Catalyst-controlled methylene insertion

About This Grant

Program Summary: Scientists invent medicines by designing molecules but spend more time making them. This disconnect often stems from subtle changes in shape (e.g., a methylene spacer or a single fluorine) that induce profound gains in function and synthetic complexity. Our goal is to invent reactions that implement these strategic changes in molecular shape. With reactions that transform leads on the benchtop into analogs on the whiteboard, we aim to break synthetic bottlenecks in the invention of molecules that improve human health. Catalyst-controlled methylene insertion: The addition of a single methylene (CH2) is a prevalent design tactic in drug discovery, as subtle changes in shape can strongly influence biological activity. Yet, unlike insertions of substituted carbenes (CR2), CH2 insertion remains underdeveloped. We have shown that iron complexes promote selective CH2 insertion into C–N bonds of amines. Expanding this platform, we have developed a catalytic solution to a recurring challenge in pharmaceutical synthesis, site-selective insertion of CH2 into N–H bonds of azoles (methylation). Using metal catalysts to control the reactivity of a CH2 donor lays the foundation for developing a wide range of reactions for insertion of CH2 into prevalent motifs in drug discovery, including C–N, C–O, N–H, and C–H bonds. C–H functionalization of complex molecules: C–H functionalization is a powerful approach to streamline synthesis of high-priority analogs in drug discovery. Yet, applications on complex molecules remain unpredictable: reactivity is often poor, isomeric mixtures are difficult to separate, and models for predicting selectivity frequently fail. Our group is tackling these challenges through complementary advances in catalyst design, analytical methods, and computation. Using C–H borylation as a model reaction, we have designed ligands that enhance catalytic activity, established supercritical fluid chromatography with chiral stationary phases as a robust platform for separating borylated regioisomers, and we are integrating ion-mobility mass spectrometry with calculated collisional cross sections to rapidly identify sites of borylation prior to isolation. Together, these approaches will enable high-throughput studies of C–H borylation on complex molecules, generating the data needed to improve reactivity and build reliable models for selectivity prediction. Beyond borylation, we aim to establish a general approach for tackling shared barriers across late-stage diversification. This program will make strategic C–H transformations into routine tools, empowering chemists to turn leads into designed analogs that tackle unmet human health needs.