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元素有机化学国家重点实验室

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【Jinpei Cheng and Xiaosong Xue's Group】Mechanism and Origins of Stereoinduction in Natural Cinchona Alkaloid Catalyzed Asymmetric Electrophilic Trifluoromethylthiolation of β-Ketoesters with N-Trifluoromethylthiophthalimide as Electrophilic SCF3 Source.

Release unit:SKLEOC   Release time:2017/11/12    Browse times:15


The trifluoromethylthio (SCF3) group enjoys a privileged rolein 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, where in 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··π·, and π···π 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.

Read more:

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