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.