Among the numerous synthetic handles that are relied upon in chemical synthesis, organic halides have served as a premier precursor for organometallic reagent preparation, cross coupling, and radical-mediated reactions. These features, coupled with their increasing presence in drug discovery make the synthesis of organic halides an attractive area for synthetic exploration. While numerous methods are established for direct halogenation of hetereocycles, decarboxylative halogenation has emerged as a remarkably valuable method for direct functional group conversion from a carboxylic acid moiety to a halogen, providing a chemoselective option for functional group interconversion. Despite the promise of this approach, these methods are heavily reliant on harsh reaction conditions as well as air and moisture-sensitive reagents. Moreover, this reaction traditionally suffers from a limited substrate scope on heteroaromatics, leaving a general catalyst system for decarboxylative halogenation elusive. Vanadium haloperoxidases (VHPOs) are a class of vanadium-dependent enzymes that perform catalytic oxidation of halide salts to the corresponding hypohalous acids using hydrogen peroxide (H2O2) as the chemical oxidant and are well documented for performing selective halogenation reactions of organic compounds in nature. They have been noted for their successful expression in E. Coli, resistance to oxidative degradation, and stability in a host of organic solvents making them prime candidates for biocatalyst development. We have recently discovered that VHPOs are capable of performing selective decarboxylative halogenations across a range of medicinally relevant heterocycles with high yields and selectivities. The details of the reaction development, substrate scope, and mechanistic insights for this reaction will be discussed herein.

Biocatalytic decarboxylative halogenation of heterocycles enabled by vanadium haloperoxidases

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