Catalytic Asymmetric Synthesis of N−N Biaryl Atropisomers

Abstract

Atropisomers featuring a restricted rotational axis have emerged as important structural scaffolds in natural products, drug design, and asymmetric synthesis. Recently, N‐N biaryl atropisomers have drawn increasing interest due to their unique structure and relatively stable axes. However, its asymmetric synthesis remains scarce compared to its well‐developed C‐C biaryl analogs. In this concept, we summarize the asymmetric synthesis of N‐N biaryl atropisomers including N‐N pyrrole‐pyrrole, N‐N pyrroleindole, N‐N indole‐indole, and N‐N indole‐carbazole, during which a series synthetic strategies are highlighted. Also, a synthetic evolution is briefly reviewed and an outlook of N‐N biaryl atropisomers synthesis is offered.

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

“…Although Cirilli and co-workers achieved N–N biaryl atropisomers with C 2 symmetry benzimidazole fragments by HPLC resolution, 10 and Higashibayashi and co-workers resolved atropisomeric enantiomers composed of 3,3′-di- tert -butyl-9,9′-bicarbazole by chiral HPLC and investigated racemization of the N–N bond, 11 the atroposelective construction of axially chiral N–N atropisomers remained unexplored until recent years. 12 Lu and Houk realized asymmetric N–H functionalization by Brønsted base catalysis to access 1-aminopyrroles and 3-amino-quinazolinones (Scheme 1b), 13 and Li and co-workers also reported the synthesis of N–N axially chiral 3-amino-quinazolinones via N -acylation and N -alkylation using the strategy of asymmetric N–H functionalization via asymmetric organocatalysis. 14 Very recently, an N-heterocyclic carbene-catalyzed amidation reaction for the atroposelective synthesis of N–N axially chiral 3-amino quinazolinones was demonstrated by the Biju group.…”

Recent Advances in Catalytic Nitrogen–Nitrogen Bond Formation Reactions

“…Until now, incorporation of a hydrazine synthon remains the most frequently used method in the synthesis of N–N bond-containing molecules. , Despite efforts on the late-stage modification of nitrogen–nitrogen bond-containing structures, direct nitrogen–nitrogen bond construction remains a highly efficient and useful way for the preparation of a substituted N–N or NN skeleton. Unlike their C–C and C–N analogues, new methods toward selective formation of bonds between nitrogen and nitrogen centers have been one of the main challenges in synthetic chemistry as both nitrogen atoms to be linked are inherently nucleophilic.…”

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

“…The incorporation of the nitrogen atom into axis results in the formation of C–N atropoisomers displaying elevated structural diversity, and the generation of C–N axially chiral molecules has garnered significant attention in recent years . However, the class of atropoisomerism stemming from rotation around the N–N single bond is often neglected in contrast to C–C and C–N atropoisomers, although the atropoisomeric N–N axis is present in several natural products and bioactive molecules including indole-derived natural products dixiamycin A (antibacterial), schischkiniin (anticancer), and N-carboline salt (antibiotics) (Scheme a) . The inherent challenges in accessing N–N axial chirality include the formation of a weak N–N bond and a low rotational barrier.…”