Computation and Development of New, Enabling Synthetic Methods

项目概要/摘要 总结 这项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。 重点之一将是最先进的计算方法，以了解立体选择性、化学选择性， 以及分子水平上的反应性，目的是设计新的，更有效的试剂，催化剂， 生物配体选择性和反应性的控制是有效合成的基本特征，但我们的研究表明， 对基本相互作用如何干扰这些方面的分子水平的理解仅仅是初步的。 此外，这些相同的基本相互作用如何在生物学背景下控制结合的许多方面是 不完全理解。 另一个重点将是通过C-C，C-O和C-N键形成的片段的氧化偶联， C-H活化化学。催化剂库将设计用于仿生反应的研究，使用两个指导 原理：1）使催化剂氧化电位与在所述条件下的基底的氧化电位匹配， 考虑和2）选择可以利用氧来再生催化物质的金属。这些库 将以高通量的微尺度形式部署，以发现迄今为止无法想象的反应模式。 从所获得的数据，反应“配置文件”将被构建和新的推断反应性，选择性， 并进行了实验验证。 这项建议的基本特点是能够获得新的反应模式，以构建重要的 以有效和合理的方式进行有机结构。计算和机械的理解给了我们 解决问题和验证假设的工具。高通量微型实验允许合理的 假设进行广泛的询问，并促进优化的许多相互依存的变量， 可能的反应空间。 相关性 这项提议的根本标志是通过计算设计新反应和催化剂的能力 机械研究。目标是以有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对未开发的化学空间的利用，导致材料和 制药造福社会。为了实现这一目标，调查将集中在获得一个改进的 理解反应性和选择性。新的氧化偶联化学的发展是一个特殊的 由于更少的步数和更小的废物流而提高了效率，因此可以集中精力。在这方面的挑战 面积是由于典型有机分子中存在大量C-H键而在任何给定转化中的选择性。 使用仿生过程导致生物活性天然产物和天然产物样核心，理想的实体 在药物化学中。在工业环境之外缺乏的宝贵培训将提供给毕业生 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.