Mechanism and Origins of Stereoinduction in Natural Cinchona Alkaloid Catalyzed Asymmetric Electrophilic Trifluoromethylthiolation of β‑Keto Esters with <i>N</i>‑Trifluoromethylthiophthalimide as Electrophilic SCF₃ Source

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 β-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 β-keto esters with <i>N</i>-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 alkaloid catalyzed conjugate additions, the most preferred mode for the title 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 S_N2-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 alkaloid catalyzed asymmetric Michael additions, this catalysis mode cannot be simply extended to an asymmetric S_N2-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 (NCI) 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···O, C–H···S, C–H···π, and π···π 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