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: 10532256
• 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/10532256
• 关键词: Acids; Articulation; Binding Sites; Carbon; Chemicals; Cobalt; Coupling; Development; Drug Compounding; Drug Kinetics; Electronics; Goals; Hydrogen Bonding; Iron; Kinetics; Lead; Ligands; Manganese; Mediating; Medicine; Metabolism; Metals; Methods; Molecular; Nickel; Organic Synthesis; Oxidation-Reduction; Planet Earth; Preparation; Property; Reaction; Resolution; Route; Site; Structure; Thermodynamics; Transition Elements; Translating; Variant; antagonist; catalyst; chemical synthesis; density; design; drug discovery; drug synthesis; gamma secretase; hypocretin; inhibitor; next generation; novel strategies; rational design; receptor; restraint; 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.

项目摘要 过渡金属催化的反应已经彻底改变了化学合成，如应用于 生物活性分子和药物化合物的制备，但需要新的方法来打开新的 分子空间，并克服由当前方法产生的结构偏差。地球丰富 过渡金属，由于它们在金属-碳键合中的离子性增加， 与现有技术的贵金属催化剂相比，这些催化剂提供了不同的反应性。这项建议 描述了位点选择性C-H官能化反应的新方法，该方法利用了独特的 铁、钴和锰的性质，以可预测地区分性质的细微差异， 的C-H键，以实现互补的选择性，现有的方法。通过建立和 这些方法阐明了这种方法的一般原理，将使逆合成分析成为可能 这将转化为新分子的合理设计，这些新分子超出了目前金属催化的范围， 反应.具体地，提出了芳烃的间位选择性官能化的方法， 用于选择性制备在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， 在药物发现活动中，这种类型的药物在历史上一直没有得到充分的探索。的方法 在C（sp2）-H位点存在下C（sp3）-H键的化学选择性官能化也是 提出依赖于第一行过渡金属的独特电子性质， 制备的和模块化的氧化还原活性配体。