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程津培、薛小松团队: 天然金鸡纳碱催化不对称亲电三氟甲硫基化反应机理研究
2017-11-13

三氟甲硫基(SCF3)基团具有强吸电性和高亲脂性,将其引入生理活性分子可增强其在生物体内跨膜运输的能力,提高吸收率并增强药效。因此,三氟甲硫基化合物在医药和农药等领域具有广阔的应用前景,其合成方法也成为当前研究的热门领域。依赖于层出不穷的三氟甲硫基化试剂,合成化学家已成功实现对各类底物的三氟甲硫基化,但对映选择性的引入SCF3依然是一项极具挑战性的课题。

直至2013年,Rueping课题组和沈其龙课题组同时独立报道了在天然金鸡纳碱催化剂和亲电三氟甲硫基试剂共同作用下,以高产率和优秀的对映选择性实现对β-酮酯的不对称三氟甲硫基化。这两篇工作是不对称亲电三氟甲硫基化领域最具代表性的工作,为合成对映纯的三氟甲硫基化合物提供了便捷高效的手段。然而,对于相关反应的催化机理和SCF3转移过程的手性如何诱导这两个关键问题仍然有待阐明。

薛晓松、程津培新闻稿.png

程津培、薛小松团队近年来围绕物理有机氟化学开展了系统性的研究工作(Org. Lett. 2016, 18, 6128.; Org. Lett. 2016, 18, 264. J. Org. Chem. 2016, 81, 3119. J. Org. Chem. 2016, 81, 4280.; J. Org. Chem. 2016, 81, 9006.; J. Org. Chem. 2016, 81, 7486.; Asian J. Org. Chem. 2017. 6, 235.; J. Org. Chem. 2017. 82, 8697.;J. Org. Chem. 2017, 82, 4129.)。近期,该团队采用量化计算的手段对Rueping课题组报道的不对称亲电三氟甲硫基化反应机理和对映选择性起源进行了研究。研究结果表明:1) Wynberg离子对-氢键模型是该反应的最优催化模式; 2)SCF3 转移通过类SN2机理进行;3)反应的对映选择性由过渡态中的多重弱相互作用(包括C-H···O, C-H···F,C-H···S,C-H···p,p···p 作用及空间排斥等)协同诱导。该理论研究工作将为新反应和新催化体系的设计与开发提供理论依据。李曼博士为该工作的第一作者。

论文信息:
Man Li, Xiao-Song Xue,* and Jin-Pei Cheng. Mechanism and Origins of Stereoinduction in Natural Cinchona Alkaloid Catalyzed Asymmetric Electrophilic Trifluoromethylthiolation of β-Ketoesters with N-Trifluoromethylthiophthalimide as Electrophilic SCF3 Source. ACS Catal. 2017, 7, 7977−7986.
http://pubs.acs.org/doi/pdfplus/10.1021/acscatal.7b03007
上述研究得到了国家自然科学基金、元素有机化学国家重点实验室、化学学院、天津化学化工协同创新中心和中央高校基本科研基金的资助。


英文介绍
The trifluoromethylthio (SCF3) group enjoys a privileged role in the field of drug discovery because its incorporation into a drug molecule often leads to significantly improved pharmacokinetics and efficacy. In spite of its prime importance in the drug discovery, the stereospecific introduction of the SCF3 group into target molecules has remained an unmet challenge. A major breakthrough was made in 2013 when Rueping and Shen simultaneously and independently disclosed natural cinchona alkaloids catalyzed asymmetric electrophilic trifluoromethylthiolation of β-keto esters. However, two key issues remain obscure: a) what is the preferred mode of catalysis? and b) how is asymmetric induction accomplished? Here we report an in-depth computational exploration on the mechanism and origin of stereoinduction in cinchona alkaloid catalyzed trifluoromethylthiolation of β-keto esters with N-trifluoromethylthiophthalimide as electrophilic SCF3 source. Three mechanistic possibilities, i.e., a) the transfer-trifluoromethylthiolation, b) the Wynberg ion pair-hydrogen bonding model, and c) the Houk-Grayson bifunctional Brønsted acid-hydrogen bonding model, were evaluated with density functional theory (B3LYP-D3 and M06-2X functionals). Our calculations suggest that, in contrast to cinchona alkaloids catalyzed conjugate additions, the most preferred mode for the titled reaction is not the Houk-Grayson bifunctional Brønsted acid-hydrogen bonding model but instead the Wynberg ion pair-hydrogen bonding model, wherein the SCF3 transfer proceeds via an SN2-like mechanism. Consequently, although the Houk-Grayson bifunctional Brønsted acid−hydrogen bonding model has recently been demonstrated to be a general mechanistic model for cinchona alkaloids catalyzed asymmetric Michael additions, this catalysis mode cannot be simply extended to asymmetric SN2-type of reaction. The predicted enantioselectivities based on the Wynberg ion pair-hydrogen bonding model are in good agreement with experimental data, lending strong support to the plausibility of this mode of catalysis. Non-covalent interaction(NCI) analysis of the stereocontrolling transition state structures reveals that the enantioselectivity is mainly induced by the concerted action of multiple weak non-covalent substrate-catalyst interactions, such as C-H···O, C-H···S, C-H···p,  and p···p interactions. This contribution has not only provided insights into the mechanistic model and principles of stereocontrol by cinchona alkaloids but it should also offer help in the future design of catalysts and asymmetric electrophilic trifluoromethylthiolation reactions.