金属催化的亚甲胺叶立德的不对称[3+3]环加成反应

The 1,3-dipolar cycloaddition has been established as a reliable and powerful tool for the synthesis of heterocyclic compounds from simple starting materials.In particular, the catalytic asymmetric 1,3-dipolar [3+2] cycloaddition of azomethine ylides with electron-deficient alkenes for the enantioselective preparation of pyrrolidines probably is one of most studied asymmetric 1,3-dipolar cycloadditions and considerable progress has been made. However, in the past ten years, most of the studies in the cycloaddition chemistry of azomethine ylides focused on the development of chiral catalysts for the extension of the scope of activated alkenes. All reported dipolarophiles served as the two-atom or six-atom synthons in the asymmetric cycloaddition of azomethine ylides. It seems that other types of dipolarophiles different from activated alkenes were ignored. In all asymmetric cycloaddition of azomethine ylides, three-atom, four-atom, and other kinds of synthons have never been discovered. Obviously, development of new and efficient catalytic enantioselective higher-order cycloadditions to access chiral six-membered, seven-membered and even larger ring of heterocycles from alternative dipolarophiles constitutes a big challenge, and is highly desiralbe. In this context, this proposed research will develp novel cycloaddition reactions of azomethine ylides with other dipoles. In our preliminary study, a highly efficient Ag-catalyzed asymmetric cycloaddition reaction of azomethine ylide with azomethine imine was realized. Based on this successful Ag catalytic system, this project will design and screen various combinations of metal salts, chiral ligands with base and the reaction conditions such as solvent, temperature, concentration and time, to develop highly active and stereoselective catalytic system for achieving enantioselective [3+3] cycloaddition of various azomethine ylides with a range of azomethine imines or other kinds of 1,3-dipoles. The project will also study the reaction mechanism through DFT calculations on the basis of the energetics, to disclose the structures of the transition states and intermediates and the stereochemistry of the reaction. The project will demonstrate that azomethine ylide could also react with other kinds of 1,3-dipoles besides alkenes dipolarophile in the catalytic asymmetric cycloaddition reactions. It is the first time to expand the catalytic asymmetric [3+2] and [6+3] cycloaddition reactions of the azomethine ylide to novel [3+3] cycloaddition reactions. This proposed research will open the door to study those potential 1,3-dioles besides azomethine imines. More asymmetric higher-order cycloadditions of azomethine ylides for enantioriched heterocycles can be expected in the future.

本项目拟发展金属催化的亚甲胺叶立德与偶氮次甲基亚胺及其它1,3-偶极子的新型不对称[3+3]环加成反应。前期研究已实现了手性银催化剂催化的亚甲胺叶立德与N,N'-环状偶氮次甲基亚胺的不对称[3+3]环加成反应。以现有的银催化体系为蓝本，本项目将设计并筛选金属盐、手性配体、碱的各种组合以及溶剂、温度、浓度、时间等反应条件，发展高活性和高立体选择性的催化体系，实现金属催化的各种亚甲胺叶立德与多种多样偶氮次甲基亚胺或其它1,3-偶极子的对映选择性[3+3]环加成反应。通过量化计算研究反应机理，揭示反应中的过渡态结构和立体化学。项目将第一次例证亚甲胺叶立德在金属催化的不对称环加成反应中也可以与其它种类的1,3-偶极子进行反应，把此前亚甲胺叶立德只能进行与烯的催化不对称[3+2]、[6+3]环加成反应扩展至[3+3]环加成反应，有望开辟一个金属催化的亚甲胺叶立德参与的环加成反应的新方向和新领域。

本课题的研究以新农药创制为导向，以基于两性离子（偶极子）的环加成及环化反应为主要研究内容，发展高选择性、经济、高效的杂环化合物的合成方法学，为杂环分子的合成提供简洁、高效途径。在国家自然基金的资助下，经历四年的坚持探索，本课题主要取得了如下成果：1) 发展了原位生成的两性离子与稳定的两性离子的环加成反应，实现了从简单化合物出发，经金属催化剂活化，原位生成两性离子活性中间体，然后与另一种稳定的两性离子进行分步环加成反应，关环得到具有新型骨架结构的杂环化合物，为合成多种杂环化合物提供了简洁、高效途径。发展的主要反应包括：金属催化的亚甲胺叶立德分别与偶氮次甲基亚胺、酞嗪衍生的双氰基叶立德的[3+3]环加成反应；金属催化的1,1-环丙烷二羧酸酯与酞嗪衍生的双氰基叶立德的[3+3]环加成反应；钯催化的烯基碳酸亚乙酯与偶氮次甲基亚胺的[5+3]环加成反应；2）在金属催化剂或Brønsted酸活化下，原位生成两性离子活性中间体，然后与环庚三烯酮、贫电烯、亚胺等进行分步环加成反应，用来合成具有新型骨架的杂环化合物。发展的主要反应包括：金属催化的亚甲胺叶立德与环庚三烯酮的[6+3]环加成反应；Ni(II)催化的氮杂环丙烷与环庚三烯酮的[8+3]环加成反应；Brønsted酸催化的亚甲胺叶立德与苯醌单亚胺的[3+3]环加成反应；金属催化的亚甲胺叶立德与氮杂邻亚甲基苯醌发生串联[3+2]环加成/1,4-加成反应；钯催化的烯基环氧乙烷与亚胺的[5+2]环加成反应；3）发展了偶极子与联烯新的热环加成反应及碱促进的氮杂烯与 酞嗪衍生的叶立德的[4+3]环加成反应，可方便地合成新型杂环化合物，用来构建杂环化合物库。. 基于上述研究工作，共发表SCI论文 11 篇，其中包括 J. Am. Chem. Soc. (1 篇)、Angew. Chem. In. Ed. (1 篇)、Org. Lett. (4 篇)、Adv. Synth. Catal. (1 篇) 、J. Org. Chem. (1篇)等期刊。截止至2017年底，还有5项工作刚刚完成，正在撰稿中。.