Catalytic Asymmetric Synthesis of N—N Atropisomers

Abstract

The N-N bond is widely found in natural products and bioactive compounds. The atropisomerism of N-N bond, however, has been dismissed for a long time due to the stereotype that N-N axis is unstable. The electronic barrier stemming from the repulsive interaction between the lone pairs on the two nitrogen atoms leads to a rotationally hindered axis, resulting in stable N-N atropisomers. Since the first report in 2021, the catalytic asymmetric synthesis of N-N atropisomers has been developed rapidly into an emerging area. These reactions include asymmetric N-H bond functionalization, asymmetric desymmetrization and atroposelective de novo construction of (hetero-)aromatic rings. The N-N axially chiral compounds are valuable molecules, in terms of their potential application in chiral ligand/catalysts design and biological activity evaluation. Herein, the state-of-the-art catalytic asymmetric synthesis of N-N atropisomers is summarized.

Theoretical insights into the enantiodivergence induced by chiral phosphoric acid catalysis with a Lewis acid for the synthesis of N–N axially chiral atropisomers

“…Despite earlier efforts by Cirilli and Higashibayashi in achieving N–N biaryl atropisomers through HPLC resolution, 7,8 the atroposelective construction of N–N atropisomers remained unexplored until recently. 9 Researchers have addressed this gap by developing novel approaches (Scheme 1a). For instance, Lu/Houk and Li performed an asymmetric N–H functionalization to access N–N axially chiral 1-aminopyrroles and 3-aminoquinazolinones.…”

Pd-catalyzed asymmetric Larock reaction for the atroposelective synthesis of N─N chiral indoles

“…Consequently, catalytic and enantioselective synthesis of axially chiral indoles has become a highly important task in the past decades . In sharp contrast to the well-developed C─C or C─N axially chiral indole platforms, synthetic strategies to create indole-based biaryl scaffolds defined by a chiral N─N axis have remained in its infancy (27)(28)(29)(30) due to the synthetic challenges associated with the steric hindrance imparted by a crowded chiral N─N axis. In addition, the N─N bond may also undergo cleavage due to its oxidizing nature.…”

Catalytic atroposelective synthesis of heterobiaryls with vicinal C−C and N−N diaxes via dynamic kinetic resolution

“…Although the first consideration of N−N atropisomers can be traced back to 1931, 36 catalytic asymmetric synthesis has not been reported until recently. 37 , 38 With the appropriate bulkiness and electronic properties, N−N heterobiaryls can be atropisomeric in analogy to C−C biaryls ( Figure 1 B). In this context, enantioselective synthetic approaches to access structurally diverse indole-pyrrole, indole-carbazole, bispyrrole, and bisindole atropisomers with an N−N axis has been reported by Liu, Shi and others.…”