Chemical Reactions to Advance Drug Discovery: Stereoselective Synthesis of Heterocycles and Late-Stage Functionalization for Mechanism of Action Studies

About This Grant

The development of innovative chemical reactions is critical to advancing drug discovery and improving human health. Our laboratory focuses on addressing unmet needs in basic biomedical research through the development of selective chemical methods that impact drug discovery in two transformative ways. Research Direction 1: Stereoselective synthesis of sp3-rich N-heterocycles via photocatalytic C–H annulation We propose to develop stereoselective catalytic reactions to synthesize chiral N-heterocycles, a class of sp³- rich scaffolds prevalent in FDA-approved drugs. Our strategy employs enantioselective photocatalytic C–H annulations mediated by dual photoredox and chiral Lewis acid catalysis to generate functionalized N- heterocycles with diverse substitution patterns and stereochemical complexity. This research direction will provide streamlined access to several classes of saturated heterocycles, including morpholines, piperidines, pyrrolidines, tetrahydroquinolines, and indolines. Insights gained from mechanistic studies will inform the development of highly stereoselective processes. Research Direction 2: Late-Stage Photochemical Installation of Photocrosslinkers into Drug-Like Molecules We propose to advance chemical biology by developing methods to directly functionalize drug-like molecules for mechanism-of-action studies. Specifically, we will design novel photoaffinity labeling (PAL) reagents to facilitate the late-stage installation of photocrosslinking groups into bioactive molecules. Leveraging photochemical Minisci reactions, this approach will enable the synthesis of novel PAL probes in one step from bioactive molecules through selective C–C bond formation. This innovation addresses a critical bottleneck in drug discovery, providing a generalizable platform for PAL probe development. We anticipate this research direction will accelerate the identification of molecular targets of drug-like molecules. This NIGMS MIRA proposal leverages robust preliminary data from our laboratory, including recent advances in photochemistry and stereoselective catalysis. We will incorporate mechanistic studies and collaborations in spectroscopy, computational chemistry, and chemical biology to refine and expand the scope of our methods. Guided by the mission of the NIGMS, we propose to develop broadly useful chemical methods with far-reaching implications in synthetic chemistry, chemical biology, and pharmaceutical research. By enabling the efficient synthesis of chiral N-heterocycles and facilitating the direct conversion of drug-like molecules into PAL probes, our research proposal will contribute to the advance of drug discovery and the understanding of biological processes, ultimately laying the foundation for the improved treatment of human disease.