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 provides access to useful molecular scaffolds via C–C bond cleavage and formation. Biocatalytic semipinacol rearrangements are rare, however, and the only naturally occurring semipinacolase catalyzes a reaction that proceeds via chirality transfer on a complex natural product substrate. Herein, we report that flavin-dependent halogenases (FDHs) can catalyze enantioselective halogenative semipinacol rearrangement of pro-chiral allylic alcohols. This biocatalytic platform exhibits a broad substrate scope, affording chiral ketones bearing all-carbon quaternary stereocenters with 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.