Computation and Development of New, Enabling Synthetic Methods

新的、可行的合成方法的计算和开发

• 批准号: 10581966
• 负责人: Marisa C Kozlowski
• 金额: $ 3.39万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581966
• 关键词: Area; Binding; Biological; Biomimetics; Chemicals; Chemistry; Computing Methodologies; Coupling; Data; Development; Drug Design; Goals; Hydrogen Bonding; Industrialization; Investigation; Libraries; Ligands; Metals; Methods; Molecular; Natural Products; Natural regeneration; Oxygen; Pattern; Pharmaceutical Chemistry; Pharmacologic Substance; Problem Solving; Process; Reaction; Reagent; Research; Societies; Stream; Structure; Testing; Training; bioactive natural products; biomacromolecule; catalyst; design; graduate student; improved; oxidation; programs; small molecule; tool; wasting

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.

项目摘要/摘要 摘要 本研究计划的总体目标是开发分析、工具和方法，以 获得新的、更有效的试剂、催化剂和生物配体。 一个重点将是了解立体选择性的最先进的计算方法， 化学选择性和分子水平的反应性，目的是设计新的、更多的 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，但我们对分子水平的理解是如何基本的 干扰这些方面的互动只是初级的。此外，这些问题的许多方面是如何相同的 基本的相互作用支配着生物学背景下的结合，但人们对此还不完全了解。 另一个重点将是通过C-C、C-O和C-N键形成的碎片的氧化偶联 用C-H活化化学的方法。将设计用于仿生研究的催化剂文库 使用两个指导原则的反应：1)使催化剂氧化电位与氧化相匹配 所考虑的衬底的电位以及2)选择可以利用氧气的金属 再生催化物种。这些库将以高吞吐量的微型规模进行部署 格式，以发现迄今为止想象不到的反应模式。从获得的数据来看，反应 “概况”将被构建，关于反应性、选择性和机理的新推论将被 将在实验中进行测试。 这一提议的基本特征是能够获得新的反应模式 高效合理构建重要有机结构。计算和 机械论的理解给了我们解决问题和提出假设的工具。高 吞吐量微尺度实验允许合理的假设被广泛询问 并便于对可能的反应空间中的许多相互依赖的变量进行优化。 相关性 这一提议的基本标志是设计新反应和催化剂的能力。 通过计算和机理研究。目标是建造重要的有机结构 一种高效而理性的方式。新的合成方法极大地增加了对未开发的 化学空间，导致造福社会的材料和药品。要做到这一点 为了实现这一目标，调查将侧重于更好地了解反应性和选择性。 新的氧化偶联化学的发展是一个特别关注的问题，因为 更低的步数和更小的废流带来的效率。这一领域的挑战是 由于典型的有机化合物中存在大量的C-H键，所以在任何给定的转化中都具有选择性 分子。使用仿生过程导致生物活性天然产品和天然产品- 就像核心一样，在药物化学中也是理想的实体。无价的培训，在课外缺席 工业环境，将提供给研究生和其他同事。