有机小分子催化硅基咪唑的不对称aza-Michael反应及应用

Imidazole and its derivatives are widely used in areas of medicine and pesticide because their diverse biological activities, especially predominant anti-cancer activity. Introduction of imidazole to organic molecules via aza-Michael reaction, an atom economic reaction, is vital for organic synthesis methodology as well as application study of imidazole derivatives. However, reports of an asymmetric version of this aza-Michael reaction are sparse. Some limitations of this reaction such as special Michael acceptor, poor generality, low yield and enantioselectivity, ungenerous catalytic method, are existed to date. In this project, (trimethylsily)imidazole (TMSIM) is proposed as nucleophilic equivalent of imidazole based on the unique properties of organosilicon to study its enantioselective organocatalytic aza-Michael reactions to α,β-unsaturated carbonyl compounds and their applications in synthesis of bioactive molecules. Novel protocols for enantioselective aza-Michael reactions of TMSIM to enals, enones and α,β-unsaturated imides will be establisehed. These will settle the problems of the present asymmetric aza-Michael reaction involving imidazole, and fill up vacancy of asymmetric aza-Michael reaction with regard to TMSIM. In addition, enantiomerically enriched N-substituted imidazole derivatives possessing potential bioactivities will be obtained and lay the foundation for their application study.

咪唑类化合物大多具有良好的生物活性，在医药和农药领域发挥着重要作用，特别是在治疗肿瘤方面有显著功效。通过aza-Michael这一原子经济性反应引入咪唑基团，在有机合成方法学和咪唑衍生物应用研究上都具有积极意义。目前，咪唑为Michael供体的不对称aza-Michael反应研究非常有限，存在受体底物单一、通用性差、产率和对映选择性低、催化方法欠缺等问题。本项目基于有机硅试剂的特性，提出以三甲基硅基咪唑（TMSIM）作为咪唑的亲核等价体，研究手性有机小分子催化TMSIM与α,β-不饱和羰基化合物的不对称aza-Michael反应及在生物活性分子合成中的应用。建立TMSIM与α,β-不饱和醛、酮、酰亚胺的对映选择性aza-Michael反应新方法，解决目前咪唑参与的不对称aza-Michael反应存在的问题，设计合成具有潜在生物活性的手性N-取代咪唑衍生物，为其应用研究奠定基础。

芳香氮杂环化合物大多具有良好的生物活性，在医药和农药领域发挥着重要作用。对芳香氮杂环的aza-Michael反应研究，在有机合成方法学上和芳香氮杂环化合物的应用研究方面都具有积极意义。我们以芳香氮杂环的aza-Michael反应方法学研究为主线，以发展高选择性、原子经济和步骤经济的有机反应方法学为导向，注重拟定反应探索与启发创新相结合。通过芳香氮杂环的aza-Michael反应、氰化反应和相关反应方法学研究，建立了系列芳香氮杂环的aza-Michael反应新方法，发展了多种碳-杂键以及碳-碳键的构建方法，取得了系列学术成果，发表SCI论文20篇。