Development of Strategies for the Functionalization of Amines

项目摘要/摘要 氮杂环是药物中普遍存在的成分，对 人类健康。一种特别吸引人的含氮化合物的方法是 通过C-H键官能化对廉价易得的胺进行改性。 但是，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。这项建议的重点是 设计和开发高效实用的胺功能化方法。 主要目标是通过概念上的新的和 底物活化的方法不发达。一种策略将实现胺C-H 通过结合还原胺N-来实现氧化还原中性的键功能化 用氧化的α-官能化进行烷基化，利用亚甲基叶立德作为 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 通过一种涉及分子间氢化物转移的新方法来合成环胺类化合物。这 该方法不需要保护基团，并提供宝贵的仲胺 产品。反应是高度对映专一性的，并使后期官能化成为可能 毒品候选人。第三个目标是将简单的环胺直接转化为 阿尔法，β-双官能团胺。这将通过一种新的战略实现，该战略 包括氮烯丙基阴离子。除了针对化合物的快速制备 与已知生物活性的结构相关的努力将集中在 快速产生新的多环的特别强大的反应的发展 胺。一个优先事项是生成新的结构框架，这些框架在 目前的药物发现筛选文库。

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.