- Towards sustainable kinetic resolution, a combination of bio-catalysis, flow chemistry and bio-based solvents
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The esterification of 2-phenylpropionic acid was investigated as a model system for enzyme catalysed (CALB, Novozyme 435) reactions in bio-based solvents. A multi-parameter correlation taking into account solvent parameters was developed to explain experimental observations. A continuous flow process using p-cymene as the solvent was operated over several weeks, thus combining a sustainable solvent and flow chemistry for kinetic resolution.
- Iemhoff, Andree,Sherwood, James,McElroy, Con R.,Hunt, Andrew J.
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- Nickel/Photoredox-Catalyzed Asymmetric Reductive Cross-Coupling of Racemic α-Chloro Esters with Aryl Iodides
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A unique nickel/organic photoredox co-catalyzed asymmetric reductive cross-coupling between α-chloro esters and aryl iodides is developed. This cross-electrophile coupling reaction employs an organic reductant (Hantzsch ester), whereas most reductive cross-coupling reactions use stoichiometric metals. A diverse array of valuable α-aryl esters is formed under these conditions with high enantioselectivities (up to 94 %) and good yields (up to 88 %). α-Aryl esters represent an important family of nonsteroidal anti-inflammatory drugs. This novel synergistic strategy expands the scope of Ni-catalyzed reductive asymmetric cross-coupling reactions.
- Guan, Haixing,Mao, Jianyou,Walsh, Patrick J.,Zhang, Qianwen
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- Resolution of (RS)-2-phenylpropanoic acid by enantioselective esterification with dry microbial cells in organic solvent
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The microbial direct esterification of racemic 2-phenyl-1-propanoic acid with ethanol by lyophilized mycelium of Aspergillus oryzae MIM and Rhizopus oryzae CBS 112.07 in organic solvents has been investigated. Dry cells of Rhizopus oryzae CBS 112.07 gave the (R)-ethyl ester with high enantiomeric excess (>97%) when the biotransformation was carried out in heptane or pentadecane. Dry mycelium of Aspergillus oryzae MIM furnished the ethyl ester of (S)-(+)-2-phenylpropanoic acid with 90% enantiomeric excess when used in toluene in a temperature range of 20-40°C.
- Gandolfi, Raffaella,Gualandris, Roberto,Zanchi, Chiara,Molinari, Francesco
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- Thermally driven asymmetric domino reaction catalyzed by a thermostable esterase and its variants
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We have developed a thermally driven domino reaction for the synthesis of (S)-a-arylpropionates (profens) using a thermostable esterase from Sulfolobus tokodaii strain 7. Stereoselectivity was improved considerably by engineering of the active site. Stereoselective decarboxylation at the active site of an esterase is a new reaction for the synthesis of optically active carboxylic acids. Crown Copyright.
- Wada, Reina,Kumon, Takashi,Kourist, Robert,Ohta, Hiromichi,Uemura, Daisuke,Yoshida, Shosuke,Miyamoto, Kenji
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- Synthesis method of (S)-2-aryl propionate compound
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The invention discloses a synthesis method of a (S)-2-aryl propionate compound. The (S)-2-aryl propionate compound shown in the formula IV is obtained by taking a compound shown in a formula I and a compound shown in a formula II as raw materials and reacting under the conditions of a chiral ligand shown in a formula III, a nickel catalyst, a photocatalyst, a reducing agent and alkali under the condition of visible light. The method has the advantages of cheap and easily available raw materials, convenient generation, mild conditions, environmental protection and safety, the photocatalyst canbe recycled, the production cost is greatly reduced, the test operation is simple, less waste is generated, and the method can be developed into an industrial production method.
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Paragraph 0096-0099; 0120-0123
(2020/08/09)
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- Enantioselective Hydrogen Atom Transfer: Discovery of Catalytic Promiscuity in Flavin-Dependent 'Ene'-Reductases
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Flavin has long been known to function as a single electron reductant in biological settings, but this reactivity has rarely been observed with flavoproteins used in organic synthesis. Here we describe the discovery of an enantioselective radical dehalogenation pathway for α-bromoesters using flavin-dependent 'ene'-reductases. Mechanistic experiments support the role of flavin hydroquinone as a single electron reductant, flavin semiquinone as the hydrogen atom source, and the enzyme as the source of chirality.
- Sandoval, Braddock A.,Meichan, Andrew J.,Hyster, Todd K.
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supporting information
p. 11313 - 11316
(2017/08/30)
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- Iron-Catalyzed Enantioselective Cross-Coupling Reactions of α-Chloroesters with Aryl Grignard Reagents
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The first iron-catalyzed enantioselective cross-coupling reaction between an organometallic compound and an organic electrophile is reported. Synthetically versatile racemic α-chloro- and α-bromoalkanoates were coupled with aryl Grignard reagents in the presence of catalytic amounts of an iron salt and a chiral bisphosphine ligand, giving the products in high yields with acceptable and synthetically useful enantioselectivities (er up to 91:9). The produced α-arylalkanoates were readily converted to the corresponding α-arylalkanoic acids with high optical enrichment (er up to >99:1) via simple deprotections/recrystallizations. The results of radical probe experiments are consistent with a mechanism that involves the formation of an alkyl radical intermediate, which undergoes subsequent enantioconvergent arylation in an intermolecular manner. The developed asymmetric coupling offers not only facile and practical access to various chiral α-arylalkanoic acid derivatives, which are of significant pharmaceutical importance, but also a basis of controlling enantioselectivity in an iron-catalyzed organometallic transformation. (Chemical Equation Presented).
- Jin, Masayoshi,Adak, Laksmikanta,Nakamura, Masaharu
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supporting information
p. 7128 - 7134
(2015/06/25)
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- The organic-synthetic potential of recombinant Ene reductases: Substrate-Scope Evaluation and Process Optimization
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In this study an evaluation of the synthetic potential of a broad range of recombinant ene reductases was performed. In detail, a library of 23 ene reductases was used to screen the C=C reduction of 21 activated alkenes from different compound classes as substrates. The chosen set of substrates comprises nitroalkenes with an aryl substituent at the β-position and a methyl substituent at the α- or β-position, α,β-unsaturated carboxylic acids and their esters with and without substituents at the β-position, a range of cyclic α,β-unsaturated ketones with different ring sizes and substitution patterns and one α,β-unsaturated boronic acid. After we obtained insight into the substrate scope, several biotransformations were prioritised and further investigated in a screening of 41 reaction parameters (which included chaotropic and kosmotropic salts, polyols, buffer solutions, amino acids and organic solvents) towards their impact on the activity and enantioselectivity of the applied ene reductases. Under the optimised conditions, selected reduction processes were performed on an increased lab scale (up to 30 mL) with up to 10% substrate concentration, which led in general to both high conversion and (if chiral products were formed) enantioselectivity. Comprehensive screening: A detailed screening of 23 recombinant ene reductases for the reduction of 21 activated alkenes is performed as well as a subsequent study of the influence of 41 reaction parameters towards the enzyme activity and selectivity of selected reactions. In addition, a range of biocatalytic reductions on an increased laboratory scale are performed with substrate concentrations between 5 and 100 gL-1. EWG=Electron-withdrawing group.
- Re?, Tina,Hummel, Werner,Hanlon, Steven P.,Iding, Hans,Gr?ger, Harald
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p. 1302 - 1311
(2015/04/27)
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- Cobalt-bisoxazoline-catalyzed asymmetric kumada cross-coupling of racemic α-bromo esters with aryl grignard reagents
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The first cobalt-catalyzed asymmetric Kumada cross-coupling with high enantioselectivity has been developed. The reaction affords a unique strategy for the enantioselective arylation of α-bromo esters catalyzed by a cobalt-bisoxazoline complex. A variety of chiral α-arylalkanoic esters were prepared in excellent enantioselectivity and yield (up to 97% ee and 96% yield). The arylated products were transformed into α-arylcarboxylic acids and primary alcohols without erosion of ee. The new enantioenriched α-arylpropionic esters synthesized herein are potentially useful in the development of nonsteroidal anti-inflammatory drugs. This method was conducted on gram-scale and applied to the synthesis of highly enantioenriched (S)-fenoprofen and (S)-ar-turmerone.
- Mao, Jianyou,Liu, Feipeng,Wang, Min,Wu, Lin,Zheng, Bing,Liu, Shangzhong,Zhong, Jiangchun,Bian, Qinghua,Walsh, Patrick J.
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supporting information
p. 17662 - 17668
(2015/02/02)
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- Laboratory evolution of enantiocomplementary Candida antarctica lipase B mutants with broad substrate scope
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Candida antarctica lipase B (CALB) is a robust and easily expressed enzyme used widely in academic and industrial laboratories with many different kinds of applications. In fine chemicals production, examples include acylating kinetic resolution of racemic secondary alcohols and amines as well as desymmetrization of prochiral diols (or the reverse hydrolytic reactions). However, in the case of hydrolytic kinetic resolution of esters or esterifying kinetic resolution of acids in which chirality resides in the carboxylic acid part of the substrate, rate and stereoselectivity are generally poor. In the present study, directed evolution based on iterative saturation mutagenesis was applied to solve the latter problem. Mutants with highly improved activity and enantioselectivity relative to wild-type CALB were evolved for the hydrolytic kinetic resolution of p-nitrophenyl 2-phenylpropanoate, with the selectivity factor increasing from E = 1.2 (S) to E = 72 (S) or reverting to E = 42 (R) on an optional basis. Surprisingly, point mutations both in the acyl and alcohol pockets of CALB proved to be necessary. Some of the evolved CALB mutants are also efficient biocatalysts in the kinetic resolution of other chiral esters without performing new mutagenesis experiments. Another noteworthy result concerns the finding that enantiocomplementary CALB mutants for α-substituted carboxylic acid esters also show stereocomplementarity in the hydrolytic kinetic resolution of esters derived from chiral secondary alcohols. Insight into the source of stereoselectivity was gained by molecular dynamics simulations and docking experiments.
- Wu, Qi,Soni, Pankaj,Reetz, Manfred T.
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supporting information
p. 1872 - 1881
(2013/08/24)
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- Improvements of enzyme activity and enantioselectivity in lipase-catalyzed alcoholysis of (R,S)-azolides
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With Candida antarctica lipase B (CALB)-catalyzed alcoholysis of (R,S)-naproxenyl 1,2,4-triazolide at the optimal conditions (i.e. anhydrous MTBE as the solvent, and methanol as the acyl acceptor at 45°C) as the model system, the enzyme enantioselectivity
- Wu, An-Chi,Wang, Pei-Yun,Lin, Yi-Sheng,Kao, Min-Fang,Chen, Jin-Ru,Ciou, Jyun-Fen,Tsai, Shau-Wei
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experimental part
p. 235 - 241
(2010/11/04)
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- Triphenylphosphine dibromide: a simple one-pot esterification reagent
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We report a one-pot, expedient protocol for the conversion of carboxylic acids to their esters using excess triphenylphosphine dibromide, base, and the alcohol. The reaction gave the esterified product in moderate-to-high yields (30-95%). For chiral acids, the reaction proceeded with little or no racemization. Use of a chiral alcohol in this transformation gave the ester with retention of configuration of the stereogenic center. Information is presented indicating that esterification proceeds through the intermediate generation of an acyloxyalkoxyphosphorane and where steric interactions play an important role in the energetics of the reaction.
- Salomé, Christophe,Kohn, Harold
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supporting information; experimental part
p. 456 - 460
(2009/04/06)
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- Amidation of amines with esters catalyzed by Candida antarctica lipase (CAL)
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Candida antarctica lipase (CAL) is used to convert amines and esters into amides, especially as a chiral resoluting catalyst for the enantioselective amidation of racemic esters or racemic amines in an effort to demonstrate the ability of lipase to differentiate between enantiomeric substrates. It is a very useful synthetic method for amides. The effects of substrate modification on the yield and enantiomeric excess (ee) are studied. The R-enantiomer will react faster for racemic mixture of amine in which the amino group attaches directly to the chiral carbon, and the same for racemic mixture of ester in which the carbonyl group attaches directly to the chiral carbon. The enantioselectivity of CAL is complicated for the amidation of racemic mixture of amine with racemic mixture of ester.
- Yang, Bo,Zhang, Yanjun,Zhang, Shusheng,Izumi
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p. 1312 - 1316
(2007/10/03)
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- Enantioselective hydrolysis of various racemic α-substituted arylacetonitriles using Rhodococcus sp. CGMCC 0497
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The enantioselective hydrolysis of 17 racemic α-substituted arylacetonitriles by Rhodococcus sp. CGMCC 0497 is described. The corresponding (R)-amides and (S)-acids were obtained with excellent enantiomeric excess in most cases. The effect of steric and electronic factors on the outcome of the reactions are discussed here. The results prove that nitrile-converting enzymes are efficient tools for the synthesis of sterically unencumbered chiral α-arylpropionic acids and amides.
- Wu, Zhong-Liu,Li, Zu-Yi
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p. 3305 - 3312
(2007/10/03)
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- Enantioselective generation of benzylic stereocenters mediated by a remote sulfoxide
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Ortho-Sulfinyl-substituted benzyllithium reagents react with aldehydes and ketones to afford, after desulfurization with Raney-Nickel, stereoselective access to benzylic stereocenters [Eq. (1)]. This is the first efficient asymmetric 1,4-induction with mediation by a sulfoxide group. LDA = lithium diisopropylamide; Tol = tolyl; TIPS = triisopropylsilyl.
- Garcia Ruano, Jose L.,Carreno, M. Carmen,Toledo, Miguel A.,Aguirre, Jose M.,Aranda, M. Teresa,Fischer, Jean
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p. 2736 - 2737
(2007/10/03)
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- Remarkable Lewis acid mediated enhancement of enantioselectivity during free-radical reductions by simple chiral non-racemic stannanes
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Additions of 1 equiv, of achiral and chiral Lewis acids to free-radical reduction reactions involving (1S,2S,5R)-menthyldiphenyltin hydride 1, bis[(1S,2S,5R)-menthyl]phenyltin hydride 2, bis[1S,2S,5R)-menthyl][8-(N,N-dimethylamino)naphthyl]tin hydride 3, bis[(1R,2S,5R-menthyl] {1-(S)-N,N-dimethylaminoethyl]phenyl}tin hydride 4 or 3α-dimethylstannyl-5α-cholestane 5 result in remarkable increases in enantioselectivity.
- Dakternieks, Dainis,Dunn, Kerri,Perchyonok, V. Tamara,Schiesser, Carl H.
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p. 1665 - 1666
(2007/10/03)
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- Enantioselective Catalysis, C [1]. Decarboxylation of Malonic Acids in the Presence of Copper(I) Compounds - Not a Copper(I) Catalysis but a Base Effect
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The catalytic decarboxylation of malonic acids, claimed to be catalyzed by copper(I) compounds, has been investigated. Decarboxylation of different malonic acid derivatives (1-5) in acetonitrile was far more effective with Cu2O than with CuCl. Thus, the decarboxylation is obviously influenced by the basicity of the anion. In the decarboxylation of phenylmalonic acid (3), bis(tricyclohexylphosphane)copper(I) hydrogenphenylmalonate (6) and potassium hydrogenphenylmalonate (7) show nearly identical rate constants. It is concluded that the monoanions of the malonic acid derivatives are the reactive species undergoing decarboxylation. Further experiments are presented which demonstrate that everything that increases the concentration of the monoanions also increases the rate of decarboxylation. In the enantioselective decarboxylation of the monoethyl ester of methylphenylmalonic acid (2), the enantiomeric excess of (S)-(+)-ethyl 2-phenylpropionate could be raised to 34.5% ee using the alkaloid cinchonine.
- Brunner,Mueller,Spitzer
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p. 845 - 858
(2007/10/03)
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- Diastereoselective α-alkylation of 2-acyl-3-phenyl-l-menthopyrazoles
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N-Acylpyrazoles were α-alkylated in good yields by the treatment with alkyl halides after metalation with LDA or LiHMDS. In the case of chiral N-acylpyrazoles, e.g., 2-acyl-3-phenyl-l-menthopyrazoles (4), the α-alkylation was highly diastereoselective. The subsequent α-alkylation products could be converted into esters in good yield in the presence of BF3·OEt2 without the loss of the optical purity.
- Kashima,Fukuchi,Hosomi
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p. 7821 - 7824
(2007/10/02)
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- Chemoenzymatic synthesis of pure enantiomeric 2-aryl propionic acids
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A new chemoenzymatic procedure to obtain pure enantiomeric 2-arylpropionic acids is described. The one pot synthesis of (±)-2-arylpropionic acids is carried out by addition of dichlorocarbene to the C=O bond of arylmethylketones and hydrogenolysis of the additon product. The racemic mixture is resolved by enantiospecific hydrolysis of the racemic ethyl esters using native lipase from Candida rugosa. The good yields, the accessibility of the starting arylmethylketones and the stereospecificity of the enzymatic hydrolysis make the process interesting in order to obtain the same non steroidal antiinflammatory drugs such as Ibuprofen or Naproxen.
- Garcia,Del Campo,Llama,Sanchez-Montero,Sinisterra
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p. 8433 - 8440
(2007/10/02)
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- Stereospecific Friedel-Crafts Alkylation of Aromatic Compounds: Synthesis of Optically Active 2- and 3-Arylalkanoic Esters
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The alkylation of aromatic compounds, such as benzene, toluene, chlorobenzene, and naphthalene, with optically active (S)-alkyl 2-(sulfonyloxy)propionates and (R)-alkyl 3-(sulfonyloxy)butanoates in the presence of AlCl3 afforded optically active (S)-alkyl 2-arylpropionates and (S)-alkyl 3-arylbutanoates in fair to good chemical yields (40-84percent) and in good to excellent optical yields (61-97percent).As usually occurs in Friedel-Crafts alkylation reactions, poor regioselectivity was observed.
- Piccolo, Oreste,Azzena, Ugo,Melloni, Giovanni,Delogu, Giovanna,Valoti, Ermanno
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p. 183 - 187
(2007/10/02)
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- PHOTOCHEMICAL ACTIVATION OF THE CARBOXYL GROUP VIA N-ACYL-2-THIONOTHIAZOLIDINES
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Photolysis of N-acyl derivatives of 2-thionothiazolidine in the presence of ethanol affords ethyl esters; a mechanism involving γ-hydrogen abstraction by sulfur is postulated.
- Burton, Lester P.J.,White, James D.
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p. 3147 - 3150
(2007/10/02)
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