Development of Strategies for the Functionalization of Amines

胺功能化策略的开发

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要氮杂环是药物中普遍存在的成分，对于人类健康的一个特别有吸引力的方法是含氮化合物。通过C-H键功能化对廉价且容易获得的胺进行改性。然而，有效完成此任务的方法通常需要使用该提案的重点是昂贵的过渡金属催化剂和/或氧化剂。设计和开发有效且实用的胺官能化方法。主要目标是通过新概念对胺进行α-官能化一种尚未开发的底物活化方法将实现胺 C-H。通过结合还原性胺 N- 以氧化还原中性方式进行键功能化氧化α-官能化的烷基化，利用偶氮甲碱叶立德作为生成的水是唯一的副产品，也是唯一需要的。促进剂是廉价的羧酸第二种策略促进功能化。通过涉及分子间氢化物转移的新方法来合成环胺。方法不需要保护基团并提供有价值的仲胺产品的反应具有高度对映特异性，可实现后期功能化。第三个目标是将简单环胺直接转化为候选药物。 α，β-双官能化胺将通过一种新策略来实现：除了靶向化合物的快速制备外，还涉及氮杂烯丙基阴离子。与具有已知生物活性的结构相关，努力将集中在开发特别强大的反应，快速产生新的多环一个优先事项是生成新的结构框架，这是现有技术中所没有的。当前的药物发现筛选库。