高稳定性钌催化剂与非共价相互作用活化结合实现大位阻烯烃复分解反应

Ruthenium-catalyzed olefin metathesis is among the most efficient synthetic methods owing to its high atom and step economy. However, solutions for highly steric hindered metathesis systems are yet to be developed. Comparing with metathesis reactions of non-hindered terminal olefins, the steric demanding reactions usually require much higher temperatures, proceed significantly slower, and accompany fast decomposition of ruthenium catalysts. A plausible approach is to simultaneously improve the catalytic activity and thermal stability of ruthenium active species (RAS), which is, however, difficult to achieve only by ligand modifications of ruthenium alkylidene complexes. Herein, we hypothesize that the activity and stability of RAS can be improved by employing different strategies, and a suitable combination of these strategies is likely to effectively overcome the steric hindrance. Thus, RAS can be activated by its non-covalent interactions with the substrate or additives, and ligand modifications can be served to stabilize RAS at high temperature. Based on our previous works on hydrogen-bonding-promoted RCM and on the total synthesis of autolytimycin, we propose to carry out an in-depth study on this strategy combination. Modified second generation Hoveyda-Grubbs-type ruthenium catalysts containing indole- and benzodipyrrole-substituted N-heterocyclic carbene and electron-rich benzylidene ligands will be designed and synthesized. These new catalysts will be evaluated in demanding model reactions to assess the effects of ligand modifications on the overall catalysis performance. A series of model substrates and steric hindered allylic alcohol substrates will also be synthesized for probing the additive- and substrate-involved activation effects in RCM reactions. The best catalysts, additives and substrate patterns will then be combined and further tested in demanding systems, and their possible synthetic applications are to be explored. This work attempts to find highly stable ruthenium catalysts for demanding olefin metathesis, to establish feasible protocols, and to contribute to the development of synthetic methods and industrial processes.

钌催化烯烃复分解具有高度原子和步骤经济性，是目前最有效的合成方法之一，但大位阻反应尚缺乏有效方法。根据大位阻反应温度高、速度慢、催化剂分解明显等特点，同时提高活性物种催化活性和热稳定性是原则可行的解决方案，但仅通过催化剂配体修饰难以实现。我们设想以不同方式改善活性和稳定性，利用添加剂或底物与活性物种的非共价相互作用实现活化，通过配体修饰提高稳定性，从而克服位阻影响。基于我们在氢键促进大位阻RCM和自溶霉素合成方面的工作，拟设计合成一类Hoveyda-Grubbs二代催化剂，研究吲哚和苯并二吡咯取代NHC配体和富电子苄基卡宾配体对催化剂整体表现的影响；通过一系列模型底物和大位阻烯丙醇底物的RCM反应，研究添加剂和底物参与的活化；再结合最佳催化剂、添加剂和底物结构建立高效反应体系并探索其应用。由于烯烃复分解的独特效率优势，发展高稳定性催化剂和大位阻反应体系将为开发新合成方法和应用工艺提供基础。

含有氮杂环卡宾（NHC）配体的钌卡宾络合物催化的烯烃复分解反应是目前最常用的合成方法之一，但大位阻反应通常要求较高温度，而且速度慢、产率低、催化剂分解明显，限制了实际应用。我们提出同时提高钌活性物种热稳定性和催化活性的解决方案，设想通过NHC修饰提高稳定性，利用添加剂或底物与活性物种的非共价相互作用实现活化，从而克服位阻影响。我们发展了一系列含有4-吲哚基侧链的新型NHC配体，得到了此类配体的铜和钯络合物，通过模型催化反应考查了引入吲哚侧链的影响，结果表明此类配体具有较好的研究前景；拓展了氢键活化大位阻烯烃关环复分解（RCM）反应的使用范围，建立了多取代2(5H)-呋喃酮和5,6-二氢-2(1H)-吡啶酮的合成方法，明确了底物结构要素对反应的影响；建立了末端烯基胺的光促合成方法，为通过RCM反应构建α,β-不饱和内酰胺提供了新的策略。在本项目的支持下，在J. Org. Chem.、Tetrahedron Lett.、《有机化学》等期刊上共发表SCI论文5篇，另有发明专利1项和SCI论文1篇在准备中。本项目成功发展了一类结构新颖的吲哚侧链NHC配体，有望用于多种金属催化反应，并为氢键效应在钌催化烯烃复分解反应中的应用提供了依据。