Enantioselective Synthesis of N-N Bisindole Atropisomers

Abstract

N-N Atropisomers are a common motif in natural products and represent a significant dimension for exploration in modern pharmaceutical and medicinal chemistry. However, the catalytic atroposelective synthesis of such molecules remains challenging, hampering meaningful development. In particular, an enantioselective synthesis of N-N bisindole atropisomers is unprecedented. Herein, the first enantioselective synthesis of N-N bisindole atropisomers via the palladium-catalyzed de novo construction of one indole skeleton is presented. A wide variety of N-N axially chiral bisindoles were generated in good yields with excellent enantioselectivities via a cascade condensation/N-arylation reaction. Structurally diverse indole-pyrrole, indole-carbazole, and non-biaryl-indole atropisomers possessing a chiral N-N axis were accessed using this protocol. Moreover, investigations using density functional theory (DFT) calculations provided insight into the reaction mechanism and enantiocontrol.

Keywords: Asymmetric Catalysis; Atropisomerism; Enantioselectivity; Indoles; Palladium.