环内N-烷基亚胺的不对称氢化及其在手性含氮杂环合成中的应用

Chiral N-containing heterocycles are one type of the most important building blocks because of their wide applications in the synthesis of natural products, pharmaceuticals, and agrochemicals. Transition metal-catalyzed asymmetric hydrogenation of cyclic N-alkyl imines is one of the most useful methods for the preparation of such type of optically active heterocycles. Despite great progress made in this field over the past decade, succesful examples of asymmetric hydrogenation of cyclic N-alkyl imines are rare in terms of enantioselectivity, catalytic activity, and generality. This project focuses on the development of highly effective and practical asymmetric hydrogenation of cyclic N-alkyl imines. First, with cationic chiral diamine-containing complexes as the catalysts, asymmetric hydrogenation,together with kinetic resolution and dynamic kinetic resolution, of different types of N-alkyl imines,including 2-substituted, 2,3- and other disubstituted substrates, will be carried out. Particular effect will be put in the asymmetric hydrogenation of the most problematic alkyl-substituted cyclic N-alkyl imines. To further improve the synthetic potential, direct asymmetric reductive amination will also be studied to provide one-pot synthetic method for chiral amines. Second, the catalytic mechanism and kinetics of this reaction will be investigated， and the origin of enantioselectivity and diastereoselectivity will also be elucidated by DFT calculations. Finally, our method will be applied to the practical synthesis of several biologically active heterocyclic compounds, which are key chiral intermediates for the synthesis of naturally occouring compounds or chiral drugs.This study will provide efficient, green and practical protocol for the synthesis of optically active heterocycles, and will be of high academic importance as well as industrial interest.

手性含氮杂环化合物是合成天然产物、农药以及手性药物的一类重要手性中间体。环内N-烷基亚胺的不对称氢化是合成手性含氮杂环化合物最有效的方法之一，但其高效高选择性的不对称氢化反应在文献中还少见报道。本项目拟采用手性二胺金属配合物为催化剂，通过直接氢化、动力学拆分、动态动力学拆分和还原胺化等方法研究不同类型环内N-烷基亚胺的不对称还原，拓展底物的适用范围，发展高效和实用的环内N-烷基亚胺的不对称氢化反应；同时，通过利用反应动力学、同位素效应、计算化学等手段深入研究该类氢化反应的催化机理，揭示反应对映选择性和非对映选择性的本质；最后将该方法应用于制备几类具有重要应用价值的手性含氮杂环化合物，发展合成手性含氮杂环化合物的新方法。

光学纯的3-取代-3,4-二氢-2H-[1,4]苯并噁嗪和吲哚啉是两类广泛存在于多种活性天然产物和手性药物中的结构单元。环内亚胺的不对称氢化是合成这些手性含氮杂环化合物最有效的方法之一。首先，以手性二胺金属钌配合物为催化剂，实现了一系列3-取代-2H-[1,4]苯并噁嗪的高效高选择性氢化，对映选择性高达99%。在该氢化反应中，改变催化剂的负离子不仅可以有效的调节氢化产物的对映选择性，还可以进一步调控氢化产物的区域选择性。其次，以手性二胺金属钌配合物为催化剂, 在不添加任何添加剂且常温常压的条件下，可以实现一系列1H-吲哚HE 3H-吲哚的不对称氢化反应。该方法可合成2位单取代、2,3位双取代以及2,3,3位三取代手性吲哚啉化合物,对映选择性最高达>99% ee，非对映选择性最高达>20:1。并且，我们首次通过不对称氢化的方法实现了消旋3,3-二取代-3H-吲哚亚胺的动力学拆分。