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.