Atropisomers beyond the C–C axis (denoted as X–Y herein) are important addition to the repertoire of axially chiral compounds, which have received much attention in recent years. Compared with conventional C–C axial chirality around biaryl and olefin axes, atropisomerism portrayed by C–N, C–O, C–B, or N–N bond was deemed to be challenging due to the relatively low rotational barriers. However, the intrinsic shorter bond length and electron-repelling effect lead to a congested hetero X–Y axis, resulting in stable axially chiral frameworks. The past two decades, especially the past few years have witnessed a rapid progress of this emerging area. A range of catalytic atroposelective approaches have been reported for the efficient synthesis of these challenging skeletons. The X–Y axially chiral compounds are valuable molecules, and they may be used as new ligands or catalysts in asymmetric catalysis or evaluated for their potential biological activities. We believe that the chemistry of atropisomers beyond C–C axial chirality will be forthcoming and blooming in the near future, taking up an important position in organic chemistry and beyond. Atropisomers beyond the C–C axis (denoted as X–Y herein) are important addition to the repertoire of axially chiral compounds, which have received much attention in recent years. Compared with conventional C–C axial chirality around biaryl and olefin axes, atropisomerism portrayed by C–N, C–O, C–B, or N–N bond was deemed to be challenging due to the relatively low rotational barriers. However, the intrinsic shorter bond length and electron-repelling effect lead to a congested hetero X–Y axis, resulting in stable axially chiral frameworks. The past two decades, especially the past few years have witnessed a rapid progress of this emerging area. A range of catalytic atroposelective approaches have been reported for the efficient synthesis of these challenging skeletons. The X–Y axially chiral compounds are valuable molecules, and they may be used as new ligands or catalysts in asymmetric catalysis or evaluated for their potential biological activities. We believe that the chemistry of atropisomers beyond C–C axial chirality will be forthcoming and blooming in the near future, taking up an important position in organic chemistry and beyond. 

Atropisomers beyond the C–C axial chirality: Advances in catalytic asymmetric synthesis

Atropisomeric C–N compounds belong to an important class of axially chiral compounds. However, whereas the asymmetric synthesis of biaryl atropisomers have been well established, general and efficient strategies to access single enantiomers of C–N atropisomers are still rare. Until recently, innovative methods have been developed, providing new opportunities for the highly stereoselective synthesis of this vital class of atropisomers. Herein, we comprehensively summarize the development in this emerging field and give some insights into future advance. Emphasis is placed on the synthetic strategies. Atropisomeric C–N compounds belong to an important class of axially chiral compounds. Herein, we comprehensively summarize the development in this emerging field and give some insights into future advance. 

Stereoselective construction of atropisomers featuring a C–N chiral axis

The first highly atroposelective construction of N-N axially chiral indole scaffolds were 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 high yields for N-pyrrolylindoles 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 activities. This work not only provides a new strategy for the atroposelective synthesis of N-N axially chiral molecules but also offers a new member of the N-N atropisomer family with promising applications in synthetic and medicinal chemistry.

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

Abstract Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a C−C stereogenic axis, there is a growing interest in less common and more challenging axially chiral C−N atropisomers. This review offers an overview of the various methodologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral C−N axes. The preparation of different families of C−N based atropisomers is then presented from anilides to chiral five‐ and six‐membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/chem.202104442

Asymmetric Synthesis of Axially Chiral C−N Atropisomers

A new strategy for the enantioselective synthesis of axially chiral 3,3'-bisindoles was devised by the direct coupling of two indole rings. This strategy makes use of the C3-umpolung reactivity of 2-indolylmethanols, which enables the catalytic asymmetric addition reaction of 2-indolylmethanols with rationally designed 2-substituted indoles, thus constructing axially chiral 3,3'-bisindole scaffolds in overall excellent yields (up to 98%) with high enantioselectivities (up to 96 : 4 er). This approach not only has overcome the challenges in constructing axially chiral five-five-membered heterobiaryls, but also represents a new application of the C3-umpolung reactivity of 2-indolylmethanols in asymmetric catalysis. More importantly, this class of axially chiral 3,3'-bisindoles can undergo a variety of post-functionalizations to give axially chiral 3,3'-bisindole-based organocatalysts, which have found their preliminary applications in asymmetric catalysis. Appendix S1: Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. 

Catalytic Asymmetric Synthesis of Axially Chiral 3,3'‐Bisindoles by Direct Coupling of Indole Rings

Nitrogen-nitrogen bonds containing motifs are ubiquitous in natural products and bioactive compounds. However, the atropisomerism arising from a restricted rotation around an N-N bond is largely overlooked. Here, we describe a method to access the first enantioselective synthesis of N-N biaryl atropisomers via a Cu-bisoxazoline-catalyzed Friedel-Crafts alkylation reaction. A wide range of axially chiral N-N bisazaheterocycle compounds were efficiently prepared in high yields with excellent enantioselectivities via desymmetrization and kinetic resolution. Heating experiments showed that the axially chiral bisazaheterocycle products have high rotational barriers.

Enantioselective Synthesis of Nitrogen-Nitrogen Biaryl Atropisomers via Copper-Catalyzed Friedel-Crafts Alkylation Reaction.

N-C Biaryl atropisomers are prevalent in natural products and bioactive drug molecules. However, the enantioselective synthesis of such molecules has not developed significantly. Particularly, the enantioselective synthesis of N-C biaryl atropisomers by stereoselective metal-catalyzed aryl amination remains unprecedented. Herein, a Pd-catalyzed cross-coupling strategy is presented for the synthesis of N-C axially chiral biaryl molecules. A broad spectrum of N-C axially chiral compounds was obtained with excellent enantioselectivities (up to 99 % ee) and good yields (up to 98 %). The practicality of this reaction was validated in the synthesis of useful biological molecules.

Qi Xu

Papers

Enantioselective Synthesis of Nitrogen-Nitrogen Biaryl Atropisomers via Copper-Catalyzed Friedel-Crafts Alkylation Reaction.

Enantioselective Synthesis of Atropisomeric Biaryls by Pd-Catalyzed Asymmetric Buchwald-Hartwig Amination