Project Summary The atomistic change of C(sp3)–H to C(sp3)–O, –N, or –C can profoundly impact the biological function and physical properties of small molecules. Traditionally, introducing these functionalities relies on functional group transformations from pre-oxidized carbon-heteroatom precursors. This approach limits the direct installation of new functionality into complex molecules, often necessitating de novo synthesis that is impractical for rapid exploration of biological function. Our proposal aims to provide selective C(sp3)–H functionalization reactions that install O, N and C in the hydrocarbon scaffold of complex molecules. This will enable late-stage functionalizations that expedite drug discovery processes, streamline total syntheses, and empower exploration of natural products as drug candidates. Our group has shown that C(sp3)–H bonds in complex molecules can be distinguished based on their electronic, steric, and stereoelectronic properties, resulting in a paradigm shift within the chemistry community that prior to 2007 viewed aliphatic C–H bonds as preparatively indistinguishable. To do this, we have discovered and commercialized iron and manganese PDP-based catalysts for C(sp3)–H oxidations; palladium(II)/sulfoxide catalysts for allylic C–H functionalization; and manganese phthalocyanine catalysts for both intra- and intermolecular C(sp3)–H aminations. These catalysts proceed with excellent levels of reactivity and selectivity in complex molecule settings, without the need for directing groups. The late-stage functionalization approach that has emerged from this work has been utilized in both industrial and academic settings. Building on this considerable foundation, we will undertake major challenges required to broaden the application of late-stage functionalization in chemical synthesis and drug discovery. We will innovate new base-metal complexes for aliphatic C–H oxidations that increase chemoselectivity for tolerance of - functionality and unprotected alcohols, as well as explore catalyst chiral recognition through non-bonding interactions. These advances will make possible new reactions such as oxidative alkylations and catalyst-controlled asymmetric induction and site-divergence. We will develop new base-metal complexes for intermolecular C–H aminations and alkylations with unprecedented selectivities, and discover new ligand types amenable to asymmetric induction. New palladium(II)/sulfoxide catalysts will be invented with an emphasis on introducing functionality in complex settings. Cross-coupling reactions will be developed where O and N are introduced as part of complex fragments. Additionally, asymmetric C–H functionalizations that feature catalyst-controlled diastereoselectivities in substrates with pre-existing stereogenic centers will be advanced. Collectively, this program will change the way synthetic chemists make and diversify complex molecules in pursuit of therapeutics, metabolites, and biological pro...