面手性二茂钌配体参与的钯催化不对称烯丙基取代反应构建生物活性手性化合物  

Pd-Catalyzed Asymmetric Allylic Substitutions Using Planar Chiral Ruthenocenes for the Construction Bioactive Chiral Compounds

作　　者：窦晓勇 刘德龙[2] 张万斌[2,3] DOU Xiaoyong;LIU Delong;ZHANG Wanbin(State Key Lab.of Coking Coal Exploitation and Comprehensive Utilization,Pingdingshan 467000;Shanghai Key Lab.for Molecular Engineering of Chiral Drugs,School of Pharmacy,Shanghai Jiao Tong University,Shanghai 200240;School of Chemistry and Chemical Engineering,Shanghai Jiao Tong University,Shanghai 200240)

机构地区：[1]炼焦煤资源开发及综合利用国家重点实验室,河南平顶山467000 [2]上海市手性药物分子工程重点实验室,上海交通大学药学院,上海200240 [3]上海交通大学化学化工学院,上海200240

出　　处：《中国医药工业杂志》2020年第5期551-563,共13页Chinese Journal of Pharmaceuticals

基　　金：国家自然科学基金(21672142.21831005、21971162)。

摘　　要：面手性二茂铁配体的合成及应用得到了迅速的发展,有些已应用于工业化生产。然而,其同族的面手性二茂钌配体还没有引起化学工作者的足够重视。由于铁与钌的原子半径不同造成2种茂金属的2个环戊二烯负离子之间的距离不同,导致2类配体具有不一样的电子和立体效应,进而表现出了不一样的不对称催化效果。本文综述了3类由二茂钌单酸或双酸衍生的面手性配体:首先,介绍了由二茂钌单酸衍生的非C2-对称1,2-二取代的二茂钌膦-唑啉配体及其应用;然后,归纳了以二茂钌双酸衍生的C2-对称双膦-唑啉配体,并发现该类配体具有非常高的空气稳定性和催化活性;最后,在合成双膦-唑啉的基础上,进一步衍生得到了基于二茂钌的只有面手性的双膦配体。这些配体被应用于钯催化的不对称烯丙基取代反应之中,构建了一系列结构新颖的具有生物活性的手性化合物。研究表明,二茂钌类手性配体在保持优异立体选择性的同时,还显示出更好的反应活性和稳定性。结合单晶X-ray试验以及不对称催化效果,本文发现了面手性配体的金属络合分子中扭角与其在催化反应中不对称诱导作用之间的对应关系,为进一步制备更高催化活性及选择性的新型配体提供了依据。The synthesis and application of chiral ferrocene ligands have developed rapidly, some of which have been used in industrialization. As the analogs of ferrocenyl ligands, however, chiral ruthenocenes have received much less attention. The distance between the two cyclopentadienyl rings in ferrocene and ruthenocene is expected to present different electronic and steric effects compared with those exhibited by ferrocene ligands, resulting in inconsistent complexation properties and catalytic behaviors. This review introduces three types of planar chiral ligands derived from ruthenocenyl monoacid or diacid. First, the synthesis and application of a non-C2-symmetric 1,2-disubstituted ruthenocene-based P,N-ligand(mono-Ru PHOX) derived from monoic acid are introduced. Then, C2-symmetric bisphosphine-bisoxazoline ligands(Ru PHOX) derived from ruthenocenyl diacid are summarized. Finally, based on the synthesis of Ru PHOX, planar chiral ruthenocene bisphosphine ligands are also discussed. These ligands have been applied to Pd-catalyzed asymmetric allylic substitutions, showing excellent reactivity and stereoselectivity for the construction of a series of chiral compounds with biological activities. Furthermore, these ligands are more air-stable than the corresponding ferrocene ligands. From the results of the single crystal X-ray analysis and the asymmetric catalytic behaviors, it could be seen that the twist angle of the two Cp rings in the Pd-complexes of the planar diphosphine ligands has an obvious effect on enantioselectivity. The relationship between the twist angle and the asymmetric catalytic behavior will assist us in the development of excellent chiral ligands.

关 键 词：面手性 二茂钌配体 钯催化烯丙基取代反应 不对称合成 手性化合物 

分 类 号：R97[医药卫生—药品]