Mechanistically Guided Development and Application of Electrochemically-Driven NHK Reactions

项目摘要/摘要 药物开发的进展往往受到创新化学品进展的限制 能够方便地合成药物分子的转化。几种常用方法的改进 在构建复杂的小分子中选择性地形成C-C键仍然是一个正在进行的过程 对合成化学领域的挑战。野崎-平山-岸信社(NHK)的反应在历史上 是在学术和工业合成中化学选择锻造C-C键的重要工具 天然产品和天然产品衍生品。尽管在以下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，稀缺的NHK化学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进。因此，这一目标是 建议是检验这样一种假设，即对已知的物理组织的透彻理解 电催化NHK方法，以动力学为基础的机理研究为指导，可以增强 强健和多功能的电化学驱动的NHK化学的进步，从而扩展 铬催化的最新知识，使复杂分子支架的合成成为可能。这部作品 首先将重点研究电催化NHK方法的反应机理 化学动力学与其他机械工具，如原位光谱分析和 电分析化学。对电化学NHK的全面物理有机认识 然后，将利用化学手段开发强大和多功能的电催化NHK 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 方法将使第一个例子的电化学NHK化学用于全合成和 一种新的反合成断链策略，用于合成一种稠密官能化的 多环天然产物，斯卡布罗内酯A。这项研究最终将使合成范围广泛 药品以及生物系统的探头。 加州理工学院的莱斯曼团队创造了创新的逆向合成 制定战略并开发新的合成方法，以实现天然产物的高效合成 具有重要的药用价值。拟议的研究将补充他们正在进行的推进 新颖的方法，展示了创新的逆合成策略，并利用 加州理工学院的世界级设施，例如他们的自动筛查设施，可以实现广泛的访问 到高通量实验。莱斯曼教授小组的这一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，但将加强我以前作为一名物理学家的培训 有机化学家，共同为我未来的学术生涯做好准备，成为一名教授。

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.