Carbon-Carbon Bond Forming Reactions Via C-H Activation

描述（由申请人提供）：过渡金属催化的碳-碳键形成反应，如金属催化的交叉偶联和烯烃复分解，已成为合成重要药物和天然存在的生物活性化合物中最广泛使用的反应。这些转化的重要性在很大程度上是由于它们具有广泛的官能团兼容性，并结合了大量不同的化合物，可以作为起始材料。金属催化的C-H键活化后的碳-碳键形成对于合成生物活性化合物具有特别强大的潜力。后过渡金属催化的碳氢活化过程具有高度官能团相容性。此外，由于几乎每种有机化合物都含有C-H键，因此C-H激活途径的起始材料的可用性是巨大的。本提案描述了两类非常重要的含氮化合物的C-H活化和功能化的强大催化方法的发展和应用。1. 亚胺定向C-H活化。芳香族和1,2-不饱和亚胺的催化烷基化反应将得到有用的和复杂的生物活性化合物。催化对映选择性烷基化可以有效地合成药物和候选药物的单对映体。1,2-不饱和亚胺的催化烯基化和电环化将得到1,2-二氢吡啶，这是合成吡啶和哌啶的非常通用的中间体。由于吡啶和哌啶在药物发现和生产中的巨大重要性，为了快速和实用地合成这些化合物，将开发烯基化/电环化序列。2. 氮杂环C-H活化。催化烷基化和芳基化氮杂环将进行。将特别强调具有重要医药意义的杂环，如吡啶、喹啉、苯二氮卓类和唑类。催化对映选择性烷基化将成为制备重要药物和候选药物单对映体的有效方法。还将进行旨在提高化学的效用和普遍性的机械研究。用于治疗人类疾病的大多数治疗剂是由合成有机化合物组成的。该提案描述了从简单前体快速制备复杂药物样化合物的强大而通用的新方法。所提出的方法将加速药物发现和更具成本效益的药物生产，同时最大限度地减少不需要的化学废物副产品。

DESCRIPTION (provided by applicant): Transition metal catalyzed carbon-carbon bond forming reactions such as metal-catalyzed cross-coupling and alkene metathesis have become some of the most extensively used reactions in the synthesis of important pharmaceutical agents and naturally occurring bioactive compounds. The importance of these transformations is in large part due to their broad functional group compatibility combined with the large and diverse array of compounds that can serve as starting materials. Metal-catalyzed C-H bond activation followed by carbon-carbon bond formation has the potential to become exceptionally powerful for the synthesis of bioactive compounds. C-H activation processes catalyzed by late transition metals are highly functional group compatible. In addition, because virtually every organic compound contains C-H bonds, the availability of starting materials for C-H activation pathways is enormous. This proposal describes the development and application of powerful catalytic methods for C-H activation and functionalization of two very important classes of nitrogen-containing compounds. 1. Imine directed C-H activation. The catalytic alkylation of aromatic and 1,2-unsaturated imines will be performed to obtain useful and complex bioactive compounds. Catalytic enantioselective alkylation will enable the efficient synthesis of single enantiomers of drugs and drug candidates. Catalytic alkenylation of 1,2-unsaturated imines followed by electrocyclization will provide 1,2-dihydropyridines, which are extremely versatile intermediates in the synthesis of pyridines and piperidines. Due to the immense importance of pyridines and piperidines in drug discovery and production, the alkenylation/electrocyclization sequence will be developed for the rapid and practical synthesis of these compounds. 2. Nitrogen heterocycle C-H activation. Catalytic alkylation and arylation of nitrogen heterocycles will be performed. A particular emphasis will be placed on heterocycles of huge pharmaceutical importance such as pyridines, quinolines, benzodiazepines and azoles. Catalytic enantioselective alkylation will be developed as an efficient method to prepare single enantiomers of important drugs and drug candidates. Mechanistic studies designed to enhance the utility and generality of the chemistry will also be pursued. The majority of therapeutic agents used to treat human disease are composed of synthetic organic compounds. This proposal describes powerful and general new methods to rapidly prepare complex, drug-like compounds from simple precursors. The proposed methods will enable accelerated drug discovery and more cost effective drug production at the same time that undesired chemical waste byproducts are minimized.