Development of a Screening Workflow for the Halogenation of Nitrogen Heterocycles with Vanadium-Dependent...

The halogenation of nitrogen heterocycles is a privileged transformation for accessing important synthetic intermediates and biologically active targets in medicinal chemistry. Despite the importance of N-heterocycle halogenation, current methods rely on reagents or catalysts that are largely unselective and produce a significant number of waste products. With an emerging interest in using halogenating enzymes to address these challenges, the vanadium-dependent haloperoxidase class of enzymes has emerged as a powerful platform for halogenation reactions under a uniquely broad set of reaction conditions. Herein, we report the development of a screening workflow for the halogenation of heterocycles with chloroperoxidase from Curvularia inaequalis (CiVCPO). Using a high-throughput screening strategy, representative model heterocycles are screened for direct chlorination and bromination reactions, and the optimized conditions are translated to an extended substrate scope in moderate to high yields. The volume of high-throughput data obtained allowed for the development of a predictive model for the substrate halogenation conditions. This screening platform is applied to established industrial intermediates and to the discovery of previously undiscovered enzymatic nitrogen-chlorine bond formation and decarboxylative halogenation reactions.