Carbon-Carbon Bond Forming Reactions Via C-H Activation

通过 C-H 活化形成碳-碳键的反应

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7993103
• 关键词: Alkenes; Alkylation; Alkynes; Analgesics; Area; Azoles; Benzodiazepines; Biological Factors; Carbon; Chemicals; Chemistry; Complex; Coupling; Development; Dihydropyridines; Electrons; Elements; Funding; Goals; Hydrogen Bonding; Imines; Isoquinolines; Metals; Methods; Nitrogen; Organic Synthesis; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Process; Reaction; Research; Research Design; Rhodium; Tetrahydroisoquinolines; Therapeutic Agents; Time; Transition Elements; base; catalyst; cost effective; design; dihydropyridine; drug candidate; drug discovery; drug production; enantiomer; functional group; human disease; incarvillateine; method development; oxidation; piperidine; pyridine; quinoline; wasting

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，如金属催化的交叉偶联和烯烃复分解反应，已成为合成重要药剂和天然存在的生物活性化合物中最广泛使用的一些反应。这些转化的重要性在很大程度上是由于它们广泛的官能团相容性以及大量不同的可用作起始材料的化合物。金属催化的C-H键活化，然后形成碳-碳键，有可能成为非常强大的生物活性化合物的合成。由后过渡金属催化的C-H活化过程是高度官能团相容的。此外，由于几乎每种有机化合物都含有C-H键，因此C-H活化途径的起始材料的可用性是巨大的。该提案描述了两类非常重要的含氮化合物的C-H活化和官能化的强大催化方法的开发和应用。1.亚胺导向的C-H活化。芳香族亚胺和1，2-不饱和亚胺的催化烷基化反应将得到有用的、复杂的生物活性化合物。催化的对映选择性烷基化反应将使药物和候选药物的单一对映体的高效合成成为可能。1，2-不饱和亚胺的催化烯基化反应和电环化反应可以得到1，2-二氢吡啶，它们是合成吡啶和哌啶的多用途中间体。由于吡啶和哌啶在药物发现和生产中的巨大重要性，烯基化/电环化序列将被开发用于这些化合物的快速和实用的合成。2.氮杂环C-H活化。将进行氮杂环的催化烷基化和芳基化。一个特别的重点将放在杂环化合物的巨大的医药重要性，如吡啶，喹啉，苯并二氮杂卓和唑。催化不对称烷基化反应是一种制备重要药物和候选药物单一对映体的有效方法。还将进行旨在提高化学品的实用性和普遍性的机制研究。用于治疗人类疾病的大多数治疗剂由合成有机化合物组成。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和通用的新方法。所提出的方法将能够加速药物发现和更具成本效益的药物生产，同时使不希望的化学废物副产物最小化。