Overcoming and embracing oxidation for the synthesis of bioactive molecules

合成有机化学是制药业发明和准备下一代救命药物的核心。随着公认的化学反应的多样性、可预测性和稳健性的增加，寻找与医学相关的分子的化学空间也在增加。因此，全球药物发现工作的持续成功与有机化学方法论的研究密切相关。这项提议寻求开发被工业合作伙伴确定为高价值的下一代化学转化，并允许他们获得以前由于缺乏可靠和有效的方法而被其药物化学团队从未探索过的分子支架。氧化在整个过程中起着核心作用。大气中的分子氧是生命所必需的，有助于有氧氧化，为身体提供燃料。然而，在制药行业进行的大多数化学反应中，好氧氧化是一种难以控制的副反应，阻碍了生产性合成。即使严格排除氧气，底物和催化剂的氧化降解也很难避免。然而，在某些情况下，氧化也可以被视为一种生产性战略，通过这种战略可以实现有价值的新转变。这项提案针对的是这两个问题。对于产生新的C-C和C-N键的交叉偶联反应，将探索加入抗氧化剂添加剂，预期的好处是将这些转化的适用性扩大到那些以前可能受到阻碍的反应，例如与敏感的硫、氧或含硼官能团的偶联。在利用氧化方面，将利用胺的瞬时氧化为羟胺来开发新的化学计量比和催化的通过氢胺化途径形成C-N键的反应，为获得饱和含氮杂环提供一种新的途径。这些方法的应用将与以前在氧化还原化学领域与这些挑战作斗争的工业合作伙伴密切合作，以进入发现新药的新分子空间。

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.