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

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.

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 1a and 1b 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 HsNIT 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-substituent 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 γ-amino acids of pharmaceutical importance.