Biocatalytic kinetic resolution for efficient and enantioselective synthesis of δ-haloalcohols and tetrahydrofurans

Expanding biocatalytic reactions to access previously inaccessible chemical transformations is of significant demand. Halohydrin dehalogenases represent a class of remarkably versatile biocatalysts that have been successfully explored in the asymmetric synthesis and transformation of epoxides as well as oxetanes. In this study, we extended their catalytic capabilities to establish a biocatalytic approach for the kinetic resolution of δ-haloalcohols. This approach enables the highly efficient and enantiocomplementary synthesis of diverse chiral δ-haloalcohols and tetrahydrofurans with good isolated yields (up to 50%) and high optical purities (up to >99% ee) on a preparative scale. These molecules are of significant interest in both synthetic and pharmaceutical chemistry. Remarkably, this biocatalytic method tolerates high substrate concentration up to 185 g/L, underscoring its synthetic potential for industrial applications. Furthermore, we propose a potential reaction mechanism based on a comprehensive analysis of various mutants and docking studies.