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

项目摘要/摘要 尽管几十年来致力于扩大药物化学家可获得的结构复杂性的研究， 有机合成仍然是药物发现的一个时间和资源密集型组成部分。要解决这个问题 挑战，合成有机化学家专注于发明新的方法来耦合广泛可用的 将积木添加到类药物产品中，扩大可直接从 简单的前驱。然而，相对较少的研究专注于增加物种的多样性和 这些容易获得的前体的复杂性。由于少数特权反应代表 大多数合成步骤是在药物发现内进行的，提供了访问广泛的构建块的途径 因为这样的转变可以极大地扩大药物化学家可获得的化学空间。朝向 因此，C-H键的官能化方法有可能彻底改变 通过在无处不在的但 传统上没有反应的地方。不幸的是，由于C-H键的丰富，这种方法经常受到影响 由于选择性差，导致异构体提纯困难，产率降低。作为一项总体战略 为了促进选择性的C-H功能化，拟议的研究将利用 金属有机骨架(MOF)，既能选择性结合有机小分子，又能高度稳定 能够裂解C(SP3)-H键的活性物种。通过在反应点附近持有特定的C-H键， 基于底物在MOF孔内的结合姿势的选择性-而不是基于每个底物的固有反应性 C-H键-可以确定官能化的位置。采用能够支持金属氧的MOF 具有底物结合连接物的物种，或者，替代地，具有带有节点的光催化连接物的MOF 包含开放的协调地点为实现这一目标提供了两种截然不同的方法。组合选择 具有已建立的开壳反应性的自由基生成可以买得起各种产品，例如卤化物， 通过minisci和Giese反应生成的硼酸酯和C-C键。总的来说，拟议的研究将提供一个 解决选择性C(SP3)-H官能化这一长期挑战的新方法，使高效 将简单的起始材料转化为用于药物发现的有价值的片段。进行这项工作 研究将提供在合成和表征所需的实验方法方面的全面培训 无机材料，包括X射线粉末衍射、电感耦合等离子体质谱、气体吸附和光物理技术。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制度环境。

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.