Abstract
The remarkable selectivity, sustainability, and efficiency afforded by biocatalytic strategies position them as complements or alternatives to traditional synthetic methods. Nevertheless, the currently narrow spectrum of enzymatic reactions available imposes limitations on synthesizing diverse desired compounds. Consequently, there continues to be a high demand for developing novel biocatalytic processes to access reactions that were previously unattainable. Herein, we report the discovery and subsequent protein engineering of a unique halohydrin dehalogenase to develop a biocatalytic platform for enantioselective formation and ring-opening of oxetanes. This biocatalytic platform, exhibiting high efficiency, excellent enantioselectivity, and broad scopes, facilitates the preparative-scale synthesis of not only both enantiomers of chiral oxetanes (up to 49% yield, >99 e.e.) but also a variety of chiral γ-substituted alcohols (up to 53% yield, >99 e.e.). Additionally, both the enantioselective oxetane formation and ring-opening processes have been proven scalable for large-scale transformations (20 mmol) at high substrate concentrations (200 mM), and can be integrated efficiently in a one-pot, one-catalyst cascade system. Moreover, useful derivatizations highlight the potential synthetic applications of the biocatalytic platform. This work expands the enzymatic toolbox for non-natural reactions and will promote further exploration of the catalytic repertoire of halohydrin dehalogenases in synthetic and pharmaceutical chemistry.