The biological activity of organic molecules is strongly impacted by the oxygen, nitrogen and carbon functional groups on their hydrocarbon scaffolds. Classically, the practice of organic synthesis has focused on building these scaffolds while concurrently introducing this functionality. We hypothesized that, analogous to nature, a late stage oxidation strategy, i.e., direct introduction of oxidized functionality into C(sp3)-H bonds of molecule scaffolds, would provide opportunities to diversify molecular structures and streamline syntheses. Our preliminary studies using novel transition metal catalysts have validated late stage C-H oxidation as a powerful approach for streamlining synthetic sequences and directly diversifying natural products and other complex structures. Building on this strong foundation, we plan to discover new catalysts to expand the scope of C(sp3)-H functionalizations possible. These reactions will broaden the functionality that can be introduced, sites that can be accessed, and classes of natural products and medicinal compounds that can be derivatized and synthesized. The key to our approach is to develop transition metal catalysts that mediate C(sp3)-H bond cleavage and functionalization, enabling tunable control over reactivity, as well as site-, chemo-, and stereoselectivity. We have discovered and commercialized palladium/sulfoxide catalysts for allylic C-H functionalizations, iron catalysts for aliphatic C-H hydroxylations, and manganese catalysts for intramolecular C(sp3)-H aminations. These catalysts proceed with unprecedented levels of reactivity and tunable selectivities in complex molecule settings, without the need for directing groups. These reactions and the late stage derivatization approach have already begun to be utilized by pharmaceutical companies in drug discovery and metabolite identification. The major challenges in the application of this strategy as a comprehensive C(sp3)-H functionalization approach to enable drug discovery are the development of new intermolecular methods and the expanded capacity for site-, chemo-, and stereoselectivities. To overcome these challenges, we will develop 1) new palladium/sulfoxide complexes for catalyst-controlled asymmetric induction and complex fragment couplings; 2) new base metal complexes for aliphatic C-H hydroxylations that proceed with alternate catalyst-controlled, predictable site selectivities and increased tolerance of ?-systems and nitrogen-containing compounds; and 3) new base metal complexes for intra- and intermolecular C-H amination and alkylations. Analogous to the impact of cross-coupling methods on C(sp2)-C(sp2) bond formation in drug discovery, these reactions will ultimately empower scientists to form C(sp3)-O, -N, and -C bonds from ubiquitous C(sp3)-H bonds in complex molecule scaffolds. This will reinvigorate efforts to explore natural products and other complex molecules as sources of medicines and biological research tools.
The introduction of oxygen, nitrogen, and carbon functionality into small molecules has been demonstrated to alter their physical properties and influence their interactions with biomolecular targets, ultimately impacting their effectiveness as drugs. Current chemical methods to introduce this functionality into natural products and other complex small molecule drug candidates are largely limited to lengthy chemical manipulations or de novo syntheses, presenting significant technological challenges to drug discovery. The goal of our program is to develop novel transition metal mediated catalytic methods to directly and selectively add new functionality to molecules via the oxidation and functionalization of ubiquitous C(sp3)-H bonds, ultimately accelerating the discovery of new natural product- and other complex small molecule-based therapeutics.
| Clark, Joseph R; Feng, Kaibo; Sookezian, Anasheh et al. (2018) Manganese-catalysed benzylic C(sp3)-H amination for late-stage functionalization. Nat Chem 10:583-591 |
| Griffin, Jennifer R; Wendell, Chloe I; Garwin, Jacob A et al. (2017) Catalytic C(sp3)-H Alkylation via an Iron Carbene Intermediate. J Am Chem Soc 139:13624-13627 |
| Nanjo, Takeshi; de Lucca Jr, Emilio C; White, M Christina (2017) Remote, Late-Stage Oxidation of Aliphatic C-H Bonds in Amide-Containing Molecules. J Am Chem Soc 139:14586-14591 |
