期刊
ACS CATALYSIS
卷 7, 期 11, 页码 7977-7986出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.7b03007
关键词
trifluoromethylthiolation; asymmetric catalysis; Cinchona alkaloid; density functional calculation; noncovalent interaction
资金
- Natural Science Foundation of China (NSFC) [21390400, 21402099, 21772098]
- Collaborative Innovation Center of Chemical Science and Engineering (Tianjin)
- State Key Laboratory on Elemento-organic Chemistry
- Fundamental Research Funds for the Central Universities
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 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 alkaloid catalyzed asymmetric electrophilic trifluoromethylthiolation of beta-keto esters. However, two key issues remain obscure. (a) What is the preferred mode of catalysis? (b) How is asymmetric induction accomplished? Here we report an in-depth computational exploration into the mechanism and origin of stereoinduction in Cinchona alkaloid catalyzed trifluoromethylthiolation of beta-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 Bronsted acid-hydrogen bonding model, were evaluated with density functional theory (B3LYP-D3 and M06-2X functionals). Our calculations suggest that, in contrast to Cinchona alkaloid catalyzed conjugate additions, the most preferred mode for the title reaction is not the Houk Grayson bifunctional Bronsted acid-hydrogen bonding model but instead the Wynberg ion pair-hydrogen bonding model, wherein the SCF3 transfer proceeds via an S(N)2-like mechanism. Consequently, although the Houk-Grayson bifunctional Brensted acid hydrogen bonding model has recently been demonstrated to be a general mechanistic model for Cinchona alkaloid catalyzed asymmetric Michael additions, this catalysis mode cannot be simply extended to an asymmetric S(N)2-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. Noncovalent interaction (NCl) analysis of the stereocontrolling transition state structures reveals that the enantioselectivity is mainly induced by the concerted action of multiple weak noncovalent substrate catalyst interactions, such as C-H center dot center dot center dot O, C-H center dot center dot center dot S, C-H H center dot center dot center dot pi, and pi center dot center dot center dot pi interactions. Not only has this contribution provided insights into the mechanistic model and principles of stereocontrol by Cinchona alkaloids but also it should offer help in the future design of catalysts and asymmetric electrophilic trifluoromethylthiolation reactions.
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