可调控的氢键- - 手性膦二茂铁催化剂的设计、合成及应用

Recently the bifunctional organocatalytic reaction with the aid of hydrogen bond activation is one of highlight researches. Its characterization is that high catalytic activity and good stereo-control could be realized through the hydrogen bond between the substrates and the organocatalysts. However, most of the reported organocatalytic reactions have some disadvantages such as the poor stability and uneasy recycle of organocatalysts, limited substrates and low stereoselectivity in catalytic reaction. Using the regulable organic synthetic methods, a series of bifuctional chiral ferrocenylphosphines will be prepared by introduction of planar chiral phosphines and central chiral Bronsted acids- - phosphoric acid derivatives on the ferrocene framework, the hydrogen bond activation of which can be controlled and adjusted by sulfuration, sulfonylation and bispolyphosphorylation of Bronsted acids. These new organocatalysts are stable enough and highly active to promote the asymmetric Baylis-Hillman reaction and asymmetric reactions using Baylis-Hillman adducts, alkynes or allenic compounds as substrates and further applied to prepare some important drugs and intermediates. The reuse of these organocatalysts will be studied. A plausible catalytic mechanism and the relationship between the organocatalyst structure and their catalytic acivities will be elucidated with the aide of 15P NMR, MS and MATRIX-MF Process Spectrometer for Reaction Monitoring Applications. Our project can provide the theoretic support for the application of these new organocatalysts in industry.

基于氢键活化的双官能有机催化反应是近年来研究热点之一，其特征是催化剂通过其OH或NH基团与反应底物形成氢键，从而实现良好的催化活性及手性控制。然而已报道的大多数有机膦催化反应存在催化剂不太稳定、难以回收套用、底物适应范围较窄、立体选择性不高等问题。本项目运用可调控有机合成手段，在二茂铁骨架上引入平面手性叔膦和中心手性Bronsted酸- - 磷酸衍生物，通过硫代、磺酰化、磷酸二聚等手段调控Bronsted酸氢键活化功能，制备双官能手性膦二茂铁催化剂，同时增强稳定性和催化活性；以不对称Baylis-Hillman反应、Baylis-Hillman加成物、炔烃、联烯等参与的不对称反应来检验其催化活性，并应用于医药中间体的合成中；探索新催化剂回收套用方法；借助核磁共振磷谱、质谱、在线反应红外分析系统研究其催化机理，揭示催化剂结构与性能之间的一般规律，为双官能手性膦二茂铁催化剂的工业应用奠定理论基础。

本项目利用有机可调控手段合成，设计合成了一系列基于二茂铁骨架的双官能化有机催化剂----手性膦二茂铁催化剂。项目研究之初，我们以二茂铁为骨架，同时引入平面手性的“Lewis碱”叔膦和中心手性“Brnsted酸”基团，将二茂铁膦与Brnsted酸有机嫁接，设计并合成一系列同时具有氢键和亲核性的双官能手性膦二茂铁催化剂，研究表明，含双官能团手性膦二茂铁催化剂有较高的稳定性和催化效果，可用来催化Baylis-Hillman加成物参与的不对称[3+2]环加成反应，反应产物的收率和ee值较高；以及Baylis-Hillman加成物参与的不对称烯丙基取代，得到ee值中等至良好，获得了较满意的研究成果，考虑了溶剂、添加剂以及催化剂回收套用问题。同时我们设计了系列实验来证实我们提出的催化机理。有关研究结果，已发表研究论文12篇，其中SCI论文8篇；申请中国发明专利3项，获授权专利2项。培养研究生9名。