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: 10830116
• 负责人: John F Hartwig
• 金额: $ 4.85万
• 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/10830116
• 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.

合成药用有机化合物的催化剂和催化反应 建议的研究重点是一系列的发现，发展和机制评价， 由过渡金属配合物催化的化学反应，为合成提供了新的途径 对人体健康很重要的有机分子。对这些反应的研究解决了几个问题， 在化学合成中的主要未满足的需求。这些未满足的需求包括发生在C-H键处的反应 具有高选择性和对辅助官能团的高耐受性; 在复杂结构中许多潜在反应点之一的化学反应;催化转化 复杂的分子来调节生物活性化合物的结构和性质; 控制立体异构体的绝对和相对构型的脂肪族亚结构的组装 中心，以创建更复杂的三维架构;和更大的机械理解 催化方法，以帮助选择或发明实现这些合成目标的催化剂和试剂。这 该计划的重点是发展和催化反应的机械理解，是一些 在药物发现和生产过程中最广泛使用的反应，以及准备 成为下一组这样的反应和催化剂，可以导致新的能力。这些 反应包括用主基试剂选择性官能化C-H键以形成有价值的 合成中间体，通过在烯烃上加成N-H键形成烷基C-N键的反应， 前所未有的效率，与有机亲电体形成碳-杂原子键的偶联过程 由铜和镍系统催化，以及由一类不寻常的混合结构催化的反应 通过用有机金属单元形式交换天然金属酶的金属而产生， 创造人工金属酶，形成具有位点选择性和立体选择性的产物， 这是用天然酶或小分子催化剂难以实现的。在所有情况下，拟议的研究 包括详细的机理分析动力学研究和独立的催化合成 中间体，以及使用这些机械数据来选择或设计下一代系统。一 这些机制研究的特别重点将放在揭示最近的性质， 发现的用于伯烷基C-H键官能化的催化剂和最近发现的铜 和镍中间体在催化交叉偶联反应中形成碳-杂原子键。