基于双环咪唑骨架的新型高效手性双功能有机小分子催化剂研究

After decades of development, asymmetric catalysis has become the main method for the synthesis of chiral drugs and its key intermediates, and relevant researches have been paid more and more attention from academia and industry. Chiral organocatalyst, as one of the three chiral catalysts which is the key of asymmetric catalytic technology, has attracted much attention because of its diverse structure, stable property and wide application. However, the traditional organocatalysts always show poor efficiency in catalysis and great difficulty in synthesis, so it still cannot meet the standard of industrial application. In view of the current trend of organocatalyst development and on the basis of our previous researches, this application will design and synthesis a series of hydrogen-bonding-assisted chiral bicyclic imidazole bifunctional organocatalysts with innovative structure, easy availability and high catalytic activity. The performance in several new types of enantioselective acylation reactions will also be studied (99% of the enantioselectivity has been obtained in the enantioselective direct C-acylation for the synthesis of quaternary amino acids). This program will introduce new examples of organocatalysts, expand efficient applications of asymmetric organocatalysis, provide the deep understanding of asymmetric catalytic mechanism and promote the industrial utilization of asymmetric catalysis.

经过几十年的发展，不对称催化已成为手性药物及其关键中间体的主要合成方法，相关研究也越来越受到学术界和产业界的重视。手性催化剂是不对称催化技术的关键，其中的有机小分子催化剂因其结构多样、性质稳定和应用广泛等优点而备受关注。但是，传统的有机小分子催化剂普遍存在因合成难度大和催化效率低引起的制备和使用成本高的问题，因而难以达到工业化应用的标准。本申请课题结合当前有机小分子催化剂研究发展趋势及课题组现有研究基础，将设计合成一系列结构创新、合成简便和效果突出的氢键辅助手性双环咪唑催化剂，并利用基于该催化剂的一些新方法和新策略解决此前尚未解决好甚至尚未解决过的不对称催化反应问题（目前在不对称直接C-酰化反应上已取得99%的对映选择性）。该课题的实现将丰富有机小分子催化剂的结构类型，拓展有机小分子催化反应的应用领域，深化不对称催化过程的机理研究，促进不对称催化技术的工业化应用。

本项目自2019年执行以来，围绕手性双环咪唑催化剂以及相关不对称催化反应进行了较为集中和深入的研究。首先设计并合成一系列（硫）脲氢键辅助的新型手性双环咪唑类双功能有机小分子催化剂，其结构新颖、原料易得而且合成简便；其次，基于手性双环咪唑催化剂，开发了不对称直接C-酰化、不对称多米诺酰化、动态动力学拆分不对称O-酰化、动态动力学拆分不对称O-磷酰化以及去对称化不对称O-酰化等多种不对称催化反应，利用π堆叠、氢键和色散力等辅助作用获得了优良的反应产率和立体选择性（ee高达99%，S/C高达500），分别实现了抗新冠病毒药物瑞德西韦、苯酞酯类手性前药以及含四取代碳手性中心杂环等手性化合物的高效不对称催化合成；最后利用实验研究和理论计算相结合的方法，研究了上述反应的催化机理和催化剂的构效关系，提出了相应的活性促进模式和立体控制原理。共发表标注该项目号的SCI论文12篇，包括Angew. Chem. Int. Ed. 7篇、ACS Catal. 1篇、Chem. Sci. 1篇和Nat. Sci. 1篇，同时申请专利3项，培养毕业硕博士研究生4名，顺利完成了本项目研究任务并达到预期目标。