基于氮杂邻联烯醌中间体的不对称催化反应研究

Asymmetric catalysis is one of the present hot topics in organic chemistry. The development of novel catalytic asymmetric reactions based on active intermediates is an important area in this research field. Recently, Much attention has been paid to the synthetic methodology via o-quinone methide and its analogues, that is, aza-o-quinone methide and vinylidene o-quinone methide intermediates. The corresponding catalytic asymmetric reactions have also been extensively studied. However, catalytic asymmetric reaction based on aza-vinylidene o-quinone methide intermediates has not been reported to date. These intermediates are highly reactive with multiple reactive sites due to their dearomatization structures. We will design and synthesize o-alkynyl arylamine compounds as the substrates, axially chiral aza-vinylidene o-quinone methide (aza-o-VQM) intermediates will be formed in situ in the presence of chiral catalyst, followed by asymmetric nucleophilic addition, bifunctionalization and aza-Diels-Aldel reactions. A series of axially chiral compounds and chiral azacyclic ring products with important application value will be obtained. We expect that products will be obtained in high yields and excellent enantioselectivities by screening of catalysts and optimization of reaction conditions. The mechanisms of catalytic asymmetric reactions based on aza-o-VQM intermediates will be deeply studied, contributing our efforts to the progress in organic synthetic chemistry based on active intermediates.

不对称催化是当今有机化学研究的热点之一。发展新的基于活性中间体的不对称催化反应是这一领域的重要研究方向。近年来，通过邻亚甲基醌及其类似物氮杂邻亚甲基醌和邻联烯醌中间体的合成方法受到人们的广泛关注，相应的不对称催化反应也被大量研究和报道。然而，基于氮杂邻联烯醌中间体的不对称催化合成方法目前还未见文献报道。这类中间体由于其去芳构化的结构具有很高的反应活性和多个反应位点。本申请课题设计与合成了邻炔基芳胺类化合物作为反应底物，在手性催化剂作用下原位形成轴手性氮杂邻联烯醌中间体，随后进行不对称亲核加成、双官能化和杂Diels–Aldel反应，生成一系列具有重要应用价值的轴手性化合物和手性氮杂环产物。期待通过筛选催化剂和优化反应条件，获得高产率和高对映选择性的目标产物。探索基于氮杂邻联烯醌中间体的不对称催化反应的机理，推动基于活性中间体的有机合成化学的发展。

发展基于活性中间体的不对称催化反应是合成手性化合物的重要方法。本项目以邻炔基芳胺类化合物作为反应底物，在手性催化剂作用下原位形成轴手性氮杂邻联烯醌中间体，随后进行反应，生成具有重要应用价值的手性化合物。利用这一策略实现了基于氮杂邻联烯醌中间体的分子内不对称硫化芳基化反应，合成了一类官能化的烯烃-芳基类轴手性化合物。该反应不仅适用于亲电芳硫基化反应，同时也适用于亲电三氟甲硫基化反应，手性产物收率最高达96%，ee值最高达98%。这类轴手性化合物可以进一步转化成轴手性联芳基氨基硫醚、联芳基氨基亚砜、联芳基胺、烯基-芳基胺以及其它重要的轴手性产物。二氟甲基硫化物和卤化物是药物化学和有机合成中的一类重要的化合物。本项目发展了硫族化合物催化的偕二氟烯烃分子间亲电硫化和卤化反应来构建这些化合物。使用亲电性的硫化/卤化试剂和各种亲核试剂与偕二氟烯烃进行三组分反应，可以得到多种二氟甲基硫化物和卤化物。实现了联烯的分子内亲电硫化碳环化反应。该反应体系具有很好的区域选择性及底物适用性，烷基硫、芳基硫和三氟甲基硫试剂都在反应体系中适用。以TMSN3为亲核试剂，实现了联烯的分子间硫化叠氮化反应。本项目研究发表SCI论文四篇。