Catalytic Asymmetric Synthesis of Atropisomers Featuring an Aza Axis

Conspectus Atropisomers bearing a rotation-restricted axis are common structural units in natural products, chiral ligands, and drugs; thus, the prevalence of asymmetric synthesis has increased in recent decades. Research into atropisomers featuring an N-containing axis (N–X atropisomers) remains in its infancy compared with the well-developed C–C atropisomer analogue. Notably, N–X atropisomers could offer divergent scaffolds, which are extremely important in bioactive molecules. The asymmetric synthesis of N–X atropisomers is recognized as both appealing and challenging. Recently, we devoted our efforts to the catalytic asymmetric synthesis of N–X atropisomers, benzimidazole–aryl N–C atropisomers, indole–aryl N–C atropisomers, hydrogen-bond-assisted N–C atropisomers, pyrrole–pyrrole N–N atropisomers, pyrrole–indole N–N atropisomers, and indole–indole N–N atropisomers. To obtain the N–C atropisomers, an asymmetric Buchwald–Hartwig reaction of amidines or enamines was employed. Using a Pd­(OAc)2/(S)-BINAP or Pd­(OAc)2/(S)-Xyl-BINAP catalyst system, benzimidazole–aryl N–C atropisomers and indole–aryl N–C atropisomers were readily obtained. To address the issue of the reduced stability of the diarylamine axis, a six-membered intramolecular N–H–O hydrogen bond was introduced into the N–C atropisomer scaffold. A tandem N-arylation/oxidation process was used for the chiral phosphoric acid (CPA)-catalyzed asymmetric synthesis of N-aryl quinone atropisomers. For N–N atropisomers, a copper-mediated asymmetric Friedel–Crafts alkylation/arylation reaction was developed. The desymmetrization process was completed successfully via a Cu­(OTf)2/chiral bisoxazoline or (CuOTf)·Tol/bis­(phosphine) dioxide system, thereby achieving the first catalytic asymmetric synthesis of N/N bipyrrole atropisomers. Asymmetric Buchwald–Hartwig amination of enamines was utilized to provide N–N bisindole atropisomers with excellent stereogenic control. This was the first asymmetric synthesis of N–N atropisomers featuring a bisindole structural scaffold using the de novo indole construction strategy. The asymmetric N–N heterobiaryl atropisomer synthesis was substantially facilitated using palladium-catalyzed transient directing group (TDG)-mediated C–H functionalization. Atropisomeric alkenylation, allylation, or alkynylation was accomplished using the Pd­(OAc)2/l-tert-leucine system. Herein, we summarize our work on the palladium-, copper-, and CPA-catalyzed asymmetric syntheses of N–C and