Development of Haloperoxidase Enzymes for New Applications in Chemical Synthesis

Emory University, Atlanta GA

Investigators

Abstract

ABSTRACT Halogenation is a chemical reaction that is responsible for the introduction of a halogen atom including chlorine, bromine, iodine and fluorine (Cl, Br, I, F) into an organic compound. It has emerged as one of the most important reaction types for the selective synthesis of pharmaceuticals and biologically active compounds and for late- stage functionalization of drugs to enhance their therapeutic properties. Despite the importance of halogenation in drug development, current methods are largely reliant on reagents that are air- and moisture-senstive and/or unselective in the halogenation event, leading to the production of undesired halogenated byproducts. Enzymes are an attractive catalyst option for performing halogenation and halogenation-mediated reactions because of their unmatched selectivity and sustainability parameters. The overarching goal of my research group is to discover and develop halogenating enzymes for perfoming selective halogenation or halogenation-mediated reactions for chemical synthesis. Among the broad range of halogenase enzymes in nature, the vanadium- dependent haloperoxidase (VHPO) class of enzymes have been recognized as an attractive option for halogenation in chemical synthesis. These fascinating enzymes perform halogenation using inert halide salts and hydrogen peroxide as the terminal oxidant. Some additional notable features of VHPOs are their ease of access, tolerance to a broad range of solvents and temperatures and their ability to act on a wide range of substrate types. Over the next 5 years, the central goal of our research team is to expand the synthetic capabilities of this enzyme class in both halogenation-mediated and halogenation reactions for downstream application in the synthesis of biologically active compounds. In our first approach (Thrust A), we will use a concept referred to as enzymatic halide recycling to perform new biocatalytic oxidation and bond forming reactions. In this approach, a catalytic quantity halide salt is repeatedly oxidized by the enzyme to faciliate new bond formation using hydrogen peroxide as the terminal oxidant. In our second approach (Thrust B), we will develop a series of defunctionalative halogenation (replacing a functional group with a halogen) and halooxidation (addition of a halogen and an oxygen atom) reactions. Collectively, these approaches will provide a sustainable and selective catalyst platform for accessing intermediate and target compounds that are relevant to drug discovery and also dramatically expand the synthetic repertoire of halogenase enzymes for chemical synthesis.