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.