Discovery and Development of Organic Reactions Catalyzed by Transition Metals Valuable for Medicinal Chemistry

具有药物化学价值的过渡金属催化有机反应的发现和发展

• 批准号: 10316182
• 负责人: John F Hartwig
• 金额: $ 78.8万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316182
• 关键词: 3-Dimensional; Address; Alcohols; Alkenes; Architecture; Azides; Carbon; Complex; Coupled; Coupling; Data; Development; Enzymes; Evaluation; Goals; Health; Human; Hybrids; Hydrogen Bonding; Kinetics; Metals; Methods; Modification; Natural Products; Organic Synthesis; Pharmaceutical Chemistry; Pharmacologic Substance; Platinum; Process; Property; Reaction; Reagent; Research; Series; Site; Structure; System; Transition Elements; catalyst; chemical reaction; chemical synthesis; design; drug discovery; functional group; improved; metal complex; metalloenzyme; next generation; novel strategies; oxidation; polyol; small molecule

Project Summary: Discovery and Development of Organic Reactions Catalyzed by Transition-Metal Complexes Valuable for Medicinal Chemistry The proposed research focuses on the discovery, development, and mechanistic evaluation of a series of chemical reactions catalyzed by transition-metal complexes that provide new approaches to the synthesis of organic molecules that are important for human health. Research on these reactions addresses several of the major unmet needs in chemical synthesis: 1) the need for reactions that occur at C-H bonds with high selectivities and high tolerance for auxiliary functional groups; 2) the need for reactions that occur with catalyst-controlled site selectivity for one of many similar functional groups; 3) the need to functionalize complex molecules directly to modulate the structures and properties of biologically active compounds; 4) the need to assemble aliphatic sub-structures with control of the absolute and relative configurations of stereogenic centers to create more complex three-dimensional architectures; and 5) the need for greater mechanistic understanding of catalytic methods to help select or invent catalysts and reagents that achieve these synthetic goals. The types of reactions proposed for study include some of the most widely used catalytic reactions during the drug-discovery process. For example, these reactions include selective functionalizations of C-H bonds to form main group compounds that have become common synthetic intermediates. The proposed research further includes C-H bond functionalizations that form organic azides and halides that can serve as intermediates or biogically important final products. The proposed research also encompasses reactions occuring in aliphatic structures by addition and substitution reactions, including the addition of N-H bonds across unactivated alkenes with unprecedented efficiency, coupling processes forming carbon-heteroatom bonds with organic electrophiles that have rarely coupled with heteroatom nucleophiles, and coupling processes forming carbon-heteroatom and carbon-carbon bonds with unique control over the combination of regioselectivity, enantioselectivity, and diastereoselectivity. New small-molecule catalysts also will be studied that reverse the typical site selectivity observed for oxidation of alcohols, allowing modification of complex natural products, such as polyols. Finally, the proposed research includes reactions catalyzed by a new class of hybrid system generated by formally exchanging the metal of natural metalloenzymes with a platinum-group metal. These artificial metalloenzymes can form products with site-selectivity and stereoselectivity that are difficult or impossible to achieve with natural enzymes or small-molecule catalysts. In all cases, the proposed research includes detailed mechanistic analysis by kinetic stuides and independent synthesis of catalytic intermediates, as well as the use of these mechanistic data to select or design next-generation systems.

项目摘要：有机反应的发现和发展 由对药物化学有价值的过渡金属配合物催化 拟议的研究重点是一系列的发现、开发和机制评估 过渡金属配合物催化的化学反应为合成提供了新方法 对人类健康重要的有机分子。对这些反应的研究解决了几个问题 化学合成中未满足的主要需求：1）需要在C-H键上发生反应 对辅助官能团的高选择性和高耐受性； 2）需要发生的反应 对许多相似官能团之一的催化剂控制的位点选择性； 3）功能化的需要 直接复杂分子来调节生物活性化合物的结构和性质； 4） 需要通过控制绝对和相对构型来组装脂肪族子​​结构 立体中心创建更复杂的三维架构； 5）需要更大的 对催化方法的机理理解，以帮助选择或发明实现目标的催化剂和试剂 这些综合目标。提议研究的反应类型包括一些最广泛使用的反应类型 药物发现过程中的催化反应。例如，这些反应包括选择性 C-H键的官能化形成已成为常见合成的主族化合物 中间体。拟议的研究进一步包括形成有机化合物的 C-H 键功能化 叠氮化物和卤化物可以作为中间体或具有重要生物学意义的最终产品。拟议的 研究还包括通过加成和取代在脂肪族结构中发生的反应 反应，包括以前所未有的效率在未活化的烯烃上添加 N-H 键， 与很少偶联的有机亲电体形成碳-杂原子键的偶联过程 与杂原子亲核试剂，以及形成碳-杂原子和碳-碳的偶联过程 对区域选择性、对映选择性和对映体选择性的组合具有独特的控制 非对映选择性。还将研究扭转典型位点的新型小分子催化剂 观察到醇氧化的选择性，允许修饰复杂的天然产物，例如 多元醇。最后，拟议的研究包括由新型混合系统催化的反应 通过将天然金属酶的金属与铂族金属进行形式交换而产生。这些 人工金属酶可以形成具有位点选择性和立体选择性的产物，这是难以或 这是天然酶或小分子催化剂无法实现的。在所有情况下，建议 研究包括通过动力学研究进行详细的机理分析和催化的独立合成 中间体，以及使用这些机械数据来选择或设计下一代系统。