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: 10623699
• 负责人: John F Hartwig
• 金额: $ 60.15万
• 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 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623699
• 关键词: 3-Dimensional; Address; Alkenes; Architecture; Carbon; Complex; Copper; Coupling; Data; Development; Enzymes; Evaluation; Goals; Health; Human; Hybrids; Hydrogen Bonding; Kinetics; Medicine; Metals; Methods; Nickel; Organic Synthesis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Process; Production; Property; Reaction; Reagent; Research; Series; Site; Structure; System; Transition Elements; catalyst; chemical reaction; chemical synthesis; design; drug discovery; functional group; improved; invention; metal complex; metalloenzyme; next generation; novel strategies; programs; small molecule

Catalysts and Catalytic Reactions for the Synthesis of Medicinally Relevant Organic Compounds 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 important for human health. Research on these reactions addresses several of the major unmet needs in chemical synthesis. These unmet needs include reactions that occur at C-H bonds with high selectivities and high tolerance for auxiliary functional groups; the creation of catalysts that induce chemical reactions at one of many potential reaction sites in complex structures; catalytic transformations of complex molecules to modulate the structures and properties of biologically active compounds; assembly of aliphatic sub-structures with control of the absolute and relative configurations of stereogenic centers to create more complex three-dimensional architectures; and greater mechanistic understanding of catalytic methods to help select or invent catalysts and reagents that achieve these synthetic goals. This program focuses on the development and mechanistic understanding of catalytic reactions that are some of the most widely used reactions during drug-discovery and production, as well as reactions poised to become the next set of such reactions and classes of catalysts that can lead to new capabilities. These reactions include selective functionalization of C-H bonds with main group reagents to form valuable synthetic intermediates, reactions to form alkyl C-N bonds by addition of N-H bonds across alkenes with unprecedented efficiency, coupling processes to form carbon-heteroatom bonds with organic electrophiles catalyzed by copper and nickel systems, and reactions catalyzed by an unusual class of hybrid structure generated by formally exchanging the metal of natural metalloenzymes with an organometallic unit to create artificial metalloenzymes that form products with site-selectivity and stereoselectivity that would be difficult 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. A particular focus of these mechanistic studies will be placed on revealing the properties of recently discovered catalysts for the functionalization of primary alkyl C-H bonds and recently discovered copper and nickel intermediates in catalytic cross coupling reactions to form carbon-heteroatom bonds.

催化剂和催化反应，用于合成药物相关的有机化合物 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 有机分子对人类健康很重要。这些反应的研究涉及几个 化学合成的主要未满足需求。这些未满足的需求包括在C-H键处发生的反应 具有较高的选择性和辅助官能团的耐受性；诱导催化剂的创建 复杂结构中许多潜在反应位点之一的化学反应；催化转化 复杂分子调节生物活性化合物的结构和特性； 脂肪族子结构的组装，以控制立体的绝对和相对构型 中心建立更复杂的三维体系结构；和更大的机械理解 有助于选择或发明实现这些合成目标的催化剂和试剂的催化方法。这 计划的重点是对催化反应的发展和机械理解 在药物发现和生产过程中最广泛使用的反应，以及有望 成为下一组这样的反应和一类催化剂，这些催化剂可能会导致新的功能。这些 反应包括与主要组试剂的C-H键选择性功能化以形成有价值 合成中间体，通过添加N-H键在烯烃中添加N-H键，形成烷基C-N键。 前所未有的效率，耦合过程，与有机电力液形成碳杂质键 由铜和镍系统催化，并由一类不寻常的杂种结构催化 通过正式将天然金属酶的金属与有机金属单元换成 创建人工金属酶，以现场选择性和立体选择性形成产品 天然酶或小分子催化剂很难实现。在所有情况下，拟议的研究 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。一个 这些机械研究的特别重点将放在揭示最近的特性上 发现了用于原代烷基C-H键功能化的催化剂，并最近发现了铜 和镍中间体在催化交叉耦合反应中形成碳杂质键。