Enantiomerically pure synthesis of beta-substituted gamma-butyrolactones: A key intermediate to concise synthesis of pregabalin

Abstract

[GRAPHICS] Chiral beta-substituted gamma-butyrolactones are known to be important intermediates for many biologically active compounds such as gamma-aminobutyric acid (GABA) derivatives and lignans. We have developed a general, convenient, and scalable synthetic method for enantiomerically pure beta-substituted gamma-butyrolactones, with either configuration, via nucleophilic cyclopropane ring opening of (1S,5R)- or (1R,5S)-bicyclic lactone followed by decarbethoxylation. The utility of our method was demonstrated by streamlined synthesis of pregabalin ((S)-3-isobutyl-gamma-aminobutyric acid), an anticonvulsant drug for the treatment of peripheral neuropathic pain.