Mechanistically Guided Development and Application of Electrochemically-Driven NHK Reactions

电化学驱动 NHK 反应的机械引导开发和应用

• 批准号: 10314881
• 负责人: David Edward Hill
• 金额: $ 4.5万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-03-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314881
• 关键词: Academia; Address; Aldehydes; Automobile Driving; California; Catalysis; Cathodes; Chemicals; Chemistry; Chromium; Communities; Complement; Complex; Coupling; Development; Disease; Electrochemistry; Electron Transport; Electrons; Fellowship; Future; Goals; In Situ; Industrialization; Institutes; Investigation; Ketones; Kinetics; Knowledge; Methodology; Methods; Molecular; Monitor; Natural Products; Nature; Organic Chemistry; Oxidation-Reduction; Pharmacologic Substance; Positioning Attribute; Preparation; Process; Production; Property; Reaction; Reducing Agents; Research; Spectrum Analysis; Structure; Synthesis Chemistry; Techniques; Technology; Traction; Training; Work; base; biological systems; career; catalyst; chemical kinetics; chemical reduction; cost; design; drug synthesis; forging; human disease; improved; innovation; insight; novel; professor; scaffold; screening; small molecule; tool

Project Summary/Abstract Progress in pharmaceutical development is often limited by the advancement of innovative chemical transformations that enable the expedient synthesis of drug molecules. The improvement of methods for selectively forming C–C bonds in the construction of complex small molecules remains an ongoing challenge for the field of synthetic chemistry. The Nozaki-Hiyama-Kishi (NHK) reaction has historically been an essential tool for chemoselectively forging C–C bonds in both academic and industrial synthesis of natural products and natural product derivatives. Although substantial progress has been made in developing NHK methodologies that avoid superstoichiometric amounts of Cr and facilitate valuable stereoselective transformations, scarce mechanistic knowledge of NHK chemistry has hindered any further improvements of this transformations over the past two decades. Therefore, the goal of this proposal is to examine the hypothesis that thorough physical organic understanding of known electrocatalytic NHK methodologies, guided by kinetics-based mechanistic investigations, can empower the advancement of robust and versatile electrochemically driven NHK chemistries, thereby expanding current knowledge of Cr-catalysis and enabling the synthesis of complex molecular scaffolds. This work will first focus on investigating the reaction mechanism of electrocatalytic NHK methodologies by utilizing chemical kinetics in concert with other mechanistic tools such as in-situ spectroscopy and electroanalytical chemistry. This comprehensive physical organic understanding of electrochemical NHK chemistry will then be leveraged towards the development of robust and versatile electrocatalytic NHK methodologies that enable new selectivity and reactivity. Finally, these improved electrocatalytic NHK methods will enable the first example of an electrochemical NHK chemistry utilized in total synthesis and empower a novel retrosynthetic disconnection strategy for the synthesis of a densely functionalized polycyclic natural product, Scabrolide A. This research will ultimately enable the synthesis of a wide range of pharmaceuticals, as well as probes for biological systems. The Reisman group at the California Institute of Technology creates innovative retrosynthetic strategies and develops novel synthetic methodologies towards efficient synthesis of natural products with important medicinal properties. The proposed research will complement their ongoing efforts in advancing novel methodologies, demonstrating innovative retrosynthesis strategies, and take advantage of the world-class facilities at Caltech, such as their automated screening facility that enables extensive access to high-throughput experimentation. This fellowship training position in Prof. Reisman’s group will not only improve my expertise in synthetic organic chemistry, but will enhance my prior training as a physical organic chemist, collectively preparing me for a future career in academia as a professor.

项目摘要/摘要 药物开发的进展通常受到创新化学的进步的限制 可以使药物分子的权宜合成的转化。改进方法 在复杂小分子的构建中有选择地形成C – C键是持续的 对合成化学领域的挑战。 Nozaki-Hiyama-Kishi（NHK）的反应历史上有 是化学选择性在学术和工业综合中锻造C -C键的重要工具 尽管在 开发NHK方法避免了超巨星的CR并促进价值 立体选择性转换，NHK化学的稀缺机理知识阻碍了任何 在过去的二十年中，这种转变的进一步改善。因此，目标的目标 提案是要探讨以下假设：对已知的彻底物理有机理解 在基于动力学的机理研究的指导下进行电催化NHK方法可以授权 强大的和多功能电化学驱动的NHK化学的进步，从而扩大 当前关于CR催化的知识和能够合成复杂的分子支架的知识。这项工作 首先将重点用于研究电催化NHK方法的反应机理 化学动力学与其他机械工具一起，例如原位光谱和 电子分析化学。对电化学NHK的这种全面的物理有机理解 然后，化学将利用健壮和多功能电催化NHK的发展 实现新的选择性和反应性的方法。最后，这些改进的电催化NHK 方法将使在总合成和 赋予一种新型的逆合合成断开策略，用于合成一个不官能化的 多环天然产品，scabrolide A.这项研究最终将使范围综合 药物以及生物系统的问题。 加利福尼亚理工研究所的Reisman Group创建创新的反式合成 策略并开发新的合成方法，以有效地合成天然产物 重要的医疗特性。拟议的研究将完成他们在进行前进的持续努力 新颖的方法，展示了创新的逆合合成策略，并利用 加州理工学院的世界一流设施，例如其自动筛选设施，可实现广泛的访问 进行高通量实验。在雷斯曼教授的小组中，这个奖学金培训职位不仅将 提高我在合成有机化学方面的专业知识，但会增强我先前作为身体的培训 有机化学家，为我作为教授的未来职业做准备。