Organocatalytic Atroposelective Synthesis of N−N Axially Chiral Indoles and Pyrroles by De Novo Ring Formation

Abstract

The first highly atroposelective construction of N-N axially chiral indole scaffolds was established via a new strategy of de novo ring formation. This strategy makes use of the organocatalytic asymmetric Paal-Knorr reaction of well-designed N-aminoindoles with 1,4-diketones, thus affording N-pyrrolylindoles in high yields and with excellent atroposelectivities (up to 98 % yield, 96 % ee). In addition, this strategy is applicable for the atroposelective synthesis of N-N axially chiral bispyrroles (up to 98 % yield, 97 % ee). More importantly, such N-N axially chiral heterocycles can be converted into chiral organocatalysts with applications in asymmetric catalysis, and some molecules display potent anticancer activity. This work not only provides a new strategy for the atroposelective synthesis of N-N axially chiral molecules but also offers new members of the N-N atropisomer family with promising applications in synthetic and medicinal chemistry.