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 kcat 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.