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.