Overcoming and embracing oxidation for the synthesis of bioactive molecules

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Synthetic organic chemistry lies at the center of the pharmaceutical industry's efforts to invent and prepare the next generation of life-saving drugs. As the diversity, predictability, and robustness of well-established chemical reactions grows each, so to does the amount of chemical space that gets searched for medicinally-relevant molecules. The continued success of global drug discovery efforts is thus closely tied to research in organic chemistry methodology. This proposal seeks to develop next-generation chemical transformations that have been identified by the industrial partners as being of high-value and allow them to access molecular scaffolds that have been previously unexplored by their medicinal chemistry teams due to lack of reliable and efficient methods. Oxidation plays a central role throughout. Molecular oxygen in the atmosphere is essential for life, facilitating aerobic oxidation that fuels the body. However, in most chemical reactions carried out in the pharmaceutical industry, aerobic oxidation is a difficult-to-control side reaction that hinders productive synthesis. Even with stringent efforts to exclude oxygen, oxidative degradation of substrates and catalysts can be difficult to avoid. However, in some cases, oxidation can also be embraced as a productive strategy by which valuable new transformations can be realized. This proposal targets both of these issues. For cross-coupling reactions that generate new C-C and C-N bonds, the inclusion of anti-oxidant additives will be explored with the anticipated benefit of expanding the applicability of these transformations to those that may previously have been hindered such as couplings with sensitive sulfur, oxygen, or boron-containing functional groups. Towards harnessing oxidation, the transient oxidation of amines to hydroxylamines will be exploited to develop new stoichiometric and catalytic C-N bond forming reactions via hydroamination pathways, providing a new way to access saturated nitrogen-containing heterocycles. Applications of these methods to access novel molecular space for the discovery of new drugs will be carried out in close collaboration with industrial partners who have previously struggled with these challenges in redox chemistry.