Selenide-catalyzed enantioselective synthesis of trifluoromethylthiolated tetrahydronaphthalenes by merging desymmetrization and trifluoromethylthiolation

Abstract

Trifluoromethylthiolated molecules are an important class of biologically active compounds and potential drug candidates. Because of the lack of efficient synthetic methods, catalytic enantioselective construction of these molecules is rare and remains a challenge. To expand this field, we herein disclose a bifunctional selenide-catalyzed approach for the synthesis of various chiral trifluoromethylthiolated tetrahydronaphthalenes bearing an all-carbon quaternary stereocenter with gem-diaryl-tethered alkenes and alkynes by merging desymmetrization and trifluoromethylthiolation strategy. The products are obtained in high yields with excellent enantio- and diastereo-selectivities. This method can be applied to the desymmetrization and sulfenylation of diols as well. Computational studies reveal that selenide can activate the electrophilic reagent better than sulfide, confirming the higher efficiency of selenide catalysis in these reactions. On the basis of the theoretical calculations, an acid-derived anion-binding interaction is suggested to exist in the whole pathway and accounts for the observed high selectivities.

Fig. 1

Enantioselective construction of all-carbon quaternary center-containing molecules via desymmetrization. a Known strategies for enantioselective desymmetrization. b Desymmetrization through copper-catalyzed radical pathway. c Enantioselective desymmetrization and trifluoromethylthiolation using aryl group as a nucleophile

Fig. 2

Practicability of the developed system. a Transformation of substrate with flexible chain. b Desymmetrization and sulfenylation of diols. c Gram-scale reaction and reaction at room temperature. d Recycle of the catalyst

Fig. 3

Further transformations of products. a Various transformations of 2a. b Intramolecular Pd-catalyzed C–H amination of 2o

Fig. 4

Computational studies. Change of Gibbs free energy based on computational studies

Fig. 5

Proposed mechanism. a DFT calculations for reaction pathway at 195.15 K. b Calculated transition states related to TS-I and TS-II