Development of Strategies for the Functionalization of Amines

胺功能化策略的开发

• 批准号: 8275981
• 负责人: Daniel Seidel
• 金额: $ 27.77万
• 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/8275981
• 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; Screening procedure; System; Transition Elements; Variant; Work; analog; arborescidine A; catalyst; cost; deprotonation; design; drug discovery; nitrogen compounds; novel; novel strategies; research study; 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. PUBLIC HEALTH RELEVANCE: As most pharmaceutical drugs contain nitrogen, the ability to prepare these materials in the most rapid way possible is of the utmost importance. The broad availability of drugs is directly dependent on the existence of cost-efficient methods that can reliably build complex molecular structures. The objective of this proposal is the development of powerful new methods and strategies for amine C-H bond functionalization that will facilitate rapid access to valuable building blocks for the synthesis of biologically active compounds and pharmaceuticals.

描述（由申请人提供）：对人类健康至关重要的大多数药物均由含氮化合物组成。实现这些目标的一个特别有吸引力的方法是通过 C-H 键功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很少，而且范围严重不足。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且实用的胺官能化方法。主要目标是通过概念上新的和尚未开发的底物活化方法对胺进行α-和β-官能化。主要关注点是氧化还原中性的 C-H 键官能化方法，不需要昂贵的氧化剂或贵金属催化剂。我们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结合起来，通过允许生成额外的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、偶氮甲碱叶立德和烯胺中间体进行，这些中间体可以在相对温和的条件下获得。除了以快速制备生物活性化合物（如 Epiquinamide、harmicine 和 quinazolinone 生物碱）为目标之外，我们的努力还将集中于开发快速生成新多环胺的特别强大的反应。首要任务是生成当前药物发现筛选库中所缺少的新颖结构框架。 公共卫生相关性：由于大多数药物都含有氮，因此以尽可能快速的方式制备这些材料的能力至关重要。药物的广泛可用性直接取决于是否存在能够可靠地构建复杂分子结构的经济有效的方法。该提案的目标是开发用于胺 C-H 键功能化的强大新方法和策略，这将有助于快速获得用于合成生物活性化合物和药物的有价值的构建模块。