复杂官能化手性联芳不对称催化合成研究

Chiral biaryls are important building blocks for the synthesis of natural products, pharmaceuticals, materials, agrochemicals, etc. They are also the skeletons of many chiral auxiliaries and ligands. Nowadays Suzuki-Miyaura reaction has become the strongest protocol for the preparation of achiral biaryls. However, efficient catalyst systems and chiral ligands used for asymmetric version are still very limited because of the strict requirement of steric hindrance and chiral environment match. Not to mention that the studies on synthesis of complicated multi-functionalized chiral biaryls are scare. As you know, the functional groups such as -CHO, -CO-, -COOH, -COOR, -CONH2, etc. on the biaryls can be further transformed for versatile use. So it is urgent in scientific and application view to study thoroughly the synthetic methodology via simple and direct asymmetric catalysis. As a key point in this process, other functional groups are integrated into the chiral biaryls at the same time. This will largely reduce the preparation cost and simplify the synthetic pathway for the target compounds. Based on our good researches in this field, it is planned to explore highly efficient catalyst system for the synthesis of target compounds in this project. The effects of ligand's and substrate's type, structure, electron-donating or withdrawing capability, active metal, etc. on the reaction will be investigated so as to develop novel catalyst system with high activity and enantioselectivity. All of these studies will be beneficial to further understanding on this kind of catalytic asymmetric reaction. At the same time, some new chiral ligands will also be prepared in order to enrich and develop our biaryl monophosphine ligand family with independent intellectual property. The applications of these ligands in asymmetric catalysis will also be expanded to broader field as examples.

手性联芳是天然产物、药物、材料、农用化学品等的重要构筑模块，也是形成许多手性辅助试剂和重要手性配体的骨架。近年来，Suzuki-Miyaura反应成为合成非手性联芳的最强有力手段，但由于对空间位阻和手性匹配的要求严格，不对称S-M反应合成手性联芳的有效催化剂及手性配体迄今仍非常有限，复杂官能化手性联芳不对称催化合成研究更为罕见。官能化手性联芳上的官能团如醛基、酮基、羧基、酯基、酰胺基等可进一步进行多用途转化，直接催化不对称合成具有重要的科学价值和应用前景,该技术关键是在形成轴手性联芳的同时，多用途官能团一并集成引入,这将有效降低制备成本，简化合成过程。本项目拟在以前良好工作的基础上，进行复杂官能化手性联芳高效催化体系探索，考察配体和底物类型、结构、电性、活性金属等诸要素对催化过程的影响，以期发现新型高效催化体系，揭示催化过程变化规律，进一步丰富发展自主知识产权单膦配体体系，开拓其应用领域。

手性联芳是天然产物、药物、材料、农用化学品等的重要构筑模块，也是形成许多手性辅助试剂和重要手性配体的骨架。近年来，Suzuki-Miyaura反应成为合成非手性联芳的最强有力手段，但由于对空间位阻和手性匹配的要求严格，不对称Suzuki反应合成手性联芳的有效催化剂及手性配体迄今仍非常有限，复杂官能化手性联芳不对称催化合成研究更为少见。为了完成复杂官能化手性联芳的构建，本项目设计开发了6类新型单膦配体，这些配体连同本课题组先前开发的配体以及MOP系列配体被应用于钯催化的Suzuki偶联反应，进行合成官能化手性联芳的探索。借助于底物和催化体系的设计优化，成功合成了2或2’-位含有醛基、膦酸酯、芳基氧膦、硝基等官能团或含有喹啉基结构的联芳，这些基团可以进一步多用途转化为-COOH、-CH2OH、PR2和NH2等。连同预先设计集成在底物其它位点上的基团如烷基、烷氧基、卤素等，经过一步Suzuki偶联反应，可高收率、高对映选择性地制备复杂的多官能化的手性联芳（最佳97%收率，97% ee）。该方法克服了目前不对称Suzuki反应存在的活性和对映选择性不高、底物范围窄、适应性差，制备的联芳官能团简单、难修饰转化的缺陷，大幅度降低了合成成本，简化了合成路线，显著地扩大了Suzuki反应的应用范围，尤其是在制备复杂的手性联芳方面。其间，考察了配体和底物类型、结构、电性、钯源等诸要素对催化过程的影响，并应用DFT计算对不对称催化过程进行了机理探讨。新型手性配体的开发进一步丰富发展了自主知识产权的联芳基单膦配体体系，并已成功拓展到一些其它反应中。到目前为止，已在国际知名学术期刊发表论文5篇，申请发明专利6件，其中3件已获授权，还有部分论文正在整理中。