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.