Computation and Development of New, Enabling Synthetic Methods

项目摘要/摘要 摘要 该研究计划的总体目标是开发分析、工具和方法，以实现新的、 更有效的试剂、催化剂和生物配体。 其中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， 和分子水平的反应性，目的是设计新的、更有效的试剂、催化剂和 生物配体。控制选择性和反应性是有效合成的基本特征，但我们的 在分子水平上，对基本相互作用如何扰乱这些方面的理解还只是初级的。 此外，这些相同的基本相互作用如何在生物环境中管理绑定的许多方面是 不完全理解。 另一个重点将是通过C-C、C-O和C-N键的形成来实现碎片的氧化偶联 C-H活化化学。将设计用于仿生反应研究的催化剂库，使用两种引导 原理：1)将催化剂的氧化电位与底物的氧化电位进行匹配 考虑和2)选择可以利用氧气再生催化物种的金属。这些图书馆 将以高通量微型格式部署，以发现迄今无法想象的反应模式。 从所获得的数据中，将构建反应“轮廓”，并对反应性、选择性、 并制作了机械装置，进行了实验验证。 这一提议的基本特征是能够获得新的反应模式来构建重要的 以高效和合理的方式建立有机结构。计算和机械理解为我们提供了 解决问题和提出假设的工具。高通量微规模实验允许理性 假设将被广泛询问，并有助于优化模型中许多相互依赖的变量 可能的反应空间。 相关性 这一提议的基本特征是能够通过计算设计新的反应和催化剂 和机械研究。目标是以高效和合理的方式构建重要的有机结构。 新的合成方法极大地增加了进入未开发的化学空间的途径，导致材料和 造福社会的药品。为了实现这一目标，调查将集中在获得更好的 对反应性和选择性的理解。新的氧化偶联化学的发展是一个特殊的 由于步数较少和废流较少而提高了效率，因此成为重点。这其中的挑战是 由于典型的有机分子中存在大量的C-H键，所以在任何给定的转化中，面积都是选择性的。 利用仿生过程产生具有生物活性的天然产品和类似天然产品的核心，这些都是理想的实体 在药物化学方面。在工业环境之外缺乏的宝贵培训将为毕业生提供 学生和其他同事。

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.