Mechanism-Guided Catalyst Development through Reaction Discovery Simulation

项目摘要 化学合成的进展为获得复杂的生物活性结构提供了途径 作为药品和分析工具是高度相关的。高性能反应 允许选择性地形成特定的共价键通常是通过首先揭开 它们的基本化学反应机制，因为这些机制细节为 做进一步的实验。尤其是在C-H官能化方面，Lewis酸/碱 化学和立体选择性转化，机制的发现是至关重要的，因为 实现这些反应步骤的高难度水平。这些反应的进一步发展 类型将能够有效地构建各种强大的疗法、信号 探头和天然产物。 拟议中的研究将利用第一性原理模拟来极大地加速催化剂 新型合成反应的发展。齐默尔曼小组最近开发出 反应途径发现工具特别适合于这项任务，能够 揭示意想不到的反应路径以及直观的路径，使您能够深入了解 反应性的原子论细节。在与众多反应开发小组的合作下， 这些工具已经被用来揭示几类催化剂的原理，以及 甚至允许设计新的催化剂结构。将这些方法应用于 建议的转化(镍基C-H官能化、大环内酯手性糖基化 有机催化剂、路易斯酸催化的羰基-烯烃歧化反应和氧化酶 转变)将提供所需的基本科学洞察力，以实现具有挑战性的合成 台阶。 总而言之，高选择性转化催化剂的拟议开发将 能够合成各种具有科学和治疗相关的分子， 对人类健康的治疗和研究具有深远的意义。

Project Summary Advances in chemical synthesis provide access to complex biologically active structures that are highly relevant as pharmaceuticals and analysis tools. High performance reactions that allow selective formation of specific covalent bonds are usually achieved by first uncovering their fundamental chemical reaction mechanisms, as these mechanistic details pave the way for further experimentation. Especially in the areas of C-H functionalization, Lewis acid/base chemistries, and stereoselective transformations, the discovery of mechanism is vital due to the high difficultly level in achieving these reaction steps. Further development of these reaction types will enable efficient construction of a wide variety of powerful therapeutics, signaling probes, and natural products. The proposed research will leverage first principles simulations to greatly accelerate catalyst development for novel synthetic reactions. The Zimmerman group's recently developed reaction pathway discovery tools are especially well-positioned for this task, being able to reveal unexpected reaction pathways as well as intuitive paths, giving deep insight into the atomistic details of reactivity. In collaboration with numerous reaction development groups, these tools have already been used to reveal principles for several classes of catalysts, and have even allowed new catalyst structures to be designed. Application of these methods to the proposed transformations (Ni-based C-H functionalization, macrolide glycosylation by chiral organocatalysts, Lewis-acid catalyzed carbonyl-olefin metathesis, and oxidative enzymatic transformations) will give the basic scientific insight needed to enable challenging synthetic steps. In summary, the proposed development of catalysts for highly selective transformations will enable synthesis of a variety of scientifically and therapeutically relevant molecules, with profound implications for the treatment and study of human health.