Organocatalytic atroposelective synthesis of axially chiral N , N '-pyrrolylindoles via de novo indole formation.

The first organocatalytic atroposelective synthesis of axially chiral N , N '-pyrrolylindoles based on o -alkynylanilines was successfully established via de novo indole formation catalyzed by chiral phosphoric acid (CPA). This new synthetic strategy introduced CPA-catalyzed asymmetric 5- endo-dig cyclization of new well-designed o -alkynylanilines containing a pyrrolyl unit, resulting in a wide range of axially chiral N , N '-pyrrolylindoles in high yields with exclusive regioselectivity and excellent enantioselectivity (up to 99% yield, >20 : 1 rr, 95 : 5 er). Considering the potential biological significance of N-N atropisomers, preliminary biological activity studies were performed and revealed that these structurally important N , N '-pyrrolylindoles had a low IC 50 value with promising impressive cytotoxicity against several kinds of cancer cell lines. DFT studies reveal that the N -nucleophilic cyclization mediated by CPA is the rate- and stereo-determining step, in which ligand-substrate dispersion interactions facilitate the axial chirality of the target products.