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

合成医药相关有机化合物的催化剂和催化反应 提出的研究集中在一系列的发现、发展和机制评估上。 过渡金属络合物催化的化学反应为合成提供了新的途径 对人类健康很重要的有机分子。对这些反应的研究解决了几个 化学合成中未得到满足的主要需求。这些未得到满足的需求包括发生在C-H键上的反应 具有高选择性和对辅助官能团的高度耐受性；产生的催化剂可使 在复杂结构的许多潜在反应点之一上的化学反应；催化转化 用于调节生物活性化合物的结构和性质的复杂分子； 控制立体合成的绝对构型和相对构型的脂肪族亚结构的组装 创建更复杂的三维架构的中心；以及更强的机械性理解 帮助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 课程重点是对催化反应的发展和机理的了解 在药物发现和生产过程中最广泛使用的反应，以及准备 成为下一套这样的反应和催化剂类别，可以带来新的能力。这些 反应包括C-H键与主基团试剂的选择性官能化，以形成有价值的 合成中间体，通过与烯烃加成N-H键而形成烷基C-N键的反应 前所未有的效率，与有机亲电体形成碳-杂原子键的耦合过程 由铜和镍体系催化，以及由一类特殊的杂化结构催化的反应 通过将天然金属酶的金属与有机金属单元正式交换而产生的 创造人造金属酶，形成具有位点选择性和立体选择性的产品，这将是 用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 包括由动力学研究人员进行详细的机理分析和催化剂的独立合成 中间体，以及使用这些机械数据来选择或设计下一代系统。一个 这些机制研究的特别重点将放在揭示最近的 已发现的伯烷基碳-氢键官能化催化剂和最新发现的铜 和镍中间体在催化交叉偶联反应中形成碳-杂原子键。

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.