Development of Strategies for the Functionalization of Amines

胺功能化策略的开发

• 批准号: 8549270
• 负责人: Daniel Seidel
• 金额: $ 27.17万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8549270
• 关键词: Aldehydes; Alkaloids; Amides; Amination; Amines; Amino Acids; Biological Factors; Complex; Coupling; Decarboxylation; Development; Essential Drugs; Event; Generations; Goals; Health; Human; Hydrogen Bonding; In Situ; Ions; Libraries; Metals; Methods; Modification; Molecular Structure; Nitrogen; Oxidants; Oxidation-Reduction; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Reaction; System; Transition Elements; Variant; Work; analog; arborescidine A; catalyst; cost; deprotonation; design; drug discovery; nitrogen compounds; novel; novel strategies; research study; screening; tertiary amine; tool; ylide

DESCRIPTION (provided by applicant): The majority of pharmaceutical drugs that are essential for human health consist of nitrogen containing compounds. A particularly attractive approach to these targets is the modification of cheap and readily available amines by means of C-H bond functionalization. However, methods that accomplish this task efficiently are scarce and severely lacking in scope. Moreover, the currently known approaches typically require the use of expensive transition metal catalysts and/or oxidants. This proposal is focused on the design and development of efficient and practical methods for amine functionalization. The main goal is the ?- and ?-functionalization of amines through conceptually new and underdeveloped methods of substrate activation. A major focus is on redox-neutral approaches to C-H bond functionalization that do not require expensive oxidants or precious metal catalysts. The central theme of our proposed work is to couple an oxidative C-H bond functionalization with a productive reduction event that contributes to the formation of products by allowing for the generation of additional C-C, or C-X bonds. Our proposed reactions proceed via iminium ion, azomethine ylide and enamine intermediates that can be accessed under relatively mild conditions. In addition to targeting the rapid preparation of biologically active compounds such as epiquinamide, harmicine and quinazolinone alkaloids, our efforts will center on the development of particularly powerful reactions that rapidly generate new polycylic amines. A priority is the generation of novel structural frameworks that are absent from current drug discovery screening libraries.

描述（由申请人提供）：大多数对人类健康至关重要的药物由含氮化合物组成。这些目标的一个特别有吸引力的方法是通过C-H键官能化来修饰廉价且容易获得的胺。然而，有效完成这项任务的方法是稀缺的，严重缺乏范围。此外，目前已知的方法通常需要使用昂贵的过渡金属催化剂和/或氧化剂。该提案的重点是设计和开发有效和实用的胺官能化方法。主要目标是？-然后呢？通过概念上新的和不发达的底物活化方法来官能化胺。一个主要的焦点是氧化还原中性的方法C-H键官能化，不需要昂贵的氧化剂或贵金属催化剂。我们所提出的工作的中心主题是将氧化C-H键官能化与生产性还原事件相结合，该还原事件通过允许产生额外的C-C或C-X键来促进产物的形成。我们提出的反应通过亚胺离子，甲亚胺叶立德和烯胺中间体，可以在相对温和的条件下进行。除了针对快速制备生物活性化合物，如epiquinamide，harmicine和喹唑啉酮生物碱，我们的努力将集中在特别强大的反应，快速产生新的多环胺的发展。首要任务是产生当前药物发现筛选库中不存在的新型结构框架。