Overcoming and embracing oxidation for the synthesis of bioactive molecules

克服并拥抱氧化以合成生物活性分子

• 批准号: 576253-2022
• 负责人: Newman, StephenSG
• 金额: $ 4.23万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=747572
• 关键词: Overcoming; embracing; oxidation; synthesis; bioactive

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.

合成有机化学是制药业努力发明和制备下一代救生药物的中心。随着成熟的化学反应的多样性、可预测性和鲁棒性的增长，搜索医学相关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学的研究密切相关。该提案旨在开发下一代化学转化，这些化学转化已被工业合作伙伴确定为具有高价值，并使他们能够获得药物化学团队以前由于缺乏可靠和有效的方法而未探索的分子支架。氧化在整个过程中起着核心作用。大气中的分子氧对生命至关重要，它促进有氧氧化，为身体提供燃料。然而，在制药工业中进行的大多数化学反应中，有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难以避免。然而，在某些情况下，氧化也可以作为一种生产策略，通过这种策略可以实现有价值的新转化。本提案针对这两个问题。对于产生新的C-C和C-N键的交叉偶联反应，将探索抗氧化剂添加剂的加入，其预期益处是将这些转化的适用性扩展到先前可能受到阻碍的那些，例如与敏感的含硫、氧或硼官能团的偶联。为了利用氧化，将利用胺到羟胺的瞬时氧化来开发新的化学计量和催化的C-N键形成反应，通过加氢胺化途径，提供了一种新的途径来获得饱和的含氮杂环。这些方法的应用，以获得新的分子空间，用于发现新的药物将进行与工业合作伙伴谁以前曾在氧化还原化学这些挑战的斗争密切合作。