Computation and Development of New, Enabling Synthetic Methods

项目概要/摘要 总结 该研究计划的总体目标是开发分析，工具和方法， 获得新的、更有效的试剂、催化剂和生物配体。 一个重点将是最先进的计算方法，以了解立体选择性， 化学选择性和反应性在分子水平上，目的是设计新的，更 有效的试剂、催化剂和生物配体。选择性和反应性的控制是 有效合成的基本特征，但我们在分子水平上理解如何基本 干扰这些方面的相互作用只是初步的。此外，这些相同的 在生物学背景下控制结合的基本相互作用尚未完全理解。 另一个重点将是通过C-C，C-O和C-N键形成的片段的氧化偶联 通过C-H活化化学。催化剂库将被设计用于仿生研究 反应使用两个指导原则：1）使催化剂氧化电位与氧化 2）选择可以利用氧的金属， 再生催化物质。这些库将以高通量的微尺度部署 以发现迄今为止无法想象的反应模式。根据获得的数据，反应 “配置文件”将被构建和新的推论有关的反应性，选择性，和机制， 这将被实验验证。 这项建议的基本特点是能够获得新的反应模式， 高效合理地建设重要的有机结构。计算和 机械理解给了我们解决问题和验证假设的工具。高 生产量微型实验允许合理的假设进行广泛的询问 并有助于优化可能的反应空间中的许多相互依赖的变量。 相关性 这一提议的根本标志是设计新反应和催化剂的能力 通过计算和机械研究。其目标是构建重要的有机结构， 一种有效而合理的方式。新的合成方法大大增加了对未开发的 化学空间，导致材料和药物，造福社会。实现这一 目标，调查将集中在获得更好的理解的反应性和选择性。 新的氧化偶联化学的发展是一个特别的焦点，由于增加， 更低的步骤数和更小的废物流带来更高的效率。这方面的挑战是 在任何给定的转化中，由于典型的有机化合物中存在大量的C-H键， 分子。仿生过程的使用导致生物活性天然产物和天然产物- 就像核心一样，药物化学中的理想实体。宝贵的培训，缺席以外的 工业环境，将提供给研究生和其他同事。

PROJECT SUMMARY/ABSTRACT Summary The overall objective of this research program is to develop analyses, tools, and methods to achieve new, more effective reagents, catalysts, and biological ligands. One focus will be on state-of-the-art computation methods to understand stereoselectivity, chemoselectivity, and reactivity at the molecular level with the aim of designing new, more effective reagents, catalysts, and biological ligands. The control of selectivity and reactivity are essential features of efficient synthesis, yet our molecular level understanding of how fundamental interactions perturb these aspects is only rudimentary. Further, many aspects of how these same fundamental interactions govern binding in a biological context are incompletely understood. Another focus will be on oxidative coupling of fragments via C-C, C-O, and C-N bond formation by means of C–H activation chemistry. Catalyst libraries will be designed for study of biomimetic reactions using two guiding principles: 1) matching catalyst oxidation potentials with the oxidation potentials of the substrates under consideration and 2) selecting metals that can utilize oxygen to regenerate the catalytic species. These libraries will be deployed in a high-throughput microscale format to discover reactivity patterns heretofore unimagined. From the data obtained, reaction “profiles” will be constructed and new inferences about reactivity, selectivity, and mechanism will be made, which will be tested experimentally. The fundamental hallmark of this proposal is the ability to access new reaction patterns to construct important organic structures in an efficient and rational manner. Computation and mechanistic understanding gives us the tools to solve problems and posit hypotheses. High throughput microscale experimentation permits rational hypotheses to be interrogated broadly and to facilitate optimization of the many interdependent variables in the possible reaction space. Relevance The fundamental hallmark of this proposal is the ability to design new reactions and catalysts via computation and mechanistic study. The goal is to construct important organic structures in an efficient and rational manner. New synthetic methods greatly increase access to untapped chemical space, leading to materials and pharmaceuticals that benefit society. To achieve this goal, investigations will focus on obtaining an improved understanding of reactivity and selectivity. The development of new oxidative coupling chemistry is a particular focus due to increases in efficiency from lower step counts and smaller waste streams. The challenge in this area is selectivity in any given transformation due the numerous C–H bonds present in a typical organic molecule. Use of biomimetic processes leads to bioactive natural products and natural product- like cores, desirable entities in medicinal chemistry. Invaluable training, absent outside of industrial settings, will be afforded to graduate students and other coworkers.