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

项目总结：有机反应的发现和发展 具有药物化学价值的过渡金属络合物催化作用 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新化合物提供了新的途径 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问题 化学合成中未得到满足的主要需求：1)在高碳氢键上发生反应的需求 对辅助官能团的选择性和高耐受性；2)需要与 催化剂控制的许多相似官能团之一的位置选择性；3)官能化的需要 直接调节生物活性化合物结构和性质的复杂分子；4) 需要组装脂肪族子结构，并控制其绝对和相对构型 创建更复杂的三维建筑的立体中心；以及5)对 从机理上理解催化方法，以帮助选择或发明催化剂和试剂，从而实现 这些综合目标。建议研究的反应类型包括一些最广泛使用的反应 在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键的官能化以形成已成为常见合成的主族化合物 中间体。拟议的研究还包括形成有机叠氮化合物的C-H键官能化 以及可用作中间体或具有生物重要性的最终产品的卤化物。拟议的研究 也包括通过加成和取代反应在脂肪族结构中发生的反应，包括 以前所未有的效率在未活化的烯烃间加成N-H键，耦合过程 与很少与杂原子偶联的有机亲电试剂形成碳-杂原子键 亲核试剂，以及形成碳-杂原子和碳-碳键的耦合过程，具有独特的 控制区域选择性、对映体选择性和非对映选择性的组合。新的小型- 分子催化剂也将被研究，以逆转观察到的典型的中心选择性氧化 醇，允许对复杂的天然产品进行改性，如多元醇。最后，提出了本文的研究方向 包括由一类新的杂化体系催化的反应，这种杂化体系是通过正式交换金属 具有铂族金属的天然金属酶。这些人造金属酶可以与 位点选择性和立体选择性是天然酶或小分子酶难以或不可能实现的。 分子催化剂。在所有情况下，拟议的研究都包括详细的机构动力学分析。 催化中间体的研究和独立合成，以及这些机理数据的使用 选择或设计下一代系统。

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.