Desymmetric hydrolysis of prochiral imide for S-pregabalin synthesis by rationally designed d-hydantoinase

Abstract

S-Pregabalin (S-PGB) is an effective medicine for analgesic, anticonvulsant and anxiolytic treatments. To date, enantioselective synthesis of S-PGB suffers from 50% undesired by-product that needs to be recycled via highly polluting chemical processes. In this study, we rationally engineered D-hydantoinase to desymmetrize prochiral 3-isobutyl glutarimide to yield R-3-isobutyl glutaric acid monoamide (R-IBM), the direct chiral precursor for S-PGB. The best variant (M63AL65HC317T) could produce R-IBM with great overall conversion (99% molar yield) and a high ee_p value (99.8%) in a kilogram scale synthesis. This study offers a novel green and atom-efficient route for S-PGB production.