Biocatalytic Noncanonical Enantioconvergent Synthesis of Vicinal Diols

Enantioconvergent catalysis efficiently converts racemic substrates into single enantiomer products, overcoming the 50% yield limitation of kinetic resolutions while avoiding stereoisomer separation challenges. Despite advances in enantioconvergent chemo- and biocatalysis, expanding the substrate scope and enhancing catalytic versatility remain key challenges for the broader implementation of this transformative synthetic strategy. Herein, we present a unique biocatalytic platform for the enantioconvergent synthesis of vicinal diols using racemic epoxides or β-haloalcohols as starting materials. This methodology exploits engineered halohydrin dehalogenases to catalyze nitrite-mediated epoxide ring-opening with complementary regio- and enantioselectivity, enabling complete stereoconvergence through dual O-attack pathways. A variety of epoxides and β-haloalcohols are enantioconvergently converted into the corresponding enantioenriched vicinal diols on a preparative scale, achieving isolated yields of up to 89% and optical purities as high as a 96:4 enantiomeric ratio. Additionally, the enantioconvergent mechanism is elucidated through structure determination of the engineered enzyme, complemented by molecular dynamics and quantum mechanics/molecular mechanics calculations. Our study not only expands the enzymatic toolkit for creating chiral molecules but also opens up a methodology for enantioconvergent synthesis.