Engineered Flavin-Dependent Halogenases Catalyze C–C Bond Formation via Enantioselective Semipinacol Rearrangement

The semipinacol rearrangement comprises a valuable class of synthetic organic transformations that provide access to useful molecular scaffolds via C-C bond cleavage and formation. Naturally occurring semipinacolases have thus far been limited to examples in alkaloid or polyketide biosynthesis, and the only new-to-nature semipinacolase was reported based on Brønsted acid catalysis with limited substrate scope. Herein, we report that flavin-dependent halogenases (FDHs) can catalyze enantioselective halogenative semipinacol rearrangement of prochiral allylic alcohols. This biocatalytic platform exhibits a broad substrate scope, affording chiral ketones bearing quaternary stereocenters with a high enantioselectivity. The reaction system displays a <i>k</i>_cat value of 16.86 ± 0.97 min^-1, representing the highest reported to date for FDH catalysis, and the T52G mutation was found to play a key role in reshaping the enzyme active site to enable this non-native transformation. This first example of asymmetric C-C bond construction using an FDH highlights the catalytic flexibility of these enzymes and provides access to a diverse range of enantioenriched carbocycles and heterocycles.