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.