基于烯丙基钯β-烯基氢消除的手性联烯合成研究

Allenes are not only the important segment in the structure of natural product and biologically active molecule, but also the multi-functional building block in synthetic chemistry. In this project, the research on synthesis and application of chiral allenes will be carried out based on the innovative mechanism of beta-vinylic hydrogen elimination from allyl palladium species. . Firstly, on basis of preliminary investigation, the new beta-hydrogen elimination mechanism will be further elucidated and verified by means of mass spectrometry, theoretical calculation and control experiments. Secondly, chiral allenes will be synthesized by asymmetric cross-coupling of vinyl halides and carbine precursors, or by asymmetric conversion of allyl alcohol derivatives. In order to realize an efficient asymmetric synthesis, the exploration of chiral induction mechanism and the control of competitive elimination of beta-hydrogen would be focused on. Finally, for the purpose of discovering lead compounds, screening the anti-tumor and other biological activities of the obtained chiral allenes will be performed. In addition, synthetic allenes will be introduced into the structure of rhodiola derivatives, a kind of precursors which have a fine anti-cerebral ischemia activity and undergone a related study. . This project is an innovative exploration of the basic reaction mechanism and the new chiral induction mode. Its implementation involves a comprehensive approach of cross-disciplinary integration of synthetic chemistry, mass spectrometry technology, theoretical calculation and biological research.

联烯是许多天然分子和生物活性分子的重要结构片段，也是合成化学中多功能的反应砌块。本项目拟基于烯丙基钯β-烯基氢消除这一创新性的反应机制，开展手性联烯合成和应用研究。. 首先，在预研探索的基础上，通过质谱方法、理论计算和控制实验等多种手段对发现的烯丙基钯β-烯基氢消除进行深入验证和阐释。其次，利用此核心机制，通过卡宾前体与烯基卤代物不对称交叉偶联和烯基醇衍生物不对称转化两种策略进行手性联烯合成，集中探索新机制下的手性诱导模式和竞争性β-氢消除控制等挑战性难题，实现系列手性联烯的高效不对称合成。最后，围绕合成的手性联烯，一方面进行抗肿瘤等生物活性的筛选，另一方面将合成的联烯作为结构片段接入在研中具有抗脑缺血活性的一类红景天衍生物，以期发现更高生物活性的前体药物。.本项目从源头反应机制和手性诱导模式进行创新性探索，通过合成化学、质谱分析、理论计算和生物活性测试等多学科交叉融合推进项目研究。

本项目围绕机制创新进行合成方法学研究。研究过程中成功发展了基于钯络合物烯基β-氢消除这一个关键机制的多种联烯合成方法。基于该新机制实现手性控制挑战比较大，最优可以取得14%ee。与此同时，过程中也对发现的多型1,4-钯迁移反应进行了研究，实现了钯迁移后硼化、杂芳基化、膦化和相应关键中间体双官能团化反应。总共发表9篇基金标注的SCI文章，包括影响因子大于10的论文2篇（Nat. Commun. 1篇，Acs Catal.1篇）。培养了博士后1名，博士4人，硕士2人。项目负责人冯陈国于2020年获得青年“上海市优秀学术带头人”称号。