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

项目概要：有机反应的发现与发展 具有药物化学价值的过渡金属配合物催化 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 化学合成中未满足的主要需求：1）需要在C-H键处发生反应， 对辅助官能团的高选择性和高耐受性; 2）需要与 催化剂控制的对许多相似官能团之一的位点选择性; 3）功能化的需要 直接调节生物活性化合物的结构和性质的复杂分子; 4） 需要组装脂族亚结构，控制绝对和相对构型， 立体中心，以创造更复杂的三维架构;和5）需要更大的 对催化方法的机械理解，以帮助选择或发明催化剂和试剂， 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。 药物发现过程中的催化反应。例如，这些反应包括选择性的 C-H键的官能化以形成主族化合物， 中间体的拟议的研究进一步包括C-H键官能化，形成有机 叠氮化物和卤化物，它们可以用作中间体或化学上重要的最终产物。拟议 研究还包括通过加成和取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活化的烯烃上加成N-H键， 与有机亲电体形成碳-杂原子键的偶联过程， 与杂原子亲核试剂的偶联方法，以及形成碳-杂原子和碳-碳 对区域选择性、对映选择性和对映选择性的组合具有独特控制的键， 非对映选择性新的小分子催化剂也将被研究，以扭转典型的网站 观察到醇氧化的选择性，允许修饰复杂的天然产物，如 多元醇。最后，提出的研究包括一类新的混合系统催化的反应 通过用铂族金属形式交换天然金属酶的金属而产生。这些 人工金属酶可以形成具有位点选择性和立体选择性的产物， 用天然酶或小分子催化剂是不可能实现的。在所有情况下， 研究包括详细的机理分析的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。

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.