Carbon-Carbon Bond Forming Reactions in Via C-H Activation

通过 C-H 活化形成碳-碳键的反应

• 批准号: 8776717
• 负责人: JONATHAN A ELLMAN
• 金额: $ 41.94万
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776717
• 关键词: Alcohols; Alkenes; Alkynes; Amides; Amines; Azoles; Biological Factors; Biology; Carbon; Carboxylic Acids; Chemicals; Chemistry; Complex; Coupling; Development; Dihydropyridines; Drug Compounding; Funding; Goals; Grant; Hydrogen Bonding; Imidazole; Imines; In Situ; Indoles; Isocyanates; Ketones; Mediating; Metals; Methods; Natural Product Drug; Nitrogen; Nobel Prize; Outcome; Oximes; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Production; Pyrazoles; Reaction; Reporting; Research; Therapeutic Agents; Transition Elements; United States National Institutes of Health; Urea; Variant; amino group; analog; azine; biological systems; cost; cost effective; dihydropyridine; drug candidate; drug discovery; drug production; drug synthesis; functional group; human disease; innovation; method development; novel strategies; piperidine; pyridine; small molecule; tool; wasting

DESCRIPTION (provided by applicant): Carbon-carbon bonds are present in virtually all drugs, bioactive natural products, and chemical tools for the study of biological systems. Consequently, methods for the formation of carbon-carbon bonds are of central importance to the synthesis of bioactive small molecules, with transition metal catalyzed processes such as olefin metathesis (2005 Nobel Prize) and cross coupling (2010 Nobel Prize) having a profound impact due to their high functional group compatibility. Transition metal catalyzed carbon-carbon bond formation via the direct functionalization of C-H bonds has enormous potential to accelerate drug discovery and production by eliminating the need to preactivate starting materials with halide/pseudohalide or organometallic functionality. This dramatically increases the number and variety of available inputs to enable the more efficient preparation of drug analogues necessary for drug discovery and optimization and also reduces the number of steps, cost and waste in drug production. The research funded by the NIH in the current grant cycle resulted in a number of highly significant advances with considerable impact on drug discovery and production, including (1) highly functional group compatible Rh-catalyzed methods for the direct arylation of pharmaceutically important heterocycles, including azoles and azines, for which direct ortho-arylation had not previously been reported, (2) pioneering enantioselective catalytic C-H bond functionalization, and (3) application to the efficient synthesis of complex bioactive natural products. The overall objective of this application is the development of general methods to prepare amine containing compounds through catalytic C-H bond activation and C-C bond formation. Despite the fact that a large majority of drugs contain amine functionality, only very limited examples of amine synthesis through C-H bond functionalization have been reported to date. The central hypothesis is that a broad range of amines can efficiently be prepared by the two complementary transition metal catalyzed approaches defined by the specific aims: (1) Develop efficient and general methods to prepare amine containing compounds by transition metal catalyzed activation of unreactive C-H bonds followed by addition across C-N ? bonds, and (2) Develop efficient and general methods to prepare pharmaceutically important 6-membered nitrogen heterocycles by transition metal catalyzed addition of C-H bonds across alkynes to provide azatrienes that undergo in situ C-N bond formation via electrocyclization. The expected outcomes will be the more rapid and efficient syntheses of drug like amine containing compounds by reducing the need for prefunctionalized starting materials. Because amines are present in a large majority of drugs and drug candidates, considerable positive impacts upon the pace and cost of drug discovery and production are anticipated. The research proposed in this application is innovative because it provides two new approaches for the convergent preparation of amines by C-H bond functionalization that are marked departures from previously reported strategies.

描述（由申请人提供）：几乎所有药物，生物活性天然产物和用于研究生物系统研究的化学工具中都存在碳碳键。因此，形成碳碳键的方法对于生物活性小分子的合成至关重要，其过渡金属催化的过程（例如烯烃变为）（2005年诺贝尔奖）和交叉耦合（2010年诺贝尔奖）由于其高功能组的高功能群体而产生了深远的影响。通过C-H键的直接功能化，过渡金属催化的碳 - 碳键形成具有巨大的潜力，可以通过消除具有卤化物/伪荷甲或器官金属功能的启动起始物质来加速药物发现和生产。这大大增加了可用投入的数量和种类，以使能够更有效地制备药物发现和优化所需的药物类似物，并减少药物生产中的步骤，成本和废物的数量。 The research funded by the NIH in the current grant cycle resulted in a number of highly significant advances with considerable impact on drug discovery and production, including (1) highly functional group compatible Rh-catalyzed methods for the direct arylation of pharmaceutically important heterocycles, including azoles and azines, for which direct ortho-arylation had not previously been reported, (2) pioneering enantioselective catalytic C-H bond功能化，（3）应用复杂生物活性天然产物的有效合成。该应用的总体目的是开发通过催化C-H键激活和C-C键形成制备胺的通用方法。尽管大多数药物都包含胺功能，但迄今为止，通过C-H键功能化的胺合成实例非常有限。中心假设是，可以通过特定目的定义的两种互补过渡金属催化的方法有效制备广泛的胺，（1）通过过渡金属催化的不反应C-H键激活含有胺的化合物来制备含有胺的化合物，并添加了C-n？键，以及（2）通过过渡金属催化在炔烃中催化C-H键的添加，以制备具有高效和一般方法，以制备具有强大的6元氮杂环，从而提供了通过电循环化的原位C-N键形成的叠氮化素。预期的结果将是通过减少对预官能化的起始材料的需求，将其更快，有效的药物合成（如胺含有化合物）。由于大部分药物和候选药物中都存在胺，因此预计对药物发现和生产的成本和成本会产生相当大的积极影响。本应用程序中提出的研究具有创新性，因为它为C-H键功能化提供了两种新方法，用于与先前报道的策略相偏离。