Synthesis of Chiral Bis(3-indolyl)methanes Bearing a Trifluoromethylated All-Carbon Quaternary Stereocenter via Nickel-Catalyzed Asymmetric Friedel–Crafts Alkylation Reaction

Bis­(3-indolyl)­methanes are well-known natural products with a broad range of important biological functions including cancer cell growth inhibition and antimicrobial activity. Incorporation of a trifluoromethyl group is known to have a profound effect on the parent compound’s biological activities. Here, an efficient method for the synthesis of chiral trifluoromethylated bis­(3-indolyl)­methanes via a catalytic asymmetric Friedel–Crafts (F–C) alkylation reaction has been established. Both enantiomers of the catalysis products can be obtained by tuning the chiral substituents of the catalyst. With 5 mol % of the Ni­(II)/(imidazoline–oxazoline) complex as the catalyst, the F–C reaction of indoles with β-CF3-β-(3-indolyl)­nitroalkenes proceeded well to afford a series of chiral bis­(3-indolyl)­methanes bearing a trifluoromethylated all-carbon quaternary stereocenter in generally good yields with excellent enantioselectivities (up to 98% yield and 94% ee). Furthermore, by interchanging the indole moieties of the two reactants, indole vs β-CF3-β-(3-indolyl)­nitroalkene in the F–C reaction, both enantiomers of a given trifluoromethylated bis­(3-indolyl)­methane were obtained with high enantioselectivities (89–94% ee) upon removal of the indole N-protecting group in the F–C products. The current work represents the first general catalytic enantioselective approach to the important class of trifluoromethylated bis­(3-indolyl)­methanes.