Selective C−H Halogenation of Alkenes and Alkynes Using Flavin‐Dependent Halogenases

Single component flavin‐dependent halogenases (FDHs) possess both flavin reductase and FDH activity in a single enzyme. We recently reported that the single component FDH AetF catalyzes site‐selective bromination and iodination of a variety of aromatic substrates and enantioselective bromolactonization and iodoetherification of styrenes bearing pendant carboxylic acid or alcohol substituents. Given this inherent reactivity and selectivity, we explored the utility of AetF as catalyst for alkene and alkyne C−H halogenation. We find that AetF catalyzes halogenation of a range of 1,1‐disubstituted styrenes, often with high stereoselectivity. Despite the utility of haloalkenes for cross‐coupling and other applications, accessing these compounds in a stereoselective manner typically requires functional group interconversion processes, and selective halogenation of 1,1′‐disubstituted olefins remains rare. We also establish that AetF and homologues of this enzyme can halogenate terminal alkynes. Mutagenesis studies and deuterium kinetic isotope effects are used to support a mechanistic proposal involving covalent catalysis for halogenation of unactivated alkynes by AetF homologues. These findings expand the scope of FDH catalysis and continue to show the unique utility of single component FDHs for biocatalysis. The single component flavin‐dependent halogenase AetF halogenates a range of 1,1‐disubstituted styrenes, often with high stereoselectivity, and AetF and homologues of this enzyme also halogenate terminal alkynes. These findings expand the scope of FDH catalysis, and mutagenesis studies and deuterium kinetic isotope effects provide insight into the unique utility of single component FDHs for biocatalysis.