Selective C(sp3)–H Functionalization Enabled by Metal-Organic Framework Catalysis

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PROJECT SUMMARY/ABSTRACT Despite decades of research dedicated to expanding the structural complexity accessible to medicinal chemists, organic synthesis remains a time- and resource-intensive component of drug-discovery. To address this challenge, synthetic organic chemists have focused on inventing new methodologies to couple widely available building blocks into drug-like products, expanding the range of bioactive compounds directly accessible from simple precursors. Relatively few studies, however, have focused instead on increasing the diversity and complexity of those readily accessible precursors. As a small number of privileged reactions represent the majority of synthetic steps conducted within drug discovery, providing access to a broad range of building blocks for such transformations could dramatically expand accessible chemical space for medicinal chemists. Towards this end, methods for the functionalization of C–H bonds have the potential to revolutionize the synthesis of pharmaceutically relevant fragments by enabling the introduction of valuable functionality at ubiquitous but traditionally unreactive sites. Unfortunately, due to the abundance of C–H bonds, this approach often suffers from poor selectivity, resulting in challenging purifications of isomers and diminished yields. As a general strategy to facilitate selective C–H functionalization, the proposed research will leverage the remarkable properties of metal-organic frameworks (MOFs), which can both selectively bind small organic molecules and stabilize highly reactive species capable of cleaving C(sp3)–H bonds. By holding specific C–H bonds near the site of reactivity, selectivity based on the binding pose of the substrate within the MOF pore—not the inherent reactivity of each C–H bond—can determine the functionalized position. Employing MOFs capable of supporting metal-oxo species with substrate-binding linkers or, alternatively, MOFs bearing photocatalytic linkers with nodes containing open coordination sites provides two distinct approaches to realize this aim. Combining selective radical generation with established open-shell reactivity can afford a diverse range of products such as halides, boronic esters, and C–C bonds via Minisci and Giese reactivity. Overall, the proposed research will provide a novel approach to the long-standing challenge of selective C(sp3)–H functionalization, enabling the efficient conversion of simple starting materials into valuable fragments for use in drug discovery. Conducting this research will provide thorough training in the experimental methods required to synthesize and characterize inorganic materials, including PXRD, ICP-MS, gas adsorption, and photophysical techniques. Massachusetts Institute of Technology, as one of the largest and most productive scientific research institutions in the world, possesses the facilities and institutional environment required to support these studies.