α-手性伯胺结构不仅广泛存在于药物分子中, 而且是制备众多含胺药物的关键中间体. 通过对伯胺基团进行多样性转化, 可以快速构建复杂分子. 此外, 手性伯胺本身可以作为配体或者有机催化剂应用于有机合成. 因此, 手性伯胺的高效合成方法备受关注. 目前, 直接合成手性伯胺的不对称催化方法还特别少. 过渡金属催化的不对称还原胺化是获取手性胺最直接的方法之一, 反应以简单易得的酮和胺源为原料, 在还原剂和手性金属催化剂的存在下, 可以一步合成手性胺. 然而, 与亚胺的不对称氢化相比, 不对称还原胺化的报道非常有限, 主要原因是存在酮还原这一竞争反应. 当使用铵盐为胺源时, 潜手性酮可以通过还原胺化直接转化为手性伯胺, 极具吸引力且意义重大. 然而该反应除了面临酮还原这一竞争副反应外, 还面临着其他的挑战, 包括: (1)氨气或者生成的一级胺能够与金属配位从而产生毒化作用; (2)胺配位也可以导致金属发生配体交换, 加大反应手性控制难度; (3)伯胺有可能与羰基发生二次还原胺化, 使反应产出变得极为复杂. 这些问题和挑战的解决依赖于发展合适的催化体系. 针对铵盐参与的不对称还原胺化这一挑战性课题, 我们团队在过去的几年进行了深入的研究, 本文将系统地介绍我们在该领域取得的成果.

α-Chiral primary amine subunits are widespread structural units in a large number of pharmaceutical molecules and are key intermediates toward the preparation of numerous amine-containing drugs. Versatile functionalizations on the NH₂ group also supply a quick way to construct molecular complexity. Additionally, chiral primary amines can serve as ligands or organocatalysts which can be applied in organic synthesis. Therefore, efficient synthetic routes toward chiral primary amines have attracted tremendous attention. Asymmetric chemo-catalytic reactions that are capable of directly preparing chiral primary amines remain scarce. Transition-metal-catalyzed asymmetric reductive amination (ARA), a reaction type that transforms easily available ketones and amines into chiral amines in the presence of a chiral metal-catalyst and reductant, is among the most straightforward methods to access chiral amines. However, studies on ARA are still limited compared to that on imine hydrogenation, probably due to the presence of competitive ketone reduction as the side reaction. ARA using ammonium salts as the amine sources can directly yield chiral primary amines from prochiral ketones and are thus highly attractive and of great significance. In addition to competition with ketone reduction process, this reaction also faces some other challenges, including: (1) NH₃ or the produced primary amines can coordinate to the metal center which results in catalyst poisoning effect; (2) the coordination of amine ligand to the metal center may lead to ligand exchange that enhances the challenge on asymmetric control; (3) the produced primary amines may undergo further alkylation process via double reductive amination, thus providing more complicated outcome. The existing problems and challenges in ARA require urgent development of applicable catalytic systems. Aiming to solve some challenges in the field of ARA with ammonium salts, we have carried out systematic studies and will present the latest progress achieved from our team in this account.