基于二茂铁番骨架的新型手性FLP催化剂的设计、合成与应用

"Frustrated Lewis pairs (FLP)" catalytic hydrogenation is one of the research hotspots in recent years, the catalytic mechanism of which is that hydrogen molecules can be activated by sterically hindered phosphine (or amine) and boron reagents in FLP and then reacts readily with amines to give the corresponding adducts, thus realizing the catalytic hydrogenation without nobel-metal. The main advantage of this process is to avoid heavy metals pollution problem brought from traditional noble-metal catalytic reaction. Most of the reported FLP catalysts, however, were found to have some disadvantages such as poor stability in the moisture atmosphere, limited substrates, lower stereoselectivity. In this project, by using the regulable organic synthetic methods, a series of chiral phosphine (or amine) and boron containing FLP catalysts on ferrocenophane framework are designed and prepared. The stability and catalytic activity could be enhanced through adjusting of the strength of Lewis acid (tertiary phosphine) and Lewis acid (boron), and their space distance. The catalytic activities of these prepared FLP could be assessed by catalytic asymmetric hydrogenation using imines, enamines, and silyl enol ethers et al. as substrates and further applied to prepare some important chiral drugs and intermediates. A plausible catalytic mechanism and the relationship between the structure of FLP catalyst and their catalytic activities will be elucidated with the aid of 15P NMR and MATRIX-MF Process Spectrometer for Reaction Monitoring Applications. Our project can provide the theoretic support for the application of these new type FLP catalysts in industry.

“受阻路易斯酸碱对(frustrated Lewis pairs, 简称FLP)”催化氢化反应是近年研究的热点，其机理是大位阻叔膦和硼烷通过异裂氢分子后与亚胺等发生氢化反应，从源头上避免传统贵金属催化产生的重金属污染等问题。然而已报道的大多数FLP催化剂存在稳定性较差、底物范围较窄、立体选择性不高等不足。本项目运用可调控有机合成手段，以二茂铁番(ferrocenophane)为骨架，引入手性叔膦（胺）和大位阻硼烷，制得二茂铁番骨架的手性FLP催化剂。通过调控催化剂中Lewis碱(如叔膦)和Lewis酸(如硼烷)的间距、空间位阻及酸碱强度，以提高催化剂的稳定性；以亚胺、烯胺、烯醇硅醚等参与的不对称氢化反应来检验其催化活性，将较优催化剂应用于手性医药中间体合成中。借助核磁共振磷谱、在线反应红外分析系统研究其催化机理，揭示催化剂的构效关系及一般规律，为FLP催化剂的应用奠定理论基础。

本项目利用可调控有机合成手段，首先设计合成了基于二茂铁骨架的分子内、分子间的“受阻路易斯酸碱对(frustrated Lewis pairs, 简称FLP)”催化剂，以及二茂铁番骨架的N/B体系FLP催化剂，这些催化剂在酮亚胺的氢化还原反应中表现出较高的催化活性，但立体选择性有待进一步提升，发展的合成手段对后续的催化剂设计及优化有着非常重要的参考价值。其次，探究了大位阻路易斯酸B(C6F5)3协同氨硼烷对酮类化合物进行不对称还原胺化反应，成功应用于拟钙剂西那卡塞的合成中。研究表明，B(C6F5)3还可高效催化多芳基取代的吡啶衍生物、双(吲哚基)烷烃类化合物的合成。第三，我们还设计合成了二茂铁骨架的手性PNN三齿配体，与贵金属Ir或廉价金属Mn组成的新型催化体系，高效促进芳烷基酮、二芳酮、芳基吡啶酮、α, β -不饱和酮的不对称氢化还原中，转化率在99%以上，立体选择性高达99.9%，TON值可达100,000。上述反应已成功用于苯磺酸倍他司汀、克唑替尼、大麻二酚等药物及中间体的合成中。有关研究结果，已发表SCI论文18篇；申请中国发明专利6项，获授权专利4项；培养研究生8名。