双金属协同催化体系的开发及其在立体发散的烯丙基化反应中的应用研究

Although great progress has been made in asymmetric synthesis, the synthesis of all possible stereoisomers of structural motifs containing contiguous stereogenic centers remains a challenge. Given the diversity of activation modes of metal catalysts, the design and development of cooperative bimetallic catalyst systems, in which two distinct chiral metallic catalysts allow for full control over the configuration of their respective stereocenters in desired products, thus represent a superior and efficient strategy for stereodivergent synthesis of a series of novel target products bearing contiguous chiral centers. Based on our prior work on synergistic catalysis, this project will aim to design and develop novel cooperative bimetallic catalytic systems and explore their application in a series of asymmetric allylic substitution reactions, in particular, in a stereodivergent manner. Specifically, this project will focus on the development of novel bimetallic synergistic catalytic systems based on Lewis acid activation and insertion reaction; The application of these catalysis in expanding the types of allylic substrates, such as 1,3-unsymmetric disubstituted allylic substrates, and developing new nucleophilic reagents, such as simple ketones, olefins and functionalized olefins, were then investigated; Additionally, the compatibility and cooperativity of bimetallic catalytic systems, as well as the regulation of these catalytic systems on reaction activity and selectivity (regio-, enantio- and diastereoselectivity) will be discussed. This research is expected to provide a vasatile and effective pathway towards the design and development of more novel and efficient asymmetric catalytic reactions, especially stereodivergent reactions.

尽管不对称合成已取得重要进展，但立体发散性合成含有连续手性中心分子的所有立体异构体依然是一个挑战。考虑到金属催化剂在活化方式上的多样性，通过设计和开发新型双金属协同催化体系，利用两种手性金属催化剂分别独立控制产物中各个手性中心的立体构型，有望实现一系列全新的含有连续手性中心分子的立体发散性合成。鉴于此，本项目拟在前期研究基础上，设计开发具有不同反应功能的双金属协同催化新体系，并发展新型高效、高选择性的立体发散性烯丙基取代反应。开发基于新型Lewis酸活化和基于插入反应的双金属协同催化新体系；研究催化体系在拓展烯丙基底物类型（如1,3-不对称二取代烯丙基底物）及开发新型亲核试剂（如简单酮、烯烃和官能化烯烃）方面的表现；研究双金属催化体系的兼容性与协同性并探究其调控反应活性和选择性（区域、立体和非对映选择性）的基本规律。本项目的完成有望为更多新型高效的不对称催化新反应的开发提供新思路和新方法。

尽管单催化体系已取得重要进展，但该体系仍然面临反应活性低和立体选择性差等诸多挑战。基于丰富的单催化反应模式（金属催化剂、有机催化剂和酶）以及自然界中的双核金属酶等活化模式的启发，双金属协同催化策略受到广泛关注。这主要有以下三个原因：1）反应活性高；2）立体调控方式多样 (Cat1*+Cat2)/(Cat1+Cat2*)以及(Cat1*+Cat2*)；3）立体发散性合成。..本项目研究主要集中在双手性金属协同催化体系的开发及其在不对称反应中的应用，开发了Pd/Cu，Ni/Cu和Ir/Cu三种新型的双金属协同催化体系，并用于1,3-二取代烯丙基底物的不对称烯丙基反应，不对称联烯取代反应以及不对称环加成反应中，解决了消旋底物的动态动力学不对称转化难题，非连续手性中心的构建以及螺环化合物等手性合成难题，并成功合成了乙烯类新型的非天然氨基酸、联烯和螺环内脂等具有重要潜在生物活性的分子骨架。相关研究成果共发表SCI论文12篇，其中CCS Chemistry 1篇、J. Am. Chem. Soc. 2篇、Angew. Chem. Int. Ed. 3篇、Chem. Soc. Rev 1篇和Chem. Eur. J. 3篇，申报并授权中国发明专利3项。共同培养博士生2名，硕士毕业生1名，本科毕业生3名。申请人在项目执行期间分别获得2021年上海市人民政府颁发的自然科学省部一等奖 (3/5)、上海市“科技创新行动计划”青年科技英才扬帆计划、2022年国家“万人计划”青年拔尖人才等荣誉奖励，并作邀请报告2次。