Biocatalytic Stereo-Perfect Desymmetrization of Oxetanes

The enantioselective desymmetrization of prochiral compounds
provides
a powerful strategy for accessing valuable chiral building blocks.
Herein, we report a biocatalytic platform for the intermolecular enantioselective
desymmetrization of prochiral oxetanes using an engineered halohydrin
dehalogenase. Through comprehensive enzyme screening and directed
evolution, we created an optimized biocatalyst that achieves highly
enantioselective and efficient azidolysis of 3-substituted oxetanes
on a preparative scale, affording a diverse range of chiral (R)-γ-azidoalcohols in good isolated yields (typically
>80%) and high enantiopurity (all >99% ee).
The synthetic
scalability and utility of this biocatalytic system were further demonstrated
through gram-scale reaction and downstream functionalizations, highlighting
its practical utility in synthetic and pharmaceutical applications.