Selective C(sp3)–H Functionalization Enabled by Metal-Organic Framework Catalysis

金属有机框架催化实现选择性 C(sp3)–H 官能化

• 批准号: 10679785
• 负责人: Patrick James Sarver
• 金额: $ 1.34万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2023-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10679785
• 关键词: 3-Dimensional; Address; Adsorption; Binding; Binding Sites; Carbon; Catalysis; Chemicals; Complex; Coupling; Dedications; Development; Electrons; Environment; Esters; Gases; Generations; Hydrogen; Hydrogen Bonding; Inductively Coupled Plasma Mass Spectrometry; Institution; Isomerism; Liquid substance; Massachusetts; Mediating; Medicine; Metals; Methodology; Methods; Modern Medicine; Organic Synthesis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Process; Productivity; Property; Reaction; Reporting; Research; Resources; Rest; Site; Space Medicine; Structure; Techniques; Technology; Time; Training; Work; catalyst; chemical synthesis; design; drug candidate; drug discovery; halogenation; improved; insight; invention; novel; novel strategies; oxidation; small molecule

PROJECT SUMMARY/ABSTRACT Despite decades of research dedicated to expanding the structural complexity accessible to medicinal chemists, organic synthesis remains a time- and resource-intensive component of drug-discovery. To address this challenge, synthetic organic chemists have focused on inventing new methodologies to couple widely available building blocks into drug-like products, expanding the range of bioactive compounds directly accessible from simple precursors. Relatively few studies, however, have focused instead on increasing the diversity and complexity of those readily accessible precursors. As a small number of privileged reactions represent the majority of synthetic steps conducted within drug discovery, providing access to a broad range of building blocks for such transformations could dramatically expand accessible chemical space for medicinal chemists. Towards this end, methods for the functionalization of C–H bonds have the potential to revolutionize the synthesis of pharmaceutically relevant fragments by enabling the introduction of valuable functionality at ubiquitous but traditionally unreactive sites. Unfortunately, due to the abundance of C–H bonds, this approach often suffers from poor selectivity, resulting in challenging purifications of isomers and diminished yields. As a general strategy to facilitate selective C–H functionalization, the proposed research will leverage the remarkable properties of metal-organic frameworks (MOFs), which can both selectively bind small organic molecules and stabilize highly reactive species capable of cleaving C(sp3)–H bonds. By holding specific C–H bonds near the site of reactivity, selectivity based on the binding pose of the substrate within the MOF pore—not the inherent reactivity of each C–H bond—can determine the functionalized position. Employing MOFs capable of supporting metal-oxo species with substrate-binding linkers or, alternatively, MOFs bearing photocatalytic linkers with nodes containing open coordination sites provides two distinct approaches to realize this aim. Combining selective radical generation with established open-shell reactivity can afford a diverse range of products such as halides, boronic esters, and C–C bonds via Minisci and Giese reactivity. Overall, the proposed research will provide a novel approach to the long-standing challenge of selective C(sp3)–H functionalization, enabling the efficient conversion of simple starting materials into valuable fragments for use in drug discovery. Conducting this research will provide thorough training in the experimental methods required to synthesize and characterize inorganic materials, including PXRD, ICP-MS, gas adsorption, and photophysical techniques. Massachusetts Institute of Technology, as one of the largest and most productive scientific research institutions in the world, possesses the facilities and institutional environment required to support these studies.

项目摘要/摘要 尽管几十年来的研究致力于扩大药物化学家可获得的结构复杂性， 有机合成仍然是药物发现的时间和资源密集型组成部分。为了解决这个 挑战，合成有机化学家们专注于发明新的方法来耦合广泛可用的 构建成药物样产品，扩大了生物活性化合物的范围， 简单的先驱然而，相对较少的研究集中在增加多样性和 这些容易获得的前体的复杂性。由于少数特权反应代表了 在药物发现中进行的大多数合成步骤，提供了广泛的构建模块 因为这样的转化可以极大地扩展药物化学家可访问的化学空间。朝向 为此，C-H键的官能化方法具有革命性的合成潜力， 通过能够在普遍存在的但不局限于药物的地方引入有价值的功能， 传统上不活跃的网站。不幸的是，由于C-H键的丰富，这种方法经常受到 由于选择性差，导致异构体的纯化具有挑战性和产率降低。As a general strategy 为了促进选择性C-H官能化，拟议的研究将利用 金属有机框架（MOFs），它既可以选择性地结合小的有机分子，又可以高度稳定 能够裂解C（sp3）-H键的活性物质。通过在反应位点附近保持特定的C-H键， 选择性基于MOF孔内底物的结合姿势-而不是每一种的固有反应性 C-H键-可以决定功能化的位置。采用能够负载金属氧代的M0 F 具有底物结合接头的物质，或者，可替代地，带有具有节点的光催化接头的MOF 包含开放的配位位点提供了实现这一目标的两种不同的方法。组合选择性 具有已建立的开壳反应性的自由基生成可提供多种产物如卤化物， 硼酸酯和通过Minisci和Giese反应性的C-C键。总的来说，拟议的研究将提供一个 一种新的方法来解决长期存在的选择性C（sp3）-H官能化的挑战，使有效的 将简单的起始材料转化为用于药物发现的有价值的片段。进行这项 研究将提供综合和表征所需的实验方法的全面培训 无机材料，包括PXRD、ICP-MS、气体吸附和微物理技术。马萨诸塞州 理工学院作为世界上规模最大、生产力最高的科研机构之一， 拥有支持这些研究所需的设施和机构环境。