Stereodivergent synthesis of cyclic γ-aminobutyric acid – GABA analogues

Abstract A novel synthetic route towards two series of enantiomerically pure cyclic analogues of 2,3- cis - and 2,3- trans -γ-aminobutyric acid (GABA) was developed. The route is based on the elongation and stereodivergent manipulation of a readily accessible enantiomerically pure γ-substituted α-aminolactone. The five-step route towards the 2,3- cis -substituted GABA analogues was achieved via straightforward carbon chain extension of the lactone using a non-classical Wittig reaction followed by chemoselective reduction and a protecting group switch. The five-step route towards the 2,3- trans -substituted GABA analogues employed elongation of the same aminolactone using a Horner-Wadsworth-Emmons reaction and highly stereoselective intramolecular oxa-Michael addition as the key synthetic manipulations. Altogether this chemistry has allowed the stereodivergent preparation of a novel class of GABA analogues in two diastereomeric series.