基于手性二茂铁骨架的多功能有机膦催化剂构建及其在不对称MBH反应中的应用研究

Asymmetric organocatalysis has become one of the most fascinating area in organic chemistry research and grown into three pillars of asymmetric catalysis together with biocatalysis and metal catalysis. So far, numerous organocatalysts have been rooted in several core structures. Surprisingly, ferrocene, a "privileged framework" for the construction of effective chiral ligands in metal catalysis, has not been exploited as a backbone of organocatalysts. Our previous study showed that bifunctional ferrocene organocatalysts would be a potential "ideal framework and model" for the construction of organocatalysts. In this project, a series of novel ferrocene-based multifunctional chiral phosphine organocatalysts, possessing with various stereogene and multiple functional groups (such as Lewis base, Bronsted acid, and Bronsted base), were designed and synthesized in accordance with simulating the characteristics of enzyme mutifunctional activation. Their performance (enantioselectivities and catalytic activities) in asymmetric MBH reaction would be evaluated. It would be systematically investigated for the first time that the matching of the various stereogene and the cooperation of the multi- functional groups of a series of ferrocene-based organocatalysts on enantioselectivities and catalytic activities. This study would be beneficial exploration for the development of ferrocene-based organocatalysts, and provide more types of "privileged framework" and ideal models for the construction of effective chiral organocatalysts.

不对称有机催化是当今有机化学最为活跃的研究领域之一，已与金属催化和酶催化一起成为不对称催化的三大支柱。然而，迄今报道的手性有机催化剂大多衍生于有限的几种手性骨架，而在手性金属催化剂设计中被视为"优势骨架"的二茂铁，作为有机催化剂的骨架却鲜有报道。课题组前期研究发现：双功能二茂铁有机催化剂能高对映选择性地催化一些不对称反应进行，预示二茂铁极有可能是构建有机催化剂的一个理想骨架。在此基础上，本课题模拟生物酶多功能活化的特点，在二茂铁骨架上首次引入多种立体基因及多种功能基（LB、BA、BB功能基），构建一系列结构新颖的多功能二茂铁类有机膦催化剂，并将其用于多种底物的不对称MBH反应中，系统考察多个立体基因的相互匹配以及多种功能基的协同作用，以期筛选出催化活性高、立体选择性好的二茂铁类有机催化剂。本研究将为二茂铁类有机催化剂的开发进行有益的探索，为手性有机催化剂设计提供更多的优势骨架及结构模式。

二茂铁具有独特的面手性，同时兼具刚性强、富电子性、结晶性好、易衍生化、高度稳定性等优点，是不对称金属催化中手性配体的一个“优势骨架”，而二茂铁骨架在手性有机催化剂设计中应用较少，基于独特面手性的二茂铁类有机催化剂却鲜有报道。本课题模拟生物酶多功能活化的特点，在二茂铁骨架上首次引入多种立体基因及多种功能基（LB、BA、BB功能基），设计并合成了24种多功能二茂铁类有机膦催化剂，并将其用于不同类型的MBH反应中，系统考察多个立体基因的相互匹配以及多种功能基的协同作用，总结了催化剂结构中不同的功能基、手性因素、取代基的电子效应及立体效应对催化活性和对映选择性的影响规律。在此基础上，对催化剂进行结构优化，最终筛选出2类合成简便、催化活性高、立体选择性好的催化剂。在芳香醛与丙烯酸酯的不对称MBH反应中，对映选择性高达99.7% ee，化学产率也达到了令人满意的80%。在分子内不对称MBH反应中获得了82%的化学产率以及高达96% ee的对映选择性。此外，课题组首次实现了β-硝基苯乙烯与乙醛酸乙酯的不对称MBH反应，获得56.9% ee的对映选择性。合成的双功能二茂铁类有机催化剂在与MBH反应相类似的不对称Rauhut-Currier反应中获得了98%ee的对映选择性。本研究表明二茂铁也是手性有机催化剂的一个非常优秀的骨架。