Chiral Acid-Catalyzed Atroposelective Indolization Enables Access to 1,1′-Indole-Pyrroles and Bisindoles Bearing a Chiral N–N Axis

Abstract

We present herein a highly atroposelective indolization for the efficient synthesis of 1,1′-biheteroaryls bearing a chiral N–N axis. Under the cooperative catalysis of chiral phosphoric acid and InBr3, the reactions between 2,3-diketoesters and 1,3-dione-derived enamines resulted in a highly enantioselective construction of 1,1′-pyrrole-indoles with up to 92% yield, 94% enantiomeric excess (ee), or bisindoles in up to 92% ee. Derivatizations of these compounds to diverse functionalized N–N linked axially chiral biheteroaryls have also been demonstrated.

Catalytic Asymmetric Synthesis of N−N Biaryl Atropisomers

“…[18] Recently, Yang and Zhao reported a CPA-catalyzed indolization of 2,3-diketoesters and NÀ pyrrole/ indole enamines to offer NÀ N pyrroleÀ indole atropisomers (Scheme 6). [19] Through the protocol, divergent substituted NÀ N pyrroleÀ indole atropisomers were obtained with excellent enantioselectivity. Also, NÀ N indoleÀ indole atropisomers could be accessed with an average of 81 % ee, which was lower than that of NÀ N pyrroleÀ indole atropisomers.…”

Atroposelective synthesis of N–N axially chiral pyrrolyl(aza)-quinolinone by de novo ring formation

“…Liu and Lu reported a strategy for the enantioselective synthesis of N–N bisindole atropisomers via Pd-catalyzed de novo construction of one indole skeleton. 20 Very recently, the Shi group and the Zhao/Yang group realized the organocatalytic enantioselective synthesis of axially chiral N , N ′-bisindoles via chiral phosphoric acid (CPA)-catalyzed formal (3 + 2) cycloaddition of indole-based enaminones as novel platform molecules with 2,3-diketoesters, 21 where de novo indole-ring formation is involved. 22…”

Atroposelective Synthesis of N–N Axially Chiral Indoles and Pyrroles via NHC-Catalyzed Diastereoselective (3 + 3) Annulation Strategy

“…The inherent challenges in accessing N–N axial chirality include the formation of a weak N–N bond and a low rotational barrier. Therefore, only a few established approaches have been devised for the atroposelective synthesis of N–N atropoisomers via direct N–H functionalization, desymmetrization, de novo pyrroles/indoles ring formation, or C–H activation strategies . Despite these noteworthy breakthroughs, research on generating N–N axially chiral molecules is in its nascent stage.…”