Enantioselective Biohalogenation of Spiro‐Epoxyoxindoles Enabled by Engineered Halohydrin Dehalogenases

We herein describe a biocatalytic halogenation approach that harnesses the reverse dehalogenation reaction of halohydrin dehalogenases. Through the integration of enzyme screening and structure‐guided protein engineering, a double mutant of HheC (T134S/W139M) was created for the enantioselective halogenation of spiro‐epoxyoxindoles, delivering chiral β‐haloalcohols in high yields (up to 50%) and optical purity (up to 98% ee ). Meanwhile, a nonenantioselective double mutant of HheG (I104F/N196G) was identified for the efficient halogenation of racemic or enantiopure spiro‐epoxyoxindoles, affording the corresponding β‐haloalcohols in up to 98% yield. The biohalogenation systems were performed using copper halides as the halogenating reagent under whole‐cell catalysis and exhibit satisfactory substrate generality. When cell‐free extract was used as the biocatalyst, several other halide salts were also proved effective for the biohalogenation reaction. Remarkably, seawater served as a natural halogenating agent, enabling gram‐scale synthesis of chiral β‐haloalcohols. Representative downstream transformations of chiral β‐haloalcohols further showcased the synthetic utility of the enantioselective biohalogenation platform. Together, these findings not only expand the catalytic repertoire of halohydrin dehalogenases but also provide a viable biohalogenation strategy for the synthesis of chiral β‐haloalcohols from readily available epoxides.