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.

项目总结/摘要 药物开发的进展往往受到创新化学品的进展的限制。 这些转化使得能够方便地合成药物分子。方法的改进 在复杂小分子的构建中选择性地形成C-C键仍然是一个正在进行的研究。 对合成化学领域的挑战。野崎-桧山-岸信介（NHK）的反应历史上 是在学术和工业合成中化学选择性地锻造C-C键的重要工具 天然产品和天然产品衍生物。虽然在这方面取得了实质性进展， 开发NHK方法，避免超化学计量的铬并促进有价值的 立体选择性转化，NHK化学的缺乏机械知识阻碍了任何 在过去的二十年里，这种转变得到了进一步的改善。因此，这一目标 建议是检查假设，彻底的物理有机理解已知的 电催化NHK方法，以动力学为基础的机械研究为指导，可以使 强大的和多功能的电化学驱动的NHK化学的进步，从而扩大 目前的知识铬催化和使复杂的分子支架的合成。这项工作 将首先集中研究电催化NHK方法的反应机理，利用 化学动力学与其他机械工具，如原位光谱学， 电分析化学这种全面的物理有机理解电化学NHK 然后，化学将被用于开发强大的和多功能的电催化NHK 这些方法能够实现新的选择性和反应性。最后，这些改进的电催化NHK 这些方法将使电化学NHK化学的第一个例子能够用于全合成， 赋予一种新型逆合成断开策略以合成致密功能化的 多环天然产物Scabrolide A.这项研究最终将使广泛的合成 以及用于生物系统的探针。 加州理工学院的Reisman小组创造了创新的逆合成技术 战略和开发新的合成方法，以有效合成天然产物， 重要的药用价值。拟议的研究将补充他们正在进行的努力， 新的方法，展示创新的逆合成策略，并利用 加州理工学院的世界级设施，例如他们的自动筛选设施， 到高通量实验。Reisman教授小组的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，但将加强我作为物理学家的先前训练 有机化学家，共同为我将来在学术界当教授做准备。