Asymmetric Hydrolysis of (±)-α-Substituted Carboxylic Acid Esters with Microorganisms

Iriuchijima, Shinobu; Keiyu, Atsuko

doi:10.1271/bbb1961.45.1389

Cited by 18 publications

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“…As chrysanthemic acids have four stereoisomers, it is difficult to effectively synthesize (1R,3R)-(+)-trans-chrysanthemic acid. For the selective production of (1R,3R)-(+)-trans-chrysanthemic acid, the microbial asymmetrical hydrolysis of chrysanthemic acid esters to the corresponding carboxylic acid has been studied (Oritani and Yamashita 1975;Iriuchijima and Keiyu 1981;Schneider et al 1984;Bhaskar et al 1994). However, it is not easy to obtain highly pure (1R,3R)-(+)-trans-chrysanthemic acid with high molecular conversion.…”

Section: Introductionmentioning

confidence: 99%

Characteristics and function ofAlcaligenessp. NBRC 14130 esterase catalysing the stereo-selective hydrolysis of ethyl chrysanthemate

Mitsukura

Shimizu

Matsushita

et al. 2010

Journal of Applied Microbiology

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Aims: Alcaligenes sp. NBRC 14130 was found as a strain hydrolysing a mixture of (±)‐trans‐ and (±)‐cis ethyl chrysanthemates to (1R,3R)‐(+)‐trans‐chrysanthemic acid. The Alcaligenes cells also have hydrolytic activity for 6‐aminohexanoate‐cyclic dimer (6‐AHCD, 1,8‐diazacyclotetradecane‐2,9‐dione). The correlation of function on the enzyme from the Alcaligenes strain with hydrolysis activities for both ethyl chrysanthemate and 6‐AHCD was demonstrated. Methods and Results: The esterase was purified to homogeneity. The purified esterase hydrolysed 20 mmol l−1 ester including the four stereoisomers to the corresponding (+)‐trans acid with a 37% molar conversion of ethyl (+)‐trans chrysanthemate. The esterase showed high hydrolytic activity for various short‐chain fatty acid esters, n‐hexane amide and 6‐AHCD. The amino acid sequence of the Alcaligenes esterase was identical to that of Arthrobacter 6‐AHCD hydrolase (EC 3.5.2.12) and similar to that of fatty acid amide hydrolase (EC 3.5.1.4) from Rattus norvegicus, having both serine and lysine residues of the catalytic site and the consensus motif Gly‐X‐Ser‐X‐Gly. Conclusion: The stereo‐selective hydrolytic activity was found in Alcaligenes sp. NBRC14130 by screening of ethyl chrysanthemate‐hydrolysing activity in micro‐organisms, and the purified esterase also acted on fatty acid esters and amides. Significance and Impact of the Study: This study has demonstrated that there are great differences in the enzymatic properties, amino acid sequence and catalytic motif of esterases in both Alcaligenes and Arthrobacter globiformis with excellent stereo‐selectivity for (+)‐trans‐ethyl chrysanthemate, but the amino acid sequence of Alcaligenes esterase is identical to that of Arthrobacter 6‐AHCD hydrolase.

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Section: Introductionmentioning

confidence: 99%

Characteristics and function ofAlcaligenessp. NBRC 14130 esterase catalysing the stereo-selective hydrolysis of ethyl chrysanthemate

Mitsukura

Shimizu

Matsushita

et al. 2010

Journal of Applied Microbiology

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Enzymatic resolution of (S)‐(+)‐naproxen in a continuous reactor

Battistel

Bianchi

Cesti

et al. 1991

Biotech & Bioengineering

110

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An enzymatic method for the continuous production of (S)-(+)-2-(6-methoxy-2-naphthyl) propionic acid (Naproxen) has been developed. The process consists of a stereoselective hydrolysis of the racemic Naproxen ethoxyethyl ester catalyzed by Candida cylindracea lipase. The reaction has been carried out in a continuous-flow closed-loop column bioreactor packed with Amberlite XAD-7, a slightly polor resin on which the lipase has been immobilized by adsorption. Various immobilization conditions as well as the properties of the immobilized lipase have been studied. The performance and the productivity of the bioreactor were evaluated as a function of the critical reaction parameters such as temperature, substrate concentration, and product inhibition. By using a 500-mL column bioreactor, 1.8 kg of optically pure (S)-(+)-Naproxen were produced after 1200 h of continuous operation with a slight loss of the enzymatic activity.

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Resolution of rac‐ketoprofen esters by enzymatic reactions in organic media

Palomer¹,

Cabré²,

Ginesta³

et al. 1993

Chirality

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Enzyme-catalyzed reactions in organic media of ruc-ketoprofen esters with different nucleophiles such as alcohols, amines, and water have been studied. Among the parameters optimized are the enzyme, the activated substrate, and the solvent. With the enzymes used in this study the preferred substrate was the trifluoroethyl ester of YUCketoprofen (ruc-2), whose (Rbenantiomer reacted preferentially. The enzyme of choice was the lipase M-AP-10 from Mucor miehei and best results were obtained with diisopropyl ether as solvent. Three different methods have been scaled-up for the resolution of 75-150 g of substrate: transesterification with l-butano1(90% yield of (S)-ketoprofen, 88% ee), transesterification with 2-(2-pyridyl)ethanol (94% yield, 92% ee), and hydrolysis in wet organic solvent (93% yield, 97% ee). Despite the comparable chemical and optical yields obtained with these three methods, the use of 2-(2-pyridyl)ethanol and the hydrolysis allowed a much easier work-up and isolation of the desired (+)-(S)-ketoprofen.o 1993 Wiey-Liss, Inc. KEY WORDS: lipases, amano M-AP-10, transesterification, hydrolysis, aminolysisThe pharmacological properties of racemic compounds are considerably more complex than those of enantiomerically pure substances. It is now widely recognized that the stereochemistry of drugs must be considered in all stages of drug development and that pure enantiomers must be used whenever the pharmacodynamic or pharmacokinetic data so warrant. ' The synthetic chemists are meeting this goal by developing new technologies to obtain optically pure compounds in preparative amounts. 2-Arylpropionic acids are an important classof nonsteroidal antiinflammatory drugs (NSAIDs) which are used in therapeutics as racemic mixtures, with the exception of (+)-(3-naproxen and (+)-(3-flunoxaprofen. However, the pharmacological activity of this class is mainly due to the 6)-enantiomers, their (R)-antipodes being essentially inactive as inhibitors of prostaglandin synthesis.2 Thus, considerable efforts have been made to synthesize pure enantiomers of 2-arylpropionic acids. One described method is the kinetic resolution of 2-arylpropionic acid esters by stereoselective hydrolysis in aqueous media, catalyzed by enzymes (lipases, 3-7 esterases,' or proteases') or by microorganisms. 'u-" In particular, enzymatic hydrolysis has been applied to the resolution of ruc-ketoprofen, one of the most potent and widely used members of this class of drugs.14 These biotransformations have been carried out in aqueous buffer giving the R-or S-acid with low enantiomeric excess. 5*73 To enhance the enantioselectivity of the reaction, a costly and time-consuming purification of the commercial L-1754 Candiaiz cylindraceu lipase is required.7 Recently, it has been shown that many biocatalytic reactions can proceed with high enantioselectivity when carried out i~i organic media. 14, l5 Lipases are stable and active in apolar organic solvents, being able to catalyze reactions of the ester function with several nucleophiles. ' %' ' Thes...

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Asymmetric Hydrolysis of (±)-α-Substituted Carboxylic Acid Esters with Microorganisms

Cited by 18 publications

References 0 publications

Characteristics and function ofAlcaligenessp. NBRC 14130 esterase catalysing the stereo-selective hydrolysis of ethyl chrysanthemate

Characteristics and function ofAlcaligenessp. NBRC 14130 esterase catalysing the stereo-selective hydrolysis of ethyl chrysanthemate

Enzymatic resolution of (S)‐(+)‐naproxen in a continuous reactor

Resolution of rac‐ketoprofen esters by enzymatic reactions in organic media

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