双功能手性双核铜催化四氢异喹啉的需氧不对称交叉脱氢偶联反应研究

Chiral tetrahydroisoquinoline structure widely exist in a variety of biologically and pharmaceutically active natural products. Asymmetric cross-dehydrogenative coupling is one of the most desirable methods for the synthesis of such chiral compounds. However, the activities and scope of substrates in this reaction, as well as the stereoselectivities of products have not been satisfactorily solved. A typical strategy for the control of stereoselectivity in asymmetric cross-dehydrogenative coupling reactions is the use of chiral catalysts to activate nucleophiles. The problem with this strategy is that different types of nucleophiles require different chiral catalysts. Based on our previous studies, we propose to design and synthesize bifunctional chiral binuclear copper complexes for asymmetric cross-dehydrogenative coupling reactions. The chiral copper complex will be transformed to be an anion to form an ion pair with the in-situ generated electrophile-iminium cation, which could then be trapped by a variety of nucleophiles to produce coupled products. The stereochemistry of the products could be controlled by chirality of the chiral anion. This strategy will likely solve the problem of different chiral catalysts for different types of nucleophiles, and provide a new approach for asymmetric cross-dehydrogenation coupling reactions. This project will systematically modulate the electronic properties and spatial structure of the ligands, revealing the structure-activity relationship between the catalyst and the reactivity and selectivity. In addition, some challenges in cross-dehydrogenation coupling reactions will be addressed by employing a electrophilic and nucleophilic dual activation strategy.

手性四氢异喹啉结构广泛存在于各种具有生物和药物活性的天然产物分子中。不对称交叉脱氢偶联反应是当前合成该类手性化合物的理想方法之一。然而，该反应中底物的活性和普适性以及目标产物的立体选择性问题长期以来未能圆满解决。已报道的不对称交叉脱氢偶联反应，一般通过使用手性催化剂活化亲核试剂的策略实现立体控制，不同类型亲核试剂需要不同手性催化剂。基于前期研究基础，本项目拟设计合成双功能手性双核铜催化剂，通过手性抗衡阴离子导向催化策略，活化反应过程中生成的亲电试剂-亚胺盐，和不同类型亲核试剂反应，得到交叉脱氢偶联产物。该策略将有可能解决不同类型亲核试剂需要不同手性催化剂的问题，为不对称交叉脱氢偶联反应提供新思路。本项目将系统调节配体的电子性能和空间结构，揭示催化剂与反应活性和选择性间的构效关系。此外，还将结合亲电试剂和亲核试剂双活化的策略，解决交叉脱氢偶联反应中的一些难题。

不对称交叉脱氢偶联反应是当前合成该类手性化合物的理想方法之一。然而，该反应中底物的活性和普适性以及目标产物的立体选择性问题长期以来未能圆满解决。已报道的不对称交叉脱氢偶联反应，一般通过使用手性催化剂活化亲核试剂的策略实现立体控制，不同类型亲核试剂需要不同手性催化剂。本项目拟设计合成双功能手性双核铜催化剂，通过手性抗衡阴离子导向催化策略，活化反应过程中生成的亲电试剂-亚胺盐，和不同类型亲核试剂反应，得到交叉脱氢偶联产物。本项目已成功建立一种双核水杨酸铜催化剂催化氧化N,N-二甲基苯胺类化合物合成N-甲基-N-苯基甲酰胺类化合物的新方法；建立一种双核水杨酸铜催化剂催化氧化异色满类化合物合成异色酮类化合物的新方法；建立一种二价钯配合物催化剂，室温下氧气球为氧化剂，四芳基锡作为芳基化试剂实现吲哚的直接2-位芳基化偶联的新方法；建立一种钯催化下1,2-二叔丁基亚砜乙烷配体促进的四芳基锡与缺电子/富电子烯烃Heck偶联的新方法；建立一种通过零价钯催化的氟化羰基化反应快速合成α-CF3丙烯酰胺的新方法。在本项目的支持下，已在ChemCatChem、Synlett已发表2篇SCI论文，发表会议论文1篇，后续待发表2篇SCI论文。