: RVO:61388963 Keywords : 1,3-dipolar cycloaddition * lithium amides * aza-Michael addition * amino acids * pyrazoles Subject RIV: CC - Organic Chemistry Impact factor: 6.364, year: 2014

  6. Enantioselective desymmetrization of prochiral cyclohexanones by organocatalytic intramolecular Michael additions to α,β-unsaturated esters.

    Science.gov (United States)

    Gammack Yamagata, Adam D; Datta, Swarup; Jackson, Kelvin E; Stegbauer, Linus; Paton, Robert S; Dixon, Darren J

    2015-04-13

    A new catalytic asymmetric desymmetrization reaction for the synthesis of enantioenriched derivatives of 2-azabicyclo[3.3.1]nonane, a key motif common to many alkaloids, has been developed. Employing a cyclohexanediamine-derived primary amine organocatalyst, a range of prochiral cyclohexanone derivatives possessing an α,β-unsaturated ester moiety linked to the 4-position afforded the bicyclic products, which possess three stereogenic centers, as single diastereoisomers in high enantioselectivity (83-99% ee) and in good yields (60-90%). Calculations revealed that stepwise C-C bond formation and proton transfer via a chair-shaped transition state dictate the exclusive endo selectivity and enabled the development of a highly enantioselective primary amine catalyst. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Enantioselective apoptosis induced by individual isomers of bifenthrin in Hep G2 cells.

    Science.gov (United States)

    Liu, Huigang; Li, Juan

    2015-03-01

    Bifenthrin (BF) has been used in racemate for agricultural purposes against soil insects, leading to increased inputs into soil environments. However, most of the studies about the toxicology research on BF were performed in its racemic form. The aim of the present study was to evaluate the enantiomer-specific cis-BF-induced apoptosis and intracellular reactive oxygen species (ROS) generation on human hepatocarcinoma cells (Hep G2). The results of cell viability assay and cytoflow assay indicated an obvious enantioselective hepatocyte toxicity of 1S-cis-BF in Hep G2 cells. 1S-cis-BF also induced ROS production, up-regulated Bax protein expression and down-regulated Bcl-2 expression levels. The present study suggested that enantioselective toxicity should be evaluated on currently used chiral pesticides, such as synthetic pyrethroids. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Ultrasound-Assisted Enantioselective Esterification of Ibuprofen Catalyzed by a Flower-Like Nanobioreactor

    Directory of Open Access Journals (Sweden)

    Baiyi An

    2016-04-01

    Full Text Available A flower-like nanobioreactor was prepared for resolution of ibuprofen in organic solvents. Ultrasound irradiation has been used to improve the enzyme performance of APE1547 (a thermophilic esterase from the archaeon Aeropyrum pernix K1 in the enantioselective esterification. Under optimum reaction conditions (ultrasound power, 225 W; temperature, 45 °C; water activity, 0.21, the immobilized APE1547 showed an excellent catalytic performance (enzyme activity, 13.26 μmol/h/mg; E value, 147.1. After ten repeated reaction batches, the nanobioreactor retained almost 100% of its initial enzyme activity and enantioselectivity. These results indicated that the combination of the immobilization method and ultrasound irradiation can enhance the enzyme performance dramatically.

  9. Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies

    KAUST Repository

    Behenna, Douglas C.; Mohr, Justin T.; Sherden, Nathaniel H.; Marinescu, Smaranda C.; Harned, Andrew M.; Tani, Kousuke; Seto, Masaki; Ma, Sandy; Nová k, Zoltá n; Krout, Michael R.; McFadden, Ryan M.; Roizen, Jennifer L.; Enquist, John A.; White, David E.; Levine, Samantha R.; Petrova, Krastina V.; Iwashita, Akihiko; Virgil, Scott C.; Stoltz, Brian M.

    2011-01-01

    α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.

  10. Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams

    KAUST Repository

    Behenna, Douglas C.

    2011-12-18

    The enantioselective synthesis of nitrogen-containing heterocycles (N-heterocycles) represents a substantial chemical research effort and resonates across numerous disciplines, including the total synthesis of natural products and medicinal chemistry. In this Article, we describe the highly enantioselective palladium-catalysed decarboxylative allylic alkylation of readily available lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams and structurally related lactams. Given the prevalence of quaternary N-heterocycles in biologically active alkaloids and pharmaceutical agents, we envisage that our method will provide a synthetic entry into the de novo asymmetric synthesis of such structures. As an entry for these investigations we demonstrate how the described catalysis affords enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the Aspidosperma alkaloids quebrachamine and rhazinilam, but that were previously only available by chiral auxiliary approaches or as racemic mixtures. © 2012 Macmillan Publishers Limited. All rights reserved.

  11. Enantioselective [3+3] atroposelective annulation catalyzed by N-heterocyclic carbenes

    KAUST Repository

    Zhao, Changgui

    2018-02-05

    Axially chiral molecules are among the most valuable substrates in organic synthesis. They are typically used as chiral ligands or catalysts in asymmetric reactions. Recent progress for the construction of these chiral molecules is mainly focused on the transition-metal-catalyzed transformations. Here, we report the enantioselective NHC-catalyzed (NHC: N-heterocyclic carbenes) atroposelective annulation of cyclic 1,3-diones with ynals. In the presence of NHC precatalyst, base, Lewis acid and oxidant, a catalytic C–C bond formation occurs, providing axially chiral α-pyrone−aryls in moderate to good yields and with high enantioselectivities. Control experiments indicated that alkynyl acyl azoliums, acting as active intermediates, are employed to atroposelectively assemble chiral biaryls and such a methodology may be creatively applied to other useful NHC-catalyzed asymmetric transformations.

  12. Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies

    Science.gov (United States)

    Behenna, Douglas C.; Mohr, Justin T.; Sherden, Nathaniel H.; Marinescu, Smaranda C.; Harned, Andrew M.; Tani, Kousuke; Seto, Masaki; Ma, Sandy; Novák, Zoltán; Krout, Michael R.; McFadden, Ryan M.; Roizen, Jennifer L.; Enquist, John A.; White, David E.; Levine, Samantha R.; Petrova, Krastina V.; Iwashita, Akihiko; Virgil, Scott C.; Stoltz, Brian M.

    2012-01-01

    α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursors: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center. PMID:22083969

  13. Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies

    KAUST Repository

    Behenna, Douglas C.

    2011-11-14

    α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.

  14. Enantioselective cytotoxicity of the insecticide bifenthrin on a human amnion epithelial (FL) cell line

    International Nuclear Information System (INIS)

    Liu Huigang; Zhao Meirong; Zhang Cong; Ma Yun; Liu Weiping

    2008-01-01

    Synthetic pyrethroids (SPs) are used in preference to organochlorines and organophosphates due to their high efficiency, low toxicity to mammals, and ready biodegradability. Previous studies reported that enantioselective toxicity of SPs occurs in aquatic toxicity. Several studies have indicated that SPs could lead to oxidative damage in humans or animals which was associated with their toxic effects. Little is known about the differences in the effects of chronic toxicity induced by individual stereoisomers of chiral SPs. The present study was therefore undertaken to evaluate the enantioselectivity in cytotoxicity, genotoxicity caused by bifenthrin (BF) on human amnion epithelial (FL) cell lines and pesticidal activity on target organism. The cell proliferation and cytoflow analysis indicated that 1S-cis-BF presented more toxic effects than 1R-cis-BF above the concentration of 7.5 mg L -1 (p > 0.05). FL cells incubated with 1S-cis-BF exhibited a dose-dependent accumulation of intracellular reactive oxygen species (ROS). In the comet assay, the number of cells with damaged DNA incubated with 1S-cis-BF was more than that with 1R-cis-BF (p 50 values of enantiomer to the target pest on Pieris rapae L. show that 1R-cis-BF was 300 times more active than 1S-cis-BF. These results indicate that the enantioselective toxicity and activity of BF between non-target organism and target organism was reversal. These implications together suggest that assessment of the environmental safety and new pesticides development with chiral centers should consider enantioselectivity

  15. Synthesis of 3-fluoro-3-aryl oxindoles: Direct enantioselective α arylation of amides

    KAUST Repository

    Wu, Linglin; Falivene, Laura; Drinkel, Emma E.; Grant, Sharday; Linden, Anthony; Cavallo, Luigi; Dorta, Reto

    2012-01-01

    Modus operandi: Catalytic access to the title compounds through a new asymmetric α-arylation protocol is reported (see scheme). These products are formed in good yields and excellent enantioselectivities by using a new and easily synthesized chiral N-heterocyclic carbene (NHC) ligand. Advanced DFT calculations reveal the properties of the NHC ligand and the mode of operation of the catalyst. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Effects of metals on enantioselective toxicity and biotransformation of cis-bifenthrin in zebrafish.

    Science.gov (United States)

    Yang, Ye; Ji, Dapeng; Huang, Xin; Zhang, Jianyun; Liu, Jing

    2017-08-01

    Co-occurrence of pyrethroids and metals in watersheds previously has been reported to pose great risk to aquatic species. Pyrethroids are a class of chiral insecticides that have been shown to have enantioselective toxicity and biotransformation. However, the influence of metals on enantioselectivity of pyrethroids has not yet been evaluated. In the present study, the effects of cadmium (Cd), copper (Cu), and lead (Pb) on the enantioselective toxicity and metabolism of cis-bifenthrin (cis-BF) were investigated in zebrafish at environmentally relevant concentrations. The addition of Cd, Cu, or Pb significantly increased the mortality of zebrafish in racemate and R-enantiomer of cis-BF-treated groups. In rac-cis-BF- or 1R-cis-BF-treated groups, the addition of Cd, Cu, or Pb caused a decrease in enantiomeric fraction (EF) and an increased ratio of R-enantiomer residues in zebrafish. In 1S-cis-BF-treated groups, coexposure to Cd led to a lower EF and decreased residue levels of S-enantiomer. In addition, coexposure to the 3 metals resulted in different biodegradation characteristics of each enantiomer accompanied with differential changes in the expression of cytochrome P450 (CYP)1, CYP2, and CYP3 genes, which might be responsible for the enantioselective biodegradation of cis-BF in zebrafish. These results suggest that the influence of coexistent metals should be considered in the ecological risk assessment of chiral pyrethroids in aquatic environments. Environ Toxicol Chem 2017;36:2139-2146. © 2017 SETAC. © 2017 SETAC.

  17. Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline

    Directory of Open Access Journals (Sweden)

    Xacobe C. Cambeiro

    2011-10-01

    Full Text Available The application of polystyrene-immobilized proline-based catalysts in packed-bed reactors for the continuous-flow, direct, enantioselective α-aminoxylation of aldehydes is described. The system allows the easy preparation of a series of β-aminoxy alcohols (after a reductive workup with excellent optical purity and with an effective catalyst loading of ca. 2.5% (four-fold reduction compared to the batch process working at residence times of ca. 5 min.

  18. A combined continuous microflow photochemistry and asymmetric organocatalysis approach for the enantioselective synthesis of tetrahydroquinolines

    Directory of Open Access Journals (Sweden)

    Erli Sugiono

    2013-11-01

    Full Text Available A continuous-flow asymmetric organocatalytic photocyclization–transfer hydrogenation cascade reaction has been developed. The new protocol allows the synthesis of tetrahydroquinolines from readily available 2-aminochalcones using a combination of photochemistry and asymmetric Brønsted acid catalysis. The photocylization and subsequent reduction was performed with catalytic amount of chiral BINOL derived phosphoric acid diester and Hantzsch dihydropyridine as hydrogen source providing the desired products in good yields and with excellent enantioselectivities.

  19. Enantioselective analysis of drugs: contributions of high-performance liquid chromatography and capillary electrophoresis

    OpenAIRE

    Bonato, Pierina Sueli; Jabor, Valquíria Aparecida Polisel; Gaitani, Cristiane Masetto de

    2005-01-01

    The demand for analytical methods suitable for accurate and reproducible determination of drug enantiomers has increased significantly in the last years. High-performance liquid chromatography (HPLC) using chiral stationary phases and capillary electrophoresis (CE) are the most important techniques used for this purpose. In this paper, the fundamental aspects of chiral separations using both techniques are presented. Some important aspects for the development of enantioselective methods, part...

  20. Copper(II)/amine synergistically catalyzed enantioselective alkylation of cyclic N-acyl hemiaminals with aldehydes.

    Science.gov (United States)

    Sun, Shutao; Mao, Ying; Lou, Hongxiang; Liu, Lei

    2015-07-07

    The first catalytic asymmetric alkylation of N-acyl quinoliniums with aldehydes has been described. A copper/amine synergistic catalytic system has been developed, allowing the addition of functionalized aldehydes to a wide range of electronically varied N-acyl quinoliniums in good yields with excellent enantiocontrol. The synergistic catalytic system was also effective for N-acyl dihydroisoquinoliniums and β-caboliniums, demonstrating the general applicability of the protocol in the enantioselective alkylation of diverse cyclic N-acyl hemiaminals.

  1. Lipase-catalyzed highly enantioselective kinetic resolution of boron-containing chiral alcohols.

    Science.gov (United States)

    Andrade, Leandro H; Barcellos, Thiago

    2009-07-16

    The first application of enzymes as catalysts to obtain optically pure boron compounds is described. The kinetic resolution of boron-containing chiral alcohols via enantioselective transesterification catalyzed by lipases was studied. Aromatic, allylic, and aliphatic secondary alcohols containing a boronate ester or boronic acid group were resolved by lipase from Candida antartica (CALB), and excellent E values (E > 200) and high enantiomeric excesses (up to >99%) of both remaining substrates and acetylated product were obtained.

  2. Lewis base catalyzed enantioselective allylic hydroxylation of Morita-Baylis-Hillman carbonates with water

    KAUST Repository

    Zhu, Bo

    2011-08-19

    A Lewis base catalyzed allylic hydroxylation of Morita-Baylis-Hillman (MBH) carbonates has been developed. Various chiral MBH alcohols can be synthesized in high yields (up to 99%) and excellent enantioselectivities (up to 94% ee). This is the first report using water as a nucleophile in asymmetric organocatalysis. The nucleophilic role of water has been verified using 18O-labeling experiments. © 2011 American Chemical Society.

  3. Enantioselective synthesis of the novel chiral sulfoxide derivative as a glycogen synthase kinase 3beta inhibitor.

    Science.gov (United States)

    Saitoh, Morihisa; Kunitomo, Jun; Kimura, Eiji; Yamano, Toru; Itoh, Fumio; Kori, Masakuni

    2010-09-01

    Glycogen synthase kinase 3beta (GSK-3beta) inhibitors are expected to be attractive therapeutic agents for the treatment of Alzheimer's disease (AD). Recently we discovered sulfoxides (S)-1 as a novel GSK-3beta inhibitor having in vivo efficacy. We investigated practical asymmetric preparation methods for the scale-up synthesis of (S)-1. The highly enantioselective synthesis of (S)-1 (94% ee) was achieved by titanium-mediated oxidation with D-(-)-diethyl tartrate on gram scale.

  4. Rhodium-catalyzed chemo-, regio-, and enantioselective addition of 2-pyridones to terminal allenes.

    Science.gov (United States)

    Li, Changkun; Kähny, Matthias; Breit, Bernhard

    2014-12-08

    A rhodium-catalyzed chemo-, regio-, and enantioselective addition of 2-pyridones to terminal allenes to give branched N-allyl 2-pyridones is reported. Preliminary mechanistic studies support the hypothesis that the reaction was initiated from the more acidic 2-hydroxypyridine form, and the initial kinetic O-allylation product was finally converted into the thermodynamically more stable N-allyl 2-pyridones. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. An iron/amine-catalyzed cascade process for the enantioselective functionalization of allylic alcohols.

    Science.gov (United States)

    Quintard, Adrien; Constantieux, Thierry; Rodriguez, Jean

    2013-12-02

    Three is a lucky number: An enantioselective transformation of allylic alcohols into β-chiral saturated alcohols has been developed by combining two distinct metal- and organocatalyzed catalytic cycles. This waste-free triple cascade process merges an iron-catalyzed borrowing-hydrogen step with an aminocatalyzed nucleophilic addition reaction. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Synthesis of 3-fluoro-3-aryl oxindoles: Direct enantioselective α arylation of amides

    KAUST Repository

    Wu, Linglin

    2012-02-06

    Modus operandi: Catalytic access to the title compounds through a new asymmetric α-arylation protocol is reported (see scheme). These products are formed in good yields and excellent enantioselectivities by using a new and easily synthesized chiral N-heterocyclic carbene (NHC) ligand. Advanced DFT calculations reveal the properties of the NHC ligand and the mode of operation of the catalyst. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. A dual Lewis base activation strategy for enantioselective carbene-catalyzed annulations.

    Science.gov (United States)

    Izquierdo, Javier; Orue, Ane; Scheidt, Karl A

    2013-07-24

    A dual activation strategy integrating N-heterocyclic carbene (NHC) catalysis and a second Lewis base has been developed. NHC-bound homoenolate equivalents derived from α,β-unsaturated aldehydes combine with transient reactive o-quinone methides in an enantioselective formal [4 + 3] fashion to access 2-benzoxopinones. The overall approach provides a general blueprint for the integration of carbene catalysis with additional Lewis base activation modes.

  8. Chiral Nickel(II) Complex Catalyzed Enantioselective Doyle-Kirmse Reaction of α-Diazo Pyrazoleamides.

    Science.gov (United States)

    Lin, Xiaobin; Tang, Yu; Yang, Wei; Tan, Fei; Lin, Lili; Liu, Xiaohua; Feng, Xiaoming

    2018-03-07

    Although high enantioselectivity of [2,3]-sigmatropic rearrangement of sulfonium ylides (Doyle-Kirmse reaction) has proven surprisingly elusive using classic chiral Rh(II) and Cu(I) catalysts, in principle it is due to the difficulty in fine discrimination of the heterotopic lone pairs of sulfur and chirality inversion at sulfur of sulfonium ylides. Here, we show that the synergistic merger of new α-diazo pyrazoleamides and a chiral N, N'-dioxide-nickel(II) complex catalyst enables a highly enantioselective Doyle-Kirmse reaction. The pyrazoleamide substituent serves as both an activating and a directing group for the ready formation of a metal-carbene- and Lewis-acid-bonded ylide intermediate in the assistance of a dual-tasking nickel(II) complex. An alternative chiral Lewis-acid-bonded ylide pathway greatly improves the product enantiopurity even for the reaction of a symmetric diallylsulfane. The majority of transformations over a series of aryl- or vinyl-substituted α-diazo pyrazoleamindes and sulfides proceed rapidly (within 5-20 min in most cases) with excellent results (up to 99% yield and 96% ee), providing a breakthrough in enantioselective Doyle-Kirmse reaction.

  9. Phytotoxicity of chiral herbicide bromacil: Enantioselectivity of photosynthesis in Arabidopsis thaliana

    International Nuclear Information System (INIS)

    Chen, Zunwei; Zou, Yuqin; Wang, Jia; Li, Meichao; Wen, Yuezhong

    2016-01-01

    With the wide application of chiral herbicides and the frequent detection of photosystem II (PSII) herbicides, it is of great importance to assess the direct effects of PSII herbicides on photosynthesis in an enantiomeric level. In the present study, the enantioselective phytotoxicity of bromacil (BRO), typical photosynthesis inhibition herbicide, on Arabidopsis thaliana was investigated. The results showed that S-BRO exhibited a greater inhibition of electron transmission in photosystem I (PSI) of A. thaliana than R-BRO by inhibiting the transcription of fnr 1. S-BRO also changed the chlorophyll fluorescence parameters Y (II), Y (NO), and Y (NPQ) to a greater extent than R-Bro. Transcription of genes psbO2, Lhcb3 and Lhcb6 was down-regulated in an enantioselective rhythm and S-BRO caused more serious influence, indicating that S-BRO did worse damage to the photosystem II (PSII) of A. thaliana than R-BRO. This study suggested that S-BRO disturbed the photosynthesis of plants to a larger extent than R-BRO and provided a new sight to evaluate the phytotoxicity of chiral herbicides. - Highlights: • It is necessary to assess the direct effects of PSII herbicides on photosynthesis. • Phytotoxicity of bromacil is investigated in an enantiomeric level. • Bromacil disturbed enantioselectively the photosystem II of Arabidopsis thaliana. • S-bromacil caused severer damage to photosynthesis of Arabidopsis than R-bromacil. • Photosynthesis should be considered for phytotoxicity assessment of herbicides.

  10. Phytotoxicity of chiral herbicide bromacil: Enantioselectivity of photosynthesis in Arabidopsis thaliana

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Zunwei; Zou, Yuqin; Wang, Jia [MOE Key Laboratory of Environmental Remediation & Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058 (China); Li, Meichao [Research Center of Analysis and Measurement, Zhejiang University of Technology, Hangzhou 310032 (China); Wen, Yuezhong, E-mail: wenyuezhong@zju.edu.cn [MOE Key Laboratory of Environmental Remediation & Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058 (China)

    2016-04-01

    With the wide application of chiral herbicides and the frequent detection of photosystem II (PSII) herbicides, it is of great importance to assess the direct effects of PSII herbicides on photosynthesis in an enantiomeric level. In the present study, the enantioselective phytotoxicity of bromacil (BRO), typical photosynthesis inhibition herbicide, on Arabidopsis thaliana was investigated. The results showed that S-BRO exhibited a greater inhibition of electron transmission in photosystem I (PSI) of A. thaliana than R-BRO by inhibiting the transcription of fnr 1. S-BRO also changed the chlorophyll fluorescence parameters Y (II), Y (NO), and Y (NPQ) to a greater extent than R-Bro. Transcription of genes psbO2, Lhcb3 and Lhcb6 was down-regulated in an enantioselective rhythm and S-BRO caused more serious influence, indicating that S-BRO did worse damage to the photosystem II (PSII) of A. thaliana than R-BRO. This study suggested that S-BRO disturbed the photosynthesis of plants to a larger extent than R-BRO and provided a new sight to evaluate the phytotoxicity of chiral herbicides. - Highlights: • It is necessary to assess the direct effects of PSII herbicides on photosynthesis. • Phytotoxicity of bromacil is investigated in an enantiomeric level. • Bromacil disturbed enantioselectively the photosystem II of Arabidopsis thaliana. • S-bromacil caused severer damage to photosynthesis of Arabidopsis than R-bromacil. • Photosynthesis should be considered for phytotoxicity assessment of herbicides.

  11. Computer-Assisted Design and Synthetic Applications of Chiral Enol Borinates: Novel, Highly Enantioselective Aldol Reagents

    Directory of Open Access Journals (Sweden)

    Gennari Cesare

    1998-01-01

    Full Text Available We have recently described the development of a quantitative transition state model for the prediction of stereoselectivity in the boron-mediated aldol reaction. This model provides qualitative insights into the factors contributing to the stereochemical outcome of a variety of reactions of synthetic importance. The force field model was used to assist the design and preparation of new chiral boron ligands derived from menthone. The chiral boron enolates were employed in various stereoselective processes, including the addition to chiral aldehydes and the reagent-controlled total synthesis of (3S,4S-statine. The chiral enolates derived from alpha-halo and alpha-oxysubstituted thioacetates were added to aldehydes and imines. Addition to imines leads to the enantioselective synthesis of chiral aziridines, a formal total synthesis of (+-thiamphenicol, and a new highly efficient synthesis of the paclitaxel (taxol® C-13 side-chain and taxol semisynthesis from baccatin III. The stereochemical outcome of the addition to imines was rationalised with the aid of computational studies. Enantioselective addition reactions of the chiral boron enolate derived from thioacetate have successfully been applied to solid phase bound aldehydes to give aldol products in comparable yields and enantioselectivities to the usual solution conditions.

  12. Modelling substrate specificity and enantioselectivity for lipases and esterases by substrate-imprinted docking

    Directory of Open Access Journals (Sweden)

    Tyagi Sadhna

    2009-06-01

    Full Text Available Abstract Background Previously, ways to adapt docking programs that were developed for modelling inhibitor-receptor interaction have been explored. Two main issues were discussed. First, when trying to model catalysis a reaction intermediate of the substrate is expected to provide more valid information than the ground state of the substrate. Second, the incorporation of protein flexibility is essential for reliable predictions. Results Here we present a predictive and robust method to model substrate specificity and enantioselectivity of lipases and esterases that uses reaction intermediates and incorporates protein flexibility. Substrate-imprinted docking starts with covalent docking of reaction intermediates, followed by geometry optimisation of the resulting enzyme-substrate complex. After a second round of docking the same substrate into the geometry-optimised structures, productive poses are identified by geometric filter criteria and ranked by their docking scores. Substrate-imprinted docking was applied in order to model (i enantioselectivity of Candida antarctica lipase B and a W104A mutant, (ii enantioselectivity and substrate specificity of Candida rugosa lipase and Burkholderia cepacia lipase, and (iii substrate specificity of an acetyl- and a butyrylcholine esterase toward the substrates acetyl- and butyrylcholine. Conclusion The experimentally observed differences in selectivity and specificity of the enzymes were reproduced with an accuracy of 81%. The method was robust toward small differences in initial structures (different crystallisation conditions or a co-crystallised ligand, although large displacements of catalytic residues often resulted in substrate poses that did not pass the geometric filter criteria.

  13. Enantioselective Characteristics and Montmorillonite-Mediated Removal Effects of α-Hexachlorocyclohexane in Laying Hens.

    Science.gov (United States)

    Liu, Xueke; Shen, Zhigang; Wang, Peng; Liu, Chang; Yao, Guojun; Zhou, Zhiqiang; Liu, Donghui

    2016-06-07

    α-Hexachlorocyclohexane (α-HCH) is a chiral organochlorine pesticide that is often ubiquitously detected in various environmental matrices and may be absorbed by the human body via food consumption, with serious detriments to human health. In this study, enantioselective degradation kinetics and residues of α-HCH in laying hens were investigated after a single dose of exposure to the pesticide, whereas enantioselectivity and residues of α-HCH in eggs, droppings, and various tissues were investigated after long-term exposure. Meanwhile, montmorillonite (MMT), a feed additive with high capacity of adsorption, was investigated for its ability to remove α-HCH from laying hens. Most non-brain tissues enantioselectively accumulated (-)-α-HCH, while (+)-α-HCH was preferentially accumulated in the brain. The enantiomer fractions (EFs) in most tissues gradually decreased, implying continuous depletion of (+)-α-HCH in laying hens. After 30 days of exposure and 31 days of elimination, the concentration of α-HCH in eggs and tissues of laying hens with MMT-containing feed was lower than that with MMT-free feed, indicating the removal effects of MMT for α-HCH in laying hens. The findings presented herein suggest that modified MMT may potentially be useful in reducing the enrichment of α-HCH in laying hens and eggs, thus lowering the risk of human intake of α-HCH.

  14. Consejo Mayor Comunitario del Porce -AZA- (Antioquia por la defensa del Territorio. Experiencia organizativa por la dignidad

    Directory of Open Access Journals (Sweden)

    Yeny Pino Franco

    2016-07-01

    Full Text Available En los municipios de Amalfi, Anori y Zaragoza del departamento de Antioquia (Colombia, se ha venido desarrollando el proyecto hidroeléctrico Porce IV, desde el 2006, con los estudios preliminares por parte de la Empresa Pública de Medellín (EPM; en el desarrollo de las primeras etapas del proyecto, las comunidades se agruparon y constituyeron lo que hoy es el Consejo Mayor Comunitario AZA (CMC, el cual, les facilitara una negociación con EPM con justicia social y dignidad para todos, donde las comunidades pudieran participar con propuestas para la negociación en los temas de indemnización y principalmente el tema de compensación.

  15. 4-Aza-1-azoniabicyclo[2.2.2]octane–2-aminobenzoate–2-aminobenzoic acid (1/1/1

    Directory of Open Access Journals (Sweden)

    Hadi D. Arman

    2011-11-01

    Full Text Available A 4-aza-1-azoniabicyclo[2.2.2]octane cation, a 2-aminobenzoate anion and a neutral 2-aminobenzoic acid molecule comprise the asymmetric unit of the title compound, C6H13N2+·C7H6NO2−·C7H7NO2. An intramolecular N—H...O hydrogen bond occurs in the anion and in the neutral 2-aminobenzoic acid molecule. The cation provides a charge-assisted N—H...O hydrogen bond to the anion, and the 2-aminobenzoic acid molecule forms an O—H...N hydrogen bond to the unprotonated amino N atom in the cation. In this way, a three-component aggregate is formed. These are connected into a three-dimensional network by amino–carboxylate N—H...O hydrogen bonds. N—H...N hydrogen bonds are also observed.

  16. Development of a General Aza-Cope Reaction Trigger Applied to Fluorescence Imaging of Formaldehyde in Living Cells.

    Science.gov (United States)

    Bruemmer, Kevin J; Walvoord, Ryan R; Brewer, Thomas F; Burgos-Barragan, Guillermo; Wit, Niek; Pontel, Lucas B; Patel, Ketan J; Chang, Christopher J

    2017-04-19

    Formaldehyde (FA) is a reactive signaling molecule that is continuously produced through a number of central biological pathways spanning epigenetics to one-carbon metabolism. On the other hand, aberrant, elevated levels of FA are implicated in disease states ranging from asthma to neurodegenerative disorders. In this context, fluorescence-based probes for FA imaging are emerging as potentially powerful chemical tools to help disentangle the complexities of FA homeostasis and its physiological and pathological contributions. Currently available FA indicators require direct modification of the fluorophore backbone through complex synthetic considerations to enable FA detection, often limiting the generalization of designs to other fluorophore classes. To address this challenge, we now present the rational, iterative development of a general reaction-based trigger utilizing 2-aza-Cope reactivity for selective and sensitive detection of FA in living systems. Specifically, we developed a homoallylamine functionality that can undergo a subsequent self-immolative β-elimination, creating a FA-responsive trigger that is capable of masking a phenol on a fluorophore or any other potential chemical scaffold for related imaging and/or therapeutic applications. We demonstrate the utility of this trigger by creating a series of fluorescent probes for FA with excitation and emission wavelengths that span the UV to visible spectral regions through caging of a variety of dye units. In particular, Formaldehyde Probe 573 (FAP573), based on a resorufin scaffold, is the most red-shifted and FA sensitive in this series in terms of signal-to-noise responses and enables identification of alcohol dehydrogenase 5 (ADH5) as an enzyme that regulates FA metabolism in living cells. The results provide a starting point for the broader use of 2-aza-Cope reactivity for probing and manipulating FA biology.

  17. Bicyclic Guanidine Catalyzed Asymmetric Tandem Isomerization Intramolecular-Diels-Alder Reaction: The First Catalytic Enantioselective Total Synthesis of (+)-alpha-Yohimbine.

    Science.gov (United States)

    Feng, Wei; Jiang, Danfeng; Kee, Choon-Wee; Liu, Hongjun; Tan, Choon-Hong

    2016-02-04

    Hydroisoquinoline derivatives were prepared in moderate to good enantioselectivities via a bicyclic guanidine-catalyzed tandem isomerization intramolecular-Diels-Alder (IMDA) reaction of alkynes. With this synthetic method, the first enantioselective synthesis of (+)-alpha-yohimbine was completed in 9 steps from the IMDA products. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Exploiting nanospace for asymmetric catalysis: confinement of immobilized, single-site chiral catalysts enhances enantioselectivity.

    Science.gov (United States)

    Thomas, John Meurig; Raja, Robert

    2008-06-01

    In the mid-1990s, it became possible to prepare high-area silicas having pore diameters controllably adjustable in the range ca. 20-200 Å. Moreover, the inner walls of these nanoporous solids could be functionalized to yield single-site, chiral, catalytically active organometallic centers, the precise structures of which could be determined using in situ X-ray absorption and FTIR and multinuclear magic angle spinning (MAS) NMR spectroscopy. This approach opened up the prospect of performing heterogeneous enantioselective conversions in a novel manner, under the spatial restrictions imposed by the nanocavities within which the reactions occur. In particular, it suggested an alternative method for preparing pharmaceutically and agrochemically useful asymmetric products by capitalizing on the notion, initially tentatively perceived, that spatial confinement of prochiral reactants (and transition states formed at the chiral active center) would provide an altogether new method of boosting the enantioselectivity of the anchored chiral catalyst. Initially, we anchored chiral single-site heterogeneous catalysts to nanopores covalently via a ligand attached to Pd(II) or Rh(I) centers. Later, we employed a more convenient and cheaper electrostatic method, relying in part on strong hydrogen bonding. This Account provides many examples of these processes, encompassing hydrogenations, oxidations, and aminations. Of particular note is the facile synthesis from methyl benzoylformate of methyl mandelate, which is a precursor in the synthesis of pemoline, a stimulant of the central nervous system; our procedure offers several viable methods for reducing ketocarboxylic acids. In addition to relying on earlier (synchrotron-based) in situ techniques for characterizing catalysts, we have constructed experimental procedures involving robotically controlled catalytic reactors that allow the kinetics of conversion and enantioselectivity to be monitored continually, and we have access to

  19. Enantioselective Effects of Metalaxyl Enantiomers on Breast Cancer Cells Metabolic Profiling Using HPLC-QTOF-Based Metabolomics

    Directory of Open Access Journals (Sweden)

    Ping Zhang

    2017-01-01

    Full Text Available In this study, an integrative high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-QTOF based metabolomics approach was performed to evaluate the enantioselective metabolic perturbations in MCF-7 cells after treatment with R-metalaxyl and S-metalaxyl, respectively. Untargeted metabolomics profile, multivariate pattern recognition, metabolites identification, and pathway analysis were determined after metalaxyl enantiomer exposure. Principal component analysis (PCA and partitial least-squares discriminant analysis (PLS-DA directly reflected the enantioselective metabolic perturbations induced by metalaxyl enantiomers. On the basis of multivariate statistical results, a total of 49 metabolites including carbohydrates, amino acids, nucleotides, fatty acids, organic acids, phospholipids, indoles, derivatives, etc. were found to be the most significantly changed metabolites and metabolic fluctuations caused by the same concentration of R-metalaxyl and S-metalaxyl were enantioselective. Pathway analysis indicated that R-metalaxyl and S-metalaxyl mainly affected the 7 and 10 pathways in MCF-7 cells, respectively, implying the perturbed pathways induced by metalaxyl enantiomers were also enantioselective. Furthermore, the significantly perturbed metabolic pathways were highly related to energy metabolism, amino acid metabolism, lipid metabolism, and antioxidant defense. Such results provide more specific insights into the enantioselective metabolic effects of chiral pesticides in breast cancer progression, reveal the underlying mechanisms, and provide available data for the health risk assessments of chiral environmental pollutants at the molecular level.

  20. Co-culture of human CD34+ cells with mesenchymal stem cells increases the survival of CD34+ cells against the 5-aza-deoxycytidine- or trichostatin A-induced cell death

    International Nuclear Information System (INIS)

    Koh, Sang Hyeok; Choi, Hyoung Soo; Park, Eun Sil; Kang, Hyoung Jin; Ahn, Hyo Seop; Shin, Hee Young

    2005-01-01

    It has been suggested that epigenetic regulation plays an important role in maintaining the stemness and lineage differentiation of hematopoietic stem cells (HSCs), 5-aza-deoxycytidine (aza-D) and Trichostatin A (TSA) being candidate additives for HSC ex vivo expansion. Although they have potent activity to maintain the stemness, they can also cause serious cell death. This study examined the effects of mesenchymal stem cells (MSCs) on the maintenance of CD34+ cells driven by aza-D and TSA in culture with the combined cytokines of thrombopoietin, flt-3 ligand, stem cell factor, interleukin-3, and interleukin-6. In cultures without MSCs, although aza-D and TSA retained the CD34 frequency 4 to 8 times more than in the cytokines alone, a large portion of cells underwent apoptotic cell death. Consequently, CD34+ cell expansion could not be achieved in any condition without MSCs. In cultures with MSCs, the total cell number was higher in aza-D or TSA than in any conditions in the cultures without MSCs. The CD34 frequency was also similar to the level in the cultures in aza-D or TSA without the MSCs. These results suggest that a co-culture of CD34+ cells with the MSCs might not simply deliver the proliferation signals but also stemness and survival signals, and overlap the action of epigenetic regulators

  1. Enantioselective small molecule synthesis by carbon dioxide fixation using a dual Brønsted acid/base organocatalyst.

    Science.gov (United States)

    Vara, Brandon A; Struble, Thomas J; Wang, Weiwei; Dobish, Mark C; Johnston, Jeffrey N

    2015-06-17

    Carbon dioxide exhibits many of the qualities of an ideal reagent: it is nontoxic, plentiful, and inexpensive. Unlike other gaseous reagents, however, it has found limited use in enantioselective synthesis. Moreover, unprecedented is a tool that merges one of the simplest biological approaches to catalysis-Brønsted acid/base activation-with this abundant reagent. We describe a metal-free small molecule catalyst that achieves the three component reaction between a homoallylic alcohol, carbon dioxide, and an electrophilic source of iodine. Cyclic carbonates are formed enantioselectively.

  2. Exploration of Cocatalyst Effects on a Bimetallic Cobalt Catalyst System: Enhanced Activity and Enantioselectivity in Epoxide Polymerization

    KAUST Repository

    Widger, Peter C. B.; Ahmed, Syud M.; Coates, Geoffrey W.

    2011-01-01

    Organic ionic compounds were synthesized and investigated as cocatalysts with a bimetallic cobalt complex for enantioselective epoxide polymerization. The identities of both the cation and the anion were systematically varied, and the subsequent reactivity was studied. The nature of the ionic cocatalyst dramatically impacted the rate and enantioselectivity of the catalyst system. The ionic cocatalyst [P(N=P(N(CH2)4)3) 4 +][tBuCO2 -] in combination with a bimetallic cobalt complex produced a catalyst system that exhibited the greatest activity and selectivity for a variety of monosubstituted epoxides. © 2011 American Chemical Society.

  3. Exploration of Cocatalyst Effects on a Bimetallic Cobalt Catalyst System: Enhanced Activity and Enantioselectivity in Epoxide Polymerization

    KAUST Repository

    Widger, Peter C. B.

    2011-07-26

    Organic ionic compounds were synthesized and investigated as cocatalysts with a bimetallic cobalt complex for enantioselective epoxide polymerization. The identities of both the cation and the anion were systematically varied, and the subsequent reactivity was studied. The nature of the ionic cocatalyst dramatically impacted the rate and enantioselectivity of the catalyst system. The ionic cocatalyst [P(N=P(N(CH2)4)3) 4 +][tBuCO2 -] in combination with a bimetallic cobalt complex produced a catalyst system that exhibited the greatest activity and selectivity for a variety of monosubstituted epoxides. © 2011 American Chemical Society.

  4. Combining the catalytic enantioselective reaction of visible-light-generated radicals with a by-product utilization system.

    Science.gov (United States)

    Huang, Xiaoqiang; Luo, Shipeng; Burghaus, Olaf; Webster, Richard D; Harms, Klaus; Meggers, Eric

    2017-10-01

    We report an unusual reaction design in which a chiral bis-cyclometalated rhodium(iii) complex enables the stereocontrolled chemistry of photo-generated carbon-centered radicals and at the same time catalyzes an enantioselective sulfonyl radical addition to an alkene. Specifically, employing inexpensive and readily available Hantzsch esters as the photoredox mediator, Rh-coordinated prochiral radicals generated by a selective photoinduced single electron reduction are trapped by allyl sulfones in a highly stereocontrolled fashion, providing radical allylation products with up to 97% ee. The hereby formed fragmented sulfonyl radicals are utilized via an enantioselective radical addition to form chiral sulfones, which minimizes waste generation.

  5. Design, Synthesis and Biological Activity of Novel Reversible Peptidyl FVIIa Inhibitors Rh-Catalyzed Enantioselective Synthesis of Diaryl Amines

    DEFF Research Database (Denmark)

    Storgaard, Morten

    functional group tolerance. Unfortunately, these -aryl tetramic acids were too unreactive and ring opening toward the synthesis of the building block did not succeed. However, -aryl tetramic acids are still interesting compounds due to their potential biological activity. The building block 3.15 (P1......-catalyzed enantioselective synthesis of diaryl amines, which is an important class of compounds (Chapter 4). For example it is found in the third generation anti-histaminic agent levocetirizine. Development of efficient synthetic routes is therefore of considerably interest. The rhodium-catalyzed enantioselective synthesis...

  6. Rhodium-catalyzed enantioselective intramolecular C-H silylation for the syntheses of planar-chiral metallocene siloles.

    Science.gov (United States)

    Zhang, Qing-Wei; An, Kun; Liu, Li-Chuan; Yue, Yuan; He, Wei

    2015-06-01

    Reported herein is the rhodium-catalyzed enantioselective C-H bond silylation of the cyclopentadiene rings in Fe and Ru metallocenes. Thus, in the presence of (S)-TMS-Segphos, the reactions took place under very mild conditions to afford metallocene-fused siloles in good to excellent yields and with ee values of up to 97%. During this study it was observed that the steric hindrance of chiral ligands had a profound influence on the reactivity and enantioselectivity of the reaction, and might hold the key to accomplishing conventionally challenging asymmetric C-H silylations. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. An enantioselective approach toward 3,4-dihydroisocoumarin through the bromocyclization of styrene-type carboxylic acids.

    Science.gov (United States)

    Chen, Jie; Zhou, Ling; Tan, Chong Kiat; Yeung, Ying-Yeung

    2012-01-20

    A facile and enantioselective approach toward 3,4-dihydroisocoumarin was developed. The method involved an amino-thiocarbamate catalyzed enantioselective bromocyclization of styrene-type carboxylic acids, yielding 3-bromo-3,4-dihydroisocoumarins with good yields and ee's. 3-Bromo-3,4-dihydroisocoumarins are versatile building blocks for various dihydroisocoumarin derivatives in which the Br group can readily be modified to achieve biologically important 4-O-type and 4-N-type 3,4-dihydroisocoumarin systems. In addition, studies indicated that, by refining some parameters, the synthetically useful 5-exo phthalide products could be achieved with good yields and ee's.

  8. Synthesis of Imidazopyridines via Copper-Catalyzed, Formal Aza-[3 + 2] Cycloaddition Reaction of Pyridine Derivatives with α-Diazo Oxime Ethers.

    Science.gov (United States)

    Park, Sangjune; Kim, Hyunseok; Son, Jeong-Yu; Um, Kyusik; Lee, Sooho; Baek, Yonghyeon; Seo, Boram; Lee, Phil Ho

    2017-10-06

    The Cu-catalyzed, formal aza-[3 + 2] cycloaddition reaction of pyridine derivatives with α-diazo oxime ethers in trifluoroethanol was used to synthesize imidazopyridines via the release of molecular nitrogen and elimination of alcohol. These methods enabled modular synthesis of a wide range of N-heterobicyclic compounds such as imidazopyridazines, imidazopyrimidines, and imidazopyrazines with an α-imino Cu-carbenoid generated from the α-diazo oxime ethers and copper.

  9. Dependence of the reactivity of five-remembered aromatic heterocycles on their structure. 2. Effect of aza substitution on the proton affinity of aminofurans

    International Nuclear Information System (INIS)

    Shokhen, M.A.; Andrianov, V.G.; Eremeev, A.V.; Barmina, S.V.

    1987-01-01

    The proton affinities of a series of aminofurans and their aza derivatives were calculated by a nonempirical method in the STO-3G basis set. A correlation was established between the proton affinities and the position of the heteroatoms in the ring. The calculation was performed by means of the Gaussian-76 program in the STO-3G basis set with the use of the geometric parameters obtained with full optimization of the molecular geometry in terms of the semiempirical MNDO method

  10. 5,6-Dihydro-5-aza-2’-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors

    OpenAIRE

    Rawson, Jonathan M.; Heineman, Richard H.; Beach, Lauren B.; Martin, Jessica L.; Schnettler, Erica K.; Dapp, Michael J.; Patterson, Steven E.; Mansky, Louis M.

    2013-01-01

    The nucleoside analog 5,6-dihydro-5-aza-2’-deoxycytidine (KP-1212) has been investigated as a first-in-class lethal mutagen of human immunodeficiency virus type-1 (HIV-1). Since a prodrug monotherapy did not reduce viral loads in Phase II clinical trials, we tested if ribonucleotide reductase inhibitors (RNRIs) combined with KP-1212 would improve antiviral activity. KP-1212 potentiated the activity of gemcitabine and resveratrol and simultaneously increased the viral mutant frequency. G-to-C ...

  11. Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

    OpenAIRE

    Li, Deyu; Fedeles, Bogdan I.; Singh, Vipender; Peng, Chunte Sam; Silvestre, Katherine J.; Simi, Allison K.; Simpson, Jeffrey H.; Tokmakoff, Andrei; Essigmann, John M.

    2014-01-01

    Unlike conventional antiviral therapy, lethal mutagenesis is a therapeutic strategy that exploits the high mutation rates of certain viruses. It works by intentionally increasing the viral mutation rate, causing excessive error accumulation and viral population collapse. The mutagenic nucleoside analog 5-aza-5,6-dihydro-2′-deoxycytidine (KP1212) is specifically designed to use lethal mutagenesis against HIV. The mechanism of KP1212 mutagenesis was proposed to involve tautomerism—the repositio...

  12. Aza-Peptidyl Michael Acceptor and Epoxide Inhibitors—Potent and Selective Inhibitors of Schistosoma mansoni and Ixodes ricinus Legumains (Asparaginyl Endopeptidases)

    Czech Academy of Sciences Publication Activity Database

    Ovat, A.; Muindi, F.; Fagan, C.; Brouner, M.; Hansell, E.; Dvořák, J.; Sojka, Daniel; Kopáček, Petr; McKerrow, J. H.; Caffrey, C. R.; Powers, J. C.

    2009-01-01

    Roč. 52, č. 22 (2009), s. 7192-7210 ISSN 0022-2623 R&D Projects: GA ČR GA206/06/0865; GA MŠk(CZ) LC06009 Institutional research plan: CEZ:AV0Z60220518 Keywords : legumain * IrAE * aza-peptide Michael acceptors Subject RIV: EC - Immunology Impact factor: 4.802, year: 2009

  13. A phosphine mediated sequential annulation process of 2-tosylaminochalcones with MBH carbonates to construct functionalized aza-benzobicyclo[4.3.0] derivatives.

    Science.gov (United States)

    Zhang, Qinglong; Zhu, Yannan; Jin, Hongxing; Huang, You

    2017-04-04

    A novel phosphine mediated sequential annulation process to construct functionalized aza-benzobicyclo[4.3.0] derivatives has been developed involving a one-pot sequential catalytic and stoichiometric process, which generates a series of benzobicyclo[4.3.0] compounds containing one quaternary center with up to 94% yield and 20 : 1 dr value. In this reaction, MBH carbonates act as 1,2,3-C 3 synthons.

  14. Optimization of catalyst-solvent system for preparation of alpha-5,6-dihydro-5-aza-2'-deoxy-[6-3H]-cytidine

    Czech Academy of Sciences Publication Activity Database

    Elbert, Tomáš

    2011-01-01

    Roč. 54, č. 5 (2011), s. 285-285 ISSN 0362-4803. [Workshop of the International Isotope Society - Central European Division. The Synthesis and Applications of Isotopes and Isotopically Labelled Compounds /17./. 23.09.2010-24.09.2010, Bad Soden] Institutional research plan: CEZ:AV0Z40550506 Keywords : tritium * labelled compounds * alfa-5,6-dihydro-5-aza-2'-deoxy-cytidine Subject RIV: CC - Organic Chemistry

  15. A new enantioselective CE method for determination of oxcarbazepine and licarbazepine after fungal biotransformation.

    Science.gov (United States)

    Bocato, Mariana Zuccherato; Bortoleto, Marcela Armelim; Pupo, Mônica Tallarico; de Oliveira, Anderson Rodrigo Moraes

    2014-10-01

    The present work describes, for the first time, the simultaneous separation of oxcarbazepine (OXC) and its active metabolite 10-hydroxy-10,11-dihydrocarbamazepine (licarbazepine, Lic) by chiral CE. The developed method was employed to monitor the enantioselective biotransformation of OXC into its active metabolite by fungi. The electrophoretic separations were performed using 10 mmol/L of a Tris-phosphate buffer solution (pH 2.5) containing 1% w/v of β-CD phosphate sodium salt (P-β-CD) as running electrolyte, -20 kV of applied voltage and a 15°C capillary temperature. The method was linear over the concentration range of 1000-30 000 ng/mL for OXC and 75-900 ng/mL for each Lic enantiomer (r ≥ 0.9952). Within-day precision and accuracy evaluated by RSD and relative errors, respectively, were lower than 15% for all analytes. The validated method was used to evaluate the enantioselective biotransformation of OXC, mediated by fungi, into its active metabolite Lic. This study showed that the fungi Glomerella cingulata (VA1) and Beuveria bassiana were able to enantioselectively metabolize the OXC into Lic after 360 h of incubation. Biotransformation by the fungus Beuveria bassiana showed 79% enantiomeric excess for (S)-(+)-Lic, while VA1 gave an enantiomeric excess of 100% for (S)-(+)-Lic. This study opens a new route to the drug (S)-(+)-licarbazepine. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Enantioselective Intramolecular CH-Insertions upon Cu-Catalyzed Decomposition of Phenyliodonium Ylides

    Directory of Open Access Journals (Sweden)

    Christelle Boléa

    2001-02-01

    Full Text Available The Cu-catalyzed intramolecular CH insertion of phenyliodonium ylide 5b has been investigated at 0° C in the presence of several chiral ligands. Enantioselectivities vary in the range of 38–72 %, and are higher than those resulting from reaction of the diazo compound 5c at 65° C. The results are consistent with a carbenoid mechanism for Cu-catalyzed decomposition of phenyliodonium ylides.

  17. Enantioselective N-Heterocyclic Carbene Catalysis via the Dienyl Acyl Azolium.

    Science.gov (United States)

    Gillard, Rachel M; Fernando, Jared E M; Lupton, David W

    2018-04-16

    Herein we report the enantioselective N-heterocyclic carbene catalyzed (4+2) annulation of the dienyl acyl azolium with enolates. The reaction exploits readily accessible acyl fluorides and TMS enol ethers to give a range of highly enantio- and diastereo-enriched cyclohexenes (most >97:3 er and >20:1 dr). The reaction was found to require high nucleophilicity NHC catalysts with mechanistic studies supporting a stepwise 1,6-addition/β-lactonization. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Organocatalytic Michael and Friedel–Crafts reactions in enantioselective synthesis of biologically active compounds

    International Nuclear Information System (INIS)

    Maltsev, O V; Beletskaya, Irina P; Zlotin, Sergei G

    2011-01-01

    Recent applications of organocatalytic Michael and Friedel–Crafts reactions in enantioselective synthesis of biologically active compounds: natural products, pharmaceutical agents and plant protection agents are reviewed. The key mechanisms of stereoinduction, types of organocatalysts and reagents used in these reactions are considered. The material is classified according to the type of newly formed bonds incorporating the asymmetric carbon atom, and the information for the most numerous C–C coupling reactions is systematized according to the natures of the electrophile and the nucleophile. The bibliography includes 433 references.

  19. Enantioselective developmental toxicity and immunotoxicity of pyraclofos toward zebrafish (Danio rerio)

    Energy Technology Data Exchange (ETDEWEB)

    Zhuang, Shulin, E-mail: shulin@zju.edu.cn [Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058 (China); Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou 310058 (China); Zhang, Zhisheng [Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058 (China); Zhang, Wenjing; Bao, Lingling [Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058 (China); Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou 310058 (China); Xu, Chao, E-mail: chaoxu@zjut.edu.cn [Research Center of Environmental Science, College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032 (China); Zhang, Hu [Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou 210021 (China)

    2015-02-15

    Highlights: • Pyraclofos has significant enantioselective aquatic toxicities to zebrafish. • Pyraclofos induces time- and concentration-dependent developmental toxicity and immunotoxicity. • The mRNA level of IL-1β gene was significantly up-regulated by pyraclofos. • Pyraclofos binds potently to IL-1β, potentially affecting IL-1β-dependent proinflammatory signal transduction. • Our in vitro and in silico studies help to understand the molecular basis for aquatic toxicity of pyraclofos. - Abstract: Pyraclofos, a relatively new organophosphorus pesticide, has shown potential ecotoxicities, however, its aquatic toxicity, especially enantioselective aquatic toxicity, remains largely unknown. Using zebrafish (Danio rerio) as a preeminent vertebrate aquatic model, the enantioselective differences in the developmental toxicity and immunotoxicity of pyraclofos were evaluated. Following 96-h exposure, pyraclofos enantiomers exhibited acute toxicity and showed lethal concentration 50 of 2.23 and 3.99 mg/L for (R)-Pyraclofos and (S)-Pyraclofos, respectively. Exposure to pyraclofos caused time- and concentration-dependent malformations such as pericardial edema, yolk sac edema, crooked bodies and hatching during the embryonic development, with markedly higher percentages of malformation at higher concentrations. The concentration-dependent immunotoxicity to zebrafish embryo exposed to low level pyraclofos was induced with significant up-regulation of mRNA levels of immune-related interleukin-1β (IL-1β) gene. (R)-Pyraclofos was consistently more toxic than (S)-Pyraclofos for the acute toxicity, developmental toxicity and immunotoxicity to zebrafish. Molecular dynamics simulations revealed that at the atomic level, (R)-Pyraclofos binds more potently to IL-1β protein than (S)-Pyraclofos. This enantioselective binding is mainly contributed by the distinct binding mode of pyraclofos enantiomers and their electrostatic interactions with IL-1β, which potentially

  20. Enantioselective biotransformation of propranolol to the active metabolite 4-hydroxypropranolol by endophytic fungi

    Directory of Open Access Journals (Sweden)

    Keyller Bastos Borges

    2011-01-01

    Full Text Available The enantioselective biotransformation of propranolol (Prop by the endophytic fungi Phomopsis sp., Glomerella cingulata, Penicillium crustosum, Chaetomium globosum and Aspergillus fumigatus was investigated by studying the kinetics of the aromatic hydroxylation reaction with the formation of 4-hydroxypropranolol (4-OH-Prop. Both Prop enantiomers were consumed by the fungi in the biotransformation process, but the 4-hydroxylation reaction yielded preferentially (--(S-4-OH-Prop. The quantity of metabolites biosynthesized varied slightly among the evaluated endophytic fungi. These results show that all investigated endophytic fungi could be used as biosynthetic tools in biotransformation processes to obtain the enantiomers of 4-OH-Prop.

  1. Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis

    Directory of Open Access Journals (Sweden)

    Dario Perdicchia

    2015-12-01

    Full Text Available 2-Piperidineethanol (1 and its corresponding N-protected aldehyde (2 were used for the synthesis of several natural and synthetic compounds. The existence of a stereocenter at position 2 of the piperidine skeleton and the presence of an easily-functionalized group, such as the alcohol, set 1 as a valuable starting material for enantioselective synthesis. Herein, are presented both synthetic and enzymatic methods for the resolution of the racemic 1, as well as an overview of synthesized natural products starting from the enantiopure 1.

  2. Enantioselective Access to Spirocyclic Sultams by Chiral Cp(x) -Rhodium(III)-Catalyzed Annulations.

    Science.gov (United States)

    Pham, Manh V; Cramer, Nicolai

    2016-02-12

    Chiral spirocyclic sultams are a valuable compound class in organic and medicinal chemistry. A rapid entry to this structural motif involves a [3+2] annulation of an N-sulfonyl ketimine and an alkyne. Although the directing-group properties of the imino group for C-H activation have been exploited, the developments of related asymmetric variants have remained very challenging. The use of rhodium(III) complexes equipped with a suitable atropchiral cyclopentadienyl ligand, in conjunction with a carboxylic acid additive, enables an enantioselective and high yielding access to such spirocyclic sultams. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

    Directory of Open Access Journals (Sweden)

    Katherine M. Byrd

    2015-04-01

    Full Text Available The conjugate addition reaction has been a useful tool in the formation of carbon–carbon bonds. The utility of this reaction has been demonstrated in the synthesis of many natural products, materials, and pharmacological agents. In the last three decades, there has been a significant increase in the development of asymmetric variants of this reaction. Unfortunately, conjugate addition reactions using α,β-unsaturated amides and lactams remain underdeveloped due to their inherently low reactivity. This review highlights the work that has been done on both diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams.

  4. Enantioselective developmental toxicity and immunotoxicity of pyraclofos toward zebrafish (Danio rerio)

    International Nuclear Information System (INIS)

    Zhuang, Shulin; Zhang, Zhisheng; Zhang, Wenjing; Bao, Lingling; Xu, Chao; Zhang, Hu

    2015-01-01

    Highlights: • Pyraclofos has significant enantioselective aquatic toxicities to zebrafish. • Pyraclofos induces time- and concentration-dependent developmental toxicity and immunotoxicity. • The mRNA level of IL-1β gene was significantly up-regulated by pyraclofos. • Pyraclofos binds potently to IL-1β, potentially affecting IL-1β-dependent proinflammatory signal transduction. • Our in vitro and in silico studies help to understand the molecular basis for aquatic toxicity of pyraclofos. - Abstract: Pyraclofos, a relatively new organophosphorus pesticide, has shown potential ecotoxicities, however, its aquatic toxicity, especially enantioselective aquatic toxicity, remains largely unknown. Using zebrafish (Danio rerio) as a preeminent vertebrate aquatic model, the enantioselective differences in the developmental toxicity and immunotoxicity of pyraclofos were evaluated. Following 96-h exposure, pyraclofos enantiomers exhibited acute toxicity and showed lethal concentration 50 of 2.23 and 3.99 mg/L for (R)-Pyraclofos and (S)-Pyraclofos, respectively. Exposure to pyraclofos caused time- and concentration-dependent malformations such as pericardial edema, yolk sac edema, crooked bodies and hatching during the embryonic development, with markedly higher percentages of malformation at higher concentrations. The concentration-dependent immunotoxicity to zebrafish embryo exposed to low level pyraclofos was induced with significant up-regulation of mRNA levels of immune-related interleukin-1β (IL-1β) gene. (R)-Pyraclofos was consistently more toxic than (S)-Pyraclofos for the acute toxicity, developmental toxicity and immunotoxicity to zebrafish. Molecular dynamics simulations revealed that at the atomic level, (R)-Pyraclofos binds more potently to IL-1β protein than (S)-Pyraclofos. This enantioselective binding is mainly contributed by the distinct binding mode of pyraclofos enantiomers and their electrostatic interactions with IL-1β, which potentially

  5. Activation of lipase from .I.Geotrichum candidum./I. and its enantioselectivity towards xenobiotic substrates

    Czech Academy of Sciences Publication Activity Database

    Kejík, Z.; Zarevúcka, Marie; Demnerová, K.

    2003-01-01

    Roč. 97, č. 5 (2003), s. 293-294 ISSN 0009-2770. [Sigma-Aldrich konference mladých chemiků, biochemiků a molekulárních biologů /3./. 04.06.2003-07.06.2003, Devět skal - Žďárské vrchy] R&D Projects: GA MŠk OC D13.10 Institutional research plan: CEZ:AV0Z4055905 Keywords : lipase * enantioselectivity Subject RIV: CC - Organic Chemistry

  6. Theoretical Study on the Aza-Diels-Alder Reaction Catalyzed by PHCl2 Lewis Acid via Pnicogen Bonding.

    Science.gov (United States)

    Yaghoobi, Fereshteh; Sohrabi Mahboub, Mahdi

    2018-03-15

    The reaction mechanism of the Aza-Diels-Alder (A-D-A) cycloaddition reaction between X 2 C═NNH 2 , where X = H, F, Cl, Br, and 1,3-butadiene catalyzed by a PHCl 2 Lewis acid was characterized using density functional theory calculations. The influences of various substituents of X on the studied reaction were analyzed using the activation strain model (ASM), which is also termed as the distortion-interaction model. Calculations showed that the smallest and largest values of the activation energies belong to the substituents of F and Br, respectively. The activation energy of the studied reactions was decreased within 8.6 kcal·mol -1 in the presence of PHCl 2 catalyst. Investigations showed that the pnicogen bonding is adequately capable of activating the A-D-A reaction. The quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis were implemented to understand the nature of C 4,Cbut ···C XIm and C 1,Cbut ···N XIm bonds at the TS structures. Additionally, the energy decomposition analysis (EDA) based on the ETS-NOCV scheme was used to characterize the nature of C 4,Cbut ···C XIm and C 1,Cbut ···N XIm bond. The results of the study mirror the fact that the PHCl 2 Lewis acid may be suggested as a simple suitable catalyst for experimental studies on the A-D-A reactions.

  7. Near-infrared fluorescent aza-BODIPY dye-loaded biodegradable polymeric nanoparticles for optical cancer imaging

    International Nuclear Information System (INIS)

    Hamon, Casey L.; Dorsey, Christopher L.; Özel, Tuğba; Barnes, Eugenia M.; Hudnall, Todd W.; Betancourt, Tania

    2016-01-01

    Nanoparticles are being readily investigated as carriers for the delivery of imaging and therapeutic agents for the detection, monitoring, and treatment of cancer and other diseases. In the present work, the preparation of biodegradable polymeric nanoparticles loaded with a near-infrared fluorescent aza-boron dipyrromethene (NIR-BODIPY) derivative, and their use as contrast agents for optical imaging in cancer are described. Nanoparticles were prepared by nanoprecipitation of amphiphilic block copolymers of poly(lactic acid) and poly(ethylene glycol). The size, morphology, dye loading, spectral properties, quantum yield, cytocompatibility, and in vitro NIR imaging potential of the nanoparticles in breast and ovarian cancer cells were evaluated. Spherical nanoparticles of 30–70 nm in diameter were loaded with 0.73 w/w% BODIPY derivative. At this loading, the dye presented a fluorescence quantum yield in the same order of magnitude as in solution. Nanoparticle suspensions at concentrations up to 580 μg/mL were cytocompatible to breast (MDA-MB-231) and ovarian (SKOV-3 and Caov-3) cancer cells after a four-hour incubation period. Fluorescence microscopy images demonstrated the ability of the nanoparticles to act as imaging agents in all three cell lines in as little as 1 hour. The results shown indicate the potential of these NIR-BODIPY-loaded nanoparticles as contrast agents for near-infrared optical imaging in cancer.Graphical abstract

  8. 5-Aza-2'-deoxycytidine acts as a modulator of chondrocyte hypertrophy and maturation in chick caudal region chondrocytes in culture.

    Science.gov (United States)

    Haq, Samina Hyder

    2016-06-01

    This study was carried out to explore the effect of DNA hypomethylation on chondrocytes phenotype, in particular the effect on chondrocyte hypertrophy, maturation, and apoptosis. Chondrocytes derived from caudal region of day 17 embryonic chick sterna were pretreated with hypomethylating drug 5-aza-2'-deoxycytidine for 48 hours and then maintained in the normal culture medium for up to 14 days. Histological studies showed distinct morphological changes occurred in the pretreated cultures when compared to the control cultures. The pretreated chondrocytes after 7 days in culture became bigger in size and acquired more flattened fibroblastic phenotype as well as a loss of cartilage specific extracellular matrix. Scanning electron microscopy at day 7 showed chondrocytes to have increased in cell volume and at day 14 in culture the extracellular matrix of the pretreated cultures showed regular fibrillar structure heavily embedded with matrix vesicles, which is the characteristic feature of chondrocyte hypertrophy. Transmission electron microscopic studies indicated the terminal fate of the hypertrophic cells in culture. The pretreated chondrocytes grown for 14 days in culture showed two types of cells: dark cells which had condense chromatin in dark patches and dark cytoplasm. The other light chondrocytes appeared to be heavily loaded with endoplasmic reticulum indicative of very active protein and secretory activity; their cytoplasm had large vacuoles and disintegrating cytoplasm. The biosynthetic profile showed that the pretreated cultures were actively synthesizing and secreting type X collagen and alkaline phosphatase as a major biosynthetic product.

  9. Near-infrared fluorescent aza-BODIPY dye-loaded biodegradable polymeric nanoparticles for optical cancer imaging

    Energy Technology Data Exchange (ETDEWEB)

    Hamon, Casey L.; Dorsey, Christopher L. [Texas State University, Department of Chemistry and Biochemistry (United States); Özel, Tuğba [Texas State University, Materials Science, Engineering, and Commercialization Program (United States); Barnes, Eugenia M.; Hudnall, Todd W.; Betancourt, Tania, E-mail: tb26@txstate.edu [Texas State University, Department of Chemistry and Biochemistry (United States)

    2016-07-15

    Nanoparticles are being readily investigated as carriers for the delivery of imaging and therapeutic agents for the detection, monitoring, and treatment of cancer and other diseases. In the present work, the preparation of biodegradable polymeric nanoparticles loaded with a near-infrared fluorescent aza-boron dipyrromethene (NIR-BODIPY) derivative, and their use as contrast agents for optical imaging in cancer are described. Nanoparticles were prepared by nanoprecipitation of amphiphilic block copolymers of poly(lactic acid) and poly(ethylene glycol). The size, morphology, dye loading, spectral properties, quantum yield, cytocompatibility, and in vitro NIR imaging potential of the nanoparticles in breast and ovarian cancer cells were evaluated. Spherical nanoparticles of 30–70 nm in diameter were loaded with 0.73 w/w% BODIPY derivative. At this loading, the dye presented a fluorescence quantum yield in the same order of magnitude as in solution. Nanoparticle suspensions at concentrations up to 580 μg/mL were cytocompatible to breast (MDA-MB-231) and ovarian (SKOV-3 and Caov-3) cancer cells after a four-hour incubation period. Fluorescence microscopy images demonstrated the ability of the nanoparticles to act as imaging agents in all three cell lines in as little as 1 hour. The results shown indicate the potential of these NIR-BODIPY-loaded nanoparticles as contrast agents for near-infrared optical imaging in cancer.Graphical abstract.

  10. Enantioselective copper-catalysed propargylic substitution: synthetic scope study and application in formal total syntheses of (+)-anisomycin and (-)-cytoxazone

    NARCIS (Netherlands)

    Detz, R.J.; Abiri, Z.; le Griel, R.; Hiemstra, H.; van Maarseveen, J.H.

    2011-01-01

    A copper catalyst with a chiral pyridine-2,6-bisoxazoline (pybox) ligand was used to convert a variety of propargylic esters with different side chains (R=Ar, Bn, alkyl) into their amine counterparts in very high yields and with good enantioselectivities (up to 90 % enantiomeric excess (ee)).

  11. Chiral separation of substituted phenylalanine analogues using chiral palladium phosphine complexes with enantioselective liquid-liquid extraction

    NARCIS (Netherlands)

    Verkuijl, B.J.V.; Schuur, B.; Minnaard, A.J.; Vries, de J.G.; Feringa, B.L.

    2010-01-01

    Chiral palladium phosphine complexes have been employed in the chiral separation of amino acids and phenylalanine analogues in particular. The use of (S)-xylyl-BINAP as a ligand for the palladium complex in enantioselective liquid–liquid extraction allowed the separation of the phenylalanine

  12. Enantioselective Effects of o,p'-DDT on Cell Invasion and Adhesion of Breast Cancer Cells: Chirality in Cancer Development.

    Science.gov (United States)

    He, Xiangming; Dong, Xiaowu; Zou, Dehong; Yu, Yang; Fang, Qunying; Zhang, Quan; Zhao, Meirong

    2015-08-18

    The o,p'-dichlorodiphenyltrichloroethane (DDT) with a chiral center possesses enantioselective estrogenic activity, in which R-(-)-o,p'-DDT exerts a more potent estrogenic effect than S-(+)-o,p'-DDT. Although concern regarding DDT exposure and breast cancer has increased in recent decades, the mode of enantioselective action of o,p'-DDT in breast cancer development is still unknown. Herein, we conducted a systematic study of the effect of o,p'-DDT on stereoselective breast tumor cell progression in a widely used in vitro breast tumor cell model, MCF-7 cells. We demonstrated that R-(-)-o,p'-DDT promoted more cancer cell invasion mediated by the human estrogen receptor (ER) by inducing invasion-promoted genes (matrix metalloproteinase-2 and -9 and human telomerase reverse transcriptase) and inhibiting invasion-inhibited genes (tissue inhibitor of metalloproteinase-1 and -4). Molecular docking verified that the binding affinity between R-(-)-o,p'-DDT and human ER was stronger than that of S-(+)-o,p'-DDT. The enantioselective-induced decrease in cell-to-cell adhesion may involve the downregulation of adhesion-promoted genes (E-cadherin and β-catenin). For the first time, these results reveal that estrogenic-like chiral compounds are of significant concern in the progression of human cancers and that human health risk assessment of chiral chemicals should consider enantioselectivity.

  13. Proof of concept for continuous enantioselective liquid-liquid extraction in capillary microreactors using 1-octanol as a sustainable solvent

    NARCIS (Netherlands)

    Susanti, S.; Meinds, Tim G.; Pinxterhuis, Erik B.; Schuur, Boelo; De Vries, Johannes G.; Feringa, Ben L.; Winkelman, Jozef G.M.; Yue, Jun; Heeres, Hero J.

    2017-01-01

    The use of capillary microreactors for enantioselective liquid-liquid extraction (ELLE) was successfully demonstrated using a model system consisting of a buffered aqueous amino acid derivative (3,5-dinitrobenzoyl-(R,S)-leucine) solution (phosphate buffer, pH 6.58) and a chiral cinchona alkaloid

  14. A Convergent Enantioselective Total Synthesis of (-)-Perhydrohistrionicotoxin with an Intramolecular Imino Ene-type Reaction as a Key Step

    DEFF Research Database (Denmark)

    Tanner, David Ackland; Hagberg, Lars

    1998-01-01

    A convergent enantioselective total synthesis of the neurotoxic spirocyclic alkaloid (-)-perhydrohistrionicotoxin (2) is described. A Lewis acid-mediated intramolecular imine ene-type reaction was used for the key spirocyclisation step (14 to 3, with 3 being obtained as a single diastereoisomer...

  15. Organocatalytic Enantioselective Pictet-Spengler Approach to Biologically Relevant 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline Alkaloids

    NARCIS (Netherlands)

    Ruiz-Olalla, A.; Würdemann, M.A.; Wanner, M.J.; Ingemann, S.; van Maarseveen, J.H.; Hiemstra, H.

    2015-01-01

    A general procedure for the synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines was developed, based on organocatalytic, regio- and enantioselective Pictet-Spengler reactions (86-92% ee) of N-(o-nitrophenylsulfenyl)-2-arylethyl-amines with arylacetaldehydes. The presence of the

  16. DNA-Accelerated Copper Catalysis of Friedel-Crafts Conjugate Addition/Enantioselective Protonation Reactions in Water

    NARCIS (Netherlands)

    García-Fernández, Almudena; Megens, Rik P.; Villarino, Lara; Roelfes, Gerard

    2016-01-01

    DNA-induced rate acceleration has been identified as one of the key elements for the success of the DNA-based catalysis concept. Here we report on a novel DNA-based catalytic Friedel-Crafts conjugate addition/enantioselective protonation reaction in water, which represents the first example of a

  17. Synthesis of l-threitol-based crown ethers and their application as enantioselective phase transfer catalyst in Michael additions.

    Science.gov (United States)

    Rapi, Zsolt; Nemcsok, Tamás; Pálvölgyi, Ádám; Keglevich, György; Grün, Alajos; Bakó, Péter

    2017-06-01

    A few new l-threitol-based lariat ethers incorporating a monoaza-15-crown-5 unit were synthesized starting from diethyl l-tartrate. These macrocycles were used as phase transfer catalysts in asymmetric Michael addition reactions under mild conditions to afford the adducts in a few cases in good to excellent enantioselectivities. The addition of 2-nitropropane to trans-chalcone, and the reaction of diethyl acetamidomalonate with β-nitrostyrene resulted in the chiral Michael adducts in good enantioselectivities (90% and 95%, respectively). The substituents of chalcone had a significant impact on the yield and enantioselectivity in the reaction of diethyl acetoxymalonate. The highest enantiomeric excess (ee) values (99% ee) were measured in the case of 4-chloro- and 4-methoxychalcone. The phase transfer catalyzed cyclopropanation reaction of chalcone and benzylidene-malononitriles using diethyl bromomalonate as the nucleophile (MIRC reaction) was also developed. The corresponding chiral cyclopropane diesters were obtained in moderate to good (up to 99%) enantioselectivities in the presence of the threitol-based crown ethers. © 2017 Wiley Periodicals, Inc.

  18. Paralogous gene analysis reveals a highly enantioselective 1,2-O-isopropylideneglycerol caprylate esterase of Bacillus subtilis

    NARCIS (Netherlands)

    Droge, MJ; Bos, R; Quax, WJ

    Carboxylesterase NP of Bacillus subtilis Thai 1-8, characterized in 1992 as a very enantioselective (S)-naproxen esterase, was found to show no enantiopreference towards (S)-1,2-O-isopropylideneglycerol (IPG) esters. The ybfK gene was identified by the B. subtilis genome project as an unknown gene

  19. Kinetic and dynamic kinetic resolution of secondary alcohols with ionic-surfactant-coated Burkholderia cepacia lipase: substrate scope and enantioselectivity.

    Science.gov (United States)

    Kim, Cheolwoo; Lee, Jusuk; Cho, Jeonghun; Oh, Yeonock; Choi, Yoon Kyung; Choi, Eunjeong; Park, Jaiwook; Kim, Mahn-Joo

    2013-03-15

    Forty-four different secondary alcohols, which can be classified into several types (II-IX), were tested as the substrates of ionic surfactant-coated Burkholderia cepacia lipase (ISCBCL) to see its substrate scope and enantioselectivity in kinetic and dynamic kinetic resolution (KR and DKR). They include 6 boron-containing alcohols, 24 chiral propargyl alcohols, and 14 diarylmethanols. The results from the studies on KR indicate that ISCBCL accepted most of them with high enantioselectivity at ambient temperature and with useful to high enantioselectivity at elevated temperatures. In particular, ISCBCL displayed high enantioselectivity toward sterically demanding secondary alcohols (types VIII and IX) which have two bulky substituents at the hydroxymethine center. DKR reactions were performed by the combination of ISCBCL with a ruthenium-based racemization catalyst at 25-60 °C. Forty-one secondary alcohols were tested for DKR. About half of them were transformed into their acetates of high enantiopurity (>90% ee) with good yields (>80%). It is concluded that ISCBCL appears to be a superb enzyme for the KR and DKR of secondary alcohols.

  20. Combinatorial library based engineering of Candida antarctica lipase A for enantioselective transacylation of sec-alcohols in organic solvent.

    Science.gov (United States)

    Wikmark, Ylva; Svedendahl Humble, Maria; Bäckvall, Jan-E

    2015-03-27

    A method for determining lipase enantioselectivity in the transacylation of sec-alcohols in organic solvent was developed. The method was applied to a model library of Candida antarctica lipase A (CalA) variants for improved enantioselectivity (E values) in the kinetic resolution of 1-phenylethanol in isooctane. A focused combinatorial gene library simultaneously targeting seven positions in the enzyme active site was designed. Enzyme variants were immobilized on nickel-coated 96-well microtiter plates through a histidine tag (His6-tag), screened for transacylation of 1-phenylethanol in isooctane, and analyzed by GC. The highest enantioselectivity was shown by the double mutant Y93L/L367I. This enzyme variant gave an E value of 100 (R), which is a dramatic improvement on the wild-type CalA (E=3). This variant also showed high to excellent enantioselectivity for other secondary alcohols tested. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

  1. Enantioselective [2+2+2] cycloisomerisation of alkynes in the synthesis of helicenes: the search for effective chiral ligands

    Czech Academy of Sciences Publication Activity Database

    Stará, Irena G.; Andronova, Angelina; Kollárovič, Adrian; Vyskočil, Š.; Jugé, S.; Lloyd-Jones, G. C.; Guiry, P. J.; Starý, Ivo

    2011-01-01

    Roč. 76, č. 12 (2011), s. 2005-2022 ISSN 0010-0765 R&D Projects: GA ČR GA203/09/1766; GA MŠk LC512 Institutional research plan: CEZ:AV0Z40550506 Keywords : helicenes * enantioselectivity * cycloisomerisation Subject RIV: CC - Organic Chemistry Impact factor: 1.283, year: 2011

  2. Separation of racemic mixture by ultrafiltration of enantioselective micelles. 1 Effect of pH on separation and regeneration

    NARCIS (Netherlands)

    Overdevest, P.E.M.; Bruin, de T.J.M.; Riet, van 't K.; Keurentjes, J.T.F.; Padt, van der A.

    2001-01-01

    Many enantiomer separation systems are studied to meet the increasing demand for enantiopure compounds. One way to obtain pure enantiomers is to apply enantioselective micelles in ultrafiltration systems. We have studied the separation of phenylalanine (Phe) enantiomers by the ultrafiltration of

  3. Poly(propylene carbonate): Insight into the Microstructure and Enantioselective Ring-Opening Mechanism

    KAUST Repository

    Salmeia, Khalifah A.

    2012-11-13

    Different poly(propylene carbonate) (PPC) microstructures have been synthesized from the alternating copolymerization of CO 2 with both racemic propylene oxide (PO) and various mixtures of PO enantiomers using chiral salen catalysts. The microstructures of the obtained copolymers as a function of polymerization time have been analyzed by a combination of chiral GC and high-resolution NMR spectroscopy. The 13C NMR spectra of selected poly(propylene carbonate) samples were recorded using a 900 MHz ( 1H) spectrometer, showing a previously unreported fine splitting of the carbonate resonances. This allowed a detailed assignment of signals for various copolymer microstructures taking into account the specifics in their stereo- and regioirregularities. For example, the enantioselectivity preference of the (R,R-salen)Co catalyst for (S)-PO at the beginning of the copolymerization leads predominantly to (S)-PO insertion, with any (R)-PO misinsertion being followed by incorporation of (S)-PO, so that the microstructure features isolated stereoerrors. K rel calculations for the copolymerization showed around 5-fold enantioselectivity for (S)-PO over (R)-PO at short reaction time. Analysis of the copolymer microstructures obtained under various reaction conditions appears to be an additional approach to differentiate the occurrence of bimetallic and bifunctional copolymerization mechanisms that are widely discussed in the literature. © 2012 American Chemical Society.

  4. Asymmetric Construction of Benzindoloquinolizidine: Application of An Organocatalytic Enantioselective Conjugate Addition-Cyclization Cascade Reaction

    International Nuclear Information System (INIS)

    Kim, Cheolwoong; Seo, Seung Woo; Lee, Yona; Kim, Sunggon

    2014-01-01

    We have developed the synthetic methodology of enantioenriched benzindoloquinolizidines based on the organocatalytic enantioselective conjugate addition-cyclization cascade reaction of o-N-(3-indoleacetyl)amino-cinnamaldehydes with malonates followed by an acid-catalyzed intramolecular Pictet-Spengler type cyclization. The asymmetric reaction using diphenylprolinol TMS ether as an organocatalyst produces the desired products with good to excellent yields and high enantioselectivities (up to 98% ee). The evaluation of the applications of this synthetic methodology for generating enantioenriched benzindolo-quinolizidines and studies on the biological activity of these compounds against human prostate cancer in particular are now in progress. Results of these studies will be presented in due course. Many new types of chemical reactions have been developed to facilitate easier synthesis of complex compounds. Among the strategies, domino reactions, which have been utilized for the efficient and stereoselective construction of complex molecules from simple precursors in a single process, are widely used due to their high synthetic efficiency by reducing both the number of synthetic operation required and the quantities of chemicals and solvents used

  5. Preparative and mechanistic studies toward the rational development of catalytic, enantioselective selenoetherification reactions.

    Science.gov (United States)

    Denmark, Scott E; Kalyani, Dipannita; Collins, William R

    2010-11-10

    A systematic investigation into the Lewis base catalyzed, asymmetric, intramolecular selenoetherification of olefins is described. A critical challenge for the development of this process was the identification and suppression of racemization pathways available to arylseleniranium ion intermediates. This report details a thorough study of the influences of the steric and electronic modulation of the arylselenenyl group on the configurational stability of enantioenriched seleniranium ions. These studies show that the 2-nitrophenyl group attached to the selenium atom significantly attenuates the racemization of seleniranium ions. A variety of achiral Lewis bases catalyze the intramolecular selenoetherification of alkenes using N-(2-nitrophenylselenenyl)succinimide as the electrophile along with a Brønsted acid. Preliminary mechanistic studies suggest the intermediacy of ionic Lewis base-selenium(II) adducts. Most importantly, a broad survey of chiral Lewis bases revealed that 1,1'-binaphthalene-2,2'-diamine (BINAM)-derived thiophosphoramides catalyze the cyclization of unsaturated alcohols in the presence of N-(2-nitrophenylselenenyl)succinimide and methanesulfonic acid. A variety of cyclic seleno ethers were produced in good chemical yields and in moderate to good enantioselectivities, which constitutes the first catalytic, enantioselective selenofunctionalization of unactivated olefins.

  6. Characterization of an enantioselective odorant receptor in the yellow fever mosquito Aedes aegypti.

    Directory of Open Access Journals (Sweden)

    Jonathan D Bohbot

    2009-09-01

    Full Text Available Enantiomers differ only in the left or right handedness (chirality of their orientations and exhibit identical chemical and physical properties. In chemical communication systems, enantiomers can be differentially active at the physiological and behavioral levels. Only recently were enantioselective odorant receptors demonstrated in mammals while their existence in insects has remained hypothetical. Using the two-microelectrode voltage clamp of Xenopus oocytes, we show that the yellow fever mosquito, Aedes aegypti, odorant receptor 8 (AaOR8 acts as a chiral selective receptor for the (R-(--enantiomer of 1-octen-3-ol, which in the presence of other kairomones is an attractant used by blood-sucking insects to locate their hosts. In addition to steric constraints, chain length and degree of unsaturation play important roles in this recognition process. This is the first characterization of an enantioselective odorant receptor in insects and the results demonstrate that an OR alone, without helper proteins, can account for chiral specificity exhibited by olfactory sensory neurons (OSNs.

  7. A catalytic reactor for the organocatalyzed enantioselective continuous flow alkylation of aldehydes.

    Science.gov (United States)

    Porta, Riccardo; Benaglia, Maurizio; Puglisi, Alessandra; Mandoli, Alessandro; Gualandi, Andrea; Cozzi, Pier Giorgio

    2014-12-01

    The use of immobilized metal-free catalysts offers the unique possibility to develop sustainable processes in flow mode. The challenging intermolecular organocatalyzed enantioselective alkylation of aldehydes was performed for the first time under continuous flow conditions. By using a packed-bed reactor filled with readily available supported enantiopure imidazolidinone, different aldehydes were treated with three distinct cationic electrophiles. In the organocatalyzed α-alkylation of aldehydes with 1,3-benzodithiolylium tetrafluoroborate, excellent enantioselectivities, in some cases even better than those obtained in the flask process (up to 95% ee at 25 °C), and high productivity (more than 3800 h(-1) ) were obtained, which thus shows that a catalytic reactor may continuously produce enantiomerically enriched compounds. Treatment of the alkylated products with Raney-nickel furnished enantiomerically enriched α-methyl derivatives, key intermediates for active pharmaceutical ingredients and natural products. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Influence of gasoline inhalation on the enantioselective pharmacokinetics of fluoxetine in rats.

    Science.gov (United States)

    Cardoso, Juciane Lauren Cavalcanti; Lanchote, Vera Lucia; Pereira, Maria Paula Marques; Capela, Jorge Manuel Vieira; Lepera, José Salvador

    2013-03-01

    Fluoxetine is used clinically as a racemic mixture of (+)-(S) and (-)-(R) enantiomers for the treatment of depression. CYP2D6 catalyzes the metabolism of both fluoxetine enantiomers. We aimed to evaluate whether exposure to gasoline results in CYP2D inhibition. Male Wistar rats exposed to filtered air (n = 36; control group) or to 600 ppm of gasoline (n = 36) in a nose-only inhalation exposure chamber for 6 weeks (6 h/day, 5 days/week) received a single oral 10-mg/kg dose of racemic fluoxetine. Fluoxetine enantiomers in plasma samples were analyzed by a validated analytical method using LC-MS/MS. The separation of fluoxetine enantiomers was performed in a Chirobiotic V column using as the mobile phase a mixture of ethanol:ammonium acetate 15 mM. Higher plasma concentrations of the (+)-(S)-fluoxetine enantiomer were found in the control group (enantiomeric ratio AUC((+)-(S)/(-)-(R)) = 1.68). In animals exposed to gasoline, we observed an increase in AUC(0-∞) for both enantiomers, with a sharper increase seen for the (-)-(R)-fluoxetine enantiomer (enantiomeric ratio AUC((+)-(S)/(-)-(R)) = 1.07), resulting in a loss of enantioselectivity. Exposure to gasoline was found to result in the loss of enantioselectivity of fluoxetine, with the predominant reduction occurring in the clearance of the (-)-(R)-fluoxetine enantiomer (55% vs. 30%). Copyright © 2013 Wiley Periodicals, Inc.

  9. Bioaccumulation and enantioselectivity of type I and type II pyrethroid pesticides in earthworm.

    Science.gov (United States)

    Chang, Jing; Wang, Yinghuan; Wang, Huili; Li, Jianzhong; Xu, Peng

    2016-02-01

    In this study, the bioavailability and enantioselectivity differences between bifenthrin (BF, typeⅠpyrethroid) and lambad-cyhalothrin (LCT, type Ⅱ pyrethroid) in earthworm (Eisenia fetida) were investigated. The bio-soil accumulation factors (BSAFs) of BF was about 4 times greater than that of LCT. LCT was degraded faster than BF in soil while eliminated lower in earthworm samples. Compound sorption plays an important role on bioavailability in earthworm, and the soil-adsorption coefficient (K(oc)) of BF and LCT were 22 442 and 42 578, respectively. Metabolic capacity of earthworm to LCT was further studied as no significant difference in the accumulation of LCT between the high and low dose experiment was found. 3-phenoxybenzoic acid (PBCOOH), a metabolite of LCT produced by earthworm was detected in soil. The concentration of PBCOOH at high dose exposure was about 4.7 times greater than that of in low dose level at the fifth day. The bioaccumulation of BF and LCT were both enantioselective in earthworm. The enantiomer factors of BF and LCT in earthworm were approximately 0.12 and 0.65, respectively. The more toxic enantiomers ((+)-BF and (-)-LCT) had a preferential degradation in earthworm and leaded to less toxicity on earthworm for racemate exposure. In combination with other studies, a liner relationship between Log BSAF(S) and Log K(ow) was observed, and the Log BSAF(S) decreased with the increase of Log K(ow). Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Hydrothermal synthesis, crystal structures, and enantioselective adsorption property of bis(L-histidinato)nickel(II) monohydrate

    Science.gov (United States)

    Ramos, Christian Paul L.; Conato, Marlon T.

    2018-05-01

    Despite the numerous researches in metal-organic frameworks (MOFs), there are only few reports on biologically important amino acids, histidine in particular, on its use as bridging ligand in the construction of open-framework architectures. In this work, hydrothermal synthesis was used to prepare a compound based on Ni2+ and histidine. The coordination assembly of imidazole side chain of histidine with divalent nickel ions in aqueous condition yielded purple prismatic solids. Single crystal X-ray diffraction (XRD) analysis of the product revealed structure for Ni(C6H8N3O2)2 • H2O that has a monoclinic (C2) structure with lattice parameters, a = 29.41, b = 8.27, c = 6.31 Å, β = 90.01 ˚. Circular dichroism - optical rotatory dispersion (CD-ORD), Powder X-ray diffraction (PXRD) and Fourier transform - infrared spectroscopy (FT-IR) analyses are conducted to further characterize the crystals. Enantioselective adsorption analysis using racemic mixture of 2-butanol confirmed bis(L-histidinato)nickel(II) monohydrate MOF crystal's enantioselective property preferentially favoring the adsorption of (S)-2-butanol isomer.

  11. Thermostable Alcohol Dehydrogenase from Thermococcus kodakarensis KOD1 for Enantioselective Bioconversion of Aromatic Secondary Alcohols

    Science.gov (United States)

    Wu, Xi; Zhang, Chong; Orita, Izumi; Imanaka, Tadayuki

    2013-01-01

    A novel thermostable alcohol dehydrogenase (ADH) showing activity toward aromatic secondary alcohols was identified from the hyperthermophilic archaeon Thermococcus kodakarensis KOD1 (TkADH). The gene, tk0845, which encodes an aldo-keto reductase, was heterologously expressed in Escherichia coli. The enzyme was found to be a monomer with a molecular mass of 31 kDa. It was highly thermostable with an optimal temperature of 90°C and a half-life of 4.5 h at 95°C. The apparent Km values for the cofactors NAD(P)+ and NADPH were similar within a range of 66 to 127 μM. TkADH preferred secondary alcohols and accepted various ketones and aldehydes as substrates. Interestingly, the enzyme could oxidize 1-phenylethanol and its derivatives having substituents at the meta and para positions with high enantioselectivity, yielding the corresponding (R)-alcohols with optical purities of greater than 99.8% enantiomeric excess (ee). TkADH could also reduce 2,2,2-trifluoroacetophenone to (R)-2,2,2-trifluoro-1-phenylethanol with high enantioselectivity (>99.6% ee). Furthermore, the enzyme showed high resistance to organic solvents and was particularly highly active in the presence of H2O–20% 2-propanol and H2O–50% n-hexane or n-octane. This ADH is expected to be a useful tool for the production of aromatic chiral alcohols. PMID:23354700

  12. Poly(propylene carbonate): Insight into the Microstructure and Enantioselective Ring-Opening Mechanism

    KAUST Repository

    Salmeia, Khalifah A.; Vagin, Sergei; Anderson, Carly E.; Rieger, Bernhard

    2012-01-01

    Different poly(propylene carbonate) (PPC) microstructures have been synthesized from the alternating copolymerization of CO 2 with both racemic propylene oxide (PO) and various mixtures of PO enantiomers using chiral salen catalysts. The microstructures of the obtained copolymers as a function of polymerization time have been analyzed by a combination of chiral GC and high-resolution NMR spectroscopy. The 13C NMR spectra of selected poly(propylene carbonate) samples were recorded using a 900 MHz ( 1H) spectrometer, showing a previously unreported fine splitting of the carbonate resonances. This allowed a detailed assignment of signals for various copolymer microstructures taking into account the specifics in their stereo- and regioirregularities. For example, the enantioselectivity preference of the (R,R-salen)Co catalyst for (S)-PO at the beginning of the copolymerization leads predominantly to (S)-PO insertion, with any (R)-PO misinsertion being followed by incorporation of (S)-PO, so that the microstructure features isolated stereoerrors. K rel calculations for the copolymerization showed around 5-fold enantioselectivity for (S)-PO over (R)-PO at short reaction time. Analysis of the copolymer microstructures obtained under various reaction conditions appears to be an additional approach to differentiate the occurrence of bimetallic and bifunctional copolymerization mechanisms that are widely discussed in the literature. © 2012 American Chemical Society.

  13. Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography.

    Science.gov (United States)

    Kucerova, Gabriela; Kalikova, Kveta; Tesarova, Eva

    2017-06-01

    The enantioselective potential of two polysaccharide-based chiral stationary phases for analysis of chiral structurally diverse biologically active compounds was evaluated in supercritical fluid chromatography using a set of 52 analytes. The chiral selectors immobilized on 2.5 μm silica particles were tris-(3,5-dimethylphenylcarmabate) derivatives of cellulose or amylose. The influence of the polysaccharide backbone, different organic modifiers, and different mobile phase additives on retention and enantioseparation was monitored. Conditions for fast baseline enantioseparation were found for the majority of the compounds. The success rate of baseline and partial enantioseparation with cellulose-based chiral stationary phase was 51.9% and 15.4%, respectively. Using amylose-based chiral stationary phase we obtained 76.9% of baseline enantioseparations and 9.6% of partial enantioseparations of the tested compounds. The best results on cellulose-based chiral stationary phase were achieved particularly with propane-2-ol and a mixture of isopropylamine and trifluoroacetic acid as organic modifier and additive to CO 2 , respectively. Methanol and basic additive isopropylamine were preferred on amylose-based chiral stationary phase. The complementary enantioselectivity of the cellulose- and amylose-based chiral stationary phases allows separation of the majority of the tested structurally different compounds. Separation systems were found to be directly applicable for analyses of biologically active compounds of interest. © 2017 Wiley Periodicals, Inc.

  14. Enantioselective Analytical- and Preparative-Scale Separation of Hexabromocyclododecane Stereoisomers Using Packed Column Supercritical Fluid Chromatography

    Directory of Open Access Journals (Sweden)

    Nicole Riddell

    2016-11-01

    Full Text Available Hexabromocyclododecane (HBCDD is an additive brominated flame retardant which has been listed in Annex A of the Stockholm Convention for elimination of production and use. It has been reported to persist in the environment and has the potential for enantiomer-specific degradation, accumulation, or both, making enantioselective analyses increasingly important. The six main stereoisomers of technical HBCDD (i.e., the (+ and (− enantiomers of α-, β-, and γ-HBCDD were separated and isolated for the first time using enantioselective packed column supercritical fluid chromatography (pSFC separation methods on a preparative scale. Characterization was completed using published chiral liquid chromatography (LC methods and elution profiles, as well as X-ray crystallography, and the isolated fractions were definitively identified. Additionally, the resolution of the enantiomers, along with two minor components of the technical product (δ- and ε-HBCDD, was investigated on an analytical scale using both LC and pSFC separation techniques, and changes in elution order were highlighted. Baseline separation of all HBCDD enantiomers was achieved by pSFC on an analytical scale using a cellulose-based column. The described method emphasizes the potential associated with pSFC as a green method of isolating and analyzing environmental contaminants of concern.

  15. Enantioselective Analytical- and Preparative-Scale Separation of Hexabromocyclododecane Stereoisomers Using Packed Column Supercritical Fluid Chromatography.

    Science.gov (United States)

    Riddell, Nicole; Mullin, Lauren Gayle; van Bavel, Bert; Ericson Jogsten, Ingrid; McAlees, Alan; Brazeau, Allison; Synnott, Scott; Lough, Alan; McCrindle, Robert; Chittim, Brock

    2016-11-10

    Hexabromocyclododecane (HBCDD) is an additive brominated flame retardant which has been listed in Annex A of the Stockholm Convention for elimination of production and use. It has been reported to persist in the environment and has the potential for enantiomer-specific degradation, accumulation, or both, making enantioselective analyses increasingly important. The six main stereoisomers of technical HBCDD (i.e., the (+) and (-) enantiomers of α-, β-, and γ-HBCDD) were separated and isolated for the first time using enantioselective packed column supercritical fluid chromatography (pSFC) separation methods on a preparative scale. Characterization was completed using published chiral liquid chromatography (LC) methods and elution profiles, as well as X-ray crystallography, and the isolated fractions were definitively identified. Additionally, the resolution of the enantiomers, along with two minor components of the technical product (δ- and ε-HBCDD), was investigated on an analytical scale using both LC and pSFC separation techniques, and changes in elution order were highlighted. Baseline separation of all HBCDD enantiomers was achieved by pSFC on an analytical scale using a cellulose-based column. The described method emphasizes the potential associated with pSFC as a green method of isolating and analyzing environmental contaminants of concern.

  16. Bidirectional enantioselective effects of the GABAB receptor agonist baclofen in two mouse models of excessive ethanol consumption.

    Science.gov (United States)

    Kasten, Chelsea R; Blasingame, Shelby N; Boehm, Stephen L

    2015-02-01

    The GABAB receptor agonist baclofen has been studied extensively in preclinical models of alcohol-use disorders, yet results on its efficacy have been uncertain. Racemic baclofen, which is used clinically, can be broken down into separate enantiomers of the drug. Baclofen has been shown to produce enantioselective effects in behavioral assays, including those modeling reflexive and sexual behavior. The current studies sought to characterize the enantioselective effects of baclofen in two separate models of ethanol consumption. The first was a Drinking-in-the-Dark procedure that provides "binge-like" ethanol access to mice by restricting access to a 2-h period, 3 h into the dark cycle. The second was a two-bottle choice procedure that utilized selectively bred High Alcohol Preferring 1 (HAP1) mice to model chronic ethanol access. HAP1 mice are selectively bred to consume pharmacologically relevant amounts of ethanol in a 24-h two-bottle choice paradigm. The results showed that baclofen yields enantioselective effects on ethanol intake in both models, and that these effects are bidirectional. Total ethanol intake was decreased by R(+)-baclofen, while total intake was increased by S(-)-baclofen in the binge-like and chronic drinking models. Whereas overall binge-like saccharin intake was significantly reduced by R(+)-baclofen, chronic intake was not significantly altered. S(-)-baclofen did not significantly alter saccharin intake. Neither enantiomer significantly affected locomotion during binge-like reinforcer consumption. Collectively, these results demonstrate that baclofen produces enantioselective effects on ethanol consumption. More importantly, the modulation of consumption is bidirectional. The opposing enantioselective effects may explain some of the variance seen in published baclofen literature. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Interspecies differences in the enantioselectivity of epoxide hydrolases in Cryptococcus laurentii (Kufferath) C.E. Skinner and Cryptococcus podzolicus (Bab'jeva & Reshetova) Golubev

    CSIR Research Space (South Africa)

    Botes, AL

    2005-01-01

    Full Text Available Isolates representing Cryptococcus laurentii and Cryptococcus podzolicus, originating from soil of a heath land indigenous to South Africa, were screened for the presence of enantioselective epoxide hydrolases for 2, 2-disubstituted epoxides...

  18. Recyclable enantioselective catalysts based on copper(II) complexes of 2-(pyridine-2-yl)imidazolidine-4-thione: their application in asymmetric Henry reactions

    Czech Academy of Sciences Publication Activity Database

    Nováková, G.; Drabina, P.; Frumarová, Božena; Sedlák, M.

    2016-01-01

    Roč. 358, č. 15 (2016), s. 2541-2552 ISSN 1615-4150 Institutional support: RVO:61389013 Keywords : asymmetric catalysis * enantioselectivity * heterogeneous catalysis Subject RIV: CC - Organic Chemistry Impact factor: 5.646, year: 2016

  19. Observation of the Strong Electronic Coupling in Near-Infrared-Absorbing Tetraferrocene aza-Dipyrromethene and aza-BODIPY with Direct Ferrocene-α- and Ferrocene-β-Pyrrole Bonds: Toward Molecular Machinery with Four-Bit Information Storage Capacity.

    Science.gov (United States)

    Zatsikha, Yuriy V; Holstrom, Cole D; Chanawanno, Kullapa; Osinski, Allen J; Ziegler, Christopher J; Nemykin, Victor N

    2017-01-17

    The 1,3,7,9-tetraferrocenylazadipyrromethene (3) and the corresponding 1,3,5,7-tetraferrocene aza-BODIPY (4) were prepared via three and four synthetic steps, respectively, starting from ferrocenecarbaldehyde using the chalcone-type synthetic methodology. The novel tetra-iron compounds have ferrocene groups directly attached to both the α- and the β-pyrrolic positions, and the shortest Fe-Fe distance determined by X-ray crystallography for 3 was found to be ∼6.98 Å. These new compounds were characterized by UV-vis, nuclear magnetic resonance, and high-resolution electrospray ionization mass spectrometry methods, while metal-metal couplings in these systems were probed by electro- and spectroelectrochemistry, chemical oxidations, and Mössbauer spectroscopy. Electrochemical data are suggestive of the well-separated stepwise oxidations of all four ferrocene groups in 3 and 4, while spectroelectrochemical and chemical oxidation experiments allowed for characterization of the mixed-valence forms in the target compounds. Intervalence charge-transfer band analyses indicate that the mixed-valence [3] + and [4] + complexes belong to the weakly coupled class II systems in the Robin-Day classification. This interpretation was further supported by Mössbauer spectroscopy in which two individual doublets for Fe(II) and Fe(III) centers were observed in room-temperature experiments for the mixed-valence [3] n+ and [4] n+ species (n = 1-3). The electronic structure, redox properties, and UV-vis spectra of new systems were correlated with Density Functional Theory (DFT) and time-dependent DFT calculations (TDDFT), which are suggestive of a ferrocene-centered highest occupied molecular orbital and chromophore-centered lowest unoccupied molecular orbital in 3 and 4 as well as predominant spin localization at the ferrocene fragment attached to the α-pyrrolic positions in [3] + and [4] + .

  20. Treatment of Donor Cells and Reconstructed Embryos with a Combination of Trichostatin-A and 5-aza-2'-Deoxycytidine Improves the Developmental Competence and Quality of Buffalo Embryos Produced by Handmade Cloning and Alters Their Epigenetic Status and Gene Expression.

    Science.gov (United States)

    Saini, Monika; Selokar, Naresh L; Agrawal, Himanshu; Singla, Suresh Kumar; Chauhan, Manmohan Singh; Manik, Radheysham S; Palta, Prabhat

    2017-06-01

    The application of cloning technology on a large scale is limited by very low offspring rate primarily due to aberrant or incomplete epigenetic reprogramming. Trichostatin A (TSA), a histone deacetylase inhibitor, and 5-aza-2'-deoxycytidine (5-aza-dC), an inhibitor of DNA methyltransferases, are widely used for altering the epigenetic status of cloned embryos. We optimized the doses of these epigenetic modifiers for production of buffalo embryos by handmade cloning and examined whether combined treatment with these epigenetic modifiers offered any advantage over treatment with the individual epigenetic modifier. Irrespective of whether donor cells or reconstructed embryos or both were treated with 50 nM TSA +7.5 nM 5-aza-dC, (1) the blastocyst rate was significantly higher (71.6 ± 3.5, 68.3 ± 2.6, and 71.8 ± 2.4, respectively, vs. 43.1 ± 3.4 for controls, p cells or reconstructed embryos or both with the combination of TSA +5-aza-dC. Therefore, there is no advantage in treating both donor cells and reconstructed embryos when the combination of TSA and 5-aza-dC is used.

  1. Enantioselective organocatalyzed Oxa-Michael-Aldol cascade reactions: Construction of chiral 4H-chromenes with a trifluoromethylated tetrasubstituted carbon stereocenter

    KAUST Repository

    Zhang, Jing

    2015-03-13

    The first organocatalytic asymmetric synthesis of 4H-chromenes bearing a trifluoromethylated tetrasubstituted carbon center is presented. Chiral secondary amines promote the oxa-Michael-aldol cascade reaction between alkynals and 2-trifluoroacetylphenols via iminium-allenamine activation to produce pharmaceutically important heterocycles with excellent enantioselectivities. The proposed reaction can be scaled-up easily with maintenance of the excellent enantioselectivity. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Regio-, Diastereo-, and Enantioselective Nitroso-Diels-Alder Reaction of 1,3-Diene-1-carbamates Catalyzed by Chiral Phosphoric Acids.

    Science.gov (United States)

    Pous, Jonathan; Courant, Thibaut; Bernadat, Guillaume; Iorga, Bogdan I; Blanchard, Florent; Masson, Géraldine

    2015-09-23

    Chiral phosphoric acid-catalyzed asymmetric nitroso-Diels-Alder reaction of nitrosoarenes with carbamate-dienes afforded cis-3,6-disubstituted dihydro-1,2-oxazines in high yields with excellent regio-, diastereo-, and enantioselectivities. Interestingly, we observed that the catalyst is able not only to control the enantioselectivity but also to reverse the regioselectivity of the noncatalyzed nitroso-Diels-Alder reaction. The regiochemistry reversal and asynchronous concerted mechanism were confirmed by DFT calculations.

  3. Stereoselective reactions. XXXII. Enantioselective deprotonation of 4-tert-butylcyclohexanone by fluorine-containing chiral lithium amides derived from 1-phenylethylamine and 1-(1-naphthyl)ethylamine.

    Science.gov (United States)

    Aoki, K; Koga, K

    2000-04-01

    Enantioselective deprotonation of 4-tert-butylcyclohexanone was examined using 1-phenylethylamine- and 1-(1-naphthyl)ethylamine-derived chiral lithium amides having an alkyl or a fluoroalkyl substituent at the amide nitrogen. The lithium amides having a 2,2,2-trifluoroethyl group on the amide nitrogen are easily accessible in both enantiomeric forms, and were found to induce good enantioselectivity in the present reaction.

  4. A DFT study on the mechanisms for the cycloaddition reactions between 1-aza-2-azoniaallene cations and acetylenes.

    Science.gov (United States)

    Wang, Jing-mei; Li, Zhi-ming; Wang, Quan-rui; Tao, Feng-gang

    2013-01-01

    The mechanisms of cycloaddition reactions between 1-aza-2-azoniaallene cations 1 and acetylenes 2 have been investigated using the global electrophilicity and nucleophilicity of the corresponding reactants as global reactivity indexes defined within the conceptual density functional theory. The reactivity and regioselectivity of these reactions were predicted by analysis of the energies, geometries, and electronic nature of the transition state structures. The theoretical results revealed that the reaction features a tandem process: an ionic 1,3-dipolar cycloaddition to produce the cycloadducts 3 H-pyrazolium salts 3 followed by a [1,2]-shift affording the thermodynamically more stable adducts 4 or 5. The mechanism of the cycloaddition reactions can be described as an asynchronous concerted pathway with reverse electron demand. The model reaction has also been investigated at the QCISD/6-31++G(d,p) and CCSD(T)/6-31++G(d,p)//B3LYP/6-31++G(d,p) levels as well as by the DFT. The polarizable continuum model, at the B3LYP/6-31++G(d,p) level of theory, was used to study solvent effects on all the studied reactions. In solvent dichloromethane, all the initial cycloadducts 3 were obtained via direct ionic process as the result of the solvent effect. The consecutive [1,2]-shift reaction, in which intermediates 3 are rearranged to the five-membered heterocycles 4/5, is proved to be a kinetically controlled reaction, and the regioselectivity can be modulated by varying the migrant. The LOL function and RDG function based on localized electron analysis were used to analysis the covalent bond and noncovalent interactions in order to unravel the mechanism of the title reactions.

  5. The epigenetic modifiers 5-aza-2'-deoxycytidine and trichostatin A influence adipocyte differentiation in human mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    J. Zych

    2013-05-01

    Full Text Available Epigenetic mechanisms such as DNA methylation and histone modification are important in stem cell differentiation. Methylation is principally associated with transcriptional repression, and histone acetylation is correlated with an active chromatin state. We determined the effects of these epigenetic mechanisms on adipocyte differentiation in mesenchymal stem cells (MSCs derived from bone marrow (BM-MSCs and adipose tissue (ADSCs using the chromatin-modifying agents trichostatin A (TSA, a histone deacetylase inhibitor, and 5-aza-2′-deoxycytidine (5azadC, a demethylating agent. Subconfluent MSC cultures were treated with 5, 50, or 500 nM TSA or with 1, 10, or 100 µM 5azadC for 2 days before the initiation of adipogenesis. The differentiation was quantified and expression of the adipocyte genes PPARG and FABP4 and of the anti-adipocyte gene GATA2 was evaluated. TSA decreased adipogenesis, except in BM-MSCs treated with 5 nM TSA. Only treatment with 500 nM TSA decreased cell proliferation. 5azadC treatment decreased proliferation and adipocyte differentiation in all conditions evaluated, resulting in the downregulation of PPARG and FABP4 and the upregulation of GATA2. The response to treatment was stronger in ADSCs than in BM-MSCs, suggesting that epigenetic memories may differ between cells of different origins. As epigenetic signatures affect differentiation, it should be possible to direct the use of MSCs in cell therapies to improve process efficiency by considering the various sources available.

  6. Epigenetic modulation of AR gene expression in prostate cancer DU145 cells with the combination of sodium butyrate and 5'-Aza-2'-deoxycytidine.

    Science.gov (United States)

    Fialova, Barbora; Luzna, Petra; Gursky, Jan; Langova, Katerina; Kolar, Zdenek; Trtkova, Katerina Smesny

    2016-10-01

    The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. Castration-resistant prostate cancer (CRPC) is a consequence of androgen deprivation therapy. Unchecked CRPC followed by metastasis is lethal. Some CRPCs show decreased AR gene expression due to epigenetic mechanisms such as DNA methylation and histone deacetylation. The aim of this study was to epigenetically modulate the methylated state of the AR gene leading to targeted demethylation and AR gene expression in androgen-independent human prostate cancer DU145 cell line, representing the CRPC model with very low or undetectable AR levels. The cell treatment was based on single and combined applications of two epigenetic inhibitors, sodium butyrate (NaB) as histone deacetylases inhibitor and 5'-Aza-2'-deoxycytidine (Aza-dC) as DNA methyltransferases inhibitor. We found that the Aza-dC in combination with NaB may help reduce the toxicity of higher NaB concentrations in cancer cells. In normal RWPE-1 cells and even stronger in cancer DU145 cells, the combined treatment induced both AR gene expression on the mRNA level and increased histone H4 acetylation in AR gene promoter. Also activation and maintenance of G2/M cell cycle arrest and better survival in normal RWPE-1 cells compared to cancer DU145 cells were observed after the treatments. These results imply the selective toxicity effect of both inhibitors used and their potentially more effective combined use in the epigenetic therapy of prostate cancer patients.

  7. Organoboron compounds. Communication 417. Crystal and molecular structure of 4-acetoxy-4-butyl-2-methyl-3-phenyl1,4-dihydro-1-aza-3-azonia-4-boratanaphthalene

    International Nuclear Information System (INIS)

    Vorontsova, L.G.; Boldyraeva, O.G.; Chizhov, O.S.; Dorokhov, V.A.; Mikhailov, B.M.

    1985-01-01

    In order to elucidate the structure of boronitrogen heterocycles, an x-ray diffraction structural analysis was carried out on the adduct of 4-butyl-2-methyl-3-phenyl-3,4-dihydro-4-boraquinazoline with acetic acid, namely, 4-acetoxy-4-butyl-2-methyl3-phenyl-1,4-dihydro-1-aza-3-azonia-4-boratanaphthalene (DAABN). The molecular structure of DAABN is given, and the atomic coordinates and bond lengths and angles are presented in tables. the boron atom has distorted tetrahedral configuration

  8. Hydrosilylation induced by N→Si intramolecular coordination: spontaneous transformation of organosilanes into 1-aza-silole-type molecules in the absence of a catalyst.

    Science.gov (United States)

    Novák, Miroslav; Dostál, Libor; Alonso, Mercedes; De Proft, Frank; Růžička, Aleš; Lyčka, Antonín; Jambor, Roman

    2014-02-24

    Our attempts to synthesize the N→Si intramolecularly coordinated organosilanes Ph2 L(1) SiH (1 a), PhL(1) SiH2 (2 a), Ph2 L(2) SiH (3 a), and PhL(2) SiH2 (4 a) containing a CH=N imine group (in which L(1) is the C,N-chelating ligand {2-[CH=N(C6 H3 -2,6-iPr2)]C6 H4}(-) and L(2) is {2-[CH=N(tBu)]C6 H4}(-)) yielded 1-[2,6-bis(diisopropyl)phenyl]-2,2-diphenyl-1-aza-silole (1), 1-[2,6-bis(diisopropyl)phenyl]-2-phenyl-2-hydrido-1-aza-silole (2), 1-tert-butyl-2,2-diphenyl-1-aza-silole (3), and 1-tert-butyl-2-phenyl-2-hydrido-1-aza-silole (4), respectively. Isolated organosilicon amides 1-4 are an outcome of the spontaneous hydrosilylation of the CH=N imine moiety induced by N→Si intramolecular coordination. Compounds 1-4 were characterized by NMR spectroscopy and X-ray diffraction analysis. The geometries of organosilanes 1 a-4 a and their corresponding hydrosilylated products 1-4 were optimized and fully characterized at the B3LYP/6-31++G(d,p) level of theory. The molecular structure determination of 1-3 suggested the presence of a Si-N double bond. Natural bond orbital (NBO) analysis, however, shows a very strong donor-acceptor interaction between the lone pair of the nitrogen atom and the formal empty p orbital on the silicon and therefore, the calculations show that the Si-N bond is highly polarized pointing to a predominantly zwitterionic Si(+) N(-) bond in 1-4. Since compounds 1-4 are hydrosilylated products of 1 a-4 a, the free energies (ΔG298), enthalpies (ΔH298), and entropies (ΔH298) were computed for the hydrosilylation reaction of 1 a-4 a with both B3LYP and B3LYP-D methods. On the basis of the very negative ΔG298 values, the hydrosilylation reaction is highly exergonic and compounds 1 a-4 a are spontaneously transformed into 1-4 in the absence of a catalyst. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Tetrabutylammonium Bromide Media Aza-Michael Addition of 1,2,3,6-Tetrahydrophthalimide to Symmetrical Fumaric Esters and Acrylic Esters under Solvent-Free Conditions

    Directory of Open Access Journals (Sweden)

    Mohammadreza Zamanloo

    2010-10-01

    Full Text Available The aza-Michael addition of 1,2,3,6-tetrahydrophthalimide with symmetrical fumaric esters has been performed efficiently in a solvent-free system at 100 °C and using 1,4-diazabicyclo[2.2.2]octane (DABCO as a base in the presence of tetrabutylammonium bromide (TBAB. The products were obtained in good to high yields within 2.5-7.0 h. This reaction worked well on linear alkyl fumarates and was not effective with nonlinear alkyl fumarates. Although the reaction was also applicable to acrylates such as n-butyl acrylate, methacrylates and crotonates were not suitable Michael acceptors for this reaction.

  10. 4-Aza-1-azoniabicyclo?[2.2.2]octa?ne?2-amino?benzoate?2-amino?benzoic acid (1/1/1)

    OpenAIRE

    Arman, Hadi D.; Kaulgud, Trupta; Tiekink, Edward R. T.

    2011-01-01

    A 4-aza-1-azoniabicyclo[2.2.2]octane cation, a 2-aminobenzoate anion and a neutral 2-aminobenzoic acid molecule comprise the asymmetric unit of the title compound, C6H13N2+·C7H6NO2−·C7H7NO2. An intramolecular N—H...O hydrogen bond occurs in the anion and in the neutral 2-aminobenzoic acid molecule. The cation provides a charge-assisted N—H...O hydrogen bond to the anion, and the 2-aminobenzoic acid molecule forms an O—H...N hydrogen bo...

  11. Expedient synthesis of fused azepine derivatives using a sequential rhodium(II)-catalyzed cyclopropanation/1-aza-Cope rearrangement of dienyltriazoles.

    Science.gov (United States)

    Schultz, Erica E; Lindsay, Vincent N G; Sarpong, Richmond

    2014-09-08

    A general method for the formation of fused dihydroazepine derivatives from 1-sulfonyl-1,2,3-triazoles bearing a tethered diene is reported. The process involves an intramolecular cyclopropanation of an α-imino rhodium(II) carbenoid, leading to a transient 1-imino-2-vinylcyclopropane intermediate which rapidly undergoes a 1-aza-Cope rearrangement to generate fused dihydroazepine derivatives in moderate to excellent yields. The reaction proceeds with similar efficiency on gram scale. The use of catalyst-free conditions leads to the formation of a novel [4.4.0] bicyclic heterocycle. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Aza-peptidyl Michael acceptors. A new class of potent and selective inhibitors of asparaginyl endopeptidases (legumains) from evolutionarily diverse pathogens

    Czech Academy of Sciences Publication Activity Database

    Götz, M. G.; James, K. E.; Hansell, E.; Dvořák, J.; Seshaadri, A.; Sojka, Daniel; Kopáček, Petr; McKerrow, J. H.; Caffrey, C. R.; Powers, J. C.

    2008-01-01

    Roč. 51, č. 9 (2008), s. 2816-2832 ISSN 0022-2623 R&D Projects: GA MŠk(CZ) LC06009; GA ČR GA206/06/0865 Grant - others:The National Institute of Allergy and Infectious Diseases(US) AI053247; National Institute of General Medical Sciences(US) GM54404; National Institute of General Medical Sciences(US) GM61964 Institutional research plan: CEZ:AV0Z60220518 Keywords : legumain * IrAE * aza-peptide Michael acceptors Subject RIV: ED - Physiology Impact factor: 4.898, year: 2008

  13. Nano-organocatalyst: magnetically retrievable ferrite-anchored glutathione for microwave-assisted Paal–Knorr reaction, aza-Michael addition, and pyrazole synthesis

    KAUST Repository

    Polshettiwar, Vivek; Varma, Rajender S.

    2010-01-01

    Postsynthetic Surface modification of magnetic nanoparticles by glutathione imparts desirable chemical functionality and enables the generation of catalytic sites on the surfaces of ensuing organocatalysts. In this article, we discuss the developments, unique activity, and high selectivity of nano-organocatalysts for microwave-assisted Paal-Knorr reaction, aza-Michael addition, and pyrazole synthesis. Their insoluble character Coupled with paramagnetic nature enables easy separation of these nano-catalysts from the reaction mixture using external magnet, which eliminates the requirement of catalyst filtration. Published by Elsevier Ltd.

  14. Spin-Center Shift-Enabled Direct Enantioselective α-Benzylation of Aldehydes with Alcohols.

    Science.gov (United States)

    Nacsa, Eric D; MacMillan, David W C

    2018-03-07

    Nature routinely engages alcohols as leaving groups, as DNA biosynthesis relies on the removal of water from ribonucleoside diphosphates by a radical-mediated "spin-center shift" (SCS) mechanism. Alcohols, however, remain underused as alkylating agents in synthetic chemistry due to their low reactivity in two-electron pathways. We report herein an enantioselective α-benzylation of aldehydes using alcohols as alkylating agents based on the mechanistic principle of spin-center shift. This strategy harnesses the dual activation modes of photoredox and organocatalysis, engaging the alcohol by SCS and capturing the resulting benzylic radical with a catalytically generated enamine. Mechanistic studies provide evidence for SCS as a key elementary step, identify the origins of competing reactions, and enable improvements in chemoselectivity by rational photocatalyst design.

  15. Low-Mode Conformational Search Method with Semiempirical Quantum Mechanical Calculations: Application to Enantioselective Organocatalysis.

    Science.gov (United States)

    Kamachi, Takashi; Yoshizawa, Kazunari

    2016-02-22

    A conformational search program for finding low-energy conformations of large noncovalent complexes has been developed. A quantitatively reliable semiempirical quantum mechanical PM6-DH+ method, which is able to accurately describe noncovalent interactions at a low computational cost, was employed in contrast to conventional conformational search programs in which molecular mechanical methods are usually adopted. Our approach is based on the low-mode method whereby an initial structure is perturbed along one of its low-mode eigenvectors to generate new conformations. This method was applied to determine the most stable conformation of transition state for enantioselective alkylation by the Maruoka and cinchona alkaloid catalysts and Hantzsch ester hydrogenation of imines by chiral phosphoric acid. Besides successfully reproducing the previously reported most stable DFT conformations, the conformational search with the semiempirical quantum mechanical calculations newly discovered a more stable conformation at a low computational cost.

  16. 3,3'-Diaryl-BINOL phosphoric acids as enantioselective extractants of benzylic primary amines.

    Science.gov (United States)

    Verkuijl, Bastiaan J V; de Vries, Johannes G; Feringa, Ben L

    2011-01-01

    We report that 3,3'-diaryl-BINOL phosphoric acids are effective enantioselective extractants in chiral separation methods based on reactive liquid-liquid extraction. These new extractants are capable of separating racemic benzylic primary amine substrates. The effect of the nature of the substituents at the 3,3'-positions of the host were examined as well as the structure of the substrate, together with important parameters such as the organic solvent, the pH of the aqueous phase, and the host stoichiometry. Titration of the substrate with the host was monitored by FTIR, NMR, UV-Vis, and CD spectroscopy, which provided insight into the structure of the host-guest complex involved in extraction. Copyright © 2010 Wiley-Liss, Inc.

  17. Enantioselective disposition of omeprazole, pantoprazole, and lansoprazole in a same Brazilian subjects group.

    Science.gov (United States)

    Cassiano, Neila M; Oliveira, Regina V; Bernasconi, Gilberto C R; Cass, Quezia B

    2012-04-01

    This work reports the result of the enantioselective disposition of pantoprazole, omeprazole, and lansoprazole in a same group of Brazilian health subjects. Ten nongenotyped healthy subjects were used for this study. Each subject received a single oral dose of 80 mg of pantoprazole, 40 mg of omeprazole, and 30 mg of lansoprazole, and the plasma concentrations of the enantiomers were measured for 8 h postdose. For pantoprazole and omeprazole, among the 10 volunteers investigated, only one volunteer (Subject # 4) presented higher plasma concentrations of the (+)-enantiomer than those of (-)-enantiomer. Nevertheless, the area under the concentration-time curve of the (+)-lansoprazole was higher than those the (-)-lansoprazole for all subjects. The comparison of proton pump inhibitors' enantiomers disposition from a single group volunteer demonstrated that pantoprazole and omeprazole can be used to differentiate extensive from poor CYP2C19 metabolizer while lansoprazole cannot do it. Copyright © 2011 Wiley Periodicals, Inc.

  18. Calix[4]arene-Based Enantioselective Fluorescent Sensors for the Recognition of N-Acetyl-aspartate

    Institute of Scientific and Technical Information of China (English)

    QING Guang-Yan; CHEN Zhi-Hong; WANG Feng; YANG Xi; MENG Ling-Zhi; HE Yong-Bing

    2008-01-01

    Two-armed chiral anion receptors (1 and 2), calix[4]arenes bearing dansyl fluorophore and (1R,2R)- or(1S,2S)-1,2-diphenylethylenediamine binding sites, were prepared and examined for their chiral amino acid anion binding abilities by the fluorescence spectra in dimethylsulfoxide (DMSO). The results of non-linear curve fitting indicate that 1 or 2 forms a 1 : 1 stoichiometry complex with N-acetyl-L-or D-aspartate by multiple hydrogen bonding interactions, exhibiting good enantioselective fluorescent recognition for the enantiomers of N-acetyl-as-partate, [receptor 1: Kass(D)/Kass(L)=6.74; receptor 2: Kass(L)/Kass(D)=6.48]. The clear fluorescent response difference indicates that receptors 1 and 2 could be used as a fluorescent chemosensor for N-Acetyl-aspartate.

  19. Enantioanalysis of S-deprenyl using enantioselective, potentiometric membrane electrodes based on C60 derivatives

    International Nuclear Information System (INIS)

    Stefan-van Staden, Raluca-Ioana

    2010-01-01

    Enantioselective, potentiometric membrane electrodes based on (1,2-methanofullerene C 60 )-61-carboxylic acid, diethyl (1,2-methanofullerene C 60 )-61-61-dicarboxylate and tert-butyl (1,2-methanofullerene C 60 )-61-carboxylic acid were proposed for the enantioanalysis of S-deprenyl in pharmaceutical compounds. Molecular modeling calculations were performed to prove the reliability of the proposed electrodes. The different characteristics involved in this analysis were explained, namely (i) the stability of each molecule using total energy, hardness and dipole moment, and (ii) the explanation of the mechanism of interaction using intermolecular forces (moderate hydrogen bond interactions), atomic charges and electrostatic potential. Electronic structures as well as molecular interaction have been investigated using Hartree-Fock theory, 3-21G(*) basis set. Stability and feasibility of all the generated structures were supported by their respective energy minima and fundamental frequencies.

  20. Highly Enantioselective Production of (R-Halohydrins with Whole Cells of Rhodotorula rubra KCh 82 Culture

    Directory of Open Access Journals (Sweden)

    Tomasz Janeczko

    2014-12-01

    Full Text Available Biotransformation of ten α-haloacetophenones in the growing culture of the strain Rhodotorula rubra KCh 82 has been carried out. Nine of the substrates underwent an effective enantioselective reduction to the respective (R-alcohols according to Prelog’s rule, with the exception of 2-chloro-1,2-diphenylethan-1-one that was not transformed by this strain. The expected reduction proceeded without dehalogenation, leading to the respective (R-halohydrins in high yields. The use of this biocatalyst yielded (R-2-bromo-1-phenyl-ethan-1-ol (enantiomeric excess (ee = 97% and its derivatives: 4'-Bromo- (ee = 99%; 4'-Chloro- (ee > 99%; 4'-Methoxy- (ee = 96%; 3'-Methoxy- (ee = 93%; 2'-Methoxy- (ee = 98%. There were also obtained and characterized 2,4'-dichloro-, 2,2',4'-trichloro- and 2-chloro-4'-fluoro-phenyetan-1-ol with >99% of enantiomeric excesses.

  1. Highly enantioselective production of (R)-halohydrins with whole cells of Rhodotorula rubra KCh 82 culture.

    Science.gov (United States)

    Janeczko, Tomasz; Dymarska, Monika; Kostrzewa-Susłow, Edyta

    2014-12-04

    Biotransformation of ten α-haloacetophenones in the growing culture of the strain Rhodotorula rubra KCh 82 has been carried out. Nine of the substrates underwent an effective enantioselective reduction to the respective (R)-alcohols according to Prelog's rule, with the exception of 2-chloro-1,2-diphenylethan-1-one that was not transformed by this strain. The expected reduction proceeded without dehalogenation, leading to the respective (R)-halohydrins in high yields. The use of this biocatalyst yielded (R)-2-bromo-1-phenyl-ethan-1-ol (enantiomeric excess (ee) = 97%) and its derivatives: 4'-Bromo- (ee = 99%); 4'-Chloro- (ee > 99%); 4'-Methoxy- (ee = 96%); 3'-Methoxy- (ee = 93%); 2'-Methoxy- (ee = 98%). There were also obtained and characterized 2,4'-dichloro-, 2,2',4'-trichloro- and 2-chloro-4'-fluoro-phenyetan-1-ol with >99% of enantiomeric excesses.

  2. Enantioselective synthesis of no-carrier added (NCA) 6-[18F]Fluoro-L-Dopa

    International Nuclear Information System (INIS)

    Duanzhi Yin; Lan Zhang; Yongxian Wang; Ganghua Tang; First Military Medical Univ., Guangzhou; Xiaolan Tang

    2003-01-01

    6-[ 18 F]Fluoro-L-Dopa (6-FDOPA) is the analogue of L-Dopa, the biosynthesis precursor for dopamine. As a PET tracer, it was widely applied for the presynaptic dopamine function studies in human brain. The application of a chiral phase-transfer-catalyst (PTC) in enantioselective synthesis of N.C.A. 6-[ 18 F]Fluoro-L-Dopa has been developed recently. An improved procedure was described. The labeling precursor (6-Trimethylammoniumveratraldehyde Triflate) and PTC (O-Allyl-N-(9)-anthracenylcinchonidinium Bromide) were synthesized. A successful synthesis route was developed for the preparation of 6-[ 18 F]Fluoro-L-Dopa with high radiochemical yields (4-9%, decay uncorrected) and short synthesis time(80min). The radiochemical purity was over 99% and no D-isomer was detected by HPLC analysis using a chiral mobile phase. (author)

  3. Enantioselective analysis of ibuprofen and its biotransformation products in water/sediment systems,

    DEFF Research Database (Denmark)

    Sundström, Maria; Escola, Monica; Radke, Michael

    2015-01-01

    of the sediments in the aquatic systems has neither been taken in account previously. In this study, four water-sediment systems were chosen according to anthropogenic exposure and sediment conditions. A low anthropogenic impact lake (Largen), a river receiving wastewater (Fyrisån) and two sediments (anoxic......As ibuprofen degrades enantioselectively in activated sludge, the same process is assumed to occur in surface lake-water and in river-water based biofilms. Yet, the effects of the wastewater inflow, containing non-racemic ibuprofen, into natural systems have never been studied. The role......-7 days in Tvären and B1 respectively. Largen sediments, not impacted by wastewater, degraded ibuprofen faster than Fyrisån sediments did. Yet, these two sediments sediments showed no significant difference with respect to the degradation rates of the ibuprofen enantiomers. A connection between wastewater...

  4. Enantioselective rhodium/ruthenium photoredox catalysis en route to chiral 1,2-aminoalcohols.

    Science.gov (United States)

    Ma, Jiajia; Harms, Klaus; Meggers, Eric

    2016-08-09

    A rhodium-based chiral Lewis acid catalyst combined with [Ru(bpy)3](PF6)2 as a photoredox sensitizer allows for the visible-light-activated redox coupling of α-silylamines with 2-acyl imidazoles to afford, after desilylation, 1,2-amino-alcohols in yields of 69-88% and with high enantioselectivity (54-99% ee). The reaction is proposed to proceed via an electron exchange between the α-silylamine (electron donor) and the rhodium-chelated 2-acyl imidazole (electron acceptor), followed by a stereocontrolled radical-radical reaction. Substrate scope and control experiments reveal that the trimethylsilyl group plays a crucial role in this reductive umpolung of the carbonyl group.

  5. Highly enantioselective rhodium(I)-catalyzed carbonyl carboacylations initiated by C-C bond activation.

    Science.gov (United States)

    Souillart, Laetitia; Cramer, Nicolai

    2014-09-01

    The lactone motif is ubiquitous in natural products and pharmaceuticals. The Tishchenko disproportionation of two aldehydes, a carbonyl hydroacylation, is an efficient and atom-economic access to lactones. However, these reaction types are limited to the transfer of a hydride to the accepting carbonyl group. The transfer of alkyl groups enabling the formation of CC bonds during the ester formation would be of significant interest. Reported herein is such asymmetric carbonyl carboacylation of aldehydes and ketones, thus affording complex bicyclic lactones in excellent enantioselectivities. The rhodium(I)-catalyzed transformation is induced by an enantiotopic CC bond activation of a cyclobutanone and the formed rhodacyclic intermediate reacts with aldehyde or ketone groups to give highly functionalized lactones. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7.

    Science.gov (United States)

    Fang, Zhong-Ze; Wang, Haina; Cao, Yun-Feng; Sun, Dong-Xue; Wang, Li-Xuan; Hong, Mo; Huang, Ting; Chen, Jian-Xing; Zeng, Jia

    2015-03-01

    UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation conjugation reaction plays an important role in the elimination of many important clinical drugs and endogenous substances. The present study aims to investigate the enantioselective inhibition of carprofen towards UGT isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation mixture was used to screen the inhibition potential of (R)-carprofen and (S)-carprofen towards multiple UGT isoforms. The results showed that (S)-carprofen exhibited stronger inhibition potential than (R)-carprofen towards UGT2B7. However, no significant difference was observed for the inhibition of (R)-carprofen and (S)-carprofen towards other UGT isoforms. Furthermore, the inhibition kinetic behavior was compared for the inhibition of (S)-carprofen and (R)-carprofen towards UGT2B7. A Lineweaver-Burk plot showed that both (S)-carprofen and (R)-carprofen exhibited competitive inhibition towards UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameter (Ki ) was calculated to be 7.0 μM and 31.1 μM for (S)-carprofen and (R)-carprofen, respectively. Based on the standard for drug-drug interaction, the threshold for (S)-carprofen and (R)-carprofen to induce a drug-drug interaction is 0.7 μM and 3.1 μM, respectively. In conclusion, enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7 was demonstrated in the present study. Using the in vitro inhibition kinetic parameter, the concentration threshold of (S)-carprofen and (R)-carprofen to possibly induce the drug-drug interaction was obtained. Therefore, clinical monitoring of the plasma concentration of (S)-carprofen is more important than (R)-carprofen to avoid a possible drug-drug interaction between carprofen and the drugs mainly undergoing UGT2B7-catalyzed metabolism. © 2014 Wiley Periodicals, Inc.

  7. Enantioselective Degradation and Chiral Stability of Metalaxyl-M in Tomato Fruits.

    Science.gov (United States)

    Jing, Xu; Yao, Guojun; Wang, Peng; Liu, Donghui; Qi, Yanli; Zhou, Zhiqiang

    2016-05-01

    Metalaxyl is an important chiral acetanilide fungicide, and the activity almost entirely originates from the R-enantiomer. Racemic metalaxyl has been gradually replaced by the enantiopure R-enantiomer (metalaxyl-M). In this study a chiral residue analysis method for metalaxyl and the metabolite metalaxyl acid was set up based on high-performance liquid chromatography tandem mass spectroscopy (HPLC-MS/MS). The enantioselective degradation and chiral stability of metalaxyl-M in tomato fruits in two geographically distinct regions of China (Heilongjiang and Hunan Province) were evaluated and the enantioselectivity of metalaxyl acid was also investigated. Tomato plants grew under field conditions with a one-time spray application of metalaxyl-M wettable powder. It was found that R-metalaxyl was not chirally stable and the inactive S-metalaxyl was detected in tomato fruits. At day 40, S-metalaxyl derived from R-metalaxyl accounted for 32% and 26% of the total amount of metalaxyl, respectively. The metabolites R-metalaxyl acid and S-metalaxyl acid were both observed in tomato, and the ratio of S-metalaxyl acid to the sum of S- and R-metalaxyl acid was 36% and 28% at day 40, respectively. For both metalaxyl and metalaxyl acid, the half-life of the S-enantiomer was longer than the R-enantiomer. The results indicated that the enantiomeric conversion should be considered in the bioactivity evaluation and environmental pollution assessment. Chirality 28:382-386, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. Enantioselective toxicities of chiral ionic liquids 1-alkyl-3-methyl imidazolium tartrate on Scenedesmus obliquus.

    Science.gov (United States)

    Liu, Huijun; Zhang, Xiaoqiang; Dong, Ying; Chen, Caidong; Zhu, Shimin; Ma, Xiangjuan

    2015-12-01

    Ionic liquids (ILs) are being used in various industries during the last few decades, while the good solubility and high stability of ILs may pose a potential threat to the aquatic environment. Effect of chiral ionic liquids (CILs) 1-alkyl-3-methyl imidazolium tartrate (RMIM T) on Scenedesmus obliquus (S.obliquus) was studied. The growth rate inhibition and cell membrane permeability increased with increasing RMIM T concentration and increasing alkyl chain lengths. The IC50 values of D-(-)-tartrate 1-hexyl-3-methyl imidazolium (D-(-)-HMIM T) were 28.30, 12.23,10.15 and 14.41 mg/L, respectively, at 24, 48, 72 and 96h. While that of L-(+)-tartrate 1-hexyl-3-methyl imidazolium (L-(+)-HMIM T) were 15.97, 7.91, 9.43 and 12.04 mg/L respectively. The concentration of chl a, chl b and chl (a+b) decreased with increasing RMIM T concentration. The chlorophyll fluorescence parameters (F0, Fv/Fm, Fv/F0, Y(II), ETR and NPQ) were affected by RMIM T, indicating that the RMIM T will damage the PSII, inhibit the transmission of excitation energy, decrease the efficiency of photosynthesis. The results showed that there were enantioselective toxicity of RMIM T to algae, and the toxicity of L-(+)-RMIM T was greater than that of D-(-)-RMIM T, but the enantioselective difference becomes smaller with increasing exposure time, and with the increasing carbon chain length of cation, indicating that cation properties may have a larger effect on toxicity than anion properties. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Enantioselective assay for therapeutic drug monitoring of eslicarbazepine acetate: no interference with carbamazepine and its metabolites.

    Science.gov (United States)

    Alves, Gilberto; Fortuna, Ana; Sousa, Joana; Direito, Rosa; Almeida, Anabela; Rocha, Marília; Falcão, Amílcar; Soares-da-Silva, Patrício

    2010-08-01

    As add-on therapy, phase III clinical trials of eslicarbazepine acetate (ESL) conducted in patients with refractory partial-onset seizures have shown good efficacy, safety, and tolerability, even in patients taking carbamazepine (CBZ) at baseline (approximately 60% of the enrolled patients). Thus, considering the pharmacological disadvantages of CBZ and the similar efficacy spectrum of CBZ and ESL, switching to ESL may be successful in many patients. As ESL is a prodrug almost instantaneously converted to S-licarbazepine (S-Lic; approximately 95%), an interest in therapeutic drug monitoring (TDM) of S-Lic is likely to develop in the future. This study investigated the plasma concentrations of S-Lic and R-licarbazepine (R-Lic) enantiomers in patients under CBZ long-term treatment to assess the potential interference of CBZ or its metabolites in the enantioselective TDM of ESL (using S-Lic concentrations). A chiral high-performance liquid chromatography assay with ultraviolet detection (HPLC-UV) previously developed and validated by our research group was used. Twenty-four patients admitted to the Coimbra University Hospital and supposedly receiving CBZ long-term treatment were identified. Blood samples were collected from patients and serum CBZ concentrations were measured by the usual TDM protocol. Aliquots of plasma from such patients were also submitted to a chiral HPLC-UV analysis. The bioanalytical data indicated that S-Lic and R-Lic were not present at detectable concentrations in plasma samples of the CBZ-treated patients. The chromatograms generated by the analysis of patient plasma samples, when compared with those obtained from blank plasma samples spiked with S-Lic and R-Lic, clearly showed the absence of interferences at the retention times of both Lic enantiomers. These data support the usefulness of the chiral HPLC-UV method used for the enantioselective TDM of ESL (using S-Lic) for programs in which switching from CBZ to ESL is implemented.

  10. Enantioselective accumulation, metabolism and phytoremediation of lactofen by aquatic macrophyte Lemna minor.

    Science.gov (United States)

    Wang, Fang; Yi, Xiaotong; Qu, Han; Chen, Li; Liu, Donghui; Wang, Peng; Zhou, Zhiqiang

    2017-09-01

    Pesticides are frequently detected in water bodies due to the agricultural application, which may pose impacts on aquatic organisms. The enantioselective bioaccumulation and metabolism of the herbicide lactofen in aquatic floating macrophyte Lemna minor (L. minor) were studied and the potential L. minor phytoremediation was investigated. Ultra-high performance liquid chromatography - tandem mass spectrometry (UHPLC-MS-MS) analysis for lactofen and its two known metabolites in L. minor was performed. The initial concentrations of racemic lactofen, R-lactofen and S-lactofen were all 30μgL -1 in the growth solution. The distribution of lactofen and its metabolites in growth solution and L. minor was determined throughout a 5-d laboratory trial. It was observed that S-lactofen was preferentially taken up and metabolized in L. minor. After rac-lactofen exposure, the accumulation amount of S-lactofen was approximately 3-fold more than that of R-lactofen in L. minor and the metabolism rate of S-lactofen (T 1/2 =0.92 d) was significantly faster than R-lactofen (T 1/2 =1.55 d). L. minor could only slightly accelerate the metabolism and removal of lactofen in the growth solution. As for the metabolites, desethyl lactofen was found to be the major metabolite in L. minor and the growth solution, whereas the metabolite acifluorfene was undetectable. No interconversion of the two enantiomers was observed after individual enantiomer exposure, indicating they were configurationally stable. The findings of this work represented that the accumulation and metabolism of lactofen in L. minor were enantioselective, and L. minor had limited capacity for the removal of lactofen and its metabolite in water. Copyright © 2017. Published by Elsevier Inc.

  11. Comparison of liquid and supercritical fluid chromatography mobile phases for enantioselective separations on polysaccharide stationary phases.

    Science.gov (United States)

    Khater, Syame; Lozac'h, Marie-Anne; Adam, Isabelle; Francotte, Eric; West, Caroline

    2016-10-07

    Analysis and production of enantiomerically pure compounds is a major topic of interest when active pharmaceutical ingredients are concerned. Enantioselective chromatography has become a favourite both at the analytical and preparative scales. High-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) are dominating the scene and are often seen as complementary techniques. Nowadays, for economic and ecologic reasons, SFC may be preferred over normal-phase HPLC (NPLC) as it allows significant reductions in solvent consumption. However, the transfer of NPLC methods to SFC is not always straightforward. In this study, we compare the retention of achiral molecules and separation of enantiomers under supercritical fluid (carbon dioxide with ethanol or isopropanol) and liquid normal-phase (heptane with ethanol or isopropanol) elution modes with polysaccharide stationary phases in order to explore the differences between the retention and enantioseparation properties between the two modes. Chemometric methods (namely quantitative structure-retention relationships and discriminant analysis) are employed to compare the results obtained on a large set of analytes (171 achiral probes and 97 racemates) and gain some understanding on the retention and separation mechanisms. The results indicate that, contrary to popular belief, carbon dioxide - solvent SFC mobile phases are often weaker eluents than liquid mobile phases. It appears that SFC and NPLC elution modes provide different retention mechanisms. While some enantioseparations are unaffected, facilitating the transfer between the two elution modes, other enantioseparations may be drastically different due to different types and strength of interactions contributing to enantioselectivity. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Enantioselective epoxidation with chiral MN(III)(salen) catalysts: kinetic resolution of aryl-substituted allylic alcohols.

    Science.gov (United States)

    Adam, W; Humpf, H U; Roschmann, K J; Saha-Möller, C R

    2001-08-24

    A set of aryl-substituted allylic alcohols rac-2 has been epoxidized by chiral Mn(salen*) complexes 1 as the catalyst and iodosyl benzene (PhIO) as the oxygen source. Whereas one enantiomer of the allylic alcohol 2 is preferentially epoxidized to give the threo- or cis-epoxy alcohol 3 (up to 80% ee) as the main product (dr up to >95:5), the other enantiomer of 2 is enriched (up to 53% ee). In the case of 1,1-dimethyl-1,2-dihydronaphthalen-2-ol (2c), the CH oxidation to the enone 4c proceeds enantioselectively and competes with the epoxidation. The absolute configurations of the allylic alcohols 2 and their epoxides 3 have been determined by chemical correlation or CD spectroscopy. The observed diastereo- and enantioselectivities in the epoxidation reactions are rationalized in terms of a beneficial interplay between the hydroxy-directing effect and the attack along the Katsuki trajectory.

  13. A Readily Accessible Class of Chiral Cp Ligands and their Application in RuII -Catalyzed Enantioselective Syntheses of Dihydrobenzoindoles.

    Science.gov (United States)

    Wang, Shou-Guo; Park, Sung Hwan; Cramer, Nicolai

    2018-05-04

    Chiral cyclopentadienyl (Cp x ) ligands have a large application potential in enantioselective transition-metal catalysis. However, the development of concise and practical routes to such ligands remains in its infancy. We present a convenient and efficient two-step synthesis of a novel class of chiral Cp x ligands with tunable steric properties that can be readily used for complexation, giving Cp x Rh I , Cp x Ir I , and Cp x Ru II complexes. The potential of this ligand class is demonstrated with the latter in the enantioselective cyclization of azabenzonorbornadienes with alkynes, affording dihydrobenzoindoles in up to 98:2 e.r., significantly outperforming existing binaphthyl-derived Cp x ligands. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Combined experimental and theoretical study of the mechanism and enantioselectivity of palladium-catalyzed intermolecular Heck coupling

    DEFF Research Database (Denmark)

    Henriksen, Signe Teuber; Norrby, Per-Ola; Kaukoranta, Päivi

    2008-01-01

    . The steric interactions in this transition state fully account for the enantioselectivity observed with the ligands studied. The calculations also predict relative reactivity and nonlinear mixing effects for the investigated ligands; these predictions are fully validated by experimental testing. Finally......The asymmetric Heck reaction using P,N-ligands has been studied by a combination of theoretical and experimental methods. The reaction follows Halpern-style selectivity; that is, the major isomer is produced from the least favored form of the pre-insertion intermediate. The initially formed Ph......, the low conversion observed with some catalysts was found to be caused by inactivation due to weak binding of the ligand to Pd(0). Adding monodentate PPh3 alleviated the precipitation problem without deteriorating the enantioselectivity and led to one of the most effective catalytic systems to date....

  15. Kinetic Resolution of sec-Thiols by Enantioselective Oxidation with Rationally Engineered 5-(Hydroxymethyl)furfural Oxidase.

    Science.gov (United States)

    Pickl, Mathias; Swoboda, Alexander; Romero, Elvira; Winkler, Christoph K; Binda, Claudia; Mattevi, Andrea; Faber, Kurt; Fraaije, Marco W

    2018-03-05

    Various flavoprotein oxidases were recently shown to oxidize primary thiols. Herein, this reactivity is extended to sec-thiols by using structure-guided engineering of 5-(hydroxymethyl)furfural oxidase (HMFO). The variants obtained were employed for the oxidative kinetic resolution of racemic sec-thiols, thus yielding the corresponding thioketones and nonreacted R-configured thiols with excellent enantioselectivities (E≥200). The engineering strategy applied went beyond the classic approach of replacing bulky amino acid residues with smaller ones, as the active site was additionally enlarged by a newly introduced Thr residue. This residue established a hydrogen-bonding interaction with the substrates, as verified in the crystal structure of the variant. These strategies unlocked HMFO variants for the enantioselective oxidation of a range of sec-thiols. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Regioconvergent and Enantioselective Rhodium-Catalyzed Hydroamination of Internal and Terminal Alkynes: A Highly Flexible Access to Chiral Pyrazoles.

    Science.gov (United States)

    Haydl, Alexander M; Hilpert, Lukas J; Breit, Bernhard

    2016-05-04

    The rhodium-catalyzed asymmetric N-selective coupling of pyrazole derivatives with internal and terminal alkynes features an utmost chemo-, regio-, and enantioselective access to enantiopure allylic pyrazoles, readily available for incorporation in small-molecule pharmaceuticals. This methodology is distinguished by a broad substrate scope, resulting in a remarkable compatability with a variety of different functional groups. It furthermore exhibits an intriguing case of regio-, position-, and enantioselectivity in just one step, underscoring the sole synthesis of just one out of up to six possible products in a highly flexible approach to allylated pyrazoles by emanating from various internal and terminal alkynes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Enantioselective effect of bifenthrin on antioxidant enzyme gene expression and stress protein response in PC12 cells.

    Science.gov (United States)

    Lu, Xianting

    2013-07-01

    Enantioselectivity in toxicology and the health risk of chiral xenobiotics have become frontier topics interfacing chemistry and toxicology. Our previous results showed that cis-bifenthrin (cis-BF) induced cytotoxicity and apoptosis in vitro in an enantioselective manner. However, the exact molecular mechanisms of synthetic pyrethroid-induced enantioselective apoptosis and cytotoxicity have so far received limited research attention. In the present study, the expression patterns of different genes encoding heat shock protein and antioxidant enzymes were investigated by real-time quantitative PCR in rat adrenal pheochromocytoma (PC12) cells after exposure to cis-BF and its enantiomers. The results showed that exposure to 1S-cis-BF resulted in increased transcription of HSP90, HSP70, HSP60, Cu-Zn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione-s-transferase at a concentration of 5 µm and above, while exposure to 1R-cis-BF and rac-cis-BF exhibited these effects to lesser degrees. In addition, induction of antioxidant enzyme gene expression produced by 1S-cis-BF might occur, at least in part, through activation of p38 mitogen-activated protein kinases (MAPK) and extracellular regulated kinases, while increase in stress protein response produced by 1S-cis-BF might occur through the p38 MAPK signaling pathway. The results not only suggest that enantioselectivity should be considered in evaluating the ecotoxicological effects and health risk of chiral contaminants, but also will improve the understanding of molecular mechanism for chiral chemical-induced cytotoxicity. Copyright © 2012 John Wiley & Sons, Ltd.

  18. A Simple Primary Amine Catalyst for Enantioselective α-Hydroxylations and α-Fluorinations of Branched Aldehydes

    OpenAIRE

    Witten, Michael R.; Jacobsen, Eric N.

    2015-01-01

    A new primary amine catalyst for the asymmetric α-hydroxylation and α-fluorination of α-branched aldehydes is described. The products of the title transformations are generated in excellent yields and with high enantioselectivities. Both processes can be performed within short reaction times and on gram scale. The similarity in the results obtained in both reactions, combined with computational evidence, implies a common basis for stereoinduction and the possibility of a general catalytic mec...

  19. Enantioselective Direct α-Amination of Aldehydes via a Photoredox Mechanism: A Strategy for Asymmetric Amine Fragment Coupling

    OpenAIRE

    Cecere, Giuseppe; Koenig, Christian M.; Alleva, Jennifer L.; MacMillan, David W. C.

    2013-01-01

    The direct, asymmetric α-amination of aldehydes has been accomplished via a combination of photoredox and organocatalysis. Photon-generated, nitrogen-centered radicals undergo enantioselective α-addition to catalytically formed chiral enamines to directly produce stable α-amino aldehyde adducts bearing synthetically useful amine substitution patterns. Incorporation of a photolabile group on the amine precursor obviates the need to employ a photoredox catalyst in this transformation. Important...

  20. Enantioselective Collision-Activated Dissociation of Gas-Phase Tryptophan Induced by Chiral Recognition of Protonated l-Alanine Peptides

    Science.gov (United States)

    Fujihara, Akimasa; Matsuyama, Hiroki; Tajiri, Michiko; Wada, Yoshinao; Hayakawa, Shigeo

    2017-06-01

    Enantioselective dissociation in the gas phase is important for enantiomeric enrichment and chiral transmission processes in molecular clouds regarding the origin of homochirality in biomolecules. Enantioselective collision-activated dissociation (CAD) of tryptophan (Trp) and the chiral recognition ability of l-alanine peptides ( l-Ala n ; n = 2-4) were examined using a linear ion trap mass spectrometer. CAD spectra of gas-phase heterochiral H+( d-Trp)( l-Ala n ) and homochiral H+( l-Trp)( l-Ala n ) noncovalent complexes were obtained as a function of the peptide size n. The H2O-elimination product was observed in CAD spectra of both heterochiral and homochiral complexes for n = 2 and 4, and in homochiral H+( l-Trp)( l-Ala3), indicating that the proton is attached to the l-alanine peptide, and H2O loss occurs from H+( l-Ala n ) in the noncovalent complexes. H2O loss did not occur in heterochiral H+( d-Trp)( l-Ala3), where NH3 loss and (H2O + CO) loss were the primary dissociation pathways. In heterochiral H+( d-Trp)( l-Ala3), the protonation site is the amino group of d-Trp, and NH3 loss and (H2O + CO) loss occur from H+( d-Trp). l-Ala peptides recognize d-Trp through protonation of the amino group for peptide size n = 3. NH3 loss and (H2O + CO) loss from H+( d-Trp) proceeds via enantioselective CAD in gas-phase heterochiral H+( d-Trp)( l-Ala3) at room temperature, whereas l-Trp dissociation was not observed in homochiral H+( l-Trp)( l-Ala3). These results suggest that enantioselective dissociation induced by chiral recognition of l-Ala peptides through protonation could play an important role in enantiomeric enrichment and chiral transmission processes of amino acids.

  1. Sequential rhodium/palladium catalysis: enantioselective formation of dihydroquinolinones in the presence of achiral and chiral ligands.

    Science.gov (United States)

    Zhang, Lei; Qureshi, Zafar; Sonaglia, Lorenzo; Lautens, Mark

    2014-12-08

    Compatible combinations of achiral and chiral ligands can be used in rhodium/palladium catalysis to achieve highly enantioselective domino reactions. The difference in rates of catalysis and minimal effects of ligand interference confer control in the domino sequence. The "all-in-one" 1,4-conjugate arylation and C-N cross-coupling through sequential Rh/Pd catalysis provides access to enantioenriched dihydroquinolinone building blocks. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Diastereo- and enantioselective iridium-catalyzed allylation of cyclic ketone enolates: synergetic effect of ligands and barium enolates.

    Science.gov (United States)

    Chen, Wenyong; Chen, Ming; Hartwig, John F

    2014-11-12

    We report asymmetric allylic alkylation of barium enolates of cyclic ketones catalyzed by a metallacyclic iridium complex containing a phosphoramidite ligand derived from (R)-1-(2-naphthyl)ethylamine. The reaction products contain adjacent quaternary and tertiary stereocenters. This process demonstrates that unstabilized cyclic ketone enolates can undergo diastereo- and enantioselective Ir-catalyzed allylic substitution reactions with the proper choice of enolate countercation. The products of these reactions can be conveniently transformed to various useful polycarbocyclic structures.

  3. Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancer

    International Nuclear Information System (INIS)

    Lemaire, Maryse; Chabot, Guy G; Raynal, Noël JM; Momparler, Louise F; Hurtubise, Annie; Bernstein, Mark L; Momparler, Richard L

    2008-01-01

    The inactivation of tumor suppressor genes (TSGs) by aberrant DNA methylation plays an important role in the development of malignancy. Since this epigenetic change is reversible, it is a potential target for chemotherapeutic intervention using an inhibitor of DNA methylation, such as 5-aza-2'-deoxycytidine (DAC). Although clinical studies show that DAC has activity against hematological malignancies, the optimal dose-schedule of this epigenetic agent still needs to be established. Clonogenic assays were performed on leukemic and tumor cell lines to evaluate the in vitro antineoplastic activity of DAC. The reactivation of TSGs and inhibition of DNA methylation by DAC were investigated by reverse transcriptase-PCR and Line-1 assays. The in vivo antineoplastic activity of DAC administered as an i.v. infusion was evaluated in mice with murine L1210 leukemia by measurement of survival time, and in mice bearing murine EMT6 mammary tumor by excision of tumor after chemotherapy for an in vitro clonogenic assay. Increasing the DAC concentration and duration of exposure produced a greater loss of clonogenicity for both human leukemic and tumor cell lines. The reactivation of the TSGs (p57KIP2 in HL-60 leukemic cells and p16CDKN2A in Calu-6 lung carcinoma cells) and the inhibition of global DNA methylation in HL-60 leukemic cells increased with DAC concentration. In mice with L1210 leukemia and in mice bearing EMT6 tumors, the antineoplastic action of DAC also increased with the dose. The plasma level of DAC that produced a very potent antineoplastic effect in mice with leukemia or solid tumors was > 200 ng/ml (> 1 μM). We have shown that intensification of the DAC dose markedly increased its antineoplastic activity in mouse models of cancer. Our data also show that there is a good correlation between the concentrations of DAC that reduce in vitro clonogenicity, reactivate TSGs and inhibit DNA methylation. These results suggest that the antineoplastic action of DAC is

  4. Dissipation and enantioselective degradation of plant growth retardants paclobutrazol and uniconazole in open field, greenhouse, and laboratory soils.

    Science.gov (United States)

    Wu, Chengwang; Sun, Jianqiang; Zhang, Anping; Liu, Weiping

    2013-01-15

    Greenhouses are increasingly important in human food supply. Pesticides used in greenhouses play important roles in horticulture; however, little is known about their behavior in greenhouse environments. This work investigates the dissipation and enantioselctive degradation of plant growth retardants including paclobutrazol and uniconazole in soils under three conditions (i.e., open field, greenhouse, and laboratory). The dissipation and enantioselective degradation of paclobutrazol and uniconazole in greenhouse were different from those in open field; they were more persistent in greenhouse than in open field soil. Leaching produced by rainfall is responsible for the difference in dissipation. Thus, local environmental impacts may occur more easily inside greenhouses, while groundwater may be more contaminated in open field. Spike concentrations of 5, 10, and 20 times the concentrations of native residues were tested for the enantioselective dissipation of the two pesticides; the most potent enantioselective degradation of paclobutrazol and uniconazole occurred at the 10 times that of the native residues in the greenhouse environments and at 20 times native residues in open field environments. The higher soil activity in greenhouses than in open fields was thought to be responsible for such a difference. The environmental risk and regulation of paclobutrazol and uniconazole should be considered at the enantiomeric level.

  5. Different effects of clopidogrel and clarithromycin on the enantioselective pharmacokinetics of sibutramine and its active metabolites in healthy subjects.

    Science.gov (United States)

    Shinde, Dhananjay D; Kim, Ho-Sook; Choi, Jae-Seok; Pan, Wei; Bae, Soo Kyung; Yeo, Chang-Woo; Shon, Ji-Hong; Kim, Dong-Hyun; Shin, Jae Gook

    2013-05-01

    In this study, we assessed the effects of clopidogrel and clarithromycin, known CYP2B6 and CYP3A inhibitors, respectively, on the enantioselective disposition of racemic sibutramine in conjunction with CYP2B6 polymorphisms in humans. Sibutramine showed enantioselective plasma profiles with consistently higher concentrations of R-enantiomers. Clopidogrel and clarithromycin significantly increased the sibutramine plasma concentration, but their effects differed between enantiomers; a 2.2-fold versus 4.1-fold increase in the AUC in S-enantiomer and 1.8-fold versus 2.0-fold for the R-enantiomer, respectively. The AUCs of S- and R-desmethyl metabolites changed significantly during the clopidogrel phase (P sibutramine was higher in subjects with the CYP2B6*6/*6 genotype, but no statistical difference was observed among the CYP2B6 genotypes. These results suggest that the enantioselective disposition of sibutramine and its active metabolites are influenced by the altered genetic and environmental factors of CYP2B6 and CYP3A activity in vivo. © The Author(s) 2013.

  6. Regio- and Enantioselective N-Allylations of Imidazole, Benzimidazole, and Purine Heterocycles Catalyzed by Single-Component Metallacyclic Iridium Complexes

    Science.gov (United States)

    Stanley, Levi M.

    2010-01-01

    Highly regio- and enantioselective iridium-catalyzed N-allylations of benzimidazoles, imidazoles, and purines have been developed. N-Allylated benzimidazoles and imidazoles were isolated in high yields (up to 97%) with high branched-to-linear selectivity (up to 99:1) and enantioselectivity (up to 98% ee) from the reactions of benzimidazole and imidazole nucleophiles with unsymmetrical allylic carbonates in the presence of single component, ethylene-bound, metallacyclic iridium catalysts. N-Allylated purines were also obtained in high yields (up to 91%) with high N9:N7 selectivity (up to 96:4), high branched-to-linear selectivity (98:2), and high enantioselectivity (up to 98% ee) under similar conditions. The reactions encompass a range of benzimidazole, imidazole, and purine nucleophiles, as well as a variety of unsymmetrical aryl, heteroaryl, and aliphatic allylic carbonates. Competition experiments between common amine nucleophiles and the heterocyclic nitrogen nucleophiles studied in this work illustrate the effect of nucleophile pKa on the rate of iridium-catalyzed N-allylation reactions. Kinetic studies on the allylation of benzimidazole catalyzed by metallacyclic iridium-phosphoramidite complexes, in combination with studies on the deactivation of these catalysts in the presence of heterocyclic nucleophiles, provide insight into the effects of the structure of the phosphoramidite ligands on the stability of the metallacyclic catalysts. The data obtained from these studies has led to the development of N-allylations of benzimidazoles and imidazoles in the absence of an exogenous base. PMID:19480431

  7. Enantioseparation and determination of the chiral phenylpyrazole insecticide ethiprole in agricultural and environmental samples and its enantioselective degradation in soil

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qing; Shi, Haiyan; Gao, Beibei; Tian, Mingming; Hua, Xiude; Wang, Minghua, E-mail: wangmha@njau.edu.cn

    2016-01-15

    An effective method for the enantioselective determination of ethiprole enantiomers in agricultural and environmental samples was developed. The effects of solvent extraction, mobile phase and thermodynamic parameters for chiral recognition were fully investigated. Complete enantioseparation of the ethiprole enantiomers was achieved on a Lux Cellulose-2 column. The stereochemical structures of ethiprole enantiomers were also determined, and (R)-(+)-ethiprole was first eluted. The average recoveries were 82.7–104.9% with intra-day RSD of 1.7–8.2% in soil, cucumber, spinach, tomato, apple and peach under optimal conditions. Good linearity (R{sup 2} ≥ 0.9991) was obtained for all the matrix calibration curves within a range of 0.1 to 10 mg L{sup −1}. The limits of detection for both enantiomers were estimated to be 0.008 mg kg{sup −1} in soil, cucumber, spinach and tomato and 0.012 mg kg{sup −1} in apple and peach, which were lower than the maximum residue levels established in Japan. The results indicate that the proposed method is convenient and reliable for the enantioselective detection of ethiprole in agricultural and environmental samples. The behavior of ethiprole in soil was studied under field conditions and the enantioselective degradation was observed with enantiomer fraction values varying from 0.494 to 0.884 during the experiment. The (R)-(+)-ethiprole (t{sub 1/2} = 11.6 d) degraded faster than (S)-(−)-ethiprole (t{sub 1/2} = 34.7 d). This report is the first describe a chiral analytical method and enantioselective behavior of ethiprole, and these results should be extremely useful for the risk evaluation of ethiprole in food and environmental safety. - Highlights: • The ethiprole enantiomers were completely separated. • A novel method for enantioselective determination of ethiprole was developed. • The absolute configurations of ethiprole enantiomers were firstly determined. • The (R)-(+)-ethiprole was preferentially degraded in

  8. Synthesis of some novel 4-aza-tricyclo[5.2.2.0 2,6 ]undecane-3,5,8-triones from 2-trimethylsilyloxy-1,3-cyclohexadiene and 1-methoxy-1,3-cyclohexadiene

    Directory of Open Access Journals (Sweden)

    Hosapalya Thimmaiah Srinivasa

    2012-01-01

    Full Text Available The synthesis and characterization of nine novel Diels-Alder cycloadducts: the 4-aza-tricyclo[5.2.2.0 2,6] undecane-3,5,8-triones using 2-trimethylsilyloxy-1,3-cyclohexadiene and 1-methoxy-1,3-cyclohexadiene is reported. The isolated yields of the pure cycloadducts range between 75 to 95%.

  9. T3P- A Novel Catalyst for Aza-Diels-Alder Reaction: One-Pot Synthesis of Pyrano[3,2-c]quinolines and furano[3,2-c]quinolines

    Directory of Open Access Journals (Sweden)

    T. S. R. Prasanna

    2011-01-01

    Full Text Available T3P was found to be an efficient catalyst for the Aza-Diels–Alder reactions of aldimines with dihydropyran or dihydrofuran to afford the corresponding pyrano-and furo [3,2-c]quinolines in high yields with high diastereoselectivity in a short period of time.

  10. Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 2: aldol, Mannich addition reactions, deracemization and (S) to (R) interconversion of α-amino acids.

    Science.gov (United States)

    Sorochinsky, Alexander E; Aceña, José Luis; Moriwaki, Hiroki; Sato, Tatsunori; Soloshonok, Vadim

    2013-11-01

    This review provides a comprehensive treatment of literature data dealing with asymmetric synthesis of α-amino-β-hydroxy and α,β-diamino acids via homologation of chiral Ni(II) complexes of glycine Schiff bases using aldol and Mannich-type reactions. These reactions proceed with synthetically useful chemical yields and thermodynamically controlled stereoselectivity and allow direct introduction of two stereogenic centers in a single operation with predictable stereochemical outcome. Furthermore, new application of Ni(II) complexes of α-amino acids Schiff bases for deracemization of racemic α-amino acids and (S) to (R) interconversion providing additional synthetic opportunities for preparation of enantiomerically pure α-amino acids, is also reviewed. Origin of observed diastereo-/enantioselectivity in the aldol, Mannich-type and deracemization reactions, generality and limitations of these methodologies are critically discussed.

  11. The in vitro and in vivo effects of re-expressing methylated von Hippel-Lindau tumor suppressor gene in clear cell renal carcinoma with 5-aza-2'-deoxycytidine.

    Science.gov (United States)

    Alleman, Wade G; Tabios, Ray L; Chandramouli, Gadisetti V R; Aprelikova, Olga N; Torres-Cabala, Carlos; Mendoza, Arnulfo; Rogers, Craig; Rodgers, Craig; Sopko, Nikolai A; Linehan, W Marston; Vasselli, James R

    2004-10-15

    Clear cell renal carcinoma (ccRCC) is strongly associated with loss of the von Hippel-Lindau (VHL) tumor suppressor gene. The VHL gene is functionally lost through hypermethylation in up to 19% of sporadic ccRCC cases. We theorized that re-expressing VHL silenced by methylation in ccRCC cells, using a hypo-methylating agent, may be an approach to treatment in patients with this type of cancer. We test the ability of two hypo-methylating agents to re-express VHL in cell culture and in mice bearing human ccRCC and evaluate the effects of re-expressed VHL in these models. Real-time reverse transcription-PCR was used to evaluate the ability of zebularine and 5-aza-2'-deoxycytidine (5-aza-dCyd) to re-express VHL in four ccRCC cell lines with documented VHL gene silencing through hypermethylation. We evaluated if the VHL re-expressed after hypo-methylating agent treatment could recreate similar phenotypic changes in ccRCC cells observed when the VHL gene is re-expressed via transfection in cell culture and in a xenograft mouse model. Finally we evaluate global gene expression changes occurring in our cells, using microarray analysis. 5-Aza-dCyd was able to re-express VHL in our cell lines both in culture and in xenografted murine tumors. Well described phenotypic changes of VHL expression including decreased invasiveness into Matrigel, and decreased vascular endothelial growth factor and glucose transporter-1 expression were observed in the treated lines. VHL methylated ccRCC xenografted tumors were significantly reduced in size in mice treated with 5-aza-dCyd. Mice bearing nonmethylated but VHL-mutated tumors showed no tumor shrinkage with 5-aza-dCyd treatment. Hypo-methylating agents may be useful in the treatment of patients having ccRCC tumors consisting of cells with methylated VHL.

  12. Conventional and narrow bore short capillary columns with cyclodextrin derivatives as chiral selectors to speed-up enantioselective gas chromatography and enantioselective gas chromatography-mass spectrometry analyses.

    Science.gov (United States)

    Bicchi, Carlo; Liberto, Erica; Cagliero, Cecilia; Cordero, Chiara; Sgorbini, Barbara; Rubiolo, Patrizia

    2008-11-28

    The analysis of complex real-world samples of vegetable origin requires rapid and accurate routine methods, enabling laboratories to increase sample throughput and productivity while reducing analysis costs. This study examines shortening enantioselective-GC (ES-GC) analysis time following the approaches used in fast GC. ES-GC separations are due to a weak enantiomer-CD host-guest interaction and the separation is thermodynamically driven and strongly influenced by temperature. As a consequence, fast temperature rates can interfere with enantiomeric discrimination; thus the use of short and/or narrow bore columns is a possible approach to speeding-up ES-GC analyses. The performance of ES-GC with a conventional inner diameter (I.D.) column (25 m length x 0.25 mm I.D., 0.15 microm and 0.25 microm d(f)) coated with 30% of 2,3-di-O-ethyl-6-O-tert-butyldimethylsilyl-beta-cyclodextrin in PS-086 is compared to those of conventional I.D. short column (5m length x 0.25 mm I.D., 0.15 microm d(f)) and of different length narrow bore columns (1, 2, 5 and 10 m long x 0.10 mm I.D., 0.10 microm d(f)) in analysing racemate standards of pesticides and in the flavour and fragrance field and real-world-samples. Short conventional I.D. columns gave shorter analysis time and comparable or lower resolutions with the racemate standards, depending mainly on analyte volatility. Narrow-bore columns were tested under different analysis conditions; they provided shorter analysis time and resolutions comparable to those of conventional I.D. ES columns. The narrow-bore columns offering the most effective compromise between separation efficiency and analysis time are the 5 and 2m columns; in combination with mass spectrometry as detector, applied to lavender and bergamot essential oil analyses, these reduced analysis time by a factor of at least three while separation of chiral markers remained unaltered.

  13. The role of the achiral template in enantioselective transformations. Radical conjugate additions to alpha-methacrylates followed by hydrogen atom transfer.

    Science.gov (United States)

    Sibi, Mukund P; Sausker, Justin B

    2002-02-13

    We have evaluated various achiral templates (1a-g, 10, and 16) in conjunction with chiral Lewis acids in the conjugate addition of nucleophilic radicals to alpha-methacrylates followed by enantioselective H-atom transfer. Of these, a novel naphthosultam template (10) gave high enantioselectivity in the H-atom-transfer reactions with ee's up to 90%. A chiral Lewis acid derived from MgBr(2) and bisoxazoline (2) gave the highest selectivity in the enantioselective hydrogen-atom-transfer reactions. Non-C(2) symmetric oxazolines (20-25) have also been examined as ligands, and of these, compound 25 gave optimal results (87% yield and 80% ee). Insights into rotamer control in alpha-substituted acrylates and the critical role of the tetrahedral sulfone moiety in realizing high selectivity are discussed.

  14. Enantioselective analysis of fluoxetine in pharmaceutical formulations by capillary zone electrophoresis

    Directory of Open Access Journals (Sweden)

    Melania Cârcu-Dobrin

    2017-03-01

    Full Text Available Fluoxetine is an antidepressant, a selective serotonin reuptake inhibitor (SSRI used primarily in the treatment of major depression, panic disorder and obsessive compulsive disorder. Chiral separation of racemic fluoxetine is necessary due to its enantioselective metabolism. In order to develop a suitable method for chiral separation of fluoxetine, cyclodextrin (CD modified capillary electrophoresis (CE was employed. A large number of native and derivatized, neutral and ionized CD derivatives were screened to find the optimal chiral selector. As a result of this process, heptakis(2,3,6-tri-O-methyl-β-CD (TRIMEB was selected for enantiomeric discrimination. A factorial analysis study was performed by orthogonal experimental design in which several factors are varied at the same time to optimize the separation method. The optimized method (50 mM phosphate buffer, pH = 5.0, 10 mM TRIMEB, 15 °C, + 20 kV, 50 mbar/1 s, detection at 230 nm was successful for baseline separation of fluoxetine enantiomers within 5 min. Our method was validated according to ICH guidelines and proved to be sensitive, linear, accurate and precise for the chiral separation of fluoxetine.

  15. The fate and enantioselective behavior of zoxamide during wine-making process.

    Science.gov (United States)

    Pan, Xinglu; Dong, Fengshou; Liu, Na; Cheng, Youpu; Xu, Jun; Liu, Xingang; Wu, Xiaohu; Chen, Zenglong; Zheng, Yongquan

    2018-05-15

    The fate of zoxamide and its enantiomers were evaluated in detail during wine-making process. The enantiomers of zoxamide were separated and determined by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) after each processing procedure including washing, peeling, fermentation and clarification. Significant enantioselectivity was observed in all three treatments with the half-lives of R-zoxamide and S-zoxamide estimated to be 45.6 and 52.9 h in Group A, 45.0 and 52.1 h in Group B, 56.8 and 70.7 h in Group C, respectively. The results indicated that R-zoxamide degraded faster than S-zoxamide during the fermentation process. The processing factors (PFs) of each procedure were generally less than 1, and the PF of the overall process ranged from 0.019 to 0.051, which indicated that the whole process can reduce the zoxamide residue in red and white wine obviously. The results could help facilitate more accurate risk assessments of zoxamide during wine-making process. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Enantioselectively controlled release of chiral drug (metoprolol) using chiral mesoporous silica materials

    International Nuclear Information System (INIS)

    Guo Zhen; Liu Xianbin; Ng, Siu-Choon; Chen Yuan; Yang Yanhui; Du Yu

    2010-01-01

    Chiral porous materials have attracted burgeoning attention on account of their potential applications in many areas, such as enantioseparation, chiral catalysis, chemical sensors and drug delivery. In this report, chiral mesoporous silica (CMS) materials with various pore sizes and structures were prepared using conventional achiral templates (other than chiral surfactant) and a chiral cobalt complex as co-template. The synthesized CMS materials were characterized by x-ray diffraction, nitrogen physisorption, scanning electron microscope and transmission electron microscope. These CMS materials, as carriers, were demonstrated to be able to control the enantioselective release of a representative chiral drug (metoprolol). The release kinetics, as modeled by the power law equation, suggested that the release profiles of metoprolol were remarkably dependent on the pore diameter and pore structure of CMS materials. More importantly, R- and S-enantiomers of metoprolol exhibited different release kinetics on CMS compared to the corresponding achiral mesoporous silica (ACMS), attributable to the existence of local chirality on the pore wall surface of CMS materials. The chirality of CMS materials on a molecular level was further substantiated by vibrational circular dichroism measurements.

  17. BCL::EMAS — Enantioselective Molecular Asymmetry Descriptor for 3D-QSAR

    Directory of Open Access Journals (Sweden)

    Mariusz Butkiewicz

    2012-08-01

    Full Text Available Stereochemistry is an important determinant of a molecule’s biological activity. Stereoisomers can have different degrees of efficacy or even opposing effects when interacting with a target protein. Stereochemistry is a molecular property difficult to represent in 2D-QSAR as it is an inherently three-dimensional phenomenon. A major drawback of most proposed descriptors for 3D-QSAR that encode stereochemistry is that they require a heuristic for defining all stereocenters and rank-ordering its substituents. Here we propose a novel 3D-QSAR descriptor termed Enantioselective Molecular ASymmetry (EMAS that is capable of distinguishing between enantiomers in the absence of such heuristics. The descriptor aims to measure the deviation from an overall symmetric shape of the molecule. A radial-distribution function (RDF determines a signed volume of tetrahedrons of all triplets of atoms and the molecule center. The descriptor can be enriched with atom-centric properties such as partial charge. This descriptor showed good predictability when tested with a dataset of thirty-one steroids commonly used to benchmark stereochemistry descriptors (r2 = 0.89, q2 = 0.78. Additionally, EMAS improved enrichment of 4.38 versus 3.94 without EMAS in a simulated virtual high-throughput screening (vHTS for inhibitors and substrates of cytochrome P450 (PUBCHEM AID891.

  18. Enantioselectively controlled release of chiral drug (metoprolol) using chiral mesoporous silica materials

    Energy Technology Data Exchange (ETDEWEB)

    Guo Zhen; Liu Xianbin; Ng, Siu-Choon; Chen Yuan; Yang Yanhui [School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459 (Singapore); Du Yu, E-mail: du_yu@jlu.edu.cn, E-mail: yhyang@ntu.edu.sg [College of Electronic Science and Engineering, Jilin University, Changchun 130012 (China)

    2010-04-23

    Chiral porous materials have attracted burgeoning attention on account of their potential applications in many areas, such as enantioseparation, chiral catalysis, chemical sensors and drug delivery. In this report, chiral mesoporous silica (CMS) materials with various pore sizes and structures were prepared using conventional achiral templates (other than chiral surfactant) and a chiral cobalt complex as co-template. The synthesized CMS materials were characterized by x-ray diffraction, nitrogen physisorption, scanning electron microscope and transmission electron microscope. These CMS materials, as carriers, were demonstrated to be able to control the enantioselective release of a representative chiral drug (metoprolol). The release kinetics, as modeled by the power law equation, suggested that the release profiles of metoprolol were remarkably dependent on the pore diameter and pore structure of CMS materials. More importantly, R- and S-enantiomers of metoprolol exhibited different release kinetics on CMS compared to the corresponding achiral mesoporous silica (ACMS), attributable to the existence of local chirality on the pore wall surface of CMS materials. The chirality of CMS materials on a molecular level was further substantiated by vibrational circular dichroism measurements.

  19. Optimization of lipase-catalyzed enantioselective production of 1-phenyl 1-propanol using response surface methodology.

    Science.gov (United States)

    Soyer, Asli; Bayraktar, Emine; Mehmetoglu, Ulku

    2010-01-01

    Optically active 1-phenyl 1-propanol is used as a chiral building block and synthetic intermediate in the pharmaceutical industries. In this study, the enantioselective production of 1-phenyl 1-propanol was investigated systematically using response surface methodology (RSM). Before RSM was applied, the effects of the enzyme source, the type of acyl donor, and the type of solvent on the kinetic resolution of 1-phenyl 1-propanol were studied. The best results were obtained with Candida antartica lipase (commercially available as Novozym 435), vinyl laurate as the acyl donor, and isooctane as the solvent. In the RSM, substrate concentration, molar ratio of acyl donor to the substrate, amount of enzyme, temperature, and stirring rate were chosen as independent variables. The predicted optimum conditions for a higher enantiomeric excess (ee) were as follows: substrate concentration, 233 mM; molar ratio of acyl donor to substrate, 1.5; enzyme amount, 116 mg; temperature, 47 °C; and stirring rate, 161 rpm. A verification experiment conducted at these optimized conditions for maximum ee yielded 91% for 3 hr, which is higher than the predicted value of 83%. The effect of microwave on the ee was also investigated and ee reached 87% at only 5 min.

  20. Enantioselective HPLC determination of oxiracetam enantiomers and application to a pharmacokinetic study in beagle dogs.

    Science.gov (United States)

    Zhang, Qiuyang; Yang, Wei; Zhang, Qing; Yang, Yue; Li, Junxiu; Lu, Yang; Zheng, Yi; He, Jiake; Zhao, Di; Chen, Xijing

    2015-07-01

    An enantioselective high-performance liquid chromatography method was developed and validated for the determination of oxiracetam enantiomers, a cognition and memory enhancer, in beagle dog plasma. The plasma samples were prepared by methanol extraction from 200μL plasma, and then the baseline resolution was achieved on a Chiralpak ID column (250mm×4.6mm, 5μm) with mobile phase of hexane-ethanol-trifluoroacetic acid (78:22:0.1, v/v/v) at flow rate of 1.0mL/min. The column elute was monitored using ultraviolet detection at 214nm. The method was linear over concentration range 0.50-100μg/mL for both enantiomers. The relative standard deviation values for intra- and inter-day precision were 0.78-13.61 and 0.74-8.92% for (R)- and (S)-oxiracetam, respectively. The relative error values of accuracy ranged from -4.74 to 10.48% for (R)-oxiracetam and from -0.19 to 11.48% for (S)-oxiracetam. The method was successfully applied to a pharmacokinetic study of individual enantiomer and racemic oxiracetam in beagle dogs after oral administration. The disposition of the two enantiomers was not stereoselective and chiral inversion was not observed in beagle dogs. The pharmacokinetic profiles of (S)-oxiracetam were similar with racemic oxiracetam in beagle dogs. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Enantioselective Synthesis of Various Cyanohydrins Using Covalently Immobilized Preparations of Hydroxynitrile Lyase from Prunus dulcis.

    Science.gov (United States)

    Alagöz, Dilek; Tükel, S Seyhan; Yildirim, Deniz

    2015-11-01

    The carrier-based and carrier-free (cross-linked enzyme aggregate) covalent immobilizations of Prunus dulcis hydroxynitrile lyase were investigated. The immobilized preparations were tested for enantioselective carbon-carbon bond formation activity in the biphasic medium. Of the tested preparations, only cross-linked enzyme aggregate of P. dulcis hydroxynitrile lyase (PdHNL-CLEA) achieved the synthesis of (R)-mandelonitrile with 93% yield and 99% enantiopurity. PdHNL-CLEA was also used in the synthesis of various (R)-cyanohydrins from corresponding aldehydes/ketones and hydrocyanic acid. When 4-methoxybenzaldehyde, 4-methyl benzaldehyde, and 4-hydroxybenzaldehyde were used as substrates, the yield-enantiomeric excess of corresponding (R)-cyanohydrins were obtained as 95-95, 85-79, and 2-25%, respectively, after 96 h at pH 4.0 and 5 °C. For acetophenone, 4-fluoroacetophenone, 4-chloroacetophenone, 4-bromoacetophenone, and 4-iodoacetophenone, the yield-enantiomeric excess of corresponding (R)-cyanohydrins were 1-99, 20-84, 11-95, 5-99, and 3-24%, respectively at the same conditions. The results demonstrate PdHNL-CLEA can be effectively used in the synthesis of (R)-mandelonitrile.

  2. Organocatalysts for enantioselective synthesis of fine chemicals: definitions, trends and developments

    Directory of Open Access Journals (Sweden)

    Chiara Palumbo

    2015-02-01

    Full Text Available Organocatalysis, that is the use of small organic molecules to catalyze organic transformations, has been included among the most successful concepts in asymmetric catalysis, and it has been used for the enantioselective construction of C–C, C–N, C–O, C–S, C–P and C–halide bonds. Since the seminal works in early 2000, the scientific community has been paying an ever-growing attention to the use of organocatalysts for the synthesis, with high yields and remarkable stereoselectivities, of optically active fine chemicals of interest for the pharmaceutical industry. A brief overview is here presented about the two main classes of substrate activation by the catalyst: covalent organocatalysis and non-covalent organocatalysis, with a more stringent focus on some recent outcomes in the field of the latter and of hydrogen bond-based catalysis. Finally, some successful examples of heterogenization of organocatalysts are also discussed, in the view of a potential industrial exploitation.

  3. Enantioselective kappa opioid binding sites on the macrophage cell line, P388d sub 1

    Energy Technology Data Exchange (ETDEWEB)

    Carr, D.J.J.; Blalock, J.E. (Univ. of Alabama, Birmingham (USA)); DeCosta, B.R.; Jacobson, A.E.; Rice, K.C. (NIDDK, NIH, Bethesda, MD (USA))

    1991-01-01

    A kappa opioid binding site has been characterized on the macrophage cell line, P388d{sub 1}, using the kappa selective affinity ligand, ({sup 3H}(1S,2S)-(-)-trans-2-isothiocyanato-N-methyl-N-(2-(1-phrrolidinyl) cyclohexyl) benzeneacetamide ((-)BD166). The kappa site has a relative molecular mass (Mr) of 38,000 under nonreducing conditions and 42,000 under reducing conditions. Moreover, it exhibits enantioselectivity in that 1S,2S-(-)-trans-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl) benzeneacetamide ((-)-U-50,488) blocks ({sup 3}H)95{alpha},7{alpha},8{beta})-(-)-N-methyl-N-(7-(1- pyrrolidinyl)-1-oxaspiro-(4,5)-dec-8-yl)benzeneacetamide (U-69,593) binding to P388d{sub 1} cells with an IC{sub 50} = 7.0 nM whereas 1R,2R-(+)-trans-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl) benzeneacetamide ((+)U-50,488) blocks ({sup 3}H)U-69,593 binding to P388d{sub 1} cells with an IC{sub 50} = 700 nM.

  4. Engineering an enantioselective amine oxidase for the synthesis of pharmaceutical building blocks and alkaloid natural products.

    Science.gov (United States)

    Ghislieri, Diego; Green, Anthony P; Pontini, Marta; Willies, Simon C; Rowles, Ian; Frank, Annika; Grogan, Gideon; Turner, Nicholas J

    2013-07-24

    The development of cost-effective and sustainable catalytic methods for the production of enantiomerically pure chiral amines is a key challenge facing the pharmaceutical and fine chemical industries. This challenge is highlighted by the estimate that 40-45% of drug candidates contain a chiral amine, fueling a demand for broadly applicable synthetic methods that deliver target structures in high yield and enantiomeric excess. Herein we describe the development and application of a "toolbox" of monoamine oxidase variants from Aspergillus niger (MAO-N) which display remarkable substrate scope and tolerance for sterically demanding motifs, including a new variant, which exhibits high activity and enantioselectivity toward substrates containing the aminodiphenylmethane (benzhydrylamine) template. By combining rational structure-guided engineering with high-throughput screening, it has been possible to expand the substrate scope of MAO-N to accommodate amine substrates containing bulky aryl substituents. These engineered MAO-N biocatalysts have been applied in deracemization reactions for the efficient asymmetric synthesis of the generic active pharmaceutical ingredients Solifenacin and Levocetirizine as well as the natural products (R)-coniine, (R)-eleagnine, and (R)-leptaflorine. We also report a novel MAO-N mediated asymmetric oxidative Pictet-Spengler approach to the synthesis of (R)-harmicine.

  5. Gold-catalyzed tandem hydroamination/formal aza-Diels-Alder reaction of homopropargyl amino esters: a combined computational and experimental mechanistic study.

    Science.gov (United States)

    Miró, Javier; Sánchez-Roselló, María; González, Javier; del Pozo, Carlos; Fustero, Santos

    2015-03-27

    A tandem gold-catalyzed hydroamination/formal aza-Diels-Alder reaction is described. This process, which employs quaternary homopropargyl amino ester substrates, leads to the formation of an intrincate tetracyclic framework and involves the generation of four bonds and five stereocenters in a highly diastereoselective manner. Theoretical calculations have allowed us to propose a suitable mechanistic rationalization for the tandem protocol. Additionally, by studying the influence of the ligands on the rate of the gold-catalyzed reactions, it was possible to establish optimum conditions in which to perform the process with a variety of substituents on the amino ester substrates. Notably, the asymmetric version of the tandem reaction was also evaluated. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Facile Synthesis of N-Tosyl Aza-Baylis-Hillman Adducts of Acrylamide via a Pd-Catalyzed Hydration of Nitrile to Amide

    International Nuclear Information System (INIS)

    Kim, Eun Sun; Kim, Yu Mi; Kim, Jae Nyoung

    2010-01-01

    We developed an efficient palladium-catalyzed two-step protocol for the synthesis of N-tosyl aza-Baylis-Hillman adducts of acrylamide. The method involved the preparation of the corresponding Baylis-Hillman adducts of acrylonitrile and the following Pd-catalyzed hydration of nitrile with acetaldoxime. The Baylis-Hillman reaction, which involves the coupling of activated vinyl compounds with electrophiles under the catalytic influence of a tertiary amine, gives rise to adducts, so called Baylis-Hillman adducts, with a new stereocenter and has proven to be a very useful carbon-carbon bond-forming method in the synthesis of highly functionalized molecules. As the activated vinyl compounds, various compounds have been used in the Baylis-Hillman reaction including acrylates, acrylonitrile, vinyl ketones, vinyl sulfones and acrylamides. However, among the activated vinyl compounds acrylamide has not been used much for the synthesis of the corresponding Baylis-Hillman adducts due to its sluggish reactivity

  7. Enantioselective Synthesis of α-Mercapto-β-amino Esters via Rh(II)/Chiral Phosphoric Acid-Cocatalyzed Three-Component Reaction of Diazo Compounds, Thiols, and Imines.

    Science.gov (United States)

    Xiao, Guolan; Ma, Chaoqun; Xing, Dong; Hu, Wenhao

    2016-12-02

    An enantioselective method for the synthesis of α-mercapto-β-amino esters has been developed via a rhodium(II)/chiral phosphoric acid-cocatalyzed three-component reaction of diazo compounds, thiols, and imines. This transformation is proposed to proceed through enantioselective trapping of the sulfonium ylide intermediate generated in situ from the diazo compound and thiol by the phosphoric acid-activated imine. With this method, a series of α-mercapto-β-amino esters were obtained in good yields with moderate to good stereoselectivities.

  8. Copper(II)-catalyzed enantioselective hydrosilylation of halo-substituted alkyl aryl and heteroaryl ketones: asymmetric synthesis of (R)-fluoxetine and (S)-duloxetine.

    Science.gov (United States)

    Zhou, Ji-Ning; Fang, Qiang; Hu, Yi-Hu; Yang, Li-Yao; Wu, Fei-Fei; Xie, Lin-Jie; Wu, Jing; Li, Shijun

    2014-02-14

    A set of reaction conditions has been established to facilitate the non-precious copper-catalyzed enantioselective hydrosilylation of a number of structurally diverse β-, γ- or ε-halo-substituted alkyl aryl ketones and α-, β- or γ-halo-substituted alkyl heteroaryl ketones under air to afford a broad spectrum of halo alcohols in high yields and good to excellent enantioselectivities (up to 99% ee). The developed procedure has been successfully applied to the asymmetric synthesis of antidepressant drugs (R)-fluoxetine and (S)-duloxetine, which highlighted its synthetic utility.

  9. Application of a Heterogeneous Chiral Titanium Catalyst Derived from Silica-Supported 3-Aryl H8-BINOL to Enantioselective Alkylation and Arylation of Aldehydes.

    Science.gov (United States)

    Akai, Junichiro; Watanabe, Satoshi; Michikawa, Kumiko; Harada, Toshiro

    2017-07-07

    A 3-aryl H 8 -BINOL was grafted on the surface of silica gel using a hydrosilane derivative as a precursor, and the resulting silica-supported ligand (6 mol %) was employed in the enantioselective alkylation and arylation of aldehydes in the presence of Ti(O i Pr) 4 . The reactions using Et 2 Zn, Et 3 B, and aryl Grignard reagents all afforded the corresponding adducts in high enantioselectivities and yields. The silica-immobilized titanium catalyst could be reused up to 14 times without appreciable deterioration of the activity.

  10. Rhodium-Catalyzed Asymmetric N-H Functionalization of Quinazolinones with Allenes and Allylic Carbonates: The First Enantioselective Formal Total Synthesis of (-)-Chaetominine.

    Science.gov (United States)

    Zhou, Yirong; Breit, Bernhard

    2017-12-22

    An unprecedented asymmetric N-H functionalization of quinazolinones with allenes and allylic carbonates was successfully achieved by rhodium catalysis with the assistance of chiral bidentate diphosphine ligands. The high efficiency and practicality of this method was demonstrated by a low catalyst loading of 1 mol % as well as excellent chemo-, regio-, and enantioselectivities with broad functional group compatibility. Furthermore, this newly developed strategy was applied as key step in the first enantioselective formal total synthesis of (-)-chaetominine. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. An ylide transformation of rhodium(I) carbene: enantioselective three-component reaction through trapping of rhodium(I)-associated ammonium ylides by β-nitroacrylates.

    Science.gov (United States)

    Ma, Xiaochu; Jiang, Jun; Lv, Siying; Yao, Wenfeng; Yang, Yang; Liu, Shunying; Xia, Fei; Hu, Wenhao

    2014-11-24

    The chiral Rh(I)-diene-catalyzed asymmetric three-component reaction of aryldiazoacetates, aromatic amines, and β-nitroacrylates was achieved to obtain γ-nitro-α-amino-succinates in good yields and with high diastereo- and enantioselectivity. This reaction is proposed to proceed through the enantioselective trapping of Rh(I)-associated ammonium ylides by nitroacrylates. This new transformation represents the first example of Rh(I)-carbene-induced ylide transformation. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Rhodium/chiral diene-catalyzed asymmetric 1,4-addition of arylboronic acids to chromones: a highly enantioselective pathway for accessing chiral flavanones.

    Science.gov (United States)

    He, Qijie; So, Chau Ming; Bian, Zhaoxiang; Hayashi, Tamio; Wang, Jun

    2015-03-01

    Chromone has been noted to be one of the most challenging substrates in the asymmetric 1,4-addition of α,β-unsaturated carbonyl compounds. By employing the rhodium complex associated with a chiral diene ligand, (R,R)-Ph-bod*, the 1,4-addition of a variety of arylboronic acids was realized to give high yields of the corresponding flavanones with excellent enantioselectivities (≥97% ee, 99% ee for most substrates). Ring-opening side products, which would lead to erosion of product enantioselectivity, were not observed under the stated reaction conditions. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Predicting CYP2C19 Catalytic Parameters for Enantioselective Oxidations Using Artificial Neural Networks and a Chirality Code

    Science.gov (United States)

    Hartman, Jessica H.; Cothren, Steven D.; Park, Sun-Ha; Yun, Chul-Ho; Darsey, Jerry A.; Miller, Grover P.

    2013-01-01

    Cytochromes P450 (CYP for isoforms) play a central role in biological processes especially metabolism of chiral molecules; thus, development of computational methods to predict parameters for chiral reactions is important for advancing this field. In this study, we identified the most optimal artificial neural networks using conformation-independent chirality codes to predict CYP2C19 catalytic parameters for enantioselective reactions. Optimization of the neural networks required identifying the most suitable representation of structure among a diverse array of training substrates, normalizing distribution of the corresponding catalytic parameters (kcat, Km, and kcat/Km), and determining the best topology for networks to make predictions. Among different structural descriptors, the use of partial atomic charges according to the CHelpG scheme and inclusion of hydrogens yielded the most optimal artificial neural networks. Their training also required resolution of poorly distributed output catalytic parameters using a Box-Cox transformation. End point leave-one-out cross correlations of the best neural networks revealed that predictions for individual catalytic parameters (kcat and Km) were more consistent with experimental values than those for catalytic efficiency (kcat/Km). Lastly, neural networks predicted correctly enantioselectivity and comparable catalytic parameters measured in this study for previously uncharacterized CYP2C19 substrates, R- and S-propranolol. Taken together, these seminal computational studies for CYP2C19 are the first to predict all catalytic parameters for enantioselective reactions using artificial neural networks and thus provide a foundation for expanding the prediction of cytochrome P450 reactions to chiral drugs, pollutants, and other biologically active compounds. PMID:23673224

  14. Enantioselective changes in oxidative stress and toxin release in Microcystis aeruginosa exposed to chiral herbicide diclofop acid

    Energy Technology Data Exchange (ETDEWEB)

    Ye, Jing [School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418 (China); MOE Key Lab of Environmental Remediation and Ecosystem Health, College of Natural Research and Environmental Sciences, Zhejiang University, Hangzhou 310058 (China); Zhang, Ying [Department of Environmental Science, East China Normal University, Shanghai 200241 (China); Chen, Shengwen [School of Urban Development and Environment Engineering, Shanghai Second Polytechnic University, Shanghai 201209 (China); Liu, Chaonan; Zhu, Yongqiang [School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418 (China); Liu, Weiping, E-mail: wliu@zju.edu.cn [MOE Key Lab of Environmental Remediation and Ecosystem Health, College of Natural Research and Environmental Sciences, Zhejiang University, Hangzhou 310058 (China)

    2014-01-15

    Highlights: •The first study on enantioselective oxidative stress and toxin release from Microcystis aeruginosa. •Provide information for the R-enantiomer poses more oxidative stress than the S-enantiomer. •Lifecycle analysis of chiral pollutants needs more attention in environmental assessment. -- Abstract: Enantioselective oxidative stress and toxin release from Microcystis aeruginosa after exposure to the chiral herbicide diclofop acid were investigated. Racemic diclofop acid, R-diclofop acid and S-diclofop acid induced reactive oxygen species (ROS) generation, increased the concentration of malondialdehyde (MDA), enhanced the activity of superoxide dismutase (SOD) and triggered toxin release in M. aeruginosa to varying degrees. The increase in MDA concentration and SOD activity in M. aeruginosa occurred sooner after exposure to diclofop acid than when the cyanobacteria was exposed to either the R- and the S-enantiomer. In addition, enantioselective toxicity of the enantiomers was observed. The R-enantiomer trigged more ROS generation, more SOD activity and more toxin synthesis and release in M. aeruginosa cells than the S-enantiomer. Diclofop acid and its R-enantiomer may collapse the transmembrane proton gradient and destroy the cell membrane through lipid peroxidation and free radical oxidation, whereas the S-enantiomer did not demonstrate such action. R-diclofop acid inhibits the growth of M. aeruginosa in the early stage, but ultimately induced greater toxin release, which has a deleterious effect on the water column. These results indicate that more comprehensive study is needed to determine the environmental safety of the enantiomers, and application of chiral pesticides requires more direct supervision and training. Additionally, lifecycle analysis of chiral pollutants in aquatic system needs more attention to aide in the environmental assessment of chiral pesticides.

  15. Chiral Pyridinium Phosphoramide as a Dual Brønsted Acid Catalyst for Enantioselective Diels-Alder Reaction.

    Science.gov (United States)

    Nishikawa, Yasuhiro; Nakano, Saki; Tahira, Yuu; Terazawa, Kanako; Yamazaki, Ken; Kitamura, Chitoshi; Hara, Osamu

    2016-05-06

    Chiral pyridinium phosphoramide 1·HX was designed to be a new class of chiral Brønsted acid catalyst in which both the pyridinium proton and the adjacent imide-like proton activated by the electron-withdrawing pyridinium moiety could work cooperatively as strong dual proton donors. The potential of 1·HX was shown in the enantioselective Diels-Alder reactions of 1-amino dienes with various dienophiles including N-unsubstituted maleimide, which has yet to be successfully used in an asymmetric Diels-Alder reaction.

  16. Nickel(0)-catalyzed enantioselective annulations of alkynes and arylenoates enabled by a chiral NHC ligand: efficient access to cyclopentenones.

    Science.gov (United States)

    Ahlin, Joachim S E; Donets, Pavel A; Cramer, Nicolai

    2014-11-24

    Cyclopentenones are versatile structural motifs of natural products as well as reactive synthetic intermediates. The nickel-catalyzed reductive [3+2] cycloaddition of α,β-unsaturated aromatic esters and alkynes constitutes an efficient method for their synthesis. Here, nickel(0) catalysts comprising a chiral bulky C1-symmetric N-heterocyclic carbene ligand were shown to enable an efficient asymmetric synthesis of cyclopentenones from mesityl enoates and internal alkynes under mild conditions. The bulky NHC ligand provided the cyclopentenone products in very high enantioselectivity and led to a regioselective incorporation of unsymmetrically substituted alkynes. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Isoindolinones as Michael Donors under Phase Transfer Catalysis: Enantioselective Synthesis of Phthalimidines Containing a Tetrasubstituted Carbon Stereocenter

    Directory of Open Access Journals (Sweden)

    Francesco Scorzelli

    2015-05-01

    Full Text Available Readily available chiral ammonium salts derived from cinchona alkaloids have proven to be effective phase transfer catalysts in the asymmetric Michael reaction of 3-substituted isoindolinones. This protocol provides a convenient method for the construction of valuable asymmetric 3,3-disubstituted isoindolinones in high yields and  moderate to good enantioselectivity. Diastereoselectivity was also investigated in the construction of contiguous tertiary and quaternary stereocenters. The use of acrolein as Michael acceptor led to an interesting tricyclic derivative, a pyrroloisoindolinone analogue, via a tandem conjugated addition/cyclization reaction.

  18. Enantioselective semi-preparative HPLC separation of PCB metabolites and their absolute structures determined by electronic and vibrational circular dichroism

    Energy Technology Data Exchange (ETDEWEB)

    Tuan, H.P.; Larsson, C.; Huehnerfuss, H. [Hamburg Univ. (Germany). Inst. fuer Organische Chemie; Hoffmann, F.; Froeba, M. [Giessen Univ. (Germany). Inst. fuer Anorganische und Analytische Chemie; Bergmann, Aa. [Stockholm Univ. (Sweden). Dept. of Environmental Chemistry

    2004-09-15

    The present paper represents a first result of an ongoing systematic study of atropisomeric methylsulfonyl, methylthionyl, hydroxy, and methoxy metabolites of environmentally most relevant PCBs. This involves semi-preparative enantioselective HPLC separation to obtain pure atropisomers from synthesized PCB metabolite standards, their configuration estimation using the electronic circular dichroism (UV-CD) method and the determination / confirmation of these absolute configurations applying the combined vibrational circular dichroism (VCD) / ab initio approach. The following substances have been investigated: 4-HO-, 4-MeO-, 4-MeS-, 4-MeSO2-, 3-MeS- and 3-MeSO{sub 2}-CB149.

  19. 2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) is Enantioselectively Oxidized to Hydroxylated Metabolites by Rat Liver Microsomes

    Science.gov (United States)

    Wu, Xianai; Pramanik, Ananya; Duffel, Michael W.; Hrycay, Eugene G.; Bandiera, Stelvio M.; Lehmler, Hans-Joachim; Kania-Korwel, Izabela

    2011-01-01

    Developmental exposure to multiple-ortho substituted polychlorinated biphenyls (PCBs) causes adverse neurodevelopmental outcomes in laboratory animals and humans by mechanisms involving the sensitization of Ryanodine receptors (RyRs). In the case of PCB 136, the sensitization of RyR is enantiospecific, with only (-)-PCB 136 being active. However, the role of enantioselective metabolism in the developmental neurotoxicity of PCB 136 is poorly understood. The present study employed hepatic microsomes from phenobarbital (PB-), dexamethasone (DEX-) and corn oil (VEH-)treated male Sprague-Dawley rats to investigate the hypothesis that PCB 136 atropisomers are enantioselectively metabolized by P450 enzymes to potentially neurotoxic, hydroxylated PCB 136 metabolites. The results demonstrated the time- and isoform-dependent formation of three metabolites, with 5-OH-PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl-5-ol) being the major metabolite. The formation of 5-OH-PCB 136 increased with the activity of P450 2B enzymes in the microsomal preparation, which is consistent with PCB 136 metabolism by rat P450 2B1. The minor metabolite 4-OH-PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl-4-ol) was produced by a currently unidentified P450 enzymes. An enantiomeric enrichment of (-)-PCB 136 was observed in microsomal incubations due to the preferential metabolism of (+)-PCB 136 to the corresponding 5-OH-PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl-5-ol) atropisomer. 4-OH-PCB 136 displayed an enrichment of the atropisomer formed from (-)-PCB 136; however, the enrichment of this metabolite atropisomer didn't affect the enantiomeric enrichment of the parent PCB because 4-OH-PCB 136 is only a minor metabolite. Although the formation of 5- and 4-OH-PCB 136 atropisomers increased with time, the enantioselective formation of the OH-PCB metabolites resulted in constant enantiomeric enrichment, especially at later incubation times. These observations not only demonstrate that the chiral signatures of

  20. P(O)R2-Directed Enantioselective C-H Olefination toward Chiral Atropoisomeric Phosphine-Olefin Compounds.

    Science.gov (United States)

    Li, Shi-Xia; Ma, Yan-Na; Yang, Shang-Dong

    2017-04-07

    An effective synthesis of chiral atropoisomeric biaryl phosphine-olefin compounds via palladium-catalyzed enantioselective C-H olefination has been developed for the first time. The reactions are operationally simple, tolerate wide functional groups, and have a good ee value. Notably, P(O)R 2 not only acts as the directing group to direct C-H activation in order to make a useful ligand but also serves to facilitate composition of the product in a useful manner in this transformation.

  1. Enantiomerization and enantioselective bioaccumulation of benalaxyl in Tenebrio molitor larvae from wheat bran.

    Science.gov (United States)

    Gao, Yongxin; Chen, Jinhui; Wang, Huili; Liu, Chen; Lv, Xiaotian; Li, Jianzhong; Guo, Baoyuan

    2013-09-25

    The enantiomerization and enatioselecive bioaccumulation of benalaxyl by dietary exposure to Tenebrio molitor larvae under laboratory conditions were studied by HPLC-MS/MS. Exposure of enantiopure R-benalaxyl and S-benalaxyl in T. molitor larvae revealed significant enantiomerization with formation of the R enantiomers from the S enantiomers, and vice versa. Enantiomerization was not observed in wheat bran during the period of 21 days. For the bioaccumulation experiment, the enantiomer fraction in T. molitor larvae was maintained approximately at 0.6, whereas the enantiomer fraction in wheat bran was maintained at 0.5; in other words, the bioaccumulation of benalaxyl was enantioselective in T. molitor larvae. Mathematical models for a process of uptake, degradation, and enantiomerization were developed, and the rates of uptake, degradation, and enantiomerization of R-benealaxyl and S-benealaxyl were estimated, respectively. The results were that the rate of uptake of R-benalaxyl (kRa = 0.052 h(-1)) was slightly lower than that of S-benalaxyl (kSa = 0.061 h(-1)) from wheat bran; the rate of degradation of R-benalaxyl (kRd = 0.285 h(-1)) was higher than that of S-benalaxyl (kSd = 0.114 h(-1)); and the rate of enantiomerization of R-benalaxyl (kRS = 0.126 h(-1)) was higher than that of S-benalaxyl (kSR = 0.116 h(-1)). It was suggested that enantioselectivtiy was caused not only by actual degradation and metabolism but also by enantiomerization, which was an important process in the environmental fate and behavior of chiral pesticides.

  2. Albendazole-praziquantel interaction in healthy volunteers: kinetic disposition, metabolism and enantioselectivity

    Science.gov (United States)

    Lima, Renata Monteiro; Ferreira, Maria Augusta Drago; de Jesus Ponte Carvalho, Teresa Maria; Dumêt Fernandes, Bruno José; Takayanagui, Osvaldo Massaiti; Garcia, Hector Hugo; Coelho, Eduardo Barbosa; Lanchote, Vera Lucia

    2011-01-01

    AIM This study investigated the kinetic disposition, metabolism and enantioselectivity of albendazole (ABZ) and praziquantel (PZQ) administered alone and in combination to healthy volunteers. METHODS A randomized crossover study was carried out in three phases (n = 9), in which some volunteers started in phase 1 (400 mg ABZ), others in phase 2 (1500 mg PZQ), and the remaining volunteers in phase 3 (400 mg ABZ + 1500 mg PZQ). Serial blood samples were collected from 0–48 h after drug administration. Pharmacokinetic parameters were calculated using a monocompartmental model with lag time and were analyzed using the Wilcoxon test; P≤ 0.05. RESULTS The administration of PZQ increased the plasma concentrations of (+)-ASOX (albendazole sulphoxide) by 264% (AUC 0.99 vs. 2.59 µg ml−1 h), (−)-ASOX by 358% (0.14 vs. 0.50 µg ml−1 h) and albendazole sulfone (ASON) by 187% (0.17 vs. 0.32 µg ml−1 h). The administration of ABZ did not change the kinetic disposition of (+)-(S)-PZQ (–)-(R)-4-OHPZQ or (+)-(S)-4-OHPZQ, but increased the plasma concentration of (–)-(R)-PZQ by 64.77% (AUC 0.52 vs. 0.86 µg ml−1 h). CONCLUSIONS The pharmacokinetic interaction between ABZ and PZQ in healthy volunteers was demonstrated by the observation of increased plasma concentrations of ASON, both ASOX enantiomers and (–)-(R)-PZQ. Clinically, the combination of ABZ and PZQ may improve the therapeutic efficacy as a consequence of higher concentration of both active drugs. On the other hand, the magnitude of this elevation may represent an increased risk of side effects, requiring, certainly, reduction of the dosage. However, further studies are necessary to evaluate the efficacy and safety of this combination. PMID:21395645

  3. Enantioselective analysis of citalopram and escitalopram in postmortem blood together with genotyping for CYP2D6 and CYP2C19.

    Science.gov (United States)

    Carlsson, Björn; Holmgren, Anita; Ahlner, Johan; Bengtsson, Finn

    2009-03-01

    Citalopram is marketed as a racemate (50:50) mixture of the S(+)-enantiomer and R(-)-enantiomer and the active S(+)-enantiomer (escitalopram) that possess inhibitory effects. Citalopram was introduced in Sweden in 1992 and is the most frequently used antidepressant to date in Sweden. In 2002, escitalopram was introduced onto the Swedish market for treatment of depression and anxiety disorders. The main objective of this study was to investigate S(+)-citalopram [i.e., the racemic drug (citalopram) or the enantiomer (escitalopram)] present in forensic autopsy cases positive for the presence of citalopram in routine screening using a non-enantioselective bioanalytical method. Fifty out of the 270 samples found positive by gas chromatography-nitrogen-phosphorus detection were further analyzed using enantioselective high-performance liquid chromatography. The 50 cases were genotyped for CYP2D6 and CYP2C19, as these isoenzymes are implicated in the metabolism of citalopram and escitalopram. In samples positive for racemic citalopram using the screening method for forensic autopsy cases, up to 20% would have been misinterpreted in the absence of an enantioselective method. An enantioselective method is thus necessary for correct interpretation of autopsy cases, after the enantiomer has been introduced onto the market. The percentage of poor metabolizers was 6% for CYP2D6 and 8% for CYP2C19.

  4. Development of tartaric acid derived chiral guanidines and their application to catalytic enantioselective α-hydroxylation of β-dicarbonyl compounds.

    Science.gov (United States)

    Zou, Liwei; Wang, Baomin; Mu, Hongfang; Zhang, Huanrui; Song, Yuming; Qu, Jingping

    2013-06-21

    A novel library of chiral guanidines featuring a tartaric acid skeleton was developed from diethyl l-tartrate. These guanidines are easily accessed with tunable steric and electronic properties. The utilities of the guanidines were highlighted by their ability to catalyze the α-hydroxylation of β-ketoesters and β-diketones with remarkable efficiency and excellent enantioselectivity.

  5. The role of achiral pyrazolidinone templates in enantioselective Diels-Alder reactions: scope, limitations, and conformational insights.

    Science.gov (United States)

    Sibi, Mukund P; Stanley, Levi M; Nie, Xiaoping; Venkatraman, Lakshmanan; Liu, Mei; Jasperse, Craig P

    2007-01-17

    We have evaluated the role of achiral pyrazolidinone templates in conjunction with chiral Lewis acids in room temperature, enantioselective Diels-Alder cycloadditions. The role of the fluxional N(1) substituent was examined, with the bulky 1-naphthylmethyl group providing enantioselectivities up to 99% ee, while templates with smaller fluxional groups gave lower selectivities. High selectivities were also observed in reactions of 7d with chiral Lewis acids derived from relatively small chiral ligands, suggesting the pyrazolidinone templates are capable of relaying stereochemical information from the ligand to the reaction center. Lewis acids capable of adapting square planar geometries, such as Cu(OTf)2, Cu(ClO4)2, and Pd(ClO4)2, were found to be particularly effective at providing high selectivities. Additionally, substitution at the C-5 position of the pyrazolidinone templates has been shown to be critical for optimal selectivity. Reactions of the optimal pyrazolidinone appended with a number of common dienophiles and various dienes demonstrate the utility of this achiral template. Furthermore, catalytic loadings could be lowered to 2.5 mol % with essentially no loss in selectivity. Pi-Pi interactions were evaluated as a means to explain the unusually high selectivity observed at room temperature. Finally, non-C2-symmetric ligands were employed as a test to determine if chiral relay was operative.

  6. Boosting Chemical Stability, Catalytic Activity, and Enantioselectivity of Metal-Organic Frameworks for Batch and Flow Reactions.

    Science.gov (United States)

    Chen, Xu; Jiang, Hong; Hou, Bang; Gong, Wei; Liu, Yan; Cui, Yong

    2017-09-27

    A key challenge in heterogeneous catalysis is the design and synthesis of heterogeneous catalysts featuring high catalytic activity, selectivity, and recyclability. Here we demonstrate that high-performance heterogeneous asymmetric catalysts can be engineered from a metal-organic framework (MOF) platform by using a ligand design strategy. Three porous chiral MOFs with the framework formula [Mn 2 L(H 2 O) 2 ] are prepared from enantiopure phosphono-carboxylate ligands of 1,1'-biphenol that are functionalized with 3,5-bis(trifluoromethyl)-, bismethyl-, and bisfluoro-phenyl substituents at the 3,3'-position. For the first time, we show that not only chemical stability but also catalytic activity and stereoselectivity of the MOFs can be tuned by modifying the ligand structures. Particularly, the MOF incorporated with -CF 3 groups on the pore walls exhibits enhanced tolerance to water, weak acid, and base compared with the MOFs with -F and -Me groups. Under both batch and flow reaction systems, the CF 3 -containing MOF demonstrated excellent reactivity, selectivity, and recyclability, affording high yields and enantioselectivities for alkylations of indoles and pyrrole with a range of ketoesters or nitroalkenes. In contrast, the corresponding homogeneous catalysts gave low enantioselectivity in catalyzing the tested reactions.

  7. Potencial de biocatálise enantiosseletiva de lipases microbianas Potential of enantioselective biocatalysis by microbial lipases

    Directory of Open Access Journals (Sweden)

    Patrícia de O. Carvalho

    2005-08-01

    Full Text Available Microbial lipases have a great potential for commercial applications due to their stability, selectivity and broad substrate specificity because many non-natural acids, alcohols or amines can be used as the substrate. Three microbial lipases isolated from Brazilian soil samples (Aspergillus niger; Geotrichum candidum; Penicillium solitum were compared in terms of their stability and as biocatalysts in the enantioselective esterification using racemic substrates in organic medium. The lipase from Aspergillus niger showed the highest activity (18.2 U/mL and was highly thermostable, retaining 90% and 60% activity at 50 ºC and 60 ºC after 1 hour, respectively. In organic medium, this lipase provided the best results in terms of enantiomeric excess of the (S-active acid (ee = 6.1% and conversion value (c = 20% in the esterification of (R,S-ibuprofen with 1-propanol in isooctane. The esterification reaction of the racemic mixture of (R,S-2-octanol with decanoic acid proceeded with high enantioselectivity when lipase from Aspergillus niger (E = 13.2 and commercial lipase from Candida antarctica (E = 20 were employed.

  8. Enantioselective Crystallization of Sodium Chlorate in the Presence of Racemic Hydrophobic Amino Acids and Static Magnetic Fields

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    María-Paz Zorzano

    2014-06-01

    Full Text Available We study the bias induced by a weak (200 mT external magnetic field on the preferred handedness of sodium chlorate crystals obtained by slow evaporation at ambient conditions of its saturated saline solution with 20 ppm of added racemic (dl hydrophobic amino acids. By applying the Fisher test to pairs of experiments with opposing magnetic field orientation we conclude, with a confidence level of 99.7%, that at the water-air interface of this saline solution there is an enantioselective magnetic interaction that acts upon racemic mixtures of hydrophobic chiral amino acids. This interaction has been observed with the three tested racemic hydrophobic amino acids: dl-Phe, dl-Try and dl-Trp, at ambient conditions and in spite of the ubiquitous chiral organic contamination. This enantioselective magnetic dependence is not observed when there is only one handedness of added chiral amino-acid, if the added amino acid is not chiral or if there is no additive. This effect has been confirmed with a double blind test. This novel experimental observation may have implications for our view of plausible initial prebiotic scenarios and of the roles of the geomagnetic field in homochirality in the biosphere.

  9. The synthesis and characterization of 1,2-dihydroxyimino-3,6-di-aza-8,9-O-iso-butylidene nonane and its complexes with Ni(II), Cu(II), Zn(II) and Cd(II)

    International Nuclear Information System (INIS)

    Canpolat, E.; Kaya, M.; Gorgulu, A.O.

    2002-01-01

    1,2-dihydroxyimino-3,6-di-aza-8,9-O-iso-butylidene nonane (H 2 L) was synthesized starting from 1,2-O-iso-butylidene-4-aza-6-amino hexane (RNH 2 ) and antichloroglyoxime. Ni(II) and Cu(II) complexes of H 2 L have a metal:ligand ratio 1:2 and the ligand coordinates through two N atoms, as do most of the vic-dioximes. However, Zn(II) and Cd(II) complexes of H 2 L have a metal: ligand ratio 1:1 and one chloride ion and one water molecule are also coordinated to the metal ion. Structures of the ligand and its transition-metal complexes are proposed, according to elemental analysis, IR, 13 C and 1 H NMR spectra, magnetic susceptibility measurements and thermogravimetric analyses (TGA). (author)

  10. An efficient synthesis of β-amino ketone compounds through one-pot three-component Mannich-type reactions using bismuth nitrate as catalyst

    Directory of Open Access Journals (Sweden)

    S. Sheik Mansoor

    2015-07-01

    Full Text Available Three components one-pot Mannich reaction of aromatic ketone, aromatic aldehyde and aromatic amines has been efficiently catalyzed by recyclable bismuth nitrate (Bi(NO33, BN at ambient temperature to give various β-amino carbonyl compounds in high yields. This method has advantages of mild condition, no environmental pollution, and simple work-up procedures. Most importantly, β-amino carbonyl compounds with ortho-substituted aromatic amines are obtained in acceptable to moderate yields by this methodology.

  11. [Synthetic Studies of Bioactive Heterocyclic Natural Products and Fused Heterocyclic Compounds Based on the Thermal Electrocyclic or Azaelectocyclic Reaction of 6π-Electron or Aza-6π-electron Systems].

    Science.gov (United States)

    Hibino, Satoshi

    2016-01-01

    Since 1979, synthetic studies of bioactive heterocyclic natural products and condensed heteroaromatic compounds based on the thermal electrocyclic reaction of 6π-electron or aza-6π-electron systems incorporating the double bond of the principal aromatic or heteroaromatic ring have been conducted by our research group. In this review, five types of electrocyclic and azaelectrocyclic reaction are described: 1) the synthesis of the carbazole alkaloids hyellazole and 6-chlorohyellazole through the electrocyclic reaction of 2,3-bisalkenylindoles; 2) synthetic studies of the pyridocarbazole alkaloids ellipticine and olivacine through the electrocyclic reactions of the indole-2,3- and pyridine-3,4-quinodimethane intermediates; 3) synthetic studies of polysubstituted carbazole alkaloids through the allene-mediated electrocyclic reactions involving the indole 2,3-bond; 4) synthetic studies of fused pyridine rings through the azaelectrocyclic reaction of the 1-aza-6π-electron system using the oxime or oxime ether; and 5) synthetic studies of fused pyridine rings through the azaelectrocyclic reaction of the 2-aza-6π-electron system using a carbodiimide or isocyanate.

  12. Enantioselective copper catalysed intramolecular C-H insertion reactions of α-diazo-β-keto sulfones, α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones; the influence of the carbene substituent.

    Science.gov (United States)

    Shiely, Amy E; Slattery, Catherine N; Ford, Alan; Eccles, Kevin S; Lawrence, Simon E; Maguire, Anita R

    2017-03-22

    Enantioselectivities in C-H insertion reactions, employing the copper-bis(oxazoline)-NaBARF catalyst system, leading to cyclopentanones are highest with sulfonyl substituents on the carbene carbon, and furthermore, the impact is enhanced by increased steric demand on the sulfonyl substituent (up to 91%ee). Enantioselective intramolecular C-H insertion reactions of α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones are reported for the first time.

  13. Enantioselective distribution of albendazole metabolites in cerebrospinal fluid of patients with neurocysticercosis

    Science.gov (United States)

    Takayanagui, O M; Bonato, P S; Dreossi, S A C; Lanchote, V L

    2002-01-01

    Aims Albendazole (ABZ) is effective in the treatment of neurocysticercosis. ABZ undergoes extensive metabolism to (+) and (−)-albendazole sulphoxide (ASOX), which are further metabolized to albendazole sulphone (ASON). We have investigated the distribution of (+)-ASOX (−)-ASOX, and ASON in cerebrospinal fluid (CSF) of patients with neurocysticercosis. Methods Twelve patients with a diagnosis of active brain parenchymal neurocysticercosis treated with albendazole for 8 days (15 mg kg−1 day−1) were investigated. On day 8, serial blood samples were collected during the dose interval (0–12 h) and one CSF sample was taken from each patient by lumbar puncture at different time points up to 12 h after the last albendazole dose. Albendazole metabolites were determined in CSF and plasma samples by h.p.l.c. using a Chiralpak AD column and fluorescence detection. Population curves for CSF albendazole metabolite concentration vs time were constructed. Results The mean plasma/CSF ratios were 2.6 (95% CI: 1.9, 3.3) for (+)-ASOX and 2.7 (95% CI: 1.8, 3.7) for (−)-ASOX, with the two-tailed P value of 0.9873 being non-significant. These data indicate that the transport of ASOX through the blood–brain barrier is not enantioselective, but rather depends on passive diffusion. The present results suggest the accumulation of the (+)-ASOX metabolite in the CSF of patients with neurocysticercosis. The CSF AUC(+)/AUC(−) ratio was 3.4 for patients receiving albendazole every 12 h. The elimination half-life of both ASOX enantiomers in CSF was 2.5 h. ASOX was the predominant metabolite in the CSF compared with ASON; the CSF AUCASOX/AUCASON ratio was approximately 20 and the elimination half-life of ASON in CSF was 2.6 h. Conclusions We have demonstrated accumulation of the (+)-ASOX metabolite in CSF, which was about three times greater than the (−) antipode. ASOX concentrations were approximately 20 times higher than those observed for the ASON metabolite. PMID:12207631

  14. Enantioselective N-demethylation and hydroxylation of sibutramine in human liver microsomes and recombinant cytochrome p-450 isoforms.

    Science.gov (United States)

    Shinde, Dhananjay D; Kim, Min-Jung; Jeong, Eun-Sook; Kim, Yang-Weon; Lee, Ji-Woo; Shin, Jae-Gook; Kim, Dong-Hyun

    2014-01-01

    The enantioselective metabolism of sibutramine was examined using human liver microsomes (HLM) and recombinant cytochrome P-450 (CYP) isoforms. This drug is metabolized to N-mono-desmethyl- (M1) and N,N-di-desmethylsibutramine (M2), and subsequent hydroxylation results in hydroxyl M1 (HM1) and hydroxyl M2 (HM2). No significant difference was noted in formation of M1from sibutramine between R- and S-sibutramine in HLM. However, S-enantiomers of M1 and M2 were preferentially metabolized to M2, HM1, and HM2compared to R-enantiomers in HLM, and intrinsic clearance (Clint) ratios of S-enantiomers/R-enantiomers were 1.97, 4.83, and 9.94 for M2, HM1, and HM2, respectively. CYP3A4 and CYP3A5 were only involved in the formation of M1, whereas CYP2B6 and CYP2C19 were responsible for all metabolic reactions of sibutramine. CYP2C19 and CYP3A5 displayed catalytic preference for S-sibutramine to S-M1, whereas CYP2B6 and CYP3A4 showed little or no stereoselectivity in metabolism of sibutramine to M1. In the case of M2 formation, CYP2B6 metabolized S-M1 more rapidly than R-M1 with a Clint ratio of 2.14. However, CYP2C19 catalyzed less S-M1 than R-M1 and the Clint ratio of S-M1 to R-M1 was 0.65. The most significant enantioselectivity was observed in formation of HM1 from M1, and HM2 from M2. CYP2B6 and CYP2C19 exhibited preferential catalysis of formation of hydroxyl metabolites from S-enantiomers rather than R-enantiomers. These results indicate that S-sibutramine was more rapidly metabolized by CYP isoforms than R-sibutramine, and that enantioselective metabolism needs to be considered in drug interactions involving sibutramine and co-administered drugs.

  15. Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia.

    Science.gov (United States)

    Müller-Tidow, C; Tschanter, P; Röllig, C; Thiede, C; Koschmieder, A; Stelljes, M; Koschmieder, S; Dugas, M; Gerss, J; Butterfaß-Bahloul, T; Wagner, R; Eveslage, M; Thiem, U; Krause, S W; Kaiser, U; Kunzmann, V; Steffen, B; Noppeney, R; Herr, W; Baldus, C D; Schmitz, N; Götze, K; Reichle, A; Kaufmann, M; Neubauer, A; Schäfer-Eckart, K; Hänel, M; Peceny, R; Frickhofen, N; Kiehl, M; Giagounidis, A; Görner, M; Repp, R; Link, H; Kiani, A; Naumann, R; Brümmendorf, T H; Serve, H; Ehninger, G; Berdel, W E; Krug, U

    2016-03-01

    DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.

  16. Novel photoluminescence enzyme immunoassay based on supramolecular host-guest recognition using L-arginine/6-aza-2-thiothymine-stabilized gold nanocluster.

    Science.gov (United States)

    Wang, Youmei; Lu, Minghua; Tang, Dianping

    2018-06-30

    A new photoluminescence (PL) enzyme immunoassay was designed for sensitive detection of aflatoxin B 1 (AFB 1 ) via an innovative enzyme substrate, 6-aza-2-thiothymine-stabilized gold nanocluster (AAT-AuNC) with L-arginine. The enzyme substrate with strong PL intensity was formed through supramolecular host-guest assembly between guanidine group of L-arginine and AAT capped on the surface of AuNC. Upon arginase introduction, the captured L-arginine was hydrolyzed into ornithine and urea, thus resulting in the decreasing PL intensity. Based on this principle, a novel competitive-type immunoreaction was first carried out on AFB 1 -bovine serum albumin (AFB 1 -BSA) conjugate-coated microplate, using arginase-labeled anti-AFB 1 antibody as the competitor. Under the optimum conditions, the PL intensity increased with the increment of target AFB 1 , and allowed the detection of the analyte at concentrations as low as 3.2 pg mL -1 (ppt). Moreover, L-arginine-AAT-AuNC-based PL enzyme immunoassay afforded good reproducibility and acceptable specificity. In addition, the accuracy of this methodology, referring to commercial AFB 1 ELISA kit, was evaluated to analyze naturally contaminated or spiked peanut samples, giving well-matched results between two methods, thus representing a useful scheme for practical application in quantitative monitoring of mycotoxins in foodstuff. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. Uranyl-organic assemblies with the macrocyclic ligand 1, 4, 8, 11-tetra-aza-cyclo-tetradecane-1, 4, 8, 11-tetraacetate (TETA)

    International Nuclear Information System (INIS)

    Thuery, Pierre

    2010-01-01

    Three uranyl ion complexes obtained from the reaction of uranyl nitrate hexahydrate and 1, 4, 8, 11-tetra-aza-cyclo-tetradecane-1, 4, 8, 11-tetraacetic acid (H 4 TETA) were characterized by their crystal structure. The centrosymmetric macrocycle, in the [3434] conformation with either carbon or nitrogen atoms as corners, is zwitterionic, with four carboxylate groups and two or four protonated nitrogen atoms. The complexes [(UO 2 ) 2 (H 2 TETA)(C 2 O 4 )(H 2 O) 2 ] (1) and [UO 2 (H 4 TETA)(H 2 O)].NO 3 .Cl (2) were synthesized under hydrothermal conditions and 1 includes additional oxalate ligands generated in situ. Both compounds are two-dimensional polymers in which the four-fold monodentate macrocyclic ligand unites either four uranyl oxalate dinuclear species (1) or isolated uranyl ions (2). Complex 3, [UO 2 (H 2 TETA)(H 2 O)].6H 2 O, was obtained at room temperature and, although it displays the same stoichiometry as 2, it differs from it by being a three-dimensional framework. Both 2 and 3 present channels containing either counter-ions or water molecules. As often observed, the water content of the low-temperature species, 3, is higher than that of the high-temperature one, 2. (author)

  18. The Chemical Decomposition of 5-aza-2′-deoxycytidine (Decitabine): Kinetic Analyses and Identification of Products by NMR, HPLC, and Mass Spectrometry

    Science.gov (United States)

    Rogstad, Daniel K.; Herring, Jason L.; Theruvathu, Jacob A.; Burdzy, Artur; Perry, Christopher C.; Neidigh, Jonathan W.; Sowers, Lawrence C.

    2014-01-01

    The nucleoside analog 5-aza-2′-deoxycytidine (Decitabine, DAC) is one of several drugs in clinical use that inhibit DNA methyltransferases, leading to a decrease of 5-methylcytosine in newly replicated DNA and subsequent transcriptional activation of genes silenced by cytosine methylation. In addition to methyltransferase inhibition, DAC has demonstrated toxicity and potential mutagenicity, and can induce a DNA-repair response. The mechanisms accounting for these events are not well understood. DAC is chemically unstable in aqueous solutions, but there is little consensus between previous reports as to its half-life and corresponding products of decomposition at physiological temperature and pH, potentially confounding studies on its mechanism of action and long-term use in humans. Here we have employed a battery of analytical methods to estimate kinetic rates and to characterize DAC decomposition products under conditions of physiological temperature and pH. Our results indicate that DAC decomposes into a plethora of products, formed by hydrolytic opening and deformylation of the triazine ring, in addition to anomerization and possibly other changes in the sugar ring structure. We also discuss the advantages and problems associated with each analytical method used. The results reported here will facilitate ongoing studies and clinical trials aimed at understanding the mechanisms of action, toxicity, and possible mutagenicity of DAC and related analogs. PMID:19480391

  19. Enantioselective recognition of mandelic acid by a 3,6-dithiophen-2-yl-9H-carbazole-based chiral fluorescent bisboronic acid sensor.

    Science.gov (United States)

    Wu, Yubo; Guo, Huimin; James, Tony D; Zhao, Jianzhang

    2011-07-15

    We have prepared chiral fluorescent bisboronic acid sensors with 3,6-dithiophen-2-yl-9H-carbazole as the fluorophore. The thiophene moiety was used to extend the π-conjugation framework of the fluorophore in order to red-shift the fluorescence emission and, at the same time, to enhance the novel process where the fluorophore serves as the electron donor of the photoinduced electron transfer process (d-PET) of the boronic acid sensors; i.e., the background fluorescence of the sensor 1 at acidic pH is weaker compared to that at neutral or basic pH, in stark contrast to the typical a-PET boronic acid sensors (where the fluorophore serves as the electron acceptor of the photoinduced electron transfer process). The benefit of the d-PET boronic acid sensors is that the recognition of the hydroxylic acids can be achieved at acidic pH. We found that the thiophene moiety is an efficient π-conjugation linker and electron donor; as a result, the d-PET contrast ratio of the sensors upon variation of the pH is improved 10-fold when compared to the previously reported d-PET sensors without the thiophene moiety. Enantioselective recognition of tartaric acid was achieved at acid pH, and the enantioselectivity (total response K(D)I(F)(D)/K(L)I(F)(L)) is 3.3. The fluorescence enhancement (I(F)(Sample)/I(F)(Blank)) of sensor 1 upon binding with tartaric acid is 3.5-fold at pH 3.0. With the fluorescent bisboronic acid sensor 1, enantioselective recognition of mandelic acid was achieved for the first time. To the best of our knowledge, this is the first time that the mandelic acid has been enantioselectively recognized using a chiral fluorescent boronic acid sensor. Chiral monoboronic acid sensor 2 and bisboronic acid sensor 3 without the thiophene moiety failed to enantioselectively recognize mandelic acid. Our findings with the thiophene-incorporated boronic acid sensors will be important for the design of d-PET fluorescent sensors for the enantioselective recognition of

  20. Chiral relay: a novel strategy for the control and amplification of enantioselectivity in chiral Lewis acid promoted reactions.

    Science.gov (United States)

    Corminboeuf, Olivier; Quaranta, Laura; Renaud, Philippe; Liu, Mei; Jasperse, Craig P; Sibi, Mukund P

    2003-01-03

    Chiral Lewis acid catalysis has emerged as one of the premiere method to control stereochemistry. Much effort has gone into the design of superior ligands with increasing steric extension to shield distant reactive sites. We report here an alternative and complementary approach based on a "chiral relay". This strategy focuses on the improved design of achiral templates which may relay and amplify the stereochemistry from ligands. The essence of this strategy is that the chiral Lewis acid would effectively convert an achiral template into a chiral non-racemic template. This approach combines the advantages of enantioselective catalysis (substoichiometric amount of the chiral inducer) with the ones of chiral auxiliary control (efficient and predictable stereocontrol).

  1. Enantioselective Organocatalysis in Microreactors: Continuous Flow Synthesis of a (S-Pregabalin Precursor and (S-Warfarin

    Directory of Open Access Journals (Sweden)

    Riccardo Porta

    2015-08-01

    Full Text Available Continuous flow processes have recently emerged as a powerful technology for performing chemical transformations since they ensure some advantages over traditional batch procedures. In this work, the use of commercially available and affordable PEEK (Polyetheretherketone and PTFE (Polytetrafluoroethylene HPLC (High Performance Liquid Chromatography tubing as microreactors was exploited to perform organic reactions under continuous flow conditions, as an alternative to the commercial traditional glass microreactors. The wide availability of tubing with different sizes allowed quickly running small-scale preliminary screenings, in order to optimize the reaction parameters, and then to realize under the best experimental conditions a reaction scale up for preparative purposes. The gram production of some Active Pharmaceutical Ingredients (APIs such as (S-Pregabalin and (S-Warfarin was accomplished in short reaction time with high enantioselectivity, in an experimentally very simple procedure.

  2. Theoretical study on the reaction mechanisms of Michael chirality addition between propionaldehyde and nitroalkene catalyzed by an enantioselective catalyst.

    Science.gov (United States)

    Zhou, Xinming; Li, Ling; Sun, Xuejun; Wang, Yajun; Du, Dongmei; Fu, Hui

    2018-06-01

    The asymmetric Michael addition between propionaldehyde and nitroalkene catalyzed by 8-(ethoxycarbonyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid has obtained relatively high yields and excellent enantioselectivities at room temperature. In this study, the molecular structures and optical activity of the most stable conformation I are optimized at B3LYP/6-311++ G(d,p) level. We find that levorotatory conformation I catalyzing the same Michael addition can produce laevo-product A and dextrorotatory conformation I' can obtain the dextral-product A'. These results have guiding significance for further studying on the new chemzymes and the mechanism of the obtained different chiral products. © 2018 Wiley Periodicals, Inc.

  3. Regio- and Enantioselective Sequential Dehalogenation of rac-1,3-Dibromobutane by Haloalkane Dehalogenase LinB.

    Science.gov (United States)

    Gross, Johannes; Prokop, Zbyněk; Janssen, Dick; Faber, Kurt; Hall, Mélanie

    2016-08-03

    The hydrolytic dehalogenation of rac-1,3-dibromobutane catalyzed by the haloalkane dehalogenase LinB from Sphingobium japonicum UT26 proceeds in a sequential fashion: initial formation of intermediate haloalcohols followed by a second hydrolytic step to produce the final diol. Detailed investigation of the course of the reaction revealed favored nucleophilic displacement of the sec-halogen in the first hydrolytic event with pronounced R enantioselectivity. The second hydrolysis step proceeded with a regioselectivity switch at the primary position, with preference for the S enantiomer. Because of complex competition between all eight possible reactions, intermediate haloalcohols formed with moderate to good ee ((S)-4-bromobutan-2-ol: up to 87 %). Similarly, (S)-butane-1,3-diol was formed at a maximum ee of 35 % before full hydrolysis furnished the racemic diol product. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries.

    Science.gov (United States)

    Yu, Kai; Lu, Ping; Jackson, Jeffrey J; Nguyen, Thuy-Ai D; Alvarado, Joseph; Stivala, Craig E; Ma, Yun; Mack, Kyle A; Hayton, Trevor W; Collum, David B; Zakarian, Armen

    2017-01-11

    Lithium enolates derived from carboxylic acids are ubiquitous intermediates in organic synthesis. Asymmetric transformations with these intermediates, a central goal of organic synthesis, are typically carried out with covalently attached chiral auxiliaries. An alternative approach is to utilize chiral reagents that form discrete, well-defined aggregates with lithium enolates, providing a chiral environment conducive of asymmetric bond formation. These reagents effectively act as noncovalent, or traceless, chiral auxiliaries. Lithium amides are an obvious choice for such reagents as they are known to form mixed aggregates with lithium enolates. We demonstrate here that mixed aggregates can effect highly enantioselective transformations of lithium enolates in several classes of reactions, most notably in transformations forming tetrasubstituted and quaternary carbon centers. Easy recovery of the chiral reagent by aqueous extraction is another practical advantage of this one-step protocol. Crystallographic, spectroscopic, and computational studies of the central reactive aggregate, which provide insight into the origins of selectivity, are also reported.

  5. A Mixed-Ligand Chiral Rhodium(II) Catalyst Enables the Enantioselective Total Synthesis of Piperarborenine B.

    Science.gov (United States)

    Panish, Robert A; Chintala, Srinivasa R; Fox, Joseph M

    2016-04-11

    A novel, mixed-ligand chiral rhodium(II) catalyst, Rh2(S-NTTL)3(dCPA), has enabled the first enantioselective total synthesis of the natural product piperarborenine B. A crystal structure of Rh2(S-NTTL)3(dCPA) reveals a "chiral crown" conformation with a bulky dicyclohexylphenyl acetate ligand and three N-naphthalimido groups oriented on the same face of the catalyst. The natural product was prepared on large scale using rhodium-catalyzed bicyclobutanation/ copper-catalyzed homoconjugate addition chemistry in the key step. The route proceeds in ten steps with an 8% overall yield and 92% ee. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Structural basis for high substrate-binding affinity and enantioselectivity of 3-quinuclidinone reductase AtQR

    International Nuclear Information System (INIS)

    Hou, Feng; Miyakawa, Takuya; Kataoka, Michihiko; Takeshita, Daijiro; Kumashiro, Shoko; Uzura, Atsuko; Urano, Nobuyuki; Nagata, Koji; Shimizu, Sakayu; Tanokura, Masaru

    2014-01-01

    Highlights: • Crystal structure of AtQR has been determined at 1.72 Å. • NADH binding induces the formation of substrate binding site. • AtQR possesses a conserved hydrophobic wall for stereospecific binding of substrate. • Additional Glu197 residue is critical to the high binding affinity. - Abstract: (R)-3-Quinuclidinol, a useful compound for the synthesis of various pharmaceuticals, can be enantioselectively produced from 3-quinuclidinone by 3-quinuclidinone reductase. Recently, a novel NADH-dependent 3-quinuclidionone reductase (AtQR) was isolated from Agrobacterium tumefaciens, and showed much higher substrate-binding affinity (>100 fold) than the reported 3-quinuclidionone reductase (RrQR) from Rhodotorula rubra. Here, we report the crystal structure of AtQR at 1.72 Å. Three NADH-bound protomers and one NADH-free protomer form a tetrameric structure in an asymmetric unit of crystals. NADH not only acts as a proton donor, but also contributes to the stability of the α7 helix. This helix is a unique and functionally significant part of AtQR and is related to form a deep catalytic cavity. AtQR has all three catalytic residues of the short-chain dehydrogenases/reductases family and the hydrophobic wall for the enantioselective reduction of 3-quinuclidinone as well as RrQR. An additional residue on the α7 helix, Glu197, exists near the active site of AtQR. This acidic residue is considered to form a direct interaction with the amine part of 3-quinuclidinone, which contributes to substrate orientation and enhancement of substrate-binding affinity. Mutational analyses also support that Glu197 is an indispensable residue for the activity

  7. Chiral recognition with enantioselective ion exchangers based on carbamoylated cinchonan derivatives as chiral selectors for the HPLC enantioseparation

    International Nuclear Information System (INIS)

    Laemmerhofer, M.

    1996-11-01

    The high-performance liquid chromatographic (HPLC) separation of enantiomers is preferentially performed using chiral stationary phases (CSPs). If the chiral auxiliary (selector, SO) contains charged or ionizable groups one gets ion exchanger type CSPs which may bind and retain oppositely charged analytes (selectands, SAs). We prepared anion exchanger type CSPs with various quinine and quinidine carbarnates as chiral SOs immobilized either on porous or non-porous silica. These CSPs are able to resolve the enantiomers of a wide spectrum of chiral carboxylic, sulfonic, phosphonic, phosphoric acids and of many other chiral acidic solutes (e.g. N-derivatized alpha-, beta- , gamma-amino acids as 2,4-dinitrophenyl, 3,5-dinitrobenzoyl, benzoyl, acetyl, formyl, t.-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, dansyl amino acids and peptides, alpha-arylalkylcarboxylic acids as profens, alpha-aryloxyalkylcarboxylic acids, alpha-arylthioalkylcarboxylic acids and acidic drugs like etodolac, proglumide, acenocournarol, leucovorin, omeprazole, pantoprazole) employing buffered aqueous mobile phases or non-aqueous mobile phases with buffer dissolved in the organic solvent. The influence of mobile phase parameters and other experimental conditions on retention and enantioselectivity has been evaluated for isocratic and gradient elution techniques, aided by the commercial method development computer software DryLab. Several 'Quantitative Structure-Retention Relationships' (QSRR) have been derived, which allowed prediction of enantioselectivity of new analytes and moreover the optimization of the SO-structure. Spectroscopic investigations as H-NMR, FTIR of certain SO-SA-complexes have been exerted to unveil the mechanism of chiral recognition. (author)

  8. Enantioselective analysis of propranolol and 4-hydroxypropranolol by CE with application to biotransformation studies employing endophytic fungi.

    Science.gov (United States)

    Borges, Keyller Bastos; Pupo, Mônica Tallarico; Bonato, Pierina Sueli

    2009-11-01

    A CE method is described for the enantioselective analysis of propranolol (Prop) and 4-hydroxypropranolol (4-OH-Prop) in liquid Czapek medium with application in the study of the enantioselective biotransformation of Prop by endophytic fungi. The electrophoretic conditions previously optimized were as follows: an uncoated fused-silica capillary, 4% w/v carboxymethyl-beta-CD in 25 mmol/L triethylamine/phosphoric acid (H(3)PO(4)) buffer at pH 9 as running electrolyte and 17 kV of voltage. UV detection was carried out at 208 nm. Liquid-liquid extraction using diethyl ether: ethyl acetate (1:1 v/v) as extractor solvent was employed for sample preparation. The calibration curves were linear over the concentration range of 0.25-10.0 microg/mL for each 4-OH-Prop enantiomer and 0.10-10.0 microg/mL for each Prop enantiomer (r>or=0.995). Within-day and between-day relative standard deviations and relative errors for precision and accuracy were lower than 15% for all the enantiomers. Finally, the validated method was used to evaluate Prop biotransformation in its mammalian metabolite 4-OH-Prop by some selected endophytic fungi. The screening of five strains of endophytic fungi was performed and all of them could biotransform Prop to some extent. Specifically, Glomerella cingulata (VA1) biotransformed 47.8% of (-)-(S)-Prop to (-)-(S)-4-OH-Prop with no formation of (+)-(R)-4-OH-Prop in 72 h of incubation.

  9. Structural basis for high substrate-binding affinity and enantioselectivity of 3-quinuclidinone reductase AtQR

    Energy Technology Data Exchange (ETDEWEB)

    Hou, Feng; Miyakawa, Takuya [Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657 (Japan); Kataoka, Michihiko [Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai 559-8531 (Japan); Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan); Takeshita, Daijiro [Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657 (Japan); Kumashiro, Shoko [Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan); Uzura, Atsuko [Research and Development Center, Nagase and Co., Ltd., 2-2-3 Muratani, Nishi-ku, Kobe 651-2241 (Japan); Urano, Nobuyuki [Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai 559-8531 (Japan); Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan); Nagata, Koji [Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657 (Japan); Shimizu, Sakayu [Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan); Faculty of Bioenvironmental Science, Kyoto Gakuen University, Sogabe-cho, Kameoka 621-8555 (Japan); Tanokura, Masaru, E-mail: amtanok@mail.ecc.u-tokyo.ac.jp [Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657 (Japan)

    2014-04-18

    Highlights: • Crystal structure of AtQR has been determined at 1.72 Å. • NADH binding induces the formation of substrate binding site. • AtQR possesses a conserved hydrophobic wall for stereospecific binding of substrate. • Additional Glu197 residue is critical to the high binding affinity. - Abstract: (R)-3-Quinuclidinol, a useful compound for the synthesis of various pharmaceuticals, can be enantioselectively produced from 3-quinuclidinone by 3-quinuclidinone reductase. Recently, a novel NADH-dependent 3-quinuclidionone reductase (AtQR) was isolated from Agrobacterium tumefaciens, and showed much higher substrate-binding affinity (>100 fold) than the reported 3-quinuclidionone reductase (RrQR) from Rhodotorula rubra. Here, we report the crystal structure of AtQR at 1.72 Å. Three NADH-bound protomers and one NADH-free protomer form a tetrameric structure in an asymmetric unit of crystals. NADH not only acts as a proton donor, but also contributes to the stability of the α7 helix. This helix is a unique and functionally significant part of AtQR and is related to form a deep catalytic cavity. AtQR has all three catalytic residues of the short-chain dehydrogenases/reductases family and the hydrophobic wall for the enantioselective reduction of 3-quinuclidinone as well as RrQR. An additional residue on the α7 helix, Glu197, exists near the active site of AtQR. This acidic residue is considered to form a direct interaction with the amine part of 3-quinuclidinone, which contributes to substrate orientation and enhancement of substrate-binding affinity. Mutational analyses also support that Glu197 is an indispensable residue for the activity.

  10. Molecularly imprinted polymer-matrix nanocomposite for enantioselective electrochemical sensing of D- and L-aspartic acid

    International Nuclear Information System (INIS)

    Prasad, Bhim Bali; Srivastava, Amrita; Tiwari, Mahavir Prasad

    2013-01-01

    A new molecularly imprinted polymer-matrix (titanium dioxide nanoparticle/multiwalled carbon nanotubes) nanocomposite was developed for the modification of pencil graphite electrode as an enantioselective sensing probe for aspartic acid isomers, prevalent at ultra trace level in aqueous and real samples. The nanocomposite having many shape complementary cavities was synthesized adopting surface initiated-activators regenerated by electron transfer for atom transfer radical polymerization. The proposed sensor has high stability, nanocomposite uniformity, good reproducibility, and enhanced electrocatalytic activity to respond oxidative peak current of L-aspartic acid quantitatively by differential pulse anodic stripping voltammetry, without any cross-reactivity in real samples. Under the optimized operating conditions, the L-aspartic acid imprinted modified electrode showed a wide linear response for L-aspartic acid within the concentration range 9.98–532.72 ng mL −1 , with the minimum detection limit of 1.73–1.79 ng mL −1 (S/N = 3) in aqueous and real samples. Almost similar stringent limit (1.79 ng mL −1 ) was obtained with cerebrospinal fluid which is typical for the primitive diagnosis of neurological disorders, caused by an acute depletion of L-aspartic acid biomarker, in clinical settings. Highlights: • We have adopted surface initiated-activators regenerated by electron transfer for atom transfer radical polymerization. • This approach takes advantage of the nanostructured ultrathin imprinted film. • Successful enantioselective sensing and ultratrace analysis of D- and L-aspartic acid. • Stringent detection limit without any non-specific false-positive contribution

  11. Molecularly imprinted polymer-matrix nanocomposite for enantioselective electrochemical sensing of D- and L-aspartic acid

    Energy Technology Data Exchange (ETDEWEB)

    Prasad, Bhim Bali, E-mail: prof.bbpd@yahoo.com; Srivastava, Amrita; Tiwari, Mahavir Prasad

    2013-10-15

    A new molecularly imprinted polymer-matrix (titanium dioxide nanoparticle/multiwalled carbon nanotubes) nanocomposite was developed for the modification of pencil graphite electrode as an enantioselective sensing probe for aspartic acid isomers, prevalent at ultra trace level in aqueous and real samples. The nanocomposite having many shape complementary cavities was synthesized adopting surface initiated-activators regenerated by electron transfer for atom transfer radical polymerization. The proposed sensor has high stability, nanocomposite uniformity, good reproducibility, and enhanced electrocatalytic activity to respond oxidative peak current of L-aspartic acid quantitatively by differential pulse anodic stripping voltammetry, without any cross-reactivity in real samples. Under the optimized operating conditions, the L-aspartic acid imprinted modified electrode showed a wide linear response for L-aspartic acid within the concentration range 9.98–532.72 ng mL{sup −1}, with the minimum detection limit of 1.73–1.79 ng mL{sup −1} (S/N = 3) in aqueous and real samples. Almost similar stringent limit (1.79 ng mL{sup −1}) was obtained with cerebrospinal fluid which is typical for the primitive diagnosis of neurological disorders, caused by an acute depletion of L-aspartic acid biomarker, in clinical settings. Highlights: • We have adopted surface initiated-activators regenerated by electron transfer for atom transfer radical polymerization. • This approach takes advantage of the nanostructured ultrathin imprinted film. • Successful enantioselective sensing and ultratrace analysis of D- and L-aspartic acid. • Stringent detection limit without any non-specific false-positive contribution.

  12. In vitro enantioselective human liver microsomal metabolism and prediction of in vivo pharmacokinetic parameters of tetrabenazine by DLLME-CE.

    Science.gov (United States)

    Bocato, Mariana Zuccherato; de Lima Moreira, Fernanda; de Albuquerque, Nayara Cristina Perez; de Gaitani, Cristiane Masetto; de Oliveira, Anderson Rodrigo Moraes

    2016-09-05

    A new capillary electrophoresis method for the enantioselective analysis of cis- and trans- dihydrotetrabenazine (diHTBZ) after in vitro metabolism by human liver microsomes (HLMs) was developed. The chiral electrophoretic separations were performed by using tris-phosphate buffer (pH 2.5) containing 1% (w/v) carboxymethyl-β-CD as background electrolyte with an applied voltage of +15kV and capillary temperature kept at 15°C. Dispersive liquid-liquid microextraction was employed to extract the analytes from HLMs. Dichloromethane was used as extraction solvent (75μL) and acetone as disperser solvent (150μL). The method was validated according to official guidelines and showed to be linear over the concentration range of 0.29-19.57μmolL(-1) (r=0.9955) for each metabolite enantiomer. Within- and between-day precision and accuracy evaluated by relative standard deviation and relative error were lower than 15% for all enantiomers. The stability assay showed that the analytes kept stable under handling, storage and in metabolism conditions. After method validation, an enantioselective in vitro metabolism and in vivo pharmacokinetic prediction was carried out. This study showed a stereoselective metabolism and the observed kinetic profile indicated a substrate inhibition behavior. DiHTBZ enantiomers were catalyzed mainly by CYP2C19 and the predicted clearance suggests that liver metabolism is the main route for TBZ elimination which supports the literature data. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Enantioselective total synthesis of (+)-brefeldin A and 7-epi-brefeldin A.

    Science.gov (United States)

    Wu, Yikang; Shen, Xin; Yang, Yong-Qing; Hu, Qi; Huang, Jia-Hui

    2004-05-28

    A convergent enantioselective route to brefeldin A (BFA) and 7-epi-BFA was developed. The key C-4/C-5 chiral centers were established by using chiral auxiliary induced intermolecular asymmetric aldolization in the presence of TiCl(4) and TMEDA. The results with the thiazolidinethione/TiCl(4) mediated intermolecular asymmetric aldolization added some new information about the scope and limitations to the existing knowledge of that type of reactions (which so far was essentially limited to the reactions with N-propionyl thiazolidinethiones). During the course a method for protecting the liable aldol hydroxyl groups by using inexpensive TBSCl in DMF with 2,6-lutidine as the base was developed to replace the otherwise unavoidable TBSOTf procedure. Due to the excessive steric hindrance, removal of the auxiliary was much more difficult than most literature cases. Cleavage of the oxazolidinone by reduction was almost impossible. The thiazolidinethione auxiliary was relatively easier to remove. However, several reactions reported for facile removal of thiazolidinethione auxiliaries in the literature still failed. Reductive removal of the thiazolidinethione auxiliary was most effectively realized with LiBH(4) in diethyl ether in the presence of 1 equiv of MeOH (a modification of a literature procedure for removal of oxazolidinone auxiliaries in less hindered substrates). Apart from the auxiliary removal, oxidation of the alcohol into aldehyde and the deprotection of the dithiolane protecting group were also rather difficult in the present context. A range of methods were screened before final solutions were found. The five-membered ring was constructed by employing an intramolecular Mukaiyama reaction after many attempts with the intramolecular aldolization under a variety of conditions failed. The rate of elimination of the alkoxyl to form the alpha,beta-double bond of the key intermediate cyclopentenone 49 with DBU was highly solvent dependent (very sluggish in CH(2)Cl(2

  14. Chiral gold(I vs chiral silver complexes as catalysts for the enantioselective synthesis of the second generation GSK-hepatitis C virus inhibitor

    Directory of Open Access Journals (Sweden)

    María Martín-Rodríguez

    2011-07-01

    Full Text Available The synthesis of a GSK 2nd generation inhibitor of the hepatitis C virus, by enantioselective 1,3-dipolar cycloaddition between a leucine derived iminoester and tert-butyl acrylate, was studied. The comparison between silver(I and gold(I catalysts in this reaction was established by working with chiral phosphoramidites or with chiral BINAP. The best reaction conditions were used for the total synthesis of the hepatitis C virus inhibitor by a four step procedure affording this product in 99% ee and in 63% overall yield. The origin of the enantioselectivity of the chiral gold(I catalyst was justified according to DFT calculations, the stabilizing coulombic interaction between the nitrogen atom of the thiazole moiety and one of the gold atoms being crucial.

  15. Enantioselective Synthesis of Aminodiols by Sequential Rhodium-Catalysed Oxyamination/Kinetic Resolution: Expanding the Substrate Scope of Amidine-Based Catalysis.

    Science.gov (United States)

    Guasch, Joan; Giménez-Nueno, Irene; Funes-Ardoiz, Ignacio; Bernús, Miguel; Matheu, M Isabel; Maseras, Feliu; Castillón, Sergio; Díaz, Yolanda

    2018-03-26

    Regio- and stereoselective oxyamination of dienes through a tandem rhodium-catalysed aziridination-nucleophilic opening affords racemic oxazolidinone derivatives, which undergo a kinetic resolution acylation process with amidine-based catalysts (ABCs) to achieve s values of up to 117. This protocol was applied to the enantioselective synthesis of sphingosine. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Treatment with 5-Aza-2'-Deoxycytidine Induces Expression of NY-ESO-1 and Facilitates Cytotoxic T Lymphocyte-Mediated Tumor Cell Killing.

    Directory of Open Access Journals (Sweden)

    Agnes S Klar

    Full Text Available NY-ESO-1 belongs to the cancer/testis antigen (CTA family and represents an attractive target for cancer immunotherapy. Its expression is induced in a variety of solid tumors via DNA demethylation of the promoter of CpG islands. However, NY-ESO-1 expression is usually very low or absent in some tumors such as breast cancer or multiple myeloma. Therefore, we established an optimized in vitro treatment protocol for up-regulation of NY-ESO-1 expression by tumor cells using the hypomethylating agent 5-aza-2'-deoxycytidine (DAC.We demonstrated de novo induction of NY-ESO-1 in MCF7 breast cancer cells and significantly increased expression in U266 multiple myeloma cells. This effect was time- and dose-dependent with the highest expression of NY-ESO-1 mRNA achieved by the incubation of 10 μM DAC for 72 hours. NY-ESO-1 activation was also confirmed at the protein level as shown by Western blot, flow cytometry, and immunofluorescence staining. The detection and quantification of single NY-ESO-1 peptides presented at the tumor cell surface in the context of HLA-A*0201 molecules revealed an increase of 100% and 50% for MCF7 and U266 cells, respectively. Moreover, the enhanced expression of NY-ESO-1 derived peptides at the cell surface was accompanied by an increased specific lysis of MCF7 and U266 cells by HLA-A*0201/NY-ESO-1(157-165 peptide specific chimeric antigen receptor (CAR CD8+ T cells. In addition, the killing activity of CAR T cells correlated with the secretion of higher IFN-gamma levels.These results indicate that NY-ESO-1 directed immunotherapy with specific CAR T cells might benefit from concomitant DAC treatment.

  17. Unveiling NIR Aza-Boron-Dipyrromethene (BODIPY) Dyes as Raman Probes: Surface-Enhanced Raman Scattering (SERS)-Guided Selective Detection and Imaging of Human Cancer Cells.

    Science.gov (United States)

    Adarsh, Nagappanpillai; Ramya, Adukkadan N; Maiti, Kaustabh Kumar; Ramaiah, Danaboyina

    2017-10-12

    The development of new Raman reporters has attracted immense attention in diagnostic research based on surface enhanced Raman scattering (SERS) techniques, which is a well established method for ultrasensitive detection through molecular fingerprinting and imaging. Herein, for the first time, we report the unique and efficient Raman active features of the selected aza-BODIPY dyes 1-6. These distinctive attributes could be extended at the molecular level to allow detection through SERS upon adsorption onto nano-roughened gold surface. Among the newly revealed Raman reporters, the amino substituted derivative 4 showed high signal intensity at very low concentrations (ca. 0.4 μm for 4-Au). Interestingly, an efficient nanoprobe has been constructed by using gold nanoparticles as SERS substrate, and 4 as the Raman reporter (4-Au@PEG), which unexpectedly showed efficient recognition of three human cancer cells (lung: A549, cervical: HeLa, Fibrosarcoma: HT-1080) without any specific surface marker. We observed well reflected and resolved Raman mapping and characteristic signature peaks whereas, such recognition was not observed in normal fibroblast (3T3L1) cells. To confirm these findings, a SERS nanoprobe was conjugated with a specific tumour targeting marker, EGFR (Epidermal Growth Factor Receptor), a well known targeted agent for Human Fibrosarcoma (HT1080). This nanoprobe efficiently targeted the surface marker of HT1080 cells, threreby demonstrating its use as an ultrasensitive Raman probe for detection and targeted imaging, leaving normal cells unaffected. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2'-deoxycytidine.

    Science.gov (United States)

    Li, Deyu; Fedeles, Bogdan I; Singh, Vipender; Peng, Chunte Sam; Silvestre, Katherine J; Simi, Allison K; Simpson, Jeffrey H; Tokmakoff, Andrei; Essigmann, John M

    2014-08-12

    Viral lethal mutagenesis is a strategy whereby the innate immune system or mutagenic pool nucleotides increase the error rate of viral replication above the error catastrophe limit. Lethal mutagenesis has been proposed as a mechanism for several antiviral compounds, including the drug candidate 5-aza-5,6-dihydro-2'-deoxycytidine (KP1212), which causes A-to-G and G-to-A mutations in the HIV genome, both in tissue culture and in HIV positive patients undergoing KP1212 monotherapy. This work explored the molecular mechanism(s) underlying the mutagenicity of KP1212, and specifically whether tautomerism, a previously proposed hypothesis, could explain the biological consequences of this nucleoside analog. Establishing tautomerism of nucleic acid bases under physiological conditions has been challenging because of the lack of sensitive methods. This study investigated tautomerism using an array of spectroscopic, theoretical, and chemical biology approaches. Variable temperature NMR and 2D infrared spectroscopic methods demonstrated that KP1212 existed as a broad ensemble of interconverting tautomers, among which enolic forms dominated. The mutagenic properties of KP1212 were determined empirically by in vitro and in vivo replication of a single-stranded vector containing a single KP1212. It was found that KP1212 paired with both A (10%) and G (90%), which is in accord with clinical observations. Moreover, this mutation frequency is sufficient for pushing a viral population over its error catastrophe limit, as observed before in cell culture studies. Finally, a model is proposed that correlates the mutagenicity of KP1212 with its tautomeric distribution in solution.

  19. Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

    Science.gov (United States)

    Li, Deyu; Fedeles, Bogdan I.; Singh, Vipender; Peng, Chunte Sam; Silvestre, Katherine J.; Simi, Allison K.; Simpson, Jeffrey H.; Tokmakoff, Andrei; Essigmann, John M.

    2014-01-01

    Viral lethal mutagenesis is a strategy whereby the innate immune system or mutagenic pool nucleotides increase the error rate of viral replication above the error catastrophe limit. Lethal mutagenesis has been proposed as a mechanism for several antiviral compounds, including the drug candidate 5-aza-5,6-dihydro-2′-deoxycytidine (KP1212), which causes A-to-G and G-to-A mutations in the HIV genome, both in tissue culture and in HIV positive patients undergoing KP1212 monotherapy. This work explored the molecular mechanism(s) underlying the mutagenicity of KP1212, and specifically whether tautomerism, a previously proposed hypothesis, could explain the biological consequences of this nucleoside analog. Establishing tautomerism of nucleic acid bases under physiological conditions has been challenging because of the lack of sensitive methods. This study investigated tautomerism using an array of spectroscopic, theoretical, and chemical biology approaches. Variable temperature NMR and 2D infrared spectroscopic methods demonstrated that KP1212 existed as a broad ensemble of interconverting tautomers, among which enolic forms dominated. The mutagenic properties of KP1212 were determined empirically by in vitro and in vivo replication of a single-stranded vector containing a single KP1212. It was found that KP1212 paired with both A (10%) and G (90%), which is in accord with clinical observations. Moreover, this mutation frequency is sufficient for pushing a viral population over its error catastrophe limit, as observed before in cell culture studies. Finally, a model is proposed that correlates the mutagenicity of KP1212 with its tautomeric distribution in solution. PMID:25071207

  20. Antitumor evaluation and 3D-QSAR studies of a new series of the spiropyrroloquinoline isoindolinone/aza-isoindolinone derivatives by comparative molecular field analysis (CoMFA).

    Science.gov (United States)

    Sadeghzadeh, Masoud; Salahinejad, Maryam; Zarezadeh, Nahid; Ghandi, Mehdi; Baghery, Maryam Keshavarz

    2017-11-01

    In current study, antitumor activity of two series of the newly synthesized spiropyrroloquinoline isoindolinone and spiropyrroloquinoline aza-isoindolinone scaffolds was evaluated against three human breast normal and cancer cell lines (MCF-10A, MCF-7 and SK-BR-3) and compared with cytotoxicity values of doxorubicin and colchicine as the standard drugs. It was found that several compounds were endowed with cytotoxicity in the low micromolar range. Among these two series, compounds 6i, 6j, 6k and 7l, 7m, 7n, 7o containing 3-ethyl-1H-indole moiety were found to be highly effective against both cancer cell lines ranging from [Formula: see text] to [Formula: see text] in comparison with the corresponding analogs. Compared with human cancer cells, the most potent compounds did not show high cytotoxicity against human breast normal MCF-10A cells. Generally, most of the evaluated compounds 6a-l and 7a-o series showed more antitumor activity against SK-BR-3 than MCF-7 cells. Moreover, comparative molecular field analysis (CoMFA) as a popular tools of three-dimensional quantitative structure-activity relationship (3D-QSAR) studies was carried out on 27 spiropyrroloquinolineisoindolinone and spiropyrroloquinolineaza-isoindolinone derivatives with antitumor activity against on SK-BR-3 cells. The obtained CoMFA models showed statistically excellent performance, which also possessed good predictive ability for an external test set. The results confirm the important effect of molecular steric and electrostatic interactions of these compounds on in vitro cytotoxicity against SK-BR-3.

  1. CO2 as a C1-organic building block: Enantioselective electrocarboxylation of aromatic ketones with CO2catalyzed by cinchona alkaloids under mild conditions

    International Nuclear Information System (INIS)

    Chen, Bao-Li; Tu, Zhuo-Ying; Zhu, Hong-Wei; Sun, Wen-Wen; Wang, Huan; Lu, Jia-Xing

    2014-01-01

    Highlights: •Cinchona alkaloids catalysis achieve enantioselective electrocarboxylation of racemic aromatic ketones. •The applications of CO 2 enantioselective electrochemical fixation into optically active hydroxyl carboxylic acids have been expanded. •The applications of alkaloids have been expanded. •The applications of asymmetric synthesis by electrochemical methodology have been expanded. -- Abstract: The enantioselective electrocarboxylation of pro-chiral aromatic ketones (2-acetonaphthone, 1-(6-methoxy-2-naphthyl)ethanone, 1-(4-methoxy-1-naphthyl)ethanone) with atmospheric pressure of CO 2 catalyzed by cinchona alkaloids in the presence of phenol was investigated in an undivided cell for the first time to give optically active 2-hydroxy-2-arylpropionic acid. For the model compound 2-acetonaphthone, the influence of various reaction conditions, such as cathode material, current density, catalyst type, ratio of proton to catalyst and catalyst quantity, on the enantiomeric excesses (ee) and yield has been investigated. Under the optimized conditions of 2-acetonaphthone, all the aromatic ketones examined are converted into corresponding optically active 2-hydroxy-2-arylpropionic acids in moderate yield (32.2% - 41.3%) and ee (48.1% - 48.6%). In addition, the electrochemical behavior of 2-acetonaphthone has been studied by cyclic voltammetry (CV) in the absence and presence of CO 2 . Moreover, the probable reaction pathway was proposed accordingly

  2. Enantioselective column coupled electrophoresis employing large bore capillaries hyphenated with tandem mass spectrometry for ultra-trace determination of chiral compounds in complex real samples.

    Science.gov (United States)

    Piešťanský, Juraj; Maráková, Katarína; Kovaľ, Marián; Havránek, Emil; Mikuš, Peter

    2015-12-01

    A new multidimensional analytical approach for the ultra-trace determination of target chiral compounds in unpretreated complex real samples was developed in this work. The proposed analytical system provided high orthogonality due to on-line combination of three different methods (separation mechanisms), i.e. (1) isotachophoresis (ITP), (2) chiral capillary zone electrophoresis (chiral CZE), and (3) triple quadrupole mass spectrometry (QqQ MS). The ITP step, performed in a large bore capillary (800 μm), was utilized for the effective sample pretreatment (preconcentration and matrix clean-up) in a large injection volume (1-10 μL) enabling to obtain as low as ca. 80 pg/mL limits of detection for the target enantiomers in urine matrices. In the chiral CZE step, the different chiral selectors (neutral, ionizable, and permanently charged cyclodextrins) and buffer systems were tested in terms of enantioselectivity and influence on the MS detection response. The performance parameters of the optimized ITP - chiral CZE-QqQ MS method were evaluated according to the FDA guidance for bioanalytical method validation. Successful validation and application (enantioselective monitoring of renally eliminated pheniramine and its metabolite in human urine) highlighted great potential of this chiral approach in advanced enantioselective biomedical applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Spectrophotometric studies, synthesis and magnetic properties of Co(2), Cu(2), Ni(2) and UO2(6) complexes of 1,2-O-iso-propylidene-4-aza-7-aminoheptane

    International Nuclear Information System (INIS)

    Memet Sekerci

    2000-01-01

    1,2-O-iso-propylidene-4-aza-7-aminoheptane (L) is synthesized from 1-chloro-2,3-O-iso-propylidenepropane. In turn the last is prepared from the epichlorhydrine and acetone. Then the complexes of this ligand with Co(2), Cu(2), Ni(2) and UO 2 (6) salts are obtained. The structure of the ligand and its complexes is proposed according to the data of 1 H and 13 C NMR method, IR spectroscopy, element, thermogravimetric and differential thermal analyses and magnetic susceptibility measurements [ru

  4. Crystal and molecular structure of 8-acetoxy-7-aza-6-ethoxycarbonyl-7-formyl-3,4-dihydroxy-3,4-O-isopropylidene-2-oxabicyclo [3.30]octane

    International Nuclear Information System (INIS)

    Holzapfel, C.W.; Koekemoer, J.M.; Kruger, G.J.; Van Dyk, M.S.

    1985-01-01

    The structure and stereochemistry of the title compound, a 11-deoxy-11-azaprostaglandin synthon, has been determined by single-crystal X-ray diffraction methods. The dioxolane and aza-rings are cis-fused on the same side to the central furanose ring. Both the ethoxycarbonyl group on C(5) and the acetoxy-group on C(6) have a β-configuration. The conformation of the solid state structure is compared with that in chloroform solution, as evidenced by 1 H n.m.r. studies

  5. Enantioselective recognition of an isomeric ligand by a biomolecule: mechanistic insights into static and dynamic enantiomeric behavior and structural flexibility.

    Science.gov (United States)

    Peng, Wei; Ding, Fei

    2017-10-24

    Chirality is a ubiquitous basic attribute of nature, which inseparably relates to the life activity of living organisms. However, enantiomeric differences have still failed to arouse enough attention during the biological evaluation and practical application of chiral substances, and this poses a large threat to human health. In the current study, we explore the enantioselective biorecognition of a chiral compound by an asymmetric biomolecule, and then decipher the molecular basis of such a biological phenomenon on the static and, in particular, the dynamic scale. In light of the wet experiments, in silico docking results revealed that the orientation of the latter part of the optical isomer structures in the recognition domain can be greatly affected by the chiral carbon center in a model ligand molecule, and this event may induce large disparities between the static chiral bioreaction modes and noncovalent interactions (especially hydrogen bonding). Dynamic stereoselective biorecognition assays indicated that the conformational stability of the protein-(S)-diclofop system is clearly greater than the protein-(R)-diclofop adduct; and moreover, the conformational alterations of the diclofop enantiomers in the dynamic process will directly influence the conformational flexibility of the key residues found in the biorecognition region. These points enable the changing trends of biopolymer structural flexibility and free energy to exhibit significant distinctions when proteins sterically recognize the (R)-/(S)-stereoisomers. The outcomes of the energy decomposition further showed that the van der Waals' energy has roughly the same contribution to the chiral recognition biosystems, whereas the contribution of electrostatic energy to the protein-(R)-diclofop complex is notably smaller than to the protein-(S)-diclofop bioconjugate. This proves that differences in the noncovalent bonds would have a serious impact on the stereoselective biorecognition between a

  6. Single-crystal-to-single-crystal transformation and solvochromic luminescence of a dinuclear gold(I)-(aza-[18]crown-6)dithiocarbamate compound.

    Science.gov (United States)

    Tzeng, Biing-Chiau; Chao, An

    2015-01-26

    The treatment of [AuCl(SMe2 )] with an equimolar amount of NaO5 NCS2 (O5 NCS2 =(aza-[18]crown-6)dithiocarbamate) in CH3 CN gave [Au2 (O5 NCS2 )2 ]⋅2 CH3 CN (2⋅2 CH3 CN), and its crystal structure displays a dinuclear gold(I)-azacrown ether ring and an intermolecular gold(I)⋅⋅⋅gold(I) contact of 2.8355(3) Å in crystal lattices. It is noted that two other single crystals of 2⋅tert-butylbenzene⋅H2 O and 2⋅0.5 m-xylene can be successfully obtained from a single-crystal-to-single-crystal (SCSC) transformation process by immersing single crystals of 2⋅2 CH3 CN in the respective solvents, and both also show intermolecular gold(I)⋅⋅⋅gold(I) contacts of 2.9420(5) and 2.890(2)-2.902(2) Å, respectively. Significantly, the emissions of all three 2⋅solvates are well correlated with their respective intermolecular gold(I)⋅⋅⋅gold(I) contacts, where such contacts increase with 2⋅2 CH3 CN (2.8355(3) Å)energies increase with 2⋅2 CH3 CN (602 nm)<2⋅0.5 m-xylene (583 nm)<2⋅tert-butylbenzene⋅H2 O (546 nm) as well. In this regard, we further examine the solvochromic luminescence for some other aromatics, and finally their emissions are within 546-602 nm. Obviously, the above results are mostly ascribed to the occurrence of intermolecular gold(I)⋅⋅⋅gold(I) contacts in 2⋅solvates, which are induced by the presence of various solvates in the solid state, as a key role to be responsible for their solvochromic luminescence. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. One-Pot Synthesis of 2-Acylindole-3-acetylketones via Domino Aza-alkylation/Michael Reaction Using o-Aminophenyl α,β-Unsaturated Ketones Followed by Desulfonative Dehydrogenation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, A Reum; Yu, Mi Rim; Sim, Jong Tack; Kim, Sung Gon [Kyonggi Univ., Suwon (Korea, Republic of)

    2016-09-15

    The development of novel and practical synthetic methods with a minimum number of operations for the construction of bioactive structurally complex compounds is a major challenge in synthetic organic chemistry. Recently, we reported an efficient method for the stereoselective synthesis of 2,3-disubstituted indoline derivatives; cis-2,3-disubstituted indolines were obtained by the aza-alkylation/Michael cascade reaction of 2-(tosylamino)phenyl α,β-unsaturated ketones with α-bromoacetophenones in good yields and with excellent diastereoselectivities (Scheme 2, Eq. (1)). Among the available synthetic strategies, domino or cascade reactions have received wide acceptance as highly efficient and powerful methods for the synthesis of molecules with a high structural complexity. An efficient synthesis of 2,3-disubstituted indoles was developed by the domino aza-alkylation/intramolecular Michael reaction of 2-(tosylamino)phenyl α,β-unsaturated ketones with α-bromoacetophenones, followed by desulfonative dehydrogenation with DBU. The reaction afforded structurally diverse and highly functionalized 2,3-disubstituted indoles in moderate to excellent yields (up to 99%). The synthesis of 2,3-disubstituted indoles without desulfonation through DDQ-induced oxidative dehydrogenation was also achieved.

  8. Enantioselective stable isotope analysis (ESIA) — A new concept to evaluate the environmental fate of chiral organic contaminants

    International Nuclear Information System (INIS)

    Badea, Silviu-Laurentiu; Danet, Andrei-Florin

    2015-01-01

    Since 2011, the enantiospecific stable carbon isotope analysis (ESIA) has emerged as an innovative technique to assess the environmental fate of chiral emerging compounds by combining in one experimental technique both compound specific isotope analysis (CSIA) and enantioselective analysis. To date, the ESIA was applied for four classes of compounds: α-hexachlorocyclohexane (α-HCH), polar herbicides (phenoxy acids), synthetic polycyclic musk galaxolide (HHCB), and phenoxyalkanoic methyl herbicides. From an analytical point of view there are factors that are hindering the application of ESIA methods for the field samples: (i.e. amounts of target analyte, matrix effects, GC resolution) and overcoming these factors is challenging. While ESIA was shown as a mature technique for the first three abovementioned class of compounds, no isotope analysis of individual enantiomers could be performed for phenoxyalkanoic methyl herbicides. With respect to field studies, one study showed that ESIA might be a promising tool to distinguish between biotic and abiotic transformation pathways of chiral organic contaminants and even to differentiate between their aerobic and anaerobic biotransformation pathways. The development of ESIA methods for new chiral emerging contaminants in combination with development of multi-element isotope analysis will contribute to a better characterization of transformation pathways of chiral organic contaminants. - Highlights: • ESIA is an innovative technique to assess the environmental fate of chiral pollutants • Overcoming the analytical limitations of ESIA is challenging • Development of ESIA methods for new chiral emerging contaminants is needed

  9. High enantioselective Novozym 435-catalyzed esterification of (R,S)-flurbiprofen monitored with a chiral stationary phase.

    Science.gov (United States)

    Siódmiak, Tomasz; Mangelings, Debby; Vander Heyden, Yvan; Ziegler-Borowska, Marta; Marszałł, Michał Piotr

    2015-03-01

    Lipases form Candida rugosa and Candida antarctica were tested for their application in the enzymatic kinetic resolution of (R,S)-flurbiprofen by enantioselective esterification. Successful chromatographic separation with well-resolved peaks of (R)- and (S)-flurbiprofen and their esters was achieved in one run on chiral stationary phases by high-performance liquid chromatography (HPLC). In this study screening of enzymes was performed, and Novozym 435 was selected as an optimal catalyst for obtaining products with high enantiopurity. Additionally, the influence of organic solvents (dichloromethane, dichloroethane, dichloropropane, and methyl tert-butyl ether), primary alcohols (methanol, ethanol, n-propanol, and n-butanol), reaction time, and temperature on the enantiomeric ratio and conversion was tested. The high values of enantiomeric ratio (E in the range of 51.3-90.5) of the esterification of (R,S)-flurbiprofen were obtained for all tested alcohols using Novozym 435, which have a great significance in the field of biotechnological synthesis of drugs. The optimal temperature range for the performed reactions was from 37 to 45 °C. As a result of the optimization, (R)-flurbiprofen methyl ester was obtained with a high optical purity, eep = 96.3 %, after 96 h of incubation. The enantiomeric ratio of the reaction was E = 90.5 and conversion was C = 35.7 %.

  10. Higher-order human telomeric G-quadruplex DNA metalloenzymes enhance enantioselectivity in the Diels-Alder reaction.

    Science.gov (United States)

    Li, Yinghao; Jia, Guoqing; Wang, Changhao; Cheng, Mingpan; Li, Can

    2015-03-02

    Short human telomeric (HT) DNA sequences form single G-quadruplex (G4 ) units and exhibit structure-based stereocontrol for a series of reactions. However, for more biologically relevant higher-order HT G4 -DNAs (beyond a single G4 unit), the catalytic performances are unknown. Here, we found that higher-order HT G4 -DNA copper metalloenzymes (two or three G4 units) afford remarkably higher enantioselectivity (>90 % ee) and a five- to sixfold rate increase, compared to a single G4 unit, for the Diels-Alder reaction. Electron paramagnetic resonance (EPR) and enzymatic kinetic studies revealed that the distinct catalytic function between single and higher-order G4 -DNA copper metalloenzymes can be attributed to different Cu(II) coordination environments and substrate specificity. Our finding suggests that, like protein enzymes and ribozymes, higher-order structural organization is crucial for G4 -DNA-based catalysis. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. The rabbit liver microsomal biotransformation of 1,1-dialkylethylenes: enantioface selection of epoxidation and enantioselectivity of epoxide hydrolysis.

    Science.gov (United States)

    Bellucci, G; Chiappe, C; Cordoni, A; Marioni, F

    1994-01-01

    The rabbit liver microsomal biotransformation of alpha-methylstyrene (1a), 2-methyl-1-hexene (1b), 2,4,4-trimethyl-1-pentene (1c), and 1,3,3-trimethyl-1-butene (1d) has been investigated with the aim at establishing the enantioface selection of the cytochrome P-450-promoted epoxidation of the double bond and the enantioselectivity of microsomal epoxide hydrolase(mEH)-catalyzed hydrolysis of the resulting epoxides. GLC on a Chiraldex G-TA (ASTEC) column was used to determine the enantiomeric composition of the products. The epoxides 2 first produced in incubations carried out in the presence of an NADPH regenerating system were not detected, being rapidly hydrolyzed by mEH to diols 3. The enantiomeric composition of the latter showed that no enantioface selection occurred in the epoxidation of 1c and 1d, and a very low (8%) ee of the (R)-epoxide was formed from 1b. Incubation of racemic epoxides 2b-d with the microsomal fraction showed that the mEH-catalyzed hydrolysis of 2c and 2d was practically nonenantioselective, while that of 2b exhibited a selectivity E = 4.9 favoring the hydrolysis of the (S)-enantiomer. A comparison of these results with those previously obtained for linear and branched chain alkyl monosubstituted oxiranes shows that the introduction of the second alkyl substituent suppresses the selectivity of the mEH reaction of the latter and reverses that of the former substrates.

  12. Enantioselective stable isotope analysis (ESIA) — A new concept to evaluate the environmental fate of chiral organic contaminants

    Energy Technology Data Exchange (ETDEWEB)

    Badea, Silviu-Laurentiu, E-mail: badeasilviu@gmail.com [Department of Chemistry, Umeå University, SE-901 87 Umeå (Sweden); Danet, Andrei-Florin [Department of Analytical Chemistry, University of Bucharest, Faculty of Chemistry, 90-92 Panduri Str., Bucharest 050657 (Romania)

    2015-05-01

    Since 2011, the enantiospecific stable carbon isotope analysis (ESIA) has emerged as an innovative technique to assess the environmental fate of chiral emerging compounds by combining in one experimental technique both compound specific isotope analysis (CSIA) and enantioselective analysis. To date, the ESIA was applied for four classes of compounds: α-hexachlorocyclohexane (α-HCH), polar herbicides (phenoxy acids), synthetic polycyclic musk galaxolide (HHCB), and phenoxyalkanoic methyl herbicides. From an analytical point of view there are factors that are hindering the application of ESIA methods for the field samples: (i.e. amounts of target analyte, matrix effects, GC resolution) and overcoming these factors is challenging. While ESIA was shown as a mature technique for the first three abovementioned class of compounds, no isotope analysis of individual enantiomers could be performed for phenoxyalkanoic methyl herbicides. With respect to field studies, one study showed that ESIA might be a promising tool to distinguish between biotic and abiotic transformation pathways of chiral organic contaminants and even to differentiate between their aerobic and anaerobic biotransformation pathways. The development of ESIA methods for new chiral emerging contaminants in combination with development of multi-element isotope analysis will contribute to a better characterization of transformation pathways of chiral organic contaminants. - Highlights: • ESIA is an innovative technique to assess the environmental fate of chiral pollutants • Overcoming the analytical limitations of ESIA is challenging • Development of ESIA methods for new chiral emerging contaminants is needed.

  13. Molecularly imprinted polymer-matrix nanocomposite for enantioselective electrochemical sensing of D- and L-aspartic acid.

    Science.gov (United States)

    Prasad, Bhim Bali; Srivastava, Amrita; Tiwari, Mahavir Prasad

    2013-10-01

    A new molecularly imprinted polymer-matrix (titanium dioxide nanoparticle/multiwalled carbon nanotubes) nanocomposite was developed for the modification of pencil graphite electrode as an enantioselective sensing probe for aspartic acid isomers, prevalent at ultra trace level in aqueous and real samples. The nanocomposite having many shape complementary cavities was synthesized adopting surface initiated-activators regenerated by electron transfer for atom transfer radical polymerization. The proposed sensor has high stability, nanocomposite uniformity, good reproducibility, and enhanced electrocatalytic activity to respond oxidative peak current of L-aspartic acid quantitatively by differential pulse anodic stripping voltammetry, without any cross-reactivity in real samples. Under the optimized operating conditions, the L-aspartic acid imprinted modified electrode showed a wide linear response for L-aspartic acid within the concentration range 9.98-532.72 ng mL(-1), with the minimum detection limit of 1.73-1.79 ng mL(-1) (S/N=3) in aqueous and real samples. Almost similar stringent limit (1.79 ng mL(-1)) was obtained with cerebrospinal fluid which is typical for the primitive diagnosis of neurological disorders, caused by an acute depletion of L-aspartic acid biomarker, in clinical settings. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Enantio-selective molecular dynamics of (±)-o,p-DDT uptake and degradation in water-sediment system.

    Science.gov (United States)

    Ali, Imran; Alharbi, Omar M L; Alothman, Zeid A; Alwarthan, Abdulrahman

    2018-01-01

    Enantio-selective molecular dynamics of (±)-o,p-DDT uptake and degradation in water-sediment system is described. Both uptake and degradation processes of (-)-o,p-DDT were slightly higher than (+)-o,p-DDT enantiomer. The optimized parameters for uptake were 7.0μgL -1 concentration of o,p-DDT, 60min contact time, 5.0pH, 6.0gL -1 amount of reverine sediment and 25°C temperature. The maximum degradation of both (-)- and (+)-o,p-DDT was obtained with 16 days, 0.4μgL -1 concentration of o,p-DDT, pH 7 and 35°C temperature. Both uptake and degraded process followed first order rate reaction. Thermodynamic parameters indicated exothermic nature of uptake and degradation processes. Both uptake and degradation were slightly higher for (-)-enantiomer in comparison to (+)-enantiomer of o,p-DDT. It was concluded that both uptake and degradation processes are responsible for the removal of o,p-DDT from nature but uptake plays a crucial role. The percentage degradations of (-)- and (+)-o,p-DDT were 30.1 and 29.5, respectively. This study may be useful to manage o,p-DDT contamination of our earth's ecosystem. Copyright © 2017. Published by Elsevier Inc.

  15. Synergistic effects on enantioselectivity of zwitterionic chiral stationary phases for separations of chiral acids, bases, and amino acids by HPLC.

    Science.gov (United States)

    Hoffmann, Christian V; Pell, Reinhard; Lämmerhofer, Michael; Lindner, Wolfgang

    2008-11-15

    In an attempt to overcome the limited applicability scope of earlier proposed Cinchona alkaloid-based chiral weak anion exchangers (WAX) and recently reported aminosulfonic acid-based chiral strong cation exchangers (SCX), which are conceptionally restricted to oppositely charged solutes, their individual chiral selector (SO) subunits have been fused in a combinatorial synthesis approach into single, now zwitterionic, chiral SO motifs. The corresponding zwitterionic ion-exchange-type chiral stationary phases (CSPs) in fact combined the applicability spectra of the parent chiral ion exchangers allowing for enantioseparations of chiral acids and amine-type solutes in liquid chromatography using polar organic mode with largely rivaling separation factors as compared to the parent WAX and SCX CSPs. Furthermore, the application spectrum could be remarkably expanded to various zwitterionic analytes such as alpha- and beta-amino acids and peptides. A set of structurally related yet different CSPs consisting of either a quinine or quinidine alkaloid moiety as anion-exchange subunit and various chiral or achiral amino acids as cation-exchange subunits enabled us to derive structure-enantioselectivity relationships, which clearly provided strong unequivocal evidence for synergistic effects of the two oppositely charged ion-exchange subunits being involved in molecular recognition of zwitterionic analytes by zwitterionic SOs driven by double ionic coordination.

  16. α-Imino Esters in Organic Synthesis: Recent Advances.

    Science.gov (United States)

    Eftekhari-Sis, Bagher; Zirak, Maryam

    2017-06-28

    α-Imino esters are useful precursors for the synthesis of a variety of types of natural and unnatural α-amino acid derivatives, with a wide range of biological activities. Due to the adjacent ester group, α-imino esters are more reactive relative to other types of imines and undergo different kinds of reactions, including organometallics addition, metal catalyzed vinylation and alkynylation, aza-Henry, aza-Morita-Baylis-Hillman, imino-ene, Mannich-type, and cycloaddition reactions, as well as hydrogenation and reduction. This review discusses the mechanism, scope, and applications of the reactions of α-imino esters and related compounds in organic synthesis, covering the literature from the last 12 years.

  17. Enhanced catalysis and enantioselective resolution of racemic naproxen methyl ester by lipase encapsulated within iron oxide nanoparticles coated with calix[8]arene valeric acid complexes.

    Science.gov (United States)

    Sayin, Serkan; Akoz, Enise; Yilmaz, Mustafa

    2014-09-14

    In this study, two types of nanoparticles have been used as additives for the encapsulation of Candida rugosa lipase via the sol-gel method. In one case, the nanoparticles were covalently linked with a new synthesized calix[8]arene octa valeric acid derivative (C[8]-C4-COOH) to produce new calix[8]arene-adorned magnetite nanoparticles (NP-C[8]-C4-COOH), and then NP-C[8]-C4-COOH was used as an additive in the sol-gel encapsulation process. In the other case, iron oxide nanoparticles were directly added into the sol-gel encapsulation process in order to interact electrostatically with both C[8]-C4-COOH and Candida rugosa lipase. The catalytic activities and enantioselectivities of two novel encapsulated lipases (Enc-NP-C[8]-C4-COOH and Enc-C[8]-C4-COOH@Fe3O4) in the hydrolysis reaction of racemic naproxen methyl ester were evaluated. The results showed that the activity and enantioselectivity of the lipase were improved when the lipase was encapsulated in the presence of calixarene-based additives. Indeed, the encapsulated lipases have an excellent rate of enantioselectivity, with E = 371 and 265, respectively, as compared to the free enzyme (E = 137). The lipases encapsulated with C[8]-C4-COOH and iron oxide nanoparticles (Enc-C[8]-C4-COOH@Fe3O4) retained more than 86% of their initial activities after 5 repeated uses and 92% with NP-C[8]-C4-COOH.

  18. Ruthenium Catalyzed Diastereo- and Enantioselective Coupling of Propargyl Ethers with Alcohols: Siloxy-Crotylation via Hydride Shift Enabled Conversion of Alkynes to π-Allyls.

    Science.gov (United States)

    Liang, Tao; Zhang, Wandi; Chen, Te-Yu; Nguyen, Khoa D; Krische, Michael J

    2015-10-14

    The first enantioselective carbonyl crotylations through direct use of alkynes as chiral allylmetal equivalents are described. Chiral ruthenium(II) complexes modified by Josiphos (SL-J009-1) catalyze the C-C coupling of TIPS-protected propargyl ether 1a with primary alcohols 2a-2o to form products of carbonyl siloxy-crotylation 3a-3o, which upon silyl deprotection-reduction deliver 1,4-diols 5a-5o with excellent control of regio-, anti-diastereo-, and enantioselectivity. Structurally related propargyl ethers 1b and 1c bearing ethyl- and phenyl-substituents engage in diastereo- and enantioselective coupling, as illustrated in the formation of adducts 5p and 5q, respectively. Selective mono-tosylation of diols 5a, 5c, 5e, 5f, 5k, and 5m is accompanied by spontaneous cyclization to deliver the trans-2,3-disubstituted furans 6a, 6c, 6e, 6f, 6k, and 6m, respectively. Primary alcohols 2a, 2l, and 2p were converted to the siloxy-crotylation products 3a, 3l, and 3p, which upon silyl deprotection-lactol oxidation were transformed to the trans-4,5-disubstituted γ-butyrolactones 7a, 7l, and 7p. The formation of 7p represents a total synthesis of (+)-trans-whisky lactone. Unlike closely related ruthenium catalyzed alkyne-alcohol C-C couplings, deuterium labeling studies provide clear evidence of a novel 1,2-hydride shift mechanism that converts metal-bound alkynes to π-allyls in the absence of intervening allenes.

  19. Enantioselective skin permeation of ibuprofen enantiomers: mechanistic insights from ATR-FTIR and CLSM studies based on synthetic enantiomers as naphthalimide fluorescent probes.

    Science.gov (United States)

    Che, Qi-en; Quan, Peng; Mu, Mao; Zhang, Xinfu; Zhao, Hanqing; Zhang, Yu; You, Song; Xiao, Yi; Fang, Liang

    2014-10-01

    The aim of this study was to investigate the mechanisms of different skin permeability of ibuprofen racemate and enantiomers. The percutaneous permeation of ibuprofen racemate and enantiomers through rabbit normal skin and damaged skin (without stratum corneum [SC]) was investigated in vitro using side-by-side diffusion cells. With the melting temperature-membrane transport model, the flux ratio of enantiomer/racemate was calculated from their thermodynamic properties obtained by differential scanning calorimetry. Attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) study was performed to evaluate the interaction between the enantiomers and the SC. New fluorescent probes were designed and utilized in confocal laser scanning microscopy (CLSM) study for visualization of the enantioselective permeation of the enantiomers through the intact rabbit skin. The flux of (S)-ibuprofen through normal skin was significantly higher than that of (RS)-ibuprofen and (R)-ibuprofen (p skin, there was no significant difference (p > 0.05). The predicted flux ratio of (S)-ibuprofen/(RS)-ibuprofen (2.50) was in close agreement with the experimentally determined ratio (2.48). These results were supported by ATR-FTIR and CLSM studies that indicated that a chiral environment of the skin led to the enantioselective permeation of enantiomers. The chiral nature of the SC and the different physicochemical properties of the enantiomers should be taken into account in the assessment of different skin permeability of the racemate and enantiomers. The synthetic fluorescent probes used in this study could visualize the enantioselective permeation of the chiral compounds across the skin.

  20. Asymmetric Brønsted Acid Catalyzed Substitution of Diaryl Methanols with Thiols and Alcohols for the Synthesis of Chiral Thioethers and Ethers

    KAUST Repository

    Chatupheeraphat, Adisak; Liao, Hsuan-Hung; Mader, Steffen; Sako, Makoto; Sasai, Hiroaki; Atodiresei, Iuliana; Rueping, Magnus

    2016-01-01

    An enantioselective addition of thiols and alcohols to aza-ortho-quinone methides, starting from diaryl methanols, was developed. The asymmetric additions occur under mild reaction conditions in the presence of chiral phosphoric acids and furnish the corresponding adducts with excellent yields and enantioselectivities.

  1. Asymmetric Brønsted Acid Catalyzed Substitution of Diaryl Methanols with Thiols and Alcohols for the Synthesis of Chiral Thioethers and Ethers

    KAUST Repository

    Chatupheeraphat, Adisak

    2016-03-08

    An enantioselective addition of thiols and alcohols to aza-ortho-quinone methides, starting from diaryl methanols, was developed. The asymmetric additions occur under mild reaction conditions in the presence of chiral phosphoric acids and furnish the corresponding adducts with excellent yields and enantioselectivities.

  2. An enantioselective synthesis of S-[gamma]-[(4-trifluoromethyl)phenoxy]benzenepropanamine-[3-[sup 14]C] hydrochloride, an important metabolite of fluoxetine hydrochloride

    Energy Technology Data Exchange (ETDEWEB)

    Wheeler, W.J. (Lilly (Eli) and Co., Indianapolis, IN (United States). Lilly Research Labs.)

    1992-06-01

    The S-enantiomer of [gamma]-[(4-trifluoromethyl)phenoxy]benzenepropanamine-[3-[sup 14]C] hydrochloride has been prepared in eight steps from acetophenone-[carbonyl-[sup 14]C]. The key step in the synthesis involved the enantioselective reduction of R-2-chloroacetophenone-[1-[sup 14]C]with (-)-diisopinocampheyl-chloroborane in an 86.5% yield. The chlorohydrin was converted to R-phenyloxirane-[1-[sup 14]C], which was subsequently converted to the corresponding R-cyanohydrin by reaction with TMS-CN/CaO. Borane reduction and arylation, followed by salt formation yielded S-[gamma]-[(4-trifluoromethyl)phenoxy]benzenepropanamine-[3-[sup 14]C] hydrochloride. (author).

  3. An enantioselective synthesis of S-γ-[(4-trifluoromethyl)phenoxy]benzenepropanamine-[3-14C] hydrochloride, an important metabolite of fluoxetine hydrochloride

    International Nuclear Information System (INIS)

    Wheeler, W.J.

    1992-01-01

    The S-enantiomer of γ-[(4-trifluoromethyl)phenoxy]benzenepropanamine-[3- 14 C] hydrochloride has been prepared in eight steps from acetophenone-[carbonyl- 14 C]. The key step in the synthesis involved the enantioselective reduction of R-2-chloroacetophenone-[1- 14 C]with (-)-diisopinocampheyl-chloroborane in an 86.5% yield. The chlorohydrin was converted to R-phenyloxirane-[1- 14 C], which was subsequently converted to the corresponding R-cyanohydrin by reaction with TMS-CN/CaO. Borane reduction and arylation, followed by salt formation yielded S-γ-[(4-trifluoromethyl)phenoxy]benzenepropanamine-[3- 14 C] hydrochloride. (author)

  4. One-Pot Synthesis of Novel Chiral β-Amino Acid Derivatives by Enantioselective Mannich Reactions Catalyzed by Squaramide Cinchona Alkaloids

    Directory of Open Access Journals (Sweden)

    Kankan Zhang

    2013-05-01

    Full Text Available An efficient one-pot synthesis of novel β-amino acid derivatives containing a thiadiazole moiety was developed using a chiral squaramide cinchona alkaloid as organocatalyst. The reactions afforded chiral β-amino acid derivatives in moderate yields and with moderate to excellent enantioselectivities. The present study demonstrated for the first time the use of a Mannich reaction catalyzed by a chiral bifunctional organocatalyst for the one-pot synthesis of novel β-amino acid derivatives bearing a 1,3,4-thiadiazole moiety on nitrogen.

  5. Enantioselective route to 5-methyl- and 5,7-dimethyl-6,7-dihydro-5H-dibenz[c,e]azepine: secondary amines with switchable axial chirality.

    Science.gov (United States)

    Pira, Silvain L; Wallace, Timothy W; Graham, Jonathan P

    2009-04-02

    (-)-5-Methyl-6,7-dihydro-5H-dibenz[c,e]azepine 4, a new secondary amine featuring an axis-center stereochemical relay, was prepared enantioselectively from 2'-acetylbiphenyl-2-carboxylic acid, using (R)-2-phenylglycinol as an auxiliary for the control of both elements of chirality. The biaryl axis in 4 preferentially adopts the aS-configuration, with the methyl substituent pseudoequatorial, but conversion into the corresponding N-Boc derivative locks the axis into the aR-configuration, as predicted on the basis of molecular mechanics calculations.

  6. Enantioselective Total Synthesis of Antibiotic CJ-16,264, Synthesis and Biological Evaluation of Designed Analogues, and Discovery of Highly Potent and Simpler Antibacterial Agents.

    Science.gov (United States)

    Nicolaou, K C; Pulukuri, Kiran Kumar; Rigol, Stephan; Buchman, Marek; Shah, Akshay A; Cen, Nicholas; McCurry, Megan D; Beabout, Kathryn; Shamoo, Yousif

    2017-11-08

    An improved and enantioselective total synthesis of antibiotic CJ-16,264 through a practical kinetic resolution and an iodolactonization reaction to form the iodo pyrrolizidinone fragment of the molecule is described. A series of racemic and enantiopure analogues of CJ-16,264 was designed and synthesized through the developed synthetic technologies and tested against drug-resistant bacterial strains. These studies led to interesting structure-activity relationships and the identification of a number of simpler, and yet equipotent, or even more potent, antibacterial agents than the natural product, thereby setting the foundation for further investigations in the quest for new anti-infective drugs.

  7. Immobilized Burkholderia cepacia Lipase on pH-Responsive Pullulan Derivatives with Improved Enantioselectivity in Chiral Resolution

    Directory of Open Access Journals (Sweden)

    Li Xu

    2018-01-01

    Full Text Available A kind of pH-responsive particle was synthesized using modified pullulan polysaccharide. The synthesized particle possessed a series of merits, such as good dispersity, chemical stability and variability of particle size, making it a suitable carrier for enzyme immobilization. Then, Burkholderia cepacia lipase (BCL, a promising biocatalyst in transesterification reaction, was immobilized on the synthesized particle. The highest catalytic activity and immobilization efficiency were achieved at pH 6.5 because the particle size was obviously enlarged and correspondingly the adsorption surface for BCL was significantly increased. The immobilization enzyme loading was further optimized, and the derivative lipase was applied in chiral resolution. Under the optimal reaction conditions, the immobilized BCL showed a very good performance and significantly shortened the reaction equilibrium time from 30 h of the free lipase to 2 h with a conversion rate of 50.0% and ees at 99.2%. The immobilized lipase also exhibited good operational stability; after being used for 10 cycles, it still retained over 80% of its original activity. Moreover, it could keep more than 80% activity after storage for 20 days at room temperature in a dry environment. In addition, to learn the potential mechanism, the morphology of the particles and the immobilized lipase were both characterized with a scanning electron microscope and confocal laser scanning microscopy. It was found that the enlarged spherical surface of the particle in low pH values probably led to high immobilized efficiency, resulting in the improvement of enantioselectivity activity in chiral resolution.

  8. Enantioselective oxidative stress and oxidative damage caused by Rac- and S-metolachlor to Scenedesmus obliquus.

    Science.gov (United States)

    Liu, Huijun; Xia, YiLu; Cai, Weidan; Zhang, Yina; Zhang, Xiaoqiang; Du, Shaoting

    2017-04-01

    The rational use and environmental security of chiral pesticides has gained the interest of many researchers. The enantioselective effects of Rac- and S-metolachlor on oxidative stress in Scenedesmus obliquus were determined in this study. Stronger green fluorescence was observed in response to S-metolachlor treatment than to Rac-metolachlor treatment, suggesting that more reactive oxygen species (ROS) were stimulated by S-metolachlor. ROS levels following S-metolachlor treatment were 1.92-, 8.31-, and 1.08-times higher than those observed following Rac-metolachlor treatment at 0.1, 0.2, and 0.3 mg/L, respectively. Superoxide dismutase (SOD) and catalase (CAT) were stimulated with increasing herbicide concentrations, with S-metolachlor exhibiting a greater effect. Oxidative damage in terms of chlorophyll (Chl) content, cellular membrane permeability, and cellular ultrastructures of S. obliquus were investigated. Chla and Chlb contents in algae treated with Rac-metolachlor were 2-6-fold higher than those in algae treated with S-metolachlor at 0.1, 0.2, and 0.3 mg/L. The cellular membrane permeability of algae exposed to 0.3 mg/L Rac- and S-metolachlor was 6.19- and 42.5-times that of the control. Correlation analysis implied that ROS are the major factor responsible for the oxidative damage caused by Rac- and S-metolachlor. Damage to the chloroplasts and cell membrane of S. obliquus, low production of starch granules, and an increased number of vacuoles were observed upon ultrastructural morphology analysis by transmission electron microscope. These results indicate that S-metolachlor has a greater effect on S. obliquus than Rac-metolachlor. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Studies on the interactions of 5-R-3-(2-pyridyl)-1,2,4-triazines with arynes: inverse demand aza-Diels-Alder reaction versus aryne-mediated domino process.

    Science.gov (United States)

    Kopchuk, Dmitry S; Nikonov, Igor L; Khasanov, Albert F; Giri, Kousik; Santra, Sougata; Kovalev, Igor S; Nosova, Emiliya V; Gundala, Sravya; Venkatapuram, Padmavathi; Zyryanov, Grigory V; Majee, Adinath; Chupakhin, Oleg N

    2018-05-02

    The interactions between substituted 5-R-3-(pyridyl-2)-1,2,4-triazines with in situ generated substituted aryne intermediates have been studied. The reaction afforded either inverse demand (ID) aza-Diels-Alder products or 1,2,4-triazine ring rearrangement (domino) products as major ones depending on the nature of both the substituents at the C5 position of the 1,2,4-triazine core or in the aryne moiety. The structures of the key products were confirmed based on X-ray data. Based on the density functional theoretical (DFT) studies of the Diels-Alder transition state geometries, the influence of the nature of arynes on the direction of the 1,2,4-triazine transformation has been proposed.

  10. Human Leukocyte Antigen-G Is Frequently Expressed in a Multicentric Study on Glioblastoma and May Be Induced in Vitro by Combined 5-aza-2'-deoxycytidine and Interferon-γ Treatments

    DEFF Research Database (Denmark)

    Wastowski, Isabela J; Simões, Renata T; Yaghi, Layale

    2012-01-01

    -G protein expression was associated with a better long-term survival rate. The mechanisms underlying HLA-G gene expression were investigated in glioma cell lines U251MG, D247MG, and U138MG. Induction of HLA-G transcriptional activity was dependent of 5-aza-2'-deoxycytidine treatment and enhanced......Human leukocyte antigen-G (HLA-G) is a nonclassical major histocompatibility complex (MHC) class I molecule involved in immune tolerance processes, playing an important role in the maintenance of the semi-allogeneic fetus. Although HLA-G expression is restricted in normal tissues, it is broadly...... expressed in malignant tumors and may favor tumor immune escape. We analyzed HLA-G protein and mRNA expression in tumor samples from patients with glioblastoma collected in France, Denmark, and Brazil. We found HLA-G protein expression in 65 of 108 samples and mRNA in 20 of 21 samples. The absence of HLA...

  11. Cloning of an epoxide hydrolase-encoding gene from Aspergillus niger M200, overexpression in E. coli, and modification of aktivity and enantioselectivity of the enzyme by protein engineering

    Czech Academy of Sciences Publication Activity Database

    Kotík, Michael; Štěpánek, Václav; Kyslík, Pavel; Marešová, Helena

    2007-01-01

    Roč. 132, - (2007), s. 8-15 ISSN 0168-1656 R&D Projects: GA ČR GA204/06/0458 Institutional research plan: CEZ:AV0Z50200510 Keywords : protein engineering * saturation mutagenesis * enantioselectivity Subject RIV: EE - Microbiology, Virology Impact factor: 2.565, year: 2007

  12. Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Five-, Six-, and Seven-Membered β-Substituted Cyclic Enones: Enantioselective Construction of All-Carbon Quaternary Stereocenters

    KAUST Repository

    Kikushima, Kotaro; Holder, Jeffrey C.; Gatti, Michele; Stoltz, Brian M.

    2011-01-01

    The first enantioselective Pd-catalyzed construction of all-carbon quaternary stereocenters via 1,4-addition of arylboronic acids to β-substituted cyclic enones is reported. Reaction of a wide range of arylboronic acids and cyclic enones using a

  13. Simultaneous enantioselective separation of polychlorinated biphenyls and their methyl sulfone metabolites by heart-cut MDGC: determination of enantiomeric fractions in fish oils and cow liver samples.

    Science.gov (United States)

    Pérez-Fernández, Virginia; Castro-Puyana, María; González, María José; Marina, María Luisa; García, María Ángeles; Gómara, Belén

    2012-07-01

    The potential of three capillary columns based on β-cyclodextrin (i.e., Chirasil-Dex, BGB-172, and BGB-176SE) has been studied for the simultaneous enantiomeric separation of polychlorinated biphenyls (PCBs) and methylsulfonyl metabolites of PCBs (MeSO(2)-PCBs) employing a heart-cut multidimensional gas chromatographic system (heart-cut MDGC). Among the columns studied, the BGB-176SE capillary column provided the best results, allowing the simultaneous enantioselective resolution of six MeSO(2)-PCBs and six chiral PCBs; the Chirasil-Dex column did not resolve any of the studied MeSO(2)-PCBs; and a poor resolution was obtained for three MeSO(2)-PCBs when the BGB-172 column was employed. The developed method was successfully applied to two fish oil and one cow liver samples commercially available, which showed different enantioselective pattern. PCBs 91 and 176 presented a clear enrichment of the second eluted atropisomer in codfish oil, whereas in fish oil sample, slight enrichment of the first eluted atropisomer of CB45 and the second eluted atropisomer of CB136 were observed. © 2012 Wiley Periodicals, Inc.

  14. Enantioselective determination of (R)-zopiclone and (S)-zopiclone (eszopiclone) in human hair by micropulverized extraction and chiral liquid chromatography/high resolution mass spectrometry.

    Science.gov (United States)

    Miyaguchi, Hajime; Kuwayama, Kenji

    2017-10-13

    Zopiclone and its (S)-enantiomer (eszopiclone) are commonly prescribed for insomnia. Despite the high demand for enantioselective differentiation, the chiral analysis of zopiclone in hair has not been reported. In this study, a method for the enantioselective quantification of zopiclone in human hair was developed. The extraction medium and duration were optimized using real eszopiclone-positive hair samples. Specifically, micropulverized extraction with 3.0M ammonium phosphate buffer (pH 8.4) involving salting-out assisted liquid-liquid extraction with acetonitrile was utilized to minimize the degradation of zopiclone and for rapid and facile operation. On the other hand, recovery of the conventional solid-liquid extraction involved overnight soaking in 3.0M ammonium phosphate buffer (pH 8.4) was only 0.58±0.12% of the maximum recovery achieved by the present method due to the decomposition in the phosphate buffer. An excellent chiral separation (Rs=5.0) was achieved using a chiral stationary phase comprising cellulose tris(3,5-dichlorophenylcarbamate) and a volatile mobile phase of 10mM ammonium carbonate (pH 8.0)-acetonitrile (25:75, v/v). Detection was carried out using liquid chromatography/high resolution mass spectrometry (LC/HRMS) with electrospray ionization. A Q Exactive mass spectrometer equipped with a quadrupole-Orbitrap analyzer was used for detection. The concentration of 0.50pg/mg was defined as the lowest limit of quantification using 5mg of hair sample. Using the developed approach, the concentration of eszopiclone in hair after a single 2-mg dose was found to be 441pg/mg, which was higher than all the reported values regarding a single administration of zopiclone. After daily administration of racemic zopiclone (3.75mg/day), the concentrations of (R)-enantiomer and (S)-enantiomer in the black hair were 5.30-8.31ng/mg and 7.96-12.8ng/mg, respectively, and the concentration of the (S)-enantiomer was always higher than that of the (R

  15. Insight into the stereospecificity of short-chain thermus thermophilus alcohol dehydrogenase showing pro-S hydride transfer and prelog enantioselectivity.

    Science.gov (United States)

    Pennacchio, Angela; Giordano, Assunta; Esposito, Luciana; Langella, Emma; Rossi, Mosè; Raia, Carlo A

    2010-04-01

    The stereochemistry of the hydride transfer in reactions catalyzed by NAD(H)-dependent alcohol dehydrogenase from Thermus thermophilus HB27 was determined by means of (1)H-NMR spectroscopy. The enzyme transfers the pro-S hydrogen of [4R-(2)H]NADH and exhibits Prelog specificity. Enzyme-substrate docking calculations provided structural details about the enantioselectivity of this thermophilic enzyme. These results give additional insights into the diverse active site architectures of the largely versatile short-chain dehydrogenase superfamily enzymes. A feasible protocol for the synthesis of [4R-(2)H]NADH with high yield was also set up by enzymatic oxidation of 2-propanol-d(8) catalyzed by Bacillus stearothermophilus alcohol dehydrogenase.

  16. Enantioselective ProPhenol-catalyzed addition of 1,3-diynes to aldehydes to generate synthetically versatile building blocks and diyne natural products.

    Science.gov (United States)

    Trost, Barry M; Chan, Vincent S; Yamamoto, Daisuke

    2010-04-14

    A highly enantioselective method for the catalytic addition of terminal 1,3-diynes to aldehydes was developed using our dinuclear zinc ProPhenol (1) system. Furthermore, triphenylphosphine oxide was found to interact synergistically with the catalyst to substantially enhance the chiral recognition. The generality of this catalytic transformation was demonstrated with aryl, alpha,beta-unsaturated and saturated aldehydes, of which the latter were previously limited in alkynyl zinc additions. The chiral diynol products are also versatile building blocks that can be readily elaborated; this was illustrated through highly selective trans-hydrosilylations, which enabled the synthesis of a beta-hydroxyketone and enyne. Additionally, the development of this method allowed for the rapid total syntheses of several biologically important diynol-containing natural products.

  17. Simultaneous enantioselective determination of triadimefon and its metabolite triadimenol in edible vegetable oil by gel permeation chromatography and ultraperformance convergence chromatography/tandem mass spectrometry.

    Science.gov (United States)

    Yao, Zhoulin; Li, Xiaoge; Miao, Yelong; Lin, Mei; Xu, Mingfei; Wang, Qiang; Zhang, Hu

    2015-11-01

    A novel, sensitive, and efficient enantioselective method for the determination of triadimefon and its metabolite triadimenol in edible vegetable oil, was developed by gel permeation chromatography and ultraperformance convergence chromatography/tandem triple quadrupole mass spectrometry. After the vegetable oil samples were prepared using gel permeation chromatography, the eluent was collected, evaporated, and dried with nitrogen gas. The residue was redissolved by adding methanol up to a final volume of 1 mL. The analytes of six enantiomers were analyzed on Chiralpak IA-3 column (150 × 4.6 mm) using compressed liquid CO2-mixed 14 % co-solvents, comprising methanol/acetonitrile/isopropanol = 20/20/60 (v/v/v) in the mobile phase at 30 °C, and the total separation time was less than 4 min at a flow rate of 2 mL/min. Quantification was achieved using matrix-matched standard calibration curves. The overall mean recoveries for six enantiomers from vegetable oil were 90.1-97.3 %, with relative standard deviations of 0.8-5.4 % intra-day and 2.3-5.0 % inter-day at 0.5, 5, and 50 μg/kg levels. The limits of quantification were 0.5 μg/kg for all enantiomers based on five replicate extractions at the lowest fortified level in vegetable oil. Moreover, the absolute configuration of six enantiomers had been determined based on comparisons of the vibrational circular dichroism experimental spectra with the theoretical curve obtained by density functional theory calculations. Application of the proposed method to the 40 authentic vegetable oil samples from local markets suggests its potential use in enantioselective determination of triadimefon and triadimenol enantiomers. Graphical Abstract Chemical structures and UPC(2)-MS/MS separation chromatograms of triadimefon and triadimenol.

  18. Silver ion imprinted polymer nanobeads based on a aza-thioether crown containing a 1,10-phenanthroline subunit for solid phase extraction and for voltammetric and potentiometric silver sensors

    Energy Technology Data Exchange (ETDEWEB)

    Shamsipur, Mojtaba, E-mail: mshamsipur@yahoo.com [Department of Chemistry, Razi University, Kermanshah (Iran, Islamic Republic of); Hashemi, Beshare; Dehdashtian, Sara; Mohammadi, Moslem; Gholivand, Mohammad Bagher [Department of Chemistry, Razi University, Kermanshah (Iran, Islamic Republic of); Garau, Alessandra; Lippolis, Vito [Dipartimento di Scienze Chimiche e Geologiche, Universita' degli Studi di Cagliari, S.S. 554 Bivio per Sestu, 09042 Monserrato, CA (Italy)

    2014-12-10

    Highlights: • Preparation of Ag{sup +} imprinted polymeric nanobeads via precipitation polymerization. • Use of a mixed aza-thioether crown containing a 1,10-phenanthroline subunit a selective host for Ag{sup +} ion. • Highly selective, sensitive and fast recognition of traces of Ag{sup +} ions. • Use of the prepared Ag{sup +}-IIP for preparation of an Ag{sup +}-voltammetric sensor with LOD of 9.0 × 10{sup −10} M. • Use of the prepared Ag{sup +}-IIP for preparation of Ag{sup +}-ISEs with LOD of 1.2 × 10{sup −9} M 9.0 × 10{sup −10} M. - Abstract: A new nano-sized silver(I) ion-imprinted polymer (IIP) was prepared via precipitation copolymerization using ethyleneglycol dimethacrylate, as a cross-linking agent in the presence of Ag{sup +} and an aza-thioether crown containing a 1,10-phenanthroline subunit as a highly selective complexing agent. The imprint silver(I) ion was removed from the polymeric matrix using a 1.0 M HNO{sub 3} solution. The resulting powder material was characterized using IR spectroscopy and scanning electron microscopy. The SEM micrographs showed colloidal nanoparticles of about 52 nm and 75 nm in diameter and slightly irregular in shape for leached and unleached IIPs, respectively. The optimal pH for quantitative enrichment was 6.0 and maximum sorbent capacity of the prepared IIP for Ag{sup +} was 18.08 μmol g{sup −1}. The relative standard deviation and limit of detection (LOD = 3S{sub b}/m) for flame atomic absorption spectrometric determination of silver(I) ion, after its selective extraction by the prepared IIP nanobeads, were evaluated as 2.42% and 2.2 × 10{sup −8} M, respectively. The new Ag{sup +}-IIP was also applied as a suitable sensing element to the preparation of highly selective and sensitive voltammetric and potentiometric sensors for ultra trace detection of silver(I) ion in water samples, with limits of detection of 9.0 × 10{sup −10} and 1.2 × 10{sup −9} M, respectively.

  19. Highly Enantioselective Construction of Tertiary Thioethers and Alcohols via Phosphine-Catalyzed Asymmetric γ-Addition reactions of 5H-Thiazol-4-ones and 5H-Oxazol-4-ones: Scope and Mechanistic Understandings

    KAUST Repository

    Wang, Tianli

    2015-06-02

    Phosphine-catalyzed highly enantioselective γ-additions of 5H-thiazol-4-ones and 5H-oxazol-4-ones to allenoates have been developed for the first time. With the employment of amino-acid derived bifunctional phosphines, a wide range of substituted 5H-thiazol-4-one and 5H-oxazol-4-one derivatives bearing heteroarom (S or O)-containing tertiary chiral centers were constructed in high yields and excellent enantioselectivities. The reported method provides a facile access to enantioenriched tertiary thioether/alcohols. The mechanism of γ-addition reaction was investigated by performing DFT calculations, and the hydrogen bonding interactions between the Brønsted acid moiety of the phosphine catalysts and the “C=O” unit of donor molecules were shown to be crucial in asymmetric induction.

  20. Highly Enantioselective Construction of Tertiary Thioethers and Alcohols via Phosphine-Catalyzed Asymmetric γ-Addition reactions of 5H-Thiazol-4-ones and 5H-Oxazol-4-ones: Scope and Mechanistic Understandings

    KAUST Repository

    Wang, Tianli; Yu, Zhaoyuan; Hoon, Ding Long; Huang, Kuo-Wei; Lan, Yu; Lu, Yixin

    2015-01-01

    Phosphine-catalyzed highly enantioselective γ-additions of 5H-thiazol-4-ones and 5H-oxazol-4-ones to allenoates have been developed for the first time. With the employment of amino-acid derived bifunctional phosphines, a wide range of substituted 5H-thiazol-4-one and 5H-oxazol-4-one derivatives bearing heteroarom (S or O)-containing tertiary chiral centers were constructed in high yields and excellent enantioselectivities. The reported method provides a facile access to enantioenriched tertiary thioether/alcohols. The mechanism of γ-addition reaction was investigated by performing DFT calculations, and the hydrogen bonding interactions between the Brønsted acid moiety of the phosphine catalysts and the “C=O” unit of donor molecules were shown to be crucial in asymmetric induction.

  1. Purification, characterisation and expression in Saccharomyces cerevisiae of LipG7 an enantioselective, cold-adapted lipase from the Antarctic filamentous fungus Geomyces sp. P7 with unusual thermostability characteristics.

    Science.gov (United States)

    Florczak, Tomasz; Daroch, Maurycy; Wilkinson, Mark Charles; Białkowska, Aneta; Bates, Andrew Derek; Turkiewicz, Marianna; Iwanejko, Lesley Ann

    2013-06-10

    A lipase, LipG7, has been purified from the Antarctic filamentous fungus Geomyces sp. P7 which was found to be cold-adapted and able to retain/regain its activity after heat denaturation. The LipG7 exhibits 100% residual activity following 1h incubation at 100°C whilst simultaneously showing kinetic adaptations to cold temperatures. LipG7 was also found to have industrial potential as an enantioselective biocatalyst as it is able to effectively catalyse the enantioselective transesterification of a secondary alcohol. The LipG7 coding sequence has been identified and cloned using 454 pyrosequencing of the transcriptome and inverse PCR. The LipG7 protein has been heterologously expressed in Saccharomyces cerevisiae BJ5465 and shown to exhibit the same characteristics as the native protein. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Host-Guest Inclusion Complexes between Amlodipine Enantiomers in Biphasic Recognition Chiral Extraction System using Tartaric Acid and β-Cyclodextrin Derivatives as Positive Confirmation Using of their Enantioselective Extraction

    OpenAIRE

    AZZAM, Khaldun; ABDALLAH, Hassan; HALIM, Hairul; AHMAD, Maizatul; SHAIBAH, Hassan

    2015-01-01

    The current work reports an extended theoretical study from our previous experimental work for the enantioselective extraction of amlodipine enantiomers in a biphasic recognition chiral extraction system (BRCES) consisting of hydrophobic D-diisopropyl tartrate dissolved in organic phase (n-decanol) and hydrophilic hydroxypropyl-?-cyclodextrin (HP-?-CD) in aqueous phase (acetate buffer) which preferentially recognize the R-enantiomer and S-enantiomer, respectively. The calculations were simula...

  3. Enantioselective synthesis of possible diastereomers of heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol; putative structure of a conjugated diyne natural product isolated from Hydrocotyle leucocephala.

    Science.gov (United States)

    Prasad, Kavirayani R; Swain, Bandita

    2011-04-01

    Enantioselective synthesis of possible diastereomers of heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol, a structure proposed for the natural product isolated from Hydrocotyle leucocephala is accomplished. The reported spectral data of the natural product did not match those of any of the isomers that were synthesized and established that the structure proposed for the natural product is not correct and requires revision.

  4. Ring opening of 2-aza-3-borabicyclo[2.2.0]hex-5-ene, the Dewar form of 1,2-dihydro-1,2-azaborine: stepwise versus concerted mechanisms

    Directory of Open Access Journals (Sweden)

    Holger F. Bettinger

    2013-04-01

    Full Text Available The ring opening of the Dewar form of 1,2-dihydro-1,2-azaborine, 2-aza-3-borabicyclo[2.2.0]hex-5-ene (3 is investigated by theoretical methods by using multiconfiguration SCF (CASSCF and coupled cluster theory [CCSD(T] with basis sets up to polarised quadruple-zeta quality. The title compound was previously reported to form photochemically in cryogenic noble gas matrices from 1,2-dihydro-1,2-azaborine (4. Four reaction paths for the thermal ring opening of 3 to 4 could be identified. These are the conventional disrotatory and conrotatory electrocyclic ring-opening pathways where the BN unit is only a bystander. Two more favourable paths are stepwise and involve 1,3-boron–carbon interactions. The lowest energy barrier for the isomerisation reaction, 22 kcal mol−1, should be high enough for an experimental observation in solution. However, in solution the dimerisation of 3 is computed to have a very low barrier (3 kcal mol−1, and thus 3 is expected to be a short-lived reactive intermediate.

  5. Determination of the human cytochrome P450 monooxygenase catalyzing the enantioselective oxidation of 2,2',3,5',6-pentachlorobiphenyl (PCB 95) and 2,2',3,4,4',5',6-heptachlorobiphenyl (PCB 183).

    Science.gov (United States)

    Nagayoshi, Haruna; Kakimoto, Kensaku; Konishi, Yoshimasa; Kajimura, Keiji; Nakano, Takeshi

    2017-10-17

    2,2',3,5',6-Pentachlorobiphenyl (PCB 95) and 2,2',3,4,4',5',6-heptachlorobiphenyl (PCB 183) possess axial chirality and form the aS and aR enantiomers. The enantiomers of these congeners have been reported to accumulate in the human body enantioselectively via unknown mechanisms. In this study, we determined the cytochrome P450 (CYP) monooxygenase responsible for the enantioselective oxidization of PCB 95 and PCB 183, using a recombinant human CYP monooxygenase. We evaluated 13 CYP monooxygenases, namely CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, CYP3A4, CYP3A5, CYP4F2, and aromatase (CYP19), and revealed that CYP2A6 preferably oxidizes aS-PCB 95 enantioselectively; however, it did not oxidize PCB 183. The enantiomer composition was elevated from 0.5 (racemate) to 0.54. In addition, following incubation with CYP2A6, the enantiomer fraction (EF) of PCB 95 demonstrated a time-dependent increase.

  6. A new and fast DLLME-CE method for the enantioselective analysis of zopiclone and its active metabolite after fungal biotransformation.

    Science.gov (United States)

    de Albuquerque, Nayara Cristina Perez; de Gaitani, Cristiane Masetto; de Oliveira, Anderson Rodrigo Moraes

    2015-05-10

    Zopiclone (ZO) is a chiral drug that undergoes extensive metabolism to N-desmethylzopiclone (N-Des-ZO) and zopiclone-N-oxide (N-Ox-ZO). Pharmacological studies have shown (S)-N-Des-ZO metabolite presents anxiolytic activity and a patent for this metabolite was requested for anxiety treatment and related disorders. In this context, biotransformation employing fungi may be a promising strategy to obtain N-Des-ZO. To perform the biotransformation study in this work, an enantioselective method based on capillary electrophoresis (CE) and dispersive liquid-liquid microextraction (DLLME) was developed. CE analyses were carried out in sodium phosphate buffer (pH 2.5; 50mmolL(-1)) containing 0.5% (w/v) carboxymethyl-β-CD, at a constant voltage of +25kV. DLLME was conducted using 2mL of liquid culture medium pH 9.5. Chloroform (100μL) and methanol (300μL) were employed as extraction and disperser solvent, respectively. After CE and DLLME optimization, the analytical method was fully validated. The method was linear over a concentration range of 90-6000ngmL(-1) for each ZO enantiomer (r>0.999) and 50-1000ngmL(-1) for each N-Des-ZO enantiomer (r>0.998). Absolute recovery of 51 and 82% was achieved for N-Des-ZO and ZO, respectively. The accuracy and precision results agreed with the EMA (European Medicines Agency) guideline, and so did the stability study. Application of the developed method in a biotransformation study was conducted in order to investigate the ability of fungi, belonging to the genus Cunninghamella, in metabolizing ZO chiral drug. Fungi Cunninghamella elegans ATCC 10028B and Cunninghamella echinulata var elegans ATCC 8688A demonstrated to be able to enantioselectively biotransform ZO to its active metabolite, N-Des-ZO. Therefore, the proposed goals of this work, i.e. a fast DLLME-CE method and an outstanding strategy to obtain N-Des-ZO, were successfully attained. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. NUC041, a Prodrug of the DNA Methytransferase Inhibitor 5-aza-2′,2′-Difluorodeoxycytidine (NUC013, Leads to Tumor Regression in a Model of Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Richard Daifuku

    2018-04-01

    Full Text Available 5-aza-2′,2′-difluorodeoxycytidine (NUC013 has been shown to be significantly safer and more effective than decitabine in xenograft models of human leukemia and colon cancer. However, it suffers from a similar short half-life as other DNA methyltransferase inhibitors with a 5-azacytosine base, which is problematic for nucleosides that primarily target tumor cells in S phase. Because of the relative instability of 5-azanucleosides, a prodrug approach was developed to improve the pharmacology of NUC013. NUC013 was conjugated with trimethylsilanol (TMS at the 3′ and 5′ position of the sugar, rendering the molecule hydrophobic and producing 3′,5′-di-trimethylsilyl-2′,2′-difluoro-5-azadeoxycytidine (NUC041. NUC041 was designed to be formulated in a hydrophobic vehicle, protecting it from deamination and hydrolysis. In contact with blood, the TMS moieties are readily hydrolyzed to release NUC013. The half-life of NUC013 administered intravenously in mice is 20.1 min, while that of NUC013 derived from intramuscular NUC041 formulated in a pegylated-phospholipid depot is 3.4 h. In a NCI-H460 xenograft of non-small cell lung cancer, NUC013 was shown to significantly inhibit tumor growth and improve survival. Treatment with NUC041 also led to significant tumor growth inhibition. However, NUC041-treated mice had significantly more tumors ulcerate than either NUC013 treated mice or saline control mice, and such ulceration occurred at significantly lower tumor volumes. In these nude mice, tumor regression was likely mediated by the derepression of the tumor suppressor gene p53 and resultant activation of natural killer (NK cells.

  8. Enantioselective synthesis of α-phenyl- and α-(dimethylphenylsilyl)alkylboronic esters by ligand mediated stereoinductive reagent-controlled homologation using configurationally labile carbenoids.

    Science.gov (United States)

    Barsamian, Adam L; Wu, Zhenhua; Blakemore, Paul R

    2015-03-28

    Chain extension of boronic esters by the action of configurationally labile racemic lithium carbenoids in the presence of scalemic bisoxazoline ligands was explored for the enantioselective synthesis of the two title product classes. Enantioenriched 2° carbinols generated by oxidative work-up (NaOOH) of initial α-phenylalkylboronate products were obtained in 35-83% yield and 70-96% ee by reaction of B-alkyl and B-aryl neopentyl glycol boronates with a combination of O-(α-lithiobenzyl)-N,N-diisopropylcarbamate and ligand 3,3-bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl] pentane in toluene solvent (-78 °C to rt) with MgBr2·OEt2 additive. Enantioenriched α-(dimethylsilylphenylsilyl)alkylboronates were obtained in 35-69% yield and 9-57% ee by reaction of B-alkyl pinacol boronates with a combination of lithio(dimethylphenylsilyl)methyl 2,4,6-triisopropylbenzoate and ligand 2,2-bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl]propane in cumene solvent (-45 °C to -95 °C to rt). The stereochemical outcome of the second type of reaction depended on the temperature history of the organolithium·ligand complex indicating that the stereoinduction mechanism in this case involves some aspect of dynamic thermodynamic resolution.

  9. Enantioselectivity and Thermostability of a Novel Hyperhermotolerant Lipase from Geobacillus Thermodenitrificans nr68 (Lip.nr-68) on Secondary Racemic Alcohols Acetylation

    Science.gov (United States)

    Nik Him, N. R.; Ibrahim, D.

    2018-05-01

    In our previous work, a new lipase enzyme has been purified from a species identified as a Gram negative Geobacillus thermodenitrificans nr68, isolated from a hot spring in Malaysia with growth temperature of 48°C. This new lipase, called Lip.nr-68 has been characterized as a hyperthermotolerant protein with high stability at 65°C and has been showing excellent characteristics that are very much comparable yet better than some of those of well-known industrially-used lipases. It shows high activity against long-chain triglycerides with molecular weight of the purified enzyme estimated to be 33.5 kDa using SDS-PAGE analysis. This paper is focusing on hyperthermotolerant Lip.nr-68 performance in promoting for enantioselectivity activities towards three secondary racemic alcohols namely 1-phenylethanol, 1-cyclohexilethanol and 1-(naft-2-il) ethanol by acetylation with vinyl acetate. Lip.nr-68 has been confirmed to show high and usual enantioselectivitiy according to the Kazlauskas Rule towards all secondary racemic alcohols and has significantly approved as an enantiomer selective biocatalyst towards 1-phenylethanol and 1-cyclohexylethanol at 65°C. Lip.nr-68 has showed a reduction of (R) and (S) enantiomers as well as the production of 68-98% ee and almost 94% yield of 3-4 mg/ml for 1-cyclohexilethanol.

  10. Volatile Composition and Enantioselective Analysis of Chiral Terpenoids of Nine Fruit and Vegetable Fibres Resulting from Juice Industry By-Products

    Directory of Open Access Journals (Sweden)

    Alexis Marsol-Vall

    2017-01-01

    Full Text Available Fruit and vegetable fibres resulting as by-products of the fruit juice industry have won popularity because they can be valorised as food ingredients. In this regard, bioactive compounds have already been studied but little attention has been paid to their remaining volatiles. Considering all the samples, 57 volatiles were identified. Composition greatly differed between citrus and noncitrus fibres. The former presented over 90% of terpenoids, with limonene being the most abundant and ranging from 52.7% in lemon to 94.0% in tangerine flesh. Noncitrus fibres showed more variable compositions, with the predominant classes being aldehydes in apple (57.5% and peach (69.7%, esters (54.0% in pear, and terpenoids (35.3% in carrot fibres. In addition, enantioselective analysis of some of the chiral terpenoids present in the fibre revealed that the enantiomeric ratio for selected compounds was similar to the corresponding volatile composition of raw fruits and vegetables and some derivatives, with the exception of terpinen-4-ol and α-terpineol, which showed variation, probably due to the drying process. The processing to which fruit residues were submitted produced fibres with low volatile content for noncitrus products. Otherwise, citrus fibres analysed still presented a high volatile composition when compared with noncitrus ones.

  11. 天然产物Brosimacutins H和I的对映选择性全合成%First Enantioselective Synthesis of Brosimacutins H and I

    Institute of Scientific and Technical Information of China (English)

    叶子平; 杨金会; 冯尧; 马涛; 牛明杰

    2016-01-01

    Brosimacutins H和I是从巴西的Brosimum acutifolium Huber树皮中分离出的两个具有相似结构的黄酮类化合物.此树皮被巴西当地居民作为抗发炎和抗风湿的药物,并且这两种化合物具有一定的细胞活性.以廉价的羟苯乙酮和羟苯甲醛为原料完成了黄酮化合物Brosimacutins H和I的对映选择性合成.所有新化合物的结构都经过NMR,HRMS确认.%Brosimacutins H and I,isolated from the bark of brosimum acutifolium huber,are flavanoid compounds with similar structures.The bark of this plant is used in Brazilian folk medicine as an anti-inflammatory and anti-rheumatic agent,and cellular activities were reported for these two compounds.Herein the first enantio-selective synthesis of brosimacutins H and I from cheap starting material hydroxyl-acetophenone and hydroxyl benzene formaldehyde was reported.All new compounds in this study were confirmed by NMR and HRMS.

  12. Conformation and Catalytic Properties Studies of Candida rugosa Lip7 via Enantioselective Esterification of Ibuprofen in Organic Solvents and Ionic Liquids

    Directory of Open Access Journals (Sweden)

    Xiang Li

    2013-01-01

    Full Text Available Enantioselective esterification of ibuprofen was conducted to evaluate the enzyme activity and ees of lipase from Candida rugosa (CRL7 in ten conventional organic solvents and three ionic liquids. Different alcohols were tested for selecting the most suitable acyl acceptor due to the fact that the structure of alcohols (branch and length of carbon chains; location of –OH functional group could affect the enzyme activity and ees. The results of alcohol and solvent selection revealed that 1-isooctanol and isooctane were the best substrate and reaction medium, respectively, because of the highest enzyme activity and ees. Compared with the control, conformational studies via FT-IR indicate that the variations of CRL7’s secondary structure elements are probably responsible for the differences of enzyme activity and ees in the organic solvents and ionic liquids. Moreover, the effects of reaction parameters, such as molar ratio, water content, temperature, and reaction time, in the selected reaction medium, were also examined.

  13. Experimental and Model Studies on Continuous Separation of 2-Phenylpropionic Acid Enantiomers by Enantioselective Liquid-Liquid Extraction in Centrifugal Contactor Separators.

    Science.gov (United States)

    Feng, Xiaofeng; Tang, Kewen; Zhang, Pangliang; Yin, Shuangfeng

    2016-03-01

    Multistage enantioselective liquid-liquid extraction (ELLE) of 2-phenylpropionic acid (2-PPA) enantiomers using hydroxypropyl-β-cyclodextrin (HP-β-CD) as extractant was studied experimentally in a counter-current cascade of centrifugal contactor separators (CCSs). Performance of the process was evaluated by purity (enantiomeric excess, ee) and yield (Y). A multistage equilibrium model was established on the basis of single-stage model for chiral extraction of 2-PPA enantiomers and the law of mass conservation. A series of experiments on the extract phase/washing phase ratio (W/O ratio), extractant concentration, the pH value of aqueous phase, and the number of stages was conducted to verify the multistage equilibrium model. It was found that model predictions were in good agreement with the experimental results. The model was applied to predict and optimize the symmetrical separation of 2-PPA enantiomers. The optimal conditions for symmetric separation involves a W/O ratio of 0.6, pH of 2.5, and HP-β-CD concentration of 0.1 mol L(-1) at a temperature of 278 K, where eeeq (equal enantiomeric excess) can reach up to 37% and Yeq (equal yield) to 69%. By simulation and optimization, the minimum number of stages was evaluated at 98 and 106 for eeeq > 95% and eeeq > 97%. © 2016 Wiley Periodicals, Inc.

  14. Highly Enantioselective Production of Chiral Secondary Alcohols Using Lactobacillus paracasei BD101 as a New Whole Cell Biocatalyst and Evaluation of Their Antimicrobial Effects.

    Science.gov (United States)

    Yılmaz, Durmuşhan; Şahin, Engin; Dertli, Enes

    2017-11-01

    Chiral secondary alcohols are valuable intermediates for many important enantiopure pharmaceuticals and biologically active molecules. In this work, we studied asymmetric reduction of aromatic ketones to produce the corresponding chiral secondary alcohols using lactic acid bacteria (LAB) as new biocatalysts. Seven LAB strains were screened for their ability to reduce acetophenones to their corresponding alcohols. Among these strains, Lactobacillus paracasei BD101 was found to be the most successful at reducing the ketones to the corresponding alcohols. The reaction conditions were further systematically optimized for this strain and high enantioselectivity (99%) and very good yields were obtained. These secondary alcohols were further tested for their antimicrobial activities against important pathogens and significant levels of antimicrobial activities were observed although these activities were altered depending on the secondary alcohols as well as their enantiomeric properties. The current methodology demonstrates a promising and alternative green approach for the synthesis of chiral secondary alcohols of biological importance in a cheap, mild, and environmentally useful process. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

  15. Effect of the water content on the retention and enantioselectivity of albendazole and fenbendazole sulfoxides using amylose-based chiral stationary phases in organic-aqueous conditions.

    Science.gov (United States)

    Materazzo, Sabrina; Carradori, Simone; Ferretti, Rosella; Gallinella, Bruno; Secci, Daniela; Cirilli, Roberto

    2014-01-31

    Four commercially available immobilized amylose-derived CSPs (Chiralpak IA-3, Chiralpak ID-3, Chiralpak IE-3 and Chiralpak IF-3) were used in the HPLC analysis of the chiral sulfoxides albendazole (ABZ-SO) and fenbendazole (FBZ-SO) and their in vivo sulfide precursor (ABZ and FBZ) and sulfone metabolite (ABZ-SO2 and FBZ-SO2) under organic-aqueous mode. U-shape retention maps, established by varying the water content in the acetonitrile- and ethanol-water mobile phases, were indicative of two retention mechanisms operating on the same CSP. The dual retention behavior of polysaccharide-based CSPs was exploited to design greener enantioselective and chemoselective separations in a short time frame. The enantiomers of ABZ-SO and FBZ-SO were baseline resolved with water-rich mobile phases (with the main component usually being 50-65% water in acetonitrile) on the IF-3 CSP and ethanol-water 100:5 mixture on the IA-3 and IE-3 CSPs. A simultaneous separation of ABZ (or FBZ), enantiomers of the corresponding sulfoxide and sulfone was achieved on the IA-3 using ethanol-water 100:60 (acetonitrile-water 100:100 for FBZ) as a mobile phase. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Ketamine metabolites with antidepressant effects: Fast, economical, and eco-friendly enantioselective separation based on supercritical-fluid chromatography (SFC) and single quadrupole MS detection.

    Science.gov (United States)

    Fassauer, Georg M; Hofstetter, Robert; Hasan, Mahmoud; Oswald, Stefan; Modeß, Christina; Siegmund, Werner; Link, Andreas

    2017-11-30

    Increasing evidence accumulates that metabolites of the dissociative anesthetic ketamine contribute considerably to the biological effects of this drug and could be developed as next generation antidepressants, especially for acute treatment of patients with therapy-refractory major depression. Analytical methods for the simultaneous determination of the plethora of hydroxylated, dehydrogenated and/or demethylated compounds formed after administration of ketamine hydrochloride are a prerequisite for future clinical investigations and a deeper understanding of the individual role of the isomers of these metabolites. In this study, we present development and validation of a method based on supercritical-fluid chromatography (SFC) coupled to single quadrupole MS detection that allows the separation of ketamine as well as all of its relevant metabolites detected in urine of healthy volunteers. Inherently to SFC methods, the run times of the novel protocol are four times shorter than in a comparable HPLC method, the use of organic solvents is reduced and we were able to demonstrate and validate the successful enantioselective separation and quantification of R- and S-ketamine, R- and S-norketamine, R- and S-dehydronorketamine and (2R,6R)- and (2S,6S)-hydroxynorketamine isomers differing in either constitution, stereochemistry, or both, in one run. The developed method may be useful in investigating the antidepressant efficacy of ketamine in clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Enantioselective determination of triazole fungicide simeconazole in vegetables, fruits, and cereals using modified QuEChERS (quick, easy, cheap, effective, rugged and safe) coupled to gas chromatography/tandem mass spectrometry.

    Science.gov (United States)

    Li, Jing; Dong, Fengshou; Xu, Jun; Liu, Xingang; Li, Yuanbo; Shan, Weili; Zheng, Yongquan

    2011-09-19

    A rapid and effective method for enantioselective determination of simeconazole enantiomers in food products (cucumber, tomato, apple, pear, wheat and rice) has been developed. The enantiomers were resolved by capillary gas chromatography (GC) using a commercial chiral column (BGB-172) and a temperature program from 150°C (held for 1 min) and then raised at 10°C min(-1) to 240°C (held for 10 min). This enantioselective gas chromatographic separation was combined with a clean-up/enrichment procedure based on the modification of QuEChERS (quick, easy, cheap, effective, rugged and safe) method. Co-extractives were removed with graphitized carbon black/primary secondary amine (GCB/PSA) solid-phase extraction (SPE) cartridges using acetonitrile:toluene (3:1, v/v) as eluent. Gas chromatography/ion trap mass spectrometry (GC-ITMS) with electron ionization (EI) was then used for qualitative and quantitative determination of the simeconazole enantiomers. Two precursor-to-product ion transitions (m/z 121-101 and 195-153) with the best signal intensity were chosen to build the multiple-reaction monitoring (MRM) acquisition method. The limits of detection for each enantiomer of simeconazole in six food products ranged between 0.4 and 0.9 μg kg(-1), which were much lower than maximum residue levels (MRLs) established by Japan. The methodology was successfully applied for the enantioselective analysis of simeconazole enantiomers in real samples, indicating its efficacy in investigating the environmental stereochemistry of simeconazole in food matrix. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Enantioselective determination of triazole fungicide simeconazole in vegetables, fruits, and cereals using modified QuEChERS (quick, easy, cheap, effective, rugged and safe) coupled to gas chromatography/tandem mass spectrometry

    International Nuclear Information System (INIS)

    Li Jing; Dong Fengshou; Xu Jun; Liu Xingang; Li Yuanbo; Shan Weili; Zheng Yongquan

    2011-01-01

    Highlights: · Simeconazole enantiomers were baseline separated by gas chromatography. · Optical pure enantiomer was prepared and their elution order was distinguished. · Clean-up/enrichment procedure was based on the modification of QuEChERS method. · Cleanup step was further improved by solid phase extraction (SPE) technology. · Analysis of samples was accomplished by GC-MS/MS. - Abstract: A rapid and effective method for enantioselective determination of simeconazole enantiomers in food products (cucumber, tomato, apple, pear, wheat and rice) has been developed. The enantiomers were resolved by capillary gas chromatography (GC) using a commercial chiral column (BGB-172) and a temperature program from 150 deg. C (held for 1 min) and then raised at 10 deg. C min -1 to 240 deg. C (held for 10 min). This enantioselective gas chromatographic separation was combined with a clean-up/enrichment procedure based on the modification of QuEChERS (quick, easy, cheap, effective, rugged and safe) method. Co-extractives were removed with graphitized carbon black/primary secondary amine (GCB/PSA) solid-phase extraction (SPE) cartridges using acetonitrile:toluene (3:1, v/v) as eluent. Gas chromatography/ion trap mass spectrometry (GC-ITMS) with electron ionization (EI) was then used for qualitative and quantitative determination of the simeconazole enantiomers. Two precursor-to-product ion transitions (m/z 121-101 and 195-153) with the best signal intensity were chosen to build the multiple-reaction monitoring (MRM) acquisition method. The limits of detection for each enantiomer of simeconazole in six food products ranged between 0.4 and 0.9 μg kg -1 , which were much lower than maximum residue levels (MRLs) established by Japan. The methodology was successfully applied for the enantioselective analysis of simeconazole enantiomers in real samples, indicating its efficacy in investigating the environmental stereochemistry of simeconazole in food matrix.

  19. Molecular Design of a Chiral Brønsted Acid with Two Different Acidic Sites: Regio-, Diastereo-, and Enantioselective Hetero-Diels-Alder Reaction of Azopyridinecarboxylate with Amidodienes Catalyzed by Chiral Carboxylic Acid-Monophosphoric Acid.

    Science.gov (United States)

    Momiyama, Norie; Tabuse, Hideaki; Noda, Hirofumi; Yamanaka, Masahiro; Fujinami, Takeshi; Yamanishi, Katsunori; Izumiseki, Atsuto; Funayama, Kosuke; Egawa, Fuyuki; Okada, Shino; Adachi, Hiroaki; Terada, Masahiro

    2016-09-07

    A chiral Brønsted acid containing two different acidic sites, chiral carboxylic acid-monophosphoric acid 1a, was designed to be a new and effective concept in catalytic asymmetric hetero-Diels-Alder reactions of azopyridinecarboxylate with amidodienes. The multipoint hydrogen-bonding interactions among the carboxylic acid, monophosphoric acid, azopyridinecarboxylate, and amidodiene achieved high catalytic and chiral efficiency, producing substituted 1,2,3,6-tetrahydropyridazines with excellent stereocontrol in a single step. This constitutes the first example of regio-, diastereo-, and enantioselective azo-hetero-Diels-Alder reactions by chiral Brønsted acid catalysis.

  20. Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Five-, Six-, and Seven-Membered β-Substituted Cyclic Enones: Enantioselective Construction of All-Carbon Quaternary Stereocenters

    KAUST Repository

    Kikushima, Kotaro

    2011-05-11

    The first enantioselective Pd-catalyzed construction of all-carbon quaternary stereocenters via 1,4-addition of arylboronic acids to β-substituted cyclic enones is reported. Reaction of a wide range of arylboronic acids and cyclic enones using a catalyst prepared from Pd(OCOCF(3))(2) and a chiral pyridinooxazoline ligand yields enantioenriched products bearing benzylic stereocenters. Notably, this transformation is tolerant to air and moisture, providing a practical and operationally simple method of synthesizing enantioenriched all-carbon quaternary stereocenters.