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

• Published in: Science China. Chemistry Vol. 57; no. 8; pp. 1164 - 1171
• Main Authors: Duan, YiTao, Yao, PeiYuan, Ren, Jie, Han, Chao, Li, Qian, Yuan, Jing, Feng, JinHui, Wu, QiaQing, Zhu, DunMing
• Format: Journal Article
• Language: English
• Published: Heidelberg Science China Press 01.08.2014; Science Press; Springer Nature B.V
• Subjects: Amino acids; Chemistry; Chemistry and Materials Science; Chemistry, Multidisciplinary; Chemistry/Food Science; Enantiomers; Enzyme activity; Hydrolysis; Optical activity; Physical Sciences; Science & Technology; Stereoselectivity; Substitutes; Substrates; (; enzymatic desymmetrization; Pregabalin; nitrilases; Baclofen; (S)-Pregabalin; ACID; PREGABALIN; SELECTIVE HYDROLYSIS; DINITRILES; (R)-Baclofen; MICHAEL ADDITION; GENE CLONING
• ISSN: 1674-7291; 1869-1870
• DOI: 10.1007/s11426-014-5139-2

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.