Journal Article

Biocatalytic desymmetrization of 3-substituted glutaronitriles by nitrilases. A convenient chemoenzymatic access to optically active （S）-Pregabalin and （R）-Baclofen

DUAN YiTao YAO PeiYuan REN Jie HAN Chao LI Qian YUAN Jing FENG JinHui WU QiaQing ZHU DunMing

2014

Overview

Desymmetrization of prochiral 3-substituted glutaronitriles offers a new approach to access （S）-Pregabalin and （R）-Baclofen. A number of nitrilases from diverse sources were screened with 3-isobutylglutaronitriles （1a） or 3-（4＇-chlorophenyl）glutaronitriles （1b） as the substrate. Some nitrilases were found to catalyze the desymmetric hydrolysis of la and lb to form optically active 3-（cyanomethyl）-5-methylhexanoic acid （2a） and 3-（4＇-chlorophenyl）-4-cyanobutanoic acid （2b） with high enantiomeric excesse （ee）, respectively. This cannot be achieved using traditional chemical hydrolysis. Among them, AtNIT3 generated （R）-2b whereas BjNIT6402 and HsN1T produced the opposite （S）-enantiomer with high conversions and ee values. Not only the nitrilases showed different activities and stereoselectivities toward these 3-substituted glutaronitriles, the 3-substitueut of the substrates also exerted great effect on the enzyme activity and stereoselectivity. （S）-2a and （S）-2b were prepared with high yields and ee values using BjNIT6402 and HsNIT as the biocatalysts, respectively. A straightforward Curtius rearrangement of （S）-2a and （S）-2b, followed by the acidic hydrolysis, afforded （S）-Pregabalin and （R）-Baclofen. This offers a new platform methodology for the synthesis of optically active β-substituted T-amino acids of pharmaceutical importance.

• Subject: Curtius重排 / 光学活性 / 化学水解 / 巴林 / 生物催化剂 / 立体选择性 / 腈水解酶 / 酶化学