- Dynamic Kinetic Resolution of N-Protected Amino Acid Esters via Phase-Transfer Catalytic Base Hydrolysis
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Asymmetric base hydrolysis of α-chiral esters with synthetic small-molecule catalysts is described. Quaternary ammonium salts derived from quinine were used as chiral phase-transfer catalysts to promote the base hydrolysis of N-protected amino acid hexafluoroisopropyl esters in a CHCl3/NaOH (aq) via dynamic kinetic resolution, providing the corresponding products in moderate to good yields (up to 99%) with up to 96:4 er. Experimental and computational mechanistic studies using DFT calculation and pseudotransition state (pseudo-TS) conformational search afforded a TS model accounting for the origin of the stereoselectivity. The model suggested π-stacking and H-bonding interactions play essential roles in stabilizing the TS structures.
- Yamamoto, Eiji,Wakafuji, Kodai,Furutachi, Yuho,Kobayashi, Kaoru,Kamachi, Takashi,Tokunaga, Makoto
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p. 5708 - 5713
(2018/05/30)
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- Synthesis of an enantiopure thioester as key substrate for screening the sensitivity of penicillin binding proteins to inhibitors
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The synthesis of the enantiopure thioester (R)-2-(2-benzamidopropanoylthio)acetic acid was developed. After the exploration of several activation methods, reaction conditions were found for the formation of the thioester bond in the presence of propylphosphonic anhydride with high enantioselectivity (ee > 99%). The thioester activity of Penicillin Binding Proteins is helpful in research programs looking for new lead structures to overcome the problem of bacterial resistance.
- Simon, Justine F.,Bouillez, André,Frère, Jean-Marie,Luxen, André,Zervosen, Astrid
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- Structural effects of N-aromatic acyl-amino acid conjugates on their deconjugation in the cecal contents of rats: Implication in design of a colon-specific prodrug with controlled conversion rate at the target site
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N-aromatic acyl-amino acid conjugates possess a colon-targeted property, implying that such conjugates are stable and are not absorbable until reaching the large intestine in which they are microbially converted (hydrolysed) to the parent drugs that are therapeutically active. To investigate the structural effect of N-aromatic acyl-amino acid conjugates on the large intestinal deconjugation, the hydrolysis of various N-aromatic acyl-amino acid conjugates was examined in the cecal contents. On incubation of conjugates with glycine,d or/andl forms of alanine or phenylalanine in the cecal contents, the conjugates withd amino acids were not hydrolysed. The other conjugates are susceptible to the hydrolysis, the rates of which decreased as the size of the substituent on the 2-position of the amino acids increased. The conjugates with alkyl analogs (2-4 carbons) of glycine and taurine were resistant to the hydrolysis, while taurine- and glycine-conjugates were hydrolysed effectively. The hydrolysis of N-aromatic acyl-glycine conjugates was enhanced by para-substitution of electron withdrawing groups on the aromatic acyl moiety and vice versa for electron-donating groups. While a methyl, methoxy or chloro group on the ortho-position retarded the hydrolysis, a hydroxyl group on the position accelerated it. Our data may provide useful information for the design of a colon-specific prodrug with controlled conversion rate in the large intestine.
- Kong, Hyesik,Kim, Hyunjeong,Do, Heejeong,Lee, Yonghyun,Hong, Sungchae,Yoon, Jeong-Hyun,Jung, Yunjin,Kim, Young Mi
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experimental part
p. 343 - 354
(2012/04/10)
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- Organocatalytic asymmetric addition of alcohols and thiols to activated electrophiles: Efficient dynamic kinetic resolution and desymmetrization protocols
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(Chemical Equation Presented) Bifunctional urea-based cinchona alkaloid derivatives have been shown to promote highly efficient DKR reactions of azalactones using an alcohol nucleophile. The optimum catalyst is remarkably insensitive to the steric bulk of the amino acid residue, allowing alanine-, methionine-, and phenylalanine-derived azalactones to undergo DKR with unprecedented levels of enantioselectivity using a synthetic catalyst. The first DKR of these substrates by thiols and the highly enantioselective desymmetrization of a meso-glutaric anhydride by thiolysis are also reported.
- Peschiulli, Aldo,Quigley, Cormac,Tallon, Sean,Gun'ko, Yuri K.,Connon, Stephen J.
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p. 6409 - 6412
(2008/12/22)
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- Combining Magnetic Resonance Spectroscopies, Mass Spectrometry, and Molecular Dynamics: Investigation of Chiral Recognition by 2,6-di-O-Methyl-β-cyclodextrin
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EPR spectroscopy has been employed to investigate the formation of complexes between heptakis-(2,6-O-dimethyl)-β-cyclodextrin (DM-β-CD) and different enantiomeric pairs of chiral nitroxides of general structure PhCH2N(O·)CH(R)R′. Accurate equilibrium measurements of the concentrations of free and included radicals afforded the binding constant values for these nitroxides. The relationship between the stereochemistry of the DM-β-CD complexes and the thermodynamics of complexation was elucidated by correlating EPR data with 1H-1H NOE measurements carried out on the complexes between DM-β-CD and the structurally related amine precursors of nitroxides. NOE data suggested that inclusion of the stereogenic center in the DM-β-CD cavity occurs only when the R substituent linked to the chiral carbon contains an aromatic ring. For these types of complexes, molecular dynamics simulation indicated that the depth of penetration of the stereogenic center into the cyclodextrin cavity is determined by the nature of the second substituent (R′) at the asymmetric carbon and is responsible for the observed chiral selectivity. Analysis of mass spectra showed that, for the presently investigated amines, electrostatic external adducts of CDs with protonated amines are detected by ESI-MS.
- Franchi, Paola,Lucarini, Marco,Mezzina, Elisabetta,Pedulli, Gian Franco
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p. 4343 - 4354
(2007/10/03)
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- Beauveria bassiana ATCC 7159 contains an L-specific α-amino acid benzamidase
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Biotransformation of a series of racemic N-benzoyl α-amino acids by the fungus Beauveria bassiana ATCC 7159 results in isolation of the corresponding D-amino acid benzamides in high enantiomeric purity and yield.
- Holland, Herbert L.,Andreana, Peter R.,Salehzadeh-Asl, Reza,Van Vliet, Aaron,Ihasz, Nancy J.,Brown, Frances M.
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p. 667 - 672
(2007/10/03)
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- Aminophosphine phosphinites derived from chiral 1,2-diphenyl-2-aminoethanols: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation of dehydroamino acid derivatives
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A series of chiral aminophosphine phosphinites DPAMPPs was synthesized from optically active 1,2-diphenyl-2-aminoethanols. The erythro-DPAMPPs were found to serve as excellent ligands for rhodium-catalyzed asymmetric hydrogenation of dehydroamino acid derivatives. For an array of dehydroamino acid precursors, remarkably high enantioselectivity (up to 98.4% e.e.) and reactivity (the ratio of substrate/catalyst up to 10000) were observed. Some factors controlling the enantioselectivity were examined and discussed. (C) 2000 Elsevier Science Ltd.
- Lou, Rongliang,Mi, Aiqiao,Jiang, Yaozhong,Qin, Yong,Li, Zhi,Fu, Fangmin,Chan, Albert S.C
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p. 5857 - 5863
(2007/10/03)
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- Asymmetric synthesis of uncommon α-amino acids by diastereoselective alkylations of a chiral glycine equivalent
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For the purpose of practical preparations of a variety of enantiomerically pure uncommon α-amino acids, alkylations of the chiral glycine equivalent 5, which possesses axially chiral binaphthol as an auxiliary, with several electrophiles were investigated. The alkylation proceeded smoothly in satisfactory chemical yield with high diastereo-selectivities to give protected α-amino acid derivatives. The free hydroxyl group of the auxiliary played an important role for the induction of diastereoselectivity. Using (S)-1,1'-binaphthalene-2,2'-diol as a chiral auxiliary, D-α-amino acid derivatives having the unnatural (R)-configuration were predominantly obtained. Some of the alkylated products were converted into free non- proteinogenic D-α-amino acids.
- Tanaka, Kiyoshi,Ahn, Mija,Watanabe, Yukari,Fuji, Kaoru
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p. 1771 - 1782
(2007/10/03)
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- Direct resolution of optically active isomers on chiral packings containing ergoline skeletons. 5. Enantioseparation of amino acid derivatives
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A new procedure for ergot alkaloid-based chiral stationary phase preparation is described. Synthesis is based on bonding the allyl derivative of terguride to mercaptopropylsilanized silica gel. The packing exhibits higher content of chiral selector, stability, reproducibility, and enantioselectivity toward amino acids compared to that previously studied. The chromatographic behavior of amino acids with different side chains and substituent groups is investigated in order to obtain a deeper insight into the enantiodiscriminative mechanism as well as to determine the limitations and strengths of terguride as a chiral selector for this class of compounds. A variety of factors, including mobile phase parameters such as pH, ionic strength, content and nature of organic modifier, and temperature, are examined. A new procedure for ergot alkaloid-based chiral stationary phase preparation is described. Synthesis is based on bonding the allyl derivative of terguride to mercaptopropylsilanized silica gel. The packing exhibits higher content of chiral selector, stability, reproducibility, and enantioselectivity toward amino acids compared to that previously studied. The chromatographic behavior of amino acids with different side chains and substituent groups is investigated in order to obtain a deeper insight into the enantiodiscriminative mechanism as well as to determine the limitations and strengths of terguride as a chiral selector for this class of compounds. A variety of factors, including mobile phase parameters such as pH, ionic strength, content and nature of organic modifier, and temperature, are examined.
- Messina,Girelli,Flieger,Sinibaldi,Sedmera,Cvak
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p. 1191 - 1196
(2007/10/03)
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- Enantiomerically Enriched α-Methyl Amino Acids. Use of an Acyclic, Chiral Alanine-Derived Dianion with a High Diastereofacial Bias
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Hindered esters derived from N-benzoylalanine and the following chiral alcohols have been synthesized: (1) (-)-isopinocampheol, (2) (-)-trans-2-phenylcyclohexanol, and (3) (-)-8-phenylmenthol.Sequential treatment of these esters with LDA (1.2 equiv) and n-butyllithium (2.4 equiv) at -78 deg C in THF generates the corresponding chiral dianions.Alkylation of each of these with benzyl bromide reveals that only the (-)-8-phenylmenthyl auxiliary confers a high diastereofacial bias upon its derivative dianion.In fact, that dianion (6) consistently displays diastereomeric ratios in the range of 89:11 to 94:6 for alkylations with a spectrum of nine alkyl halides.If one recrystallization step is included, a single diastereomeric product may be obtained, as is demonstrated for the benzylation of 6.Of particular note, the alkylation with 3,4-bis((tert-butyldimethylsilyl)oxy)benzyl bromide (18) (94:6 diastereomeric ratio, 72percent yield) constitutes a formal synthesis of the clinically important antihypertensive (S)-α-methyl-DOPA (Aldomet), in enantiomerically enriched form.In all cases studied, yields are markedly improved, yet diastereoselectivities unchanged, by the addition of 10percent HMPA to the reaction milieu.The (-)-8-phenylmenthol chiral auxiliary is conveniently recovered via ester cleavage with KO2/18-crown-6, following alkylation.Complete deprotection affords enantiomerically enriched (S)-α-methyl amino acids, in all cases examined, indicating that dianion 6 displays a substantial bias in favor of si face alkylation.This sense of diastereoselection is consistent with a chain-extended, internal chelate model for the reactive conformation of the dianion.
- Berkowitz, David B.,Smith, Marianne K.
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p. 1233 - 1238
(2007/10/02)
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- Enzymatic Asymmetric Synthesis of α-Amino Acids. Enantioselective Cleavage of 4-Substituted Oxazolin-5-ones and Thiazolin-5-ones
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A general enzymatic asymmetric synthesis of L-α-amino acids has been developed.This method entails the use of the Pseudomonas cepacia lipase (P-30) to catalyze the enantioselective methanolysis of a variety of 4-substituted 2-phenyloxazolin-5-one derivatives in a nonpolar organic solvent to furnish optically active N-benzoyl-L-α-amino acid methyl esters (ee = 66-98 percent), which in turn is subjected to a protease-catalyzed kinetic resolution yielding enantiomerically pure N-benzoyl-L-α-amino acids.This synergistic coupling of two enzymes allows the ready preparation of L-α-amino acids of high enantiopurity in yields greater than 50 percent, an inherent advantage over conventional resolution procedures.Two proteases were found to catalyze the enantioselective hydrolysis of a variety of 4-substituted 2-phenylthiazolin-5-one derivatives to give N-(thiobenzoyl)-L-α-amino acids of high optical purity.
- Crich, Joyce Z.,Brieva, Rosario,Marquart, Peer,Gu, Rui-Lin,Flemming, Steffen,Sih, Charles J.
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p. 3252 - 3258
(2007/10/02)
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- Enzymatic enantioselective ester hydrolysis by carboxylesterase NP
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The enzymatic hydrolysis of a series of carboxylic esters by carboxylesterase NP has been investigated in order to determine the scope and limitations of this enzyme. 2-Substituted propionates were hydrolyzed with high enantioselectivity when an aromatic moiety was part of the 2-substituent.Enantioselective hydrolysis could be accomplished with several 2-arypropionates, 2-(aryloxy)propionates and N-arylalanine esters.The propionate esters yielded propionic acids as (S) enantiomers, whereas the alanine esters yielded the (R) enantiomers.Without a 2-aryl substituent, the enzymatic hydrolysis of the propionates occurred at a lower rate without acceptable enantioselectivity.In addition to 2-substituted propionates, only a few other esters were hydrolyzed with high enantioselectivity by carboxylesterase NP, such as some prochiral disubstituted malonates. 1-Phenylethylacetate was the only substrate with chirality in the alcohol part of the ester that was found to be hydrolyzed enantioselectively.Carboxylesterase NP proved to be a powerful enzyme for kinetic resolution of propionate esters with an aromatic ring containing a 2-substituent.
- Smeets, J. W. H.,Kieboom, A. P. G.
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p. 490 - 495
(2007/10/02)
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- 2,2'-BIS(DIPHENYLPHOSPHINO)-1,1'-BINAPHTHYL (BINAP). A NEW ATROPISOMERIC BIS(TRIARYL)PHOSPHINE. SYNTHESIS AND ITS USE IN THE Rh(I)-CATALYZED ASYMMETRIC HYDROGENATION OF α-(ACYLAMINO)ACRYLIC ACIDS
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Racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl has been synthesized from 2,2'-dihydroxy-1,1'-binaphthyl in two steps and resolved into optically pure (R)-(+) and (S)-(-) enantiomers by the use of (+)-di-μ-chlorobis dipalladium.This new axially dissymmetric bis(triaryl)phosphine serves as an excellent ligand for Rh(I)-catalyzed asymmetric hydrogenations of α-(acylamino)acrylic acids or esters.Factors controlling the enantioselectivity and mechanistic aspects are discussed on the basis of the 31P-NMR measurements.
- Miyashita, A.,Takaya, H.,Souchi, T.,Noyori, R.
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p. 1245 - 1253
(2007/10/02)
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- Enantiomeric Enrichment in the Hydrolysis of Oxazolones Catalyzed by Cyclodextrins or Proteolytic Enzymes
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Five 5(4H)-oxazolones bearing substituents of variable hydrophobicity and bulkiness in positions 2 and 4 have been hydrolyzed in the presence of the proteolytic enzymes chymotrypsin and subtilisin or the α- and β-cyclodextrins.The acylamino acids produced are partially deracemized.With the enzymes, an appreciable enantiomeric enrichment is obtained only when both substituents are relatively bulky; the enantioselectivities are nevertheless quite low for enzymic reactions.With chymotrypsin, an enantiomeric excess of 76percent in favor of the L isomer is observed in the hydrolysis of the 2-phenyl-4-benzyloxazolone and of 30percent in favor of the D for the 2-phenyl-4-(2-carboxamidoethyl)oxazolone.There is a general inversion of stereoselectivity between chymotrypsin and subtilisin.The hydrolysis in the presence of cyclodextrin is a multistep process with formation of an acylcyclodextrin intermediate concurrent with hydrolysis.The substituent in position 2 plays an important role in controlling the enantioselectivity.When this substituent is a phenyl, the L acylamino acid is the predominant product with an enantiomeric excess of the order of 60percent.When there is a methyl in position 2, the direction of asymmetric induction is reversed or the optical yield is close to zero.
- Daffe, V.,Fastrez, J.
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p. 3601 - 3605
(2007/10/02)
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