Earth abundant catalysts as an enabling tool for organic synthesis

地球上丰富的催化剂作为有机合成的有利工具

• 批准号: 10363925
• 负责人: PAUL J CHIRIK
• 金额: $ 33.2万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363925
• 关键词: Acids; Binding Sites; Carbon; Chemicals; Cobalt; Coupling; Development; Drug Compounding; Drug Kinetics; Electronics; Goals; Hydrogen Bonding; Iron; Kinetics; Lead; Ligands; Manganese; Mediating; Metabolism; Metals; Methods; Molecular; Nickel; Organic Synthesis; Oxidation-Reduction; Planet Earth; Preparation; Property; Reaction; Resolution; Route; Site; Structure; Thermodynamics; Transition Elements; Translating; Variant; antagonist; base; catalyst; chemical synthesis; density; design; drug discovery; drug synthesis; gamma secretase; hypocretin; inhibitor; next generation; novel strategies; rational design; receptor; scaffold; tool

Project Summary Transition metal-catalyzed reactions have revolutionized chemical synthesis as applied to the preparation of bioactive molecules and drug compounds, yet new methods are needed to open new molecular space and overcome the structural biases that arise from current methods. Earth-abundant transition metals, by virtue of their increased ionicity in metal–carbon bonding and higher density of states, offer distinct reactivity as compared to state-of-the-art precious metal catalysts. This proposal describes a new approach to site selective C–H functionalization reactions that leverages the unique properties of iron, cobalt and manganese to predictably distinguish subtle differences in the properties of C–H bonds to achieve complementary selectivity to existing methods. By establishing and articulating the general principles of this approach, these methods will enable retrosynthetic analyses that will translate to rational design of new molecules outside the reach of current metal-catalyzed reactions. Specifically, methods for the meta-selective functionalization of arenes are proposed as are new routes for the selective elaboration of heterocycles that are commonly found in lead compounds. In addition, methods are proposed to synthesize 1,3,5-trisubstiuted arene derivatives, a valuable structural type that is been historically underexplored in drug discovery campaigns. Methods for the chemoselective functionalization of C(sp3)–H bonds in the presence of C(sp2)–H sites are also proposed that rely on the unique electronic properties of first-row transition metals supported by readily prepared and modular redox-active ligands.

项目概要 过渡金属催化反应彻底改变了化学合成方法 生物活性分子和药物化合物的制备，但需要新方法来开辟新的领域 分子空间并克服当前方法产生的结构偏差。地球资源丰富 过渡金属，由于它们在金属-碳键合中增加的离子性和更高的密度 与最先进的贵金属催化剂相比，具有独特的反应活性。这个提议 描述了一种利用独特的位点选择性 C-H 官能化反应的新方法 铁、钴和锰的特性，可预测地区分特性中的细微差异 C-H 键以实现对现有方法的补充选择性。通过建立和 阐明这种方法的一般原则，这些方法将使逆合成分析成为可能 这将转化为当前金属催化范围之外的新分子的合理设计 反应。具体来说，提出了芳烃元选择性功能化的方法，如下所示 选择性精制先导化合物中常见的杂环的新途径。在 此外，还提出了合成 1,3,5-三取代芳烃衍生物的方法，这是一种有价值的结构 历史上在药物发现活动中未被充分探索的类型。方法用于 在存在 C(sp2)-H 位点的情况下，C(sp3)-H 键的化学选择性功能化也 提出依赖于容易支持的第一行过渡金属的独特电子特性 制备和模块化氧化还原活性配体。