Unmasking the Reverse Catalytic Activity of ‘Ene’-Reductases for Asymmetric Carbonyl Desaturation

Carbonyl desaturation is a fundamental reaction widely practiced in organic synthesis. While numerous methods have been developed to expand the scope of this important transformation, most of them necessitate multistep protocols, or suffer from the use of high loadings of metal or strong oxidizing conditions. Moreover, approaches that can achieve precise stereochemical control of the desaturation process are extremely rare. We report herein a novel biocatalytic platform for desymmetrizing desaturation of cyclohexanones to generate diverse cyclohexenones bearing a remote quaternary stereogenic center, by reengineering ‘ene’-reductases (EREDs) to efficiently mediate dehydrogenation, the reverse process of their native activity. This ERED-based desaturation system operates under mild conditions with air as the terminal oxidant, tolerates oxidation-sensitive or metal-incompatible functional groups, and more importantly, exhibits unparalleled stereoselectivity comparing to those achieved with small-molecule catalysts. Mechanistic investigations suggested that the reaction proceeded through a-deprotonation followed by a rate-determining b-hydride transfer.