[3+2]环加成/[3,3]重排串联策略不对称合成氮杂九元环化合物的反应研究

由于环张力和熵增不利的影响，中环化合物的构建一直是有机合成中最富有挑战性的前沿课题之一。通过分子内环化反应合成氮杂九元环化合物目前已有许多报道，但是通过分子间反应合成氮杂九元环骨架，特别是不对称合成，目前成功的例子很少。本课题拟发展N-烯基-ɑ,β-不饱和硝酮与炔、烯试剂的[3+2]环加成和[3,3]重排的串联策略不对称合成氮杂九元环化合物的方法。根据底物的设计调控反应选择性，利用手性金属催化剂实现氮杂九元环的不对称合成，进一步揭示氮杂九元环化合物中N−O键的断裂规律，合成含多个手性中心的1,7-氨基醇以及结构多样的氮杂环骨架。在此基础上，发展手性金属催化剂实现对氮杂九元环骨架的动力学拆分，并利用发展的催化体系和合成方法学实现若干稠环吲哚生物碱的合成。上述工作将为合成氮杂九元环化合物提供一条新的途径。初步的实验结果表明我们的设想是可行的。

The construction of medium-sized ring compounds is one of the most important and challenging topics in organic synthesis due to the influence of the increasing ring strain and entropy. Many methods toward intramolecular cyclization to synthesize nine-membered aza-heterocycles have been developed, but few examples for intermolecular synthesis were achieved, especially for asymmetric synthesis of these compounds. Our project focuses on the methods toward asymmetric synthesis of nine-membered aza-heterocycles through a cascade strategy of [3+2] cycloaddition / [3,3]-rearrangement from N-vinyl-ɑ,β-unsaturated nitrones with alkynes and alkenes. According to the substrate design, the reaction selectivity was controlled and asymmetric synthesis of the nine-membered aza-heterocycles was achieved using chiral metal catalysts. Furthermore, the rules of N-O bond cleavage in the nine-membered aza-heterocycles were disclosed and 1,7-amino alcohols containing multiple chiral centers and diverse nitrogen heterocycles were prepared. Based on these results, development of new chiral metal catalysts for kinetic resolution of nine-membered aza-heterocycles and preparation was studied. Finally, our developed catalytic system and methodologies were applied to prepare fused indole alkaloids. The above strategy will provide a new pathway for preparation of the nine-membered aza-heterocycles. Our primary results have shown that our design for this strategy can be used to synthesize nine-membered aza-heterocycles.