Biocatalytic Atroposelective Synthesis of Axially Chiral Styrenes via Dynamic Kinetic Resolution

Enzymatic synthesis of atropisomers has recently attracted considerable research attention, with most studies focusing on axially chiral biaryls. We report a less explored atroposelective dynamic kinetic resolution (DKR) of nonbiaryl styrenes catalyzed by imine reductases (IREDs) and alcohol dehydrogenases (ADHs). The IR189 wild type enzyme was identified to be highly active and selective; furthermore, the inversion of atroposelectivity was achieved with protein engineering. Additionally, two ADHs with enantio-complementary selectivity for the reductive DKR were identified and applied in the synthesis of axially chiral styrenes. Both IREDs and ADHs exhibited broad substrate scope, affording up to 99:1 e.r. and 99% yields for up to 29 examples. Scaled-up reactions and derivatization of optically pure products demonstrated the synthetic utility of these axially chiral styrenes. Molecular recognition mechanisms were elucidated by molecular dynamics (MD) simulations. The current strategy expands the scope of enzymatic DKR of atropisomeric compounds and significantly advances the field of biocatalytic synthesis of axially chiral compounds.