Expanding the Reactivity of Flavin-Dependent Halogenases toward Olefins via Enantioselective Intramolecular Haloetherification and Chemoenzymatic Oxidative Rearrangements

Of
the different classes of halogenases characterized to date,
flavin dependent halogenases (FDHs) are most associated with site-selective
halogenation of electron-rich arenes and enol(ate) moieties in the
biosynthesis of halogenated natural products. This capability has
made them attractive biocatalysts, and extensive efforts have been
devoted to both discovering and engineering these enzymes for different
applications. We have established that engineered FDHs can catalyze
different enantioselective halogenation processes, including halolactonization
of simple alkenes with a tethered carboxylate nucleophile. In this
study, we expand the scope of this reaction to include alcohol nucleophiles
and a greater diversity of alkene substitution patterns to access
a variety of chiral tetrahydrofurans. We also demonstrate that FDHs
can be interfaced with ketoreductases to enable halocyclization using
ketone substrates in one-pot cascade reactions and that the halocyclization
products can undergo subsequent rearrangements to form hydroxylated
and halogenated products. Together, these advances expand the utility
of FDHs for enantio- and diastereoselective olefin functionalization.