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: 10214396
• 负责人: John F Hartwig
• 金额: $ 5.32万
• 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/10214396
• 关键词: 3-Dimensional; Address; Alcohols; Alkenes; Architecture; Azides; Biological; 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：有机反应的发现和开发 由过渡金属复合物催化，对药物化学有价值 拟议的研究重点是一系列的发现，开发和机械评估 通过过渡金属复合物催化的化学反应为合成提供了新的方法 对人类健康很重要的有机分子。这些反应的研究解决了几个 化学合成的主要未满足需求：1）在C-H键处发生的反应的需求 辅助官能团的高选择性和高公差； 2）需要发生的反应 许多类似官能团之一的催化剂控制位点的选择性； 3）需要功能化 复杂分子直接调节生物活性化合物的结构和特性； 4） 需要控制脂肪族子结构，以控制的绝对和相对配置 立体生成中心，以创建更复杂的三维体系结构； 5）需要更大 对催化方法的机械理解，以帮助选择或发明实现催化剂和试剂 这些综合目标。提出的研究的反应类型包括一些最广泛使用的反应 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键的功能化以形成已成为普通合成的主要组化合物 中间人。拟议的研究进一步包括形成有机物的C-H键功能化 可以用作中间体或生物学上重要的最终产品的叠氮化物和卤化物。提议 研究还包括通过加法和替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激活的烷烃中添加N-H键， 耦合过程与很少耦合的有机亲电器形成碳杂质素键 与杂原子亲核试剂，以及形成碳杂原子和碳碳的耦合过程 对区域选择性，对映选择性和 对映选择性。还将研究新的小分子催化剂 观察到氧化醇的选择性，可以改变复杂的天然产物，例如 多元醇。最后，拟议的研究包括由新的混合系统催化的反应 通过正式将天然金属酶的金属与铂群金属换成金属而产生。这些 人工金属酶可以以困难或 天然酶或小分子催化剂无法实现。在所有情况下，提议 研究包括动力学Stuides的详细机械分析和催化的独立合成 中间体以及使用这些机械数据选择或设计下一代系统。