Carbon-Carbon Bond Forming Reactions Via C-H Activation

通过 C-H 活化形成碳-碳键的反应

基本信息

批准号：
7993103
负责人：
JONATHAN A ELLMAN
金额：
$ 38.91万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-05 至 2011-11-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：过渡金属催化的碳 - 碳键形成反应，例如金属催化的交叉偶联和烯烃分解，已成为合成重要的药物和自然发生的生物活性化合物的一些最广泛使用的反应。这些转换的重要性在很大程度上是由于它们广泛的功能群兼容性以及可以用作起始材料的大型和多样化的化合物。金属催化的C-H键激活，然后是碳 - 碳键的形成，有可能成为生物活性化合物合成的强大功能。晚期过渡金属催化的C-H激活过程是高度功能组兼容的。此外，由于几乎每个有机化合物都包含C-H键，因此C-H激活途径的起始材料的可用性是巨大的。该建议描述了强大的催化方法在C-H激活和功能化两种非常重要的含氮化合物的功能化中的开发和应用。 1。亚胺定向C-H激活。将执行芳香族和1,2不饱和的亚胺的催化烷基化，以获得有用且复杂的生物活性化合物。催化对映选择性烷基化将有效合成药物和候选药物的单一对映异构体。 1,2不饱和的亚胺随后进行电囊化的催化烷基化将提供1,2-二氢吡啶，它们在吡啶和哌啶的合成中是极具用途的中间体。由于吡啶和哌啶在药物发现和生产中的重要性非常重要，因此将开发烷基化/电囊化序列，以快速且实际的合成这些化合物。 2。氮杂环C-H激活。将进行催化烷基化和氮杂环的芳基化。特别重点将放在巨大的药物重要性的杂环上，例如吡啶，喹啉，苯二氮卓类药物和唑唑啉。将开发催化对映选择性烷基化作为准备重要药物和候选药物的单一对映异构体的有效方法。还将追求旨在增强化学效用和通用性的机械研究。用于治疗人类疾病的大多数治疗剂都是由合成有机化合物组成的。该提案描述了功能强大且一般的新方法，可以快速制备简单前体的复杂，类似药物的化合物。所提出的方法将使不受欢迎的化学废物副产品被最小化的同时，使加速的药物发现和更具成本效益的药物生产。