Electroenzymatic Cascade Synthesis of Chiral α-Substituted Aromatic Halohydrins from Alkene: A Green and Stereoselective Approach

Abstract

Chiral α-substituted aromatic halohydrins are vital intermediates in pharmaceutical development and asymmetric synthesis. Herein, we report a sustainable electroenzymatic cascade for their synthesis directly from alkene. This one-pot strategy integrates electrocatalytic halogenation/hydroxylation with ketoreductase (KRED)-catalyzed asymmetric reduction, affording the target halohydrins in excellent yields (up to 92%) and enantioselectivities (up to 99.9 %ee). Protein engineering identified the LkKRED 153E as key to achieving high stereoselectivity by optimizing the active site. This approach offers significant advantages over existing methods: elimination of expensive metal ligands, operation under mild conditions, low E-factor (4.41), high mass efficiency (26.02%), and broad substrate scope. Molecular docking elucidated the mechanism, highlighting the critical role of the LkKRED 153E in enhancing catalytic efficiency and underpinning the method's green and sustainable credentials.