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 概括 该研究计划的总体目的是开发分析，工具和方法 实现新的，更有效的试剂，催化剂和生物配体。 一个重点将放在最新的计算方法上，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，更多 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，但是我们对基本方式的分子水平的理解 相互作用扰动这些方面只是基本的。此外，这些方面的许多方面是如何相同的 基本相互作用控制着生物环境中的约束力。 另一个重点将是通过C-C，C-O和C-N键形成的片段氧化耦合 通过C – H激活化学。催化剂库将设计用于研究 使用两个指导原理的反应：1）将催化剂氧化电位与氧化匹配 考虑因素的底物的电势和2）选择可以利用氧气的金属 再生催化物种。这些库将部署在高通量微观上 格式发现反应性模式迄今为止尚未想象。从获得的数据，反应 将构建“配置文件”，并将有关反应性，选择性和机制的新推论 制作，将通过实验进行测试。 该提案的基本标志是能够访问新的反应模式 以有效和理性的方式构建重要的有机结构。计算和 机械理解为我们提供了解决问题和假设的工具。高的 吞吐量显微镜实验允许广泛审问有理假设 并促进可能在可能的反应空间中优化许多相互依存的变量。 关联 该提案的基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。目的是在 一种有效而理性的方式。新的合成方法大大增加了对未开发的访问 化学空间，导致有益于社会的材料和药物。实现这一目标 目标，调查将集中于获得对反应性和选择性的改进理解。 新的氧化耦合化学的发展是由于增加而特别的重点 较低步骤计数和较小的废物流的效率。该领域的挑战是 由于典型有机物中存在的许多C – H键，在任何给定的转换中的选择性 分子。使用仿生过程会导致生物活性天然产物和天然产物 - 像核心一样，医学化学中理想的实体。无价的培训，不在 工业环境将为研究生和其他同事提供。