Development of Strategies for the Functionalization of Amines

胺功能化策略的开发

• 批准号: 9901537
• 负责人: Daniel Seidel
• 金额: $ 28.41万
• 依托单位: UNIVERSITY OF FLORIDA
• 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 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901537
• 关键词: Address; Alkaloids; Alkylation; Amines; Anions; Benzophenones; Biological; Carboxylic Acids; Chemicals; Chemistry; Complement; Complex; Development; Essential Drugs; Funding; Generations; Goals; Health; Human; Hydrogen Bonding; Imines; Investigation; Ketones; Lead; Libraries; Ligands; Lithium Compounds; Methods; Modification; Molecular Structure; Nitrogen; Oxidants; Oxidation-Reduction; Pathway interactions; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Preparation; Reaction; Reagent; Site; Structure; System; Transition Elements; Variant; Water; base; catalyst; computer studies; cost efficient; cyclic amine; design; drug candidate; drug discovery; fenchone; novel; novel strategies; promoter; public health relevance; screening; success; ylide

Project Summary/Abstract Nitrogen heterocycles are ubiquitous components of pharmaceutical drugs essential for human health. A particularly attractive approach to nitrogen containing compounds is the modification of cheap and readily available amines via C–H bond functionalization. However, methods that efficiently accomplish this task 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 alpha-functionalization of amines through conceptually new and underdeveloped methods of substrate activation. One tactic will achieve amine C–H bond functionalization in redox-neutral fashion by combining a reductive amine N- alkylation with an oxidative alpha-functionalization, utilizing azomethine ylides as reactive intermediates. Water is generated as the only byproduct and the only required promoters are cheap carboxylic acids. A second strategy facilitates the functionalization of cyclic amines via a novel method involving intermolecular hydride transfer. This approach does not require protecting groups and provides valuable secondary amine products. Reactions are highly enantiospecific and enable late-stage functionalization of drug candidates. A third goal is the direct transformation of simple cyclic amines to alpha,beta-difunctionalized amines. This will be accomplished via a novel strategy that involves azaallyl anions. In addition to targeting the rapid preparation of compounds related to structures with known biological activities, efforts will center on the development of particularly powerful reactions that rapidly produce new polycyclic amines. A priority is the generation of new structural frameworks that are absent from current drug discovery screening libraries.

项目总结/摘要 氮杂环化合物是药物的普遍存在的组分，对于治疗癌症是必需的。 人体健康制备含氮化合物的特别有吸引力的方法是 通过C-H键官能化对廉价且易于获得的胺进行改性。 然而，有效完成此任务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 设计和开发高效实用的胺官能化方法。 主要目标是通过概念上新的和功能化的胺的α-官能化。 底物活化方法不发达。一种策略将实现胺C-H 通过将还原胺N- 用氧化α-官能化进行烷基化，利用甲亚胺叶立德作为 活性中间体。水是唯一的副产品，也是唯一需要的 促进剂是廉价的羧酸。第二种策略促进了功能化 环胺通过一种新的方法，涉及分子间氢化物转移。这 该方法不需要保护基团，并提供有价值的仲胺 产品.反应是高度对映体特异性的，并且使得能够在后期官能化。 候选药物第三个目标是将简单的环胺直接转化为 α，β-双官能化胺。这将通过一种新的战略来实现， 涉及氮杂烯丙基阴离子。除了针对快速制备化合物 与已知生物活性的结构相关，努力将集中在 发展特别强大的反应，迅速产生新的多环 胺。一个优先事项是建立新的结构框架， 药物发现筛选文库。