Intermolecular Heterocycle Synthesis Enabled by Enzymatic Halide Recycling with Vanadium-Dependent Haloperoxidases

The enzymatic synthesis of heterocycles is an emerging biotechnology for the sustainable construction of societally important molecules. Herein, we describe an enzyme-mediated strategy for the oxidative dimerization of thioamides enabled by enzymatic halide recycling by vanadium-dependent haloperoxidase enzymes. This approach allows for intermolecular biocatalytic bond formation using a catalytic quantity of halide salt and hydrogen peroxide as the terminal oxidant. The established method is applied to a diverse range of thioamides to generate the corresponding 1,2,4-thiadiazoles in moderate to high yield and with excellent chemoselectivity. Mechanistic experiments suggest that the reaction proceeds through two distinct enzyme-mediated sulfur halogen- ation events that are critical for heterocycle formation. Molecular docking experiments provide insight into reactivity differences between biocatalysts used in the study. Finally, the developed biocatalytic oxidative dimerization is applied to a preparative scale chemoenzymatic synthesis of the anticancer agent penicilliumthiamine B. These studies demonstrate that enzymatic halide recycling is a promising platform for new-to-nature intermolecular bond formation.