碱土金属催化烯烃不对称反马氢胺化构建β-手性胺

β-chiral amines are a privileged structural subclass, which are present in a broad range of natural products, pharmaceuticals and bioactive compounds. Although several strategies for the enantioselective construction of β-chiral amines have been devised, they either require stoichiometric metal complexes or multi-step sequences. The ability to construct β-chiral amines through the catalytic intermolecular anti-markovnikov hydroamination addition of primary and secondary amines to alkenes, represents a direct, atom-economical and environmentally benign strategy. Interestingly, a variety of transition metal, rare earth metal, alkali and alkaline earth metal-catalyzed intermolecular anti-markovnikov hydroamination reactions have been reported. Nevertheless, relatively few examples of the asymmetric metal-catalyzed intermolecular anti-markovnikov hydroamination, which involves the direct insertion of the N-H bond across the olefin, have been reported. Furthermore, the utilization of alkaline earth metal complexes in the asymmetric alkene hydroamination has a number of advantages over conventional transition metal-complexes, owing to their abundance, biocompatibility and chemical behavior. Nevertheless, the alkaline earth metal-catalyzed asymmetric hydroamination remains challenging, which merits the development of a highly chemo-, regio- and enantioselective anti-markovnikov hydroamination of 1,1-disubstituted alkenes, which is likely to have important of academic and industrial value.We anticipated that alkaline earth metal-catalyzed asymmetric anti-markovnikov hydroamination with rigid and steric bulkly ligands would provide a efficient strategy for the construction of β-chiral amines.

β-手性胺是一类重要的骨架结构，普遍存在于天然产物、具有生物活性的有机小分子以及药物中。尽管文献中已报道多种不对称合成β-手性胺的策略。但烯烃与一级或二级胺的分子间反马氢胺化是一种原子经济性、环境友好型和高效直接合成β-手性胺的策略。过渡金属，稀土金属, 碱金属和碱土金属都能有效催化该类反应，但是金属催化烯烃插入N-H键的不对称反马氢胺化的例子至今未有报道。与过渡金属相比，碱土金属具有较好的生物适应性和环境兼容性，在不对称氢胺化方面具有较强的应用前景。因此，设计新型的手性碱土金属络合物高区域和高对映选择性地实现烯烃的反马氢胺化，具有重要的学术价值和潜在的商业前景。本项目拟发展碱土金属与含半稳定臂手性配体形成具有催化活性的手性碱土金属络合物，实现催化1,1-二取代烯烃与一级胺、二级胺或芳胺分子间的不对称反马氢胺化，为构建β-手性胺提供一条便捷有效的合成方法。

β-手性胺是一类重要的骨架结构，普遍存在于天然产物、具有生物活性的有机小分子以及药物中。金属催化烯烃分子间不对称反马氢胺化是一种高效构建β-手性胺骨架结构的策略。然而大量的工作主要集中于分子内的不对称氢胺化，对于分子间的不对称氢胺化鲜有报道，主要原因在于分子间烯烃金属胺化的高熵需求。而碱土金属参与催化简单烯烃的反马氢胺化具有良好的效果，因此需要设计新型的手性配体，实现碱土金属在催化分子间不对称氢胺化的研究空白。我们成功设计合成了具有刚性骨架结构的N,N,O三齿手性配体L1-L5，并将其应用于1,1-二取代烯烃与苄胺或吡咯的分子间反马氢胺化反应，具有一定的催化活性，但对映选择性较差。