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

Rational design and atroposelective synthesis of N–N axially chiral compounds

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

In recent years, asymmetric catalysis of ynamides has attracted much attention, but these reactions mostly constructed central chirality, except for few examples on the synthesis of axially chiral compounds which exclusively relied on noble-metal catalysis. Herein, a facile access to axially chiral N-heterocycles enabled by chiral Brønsted acid-catalyzed 5-endo-dig cyclization of ynamides is disclosed, which represents the first metal-free protocol for the construction of axially chiral compounds from ynamides. This method allows the practical and atom-economical synthesis of valuable N-arylindoles in excellent yields with generally excellent enantioselectivities. Moreover, organocatalysts and ligands based on such axially chiral N-arylindole skeletons are demonstrated to be applicable to asymmetric catalysis.

Synthesis of Axially Chiral N-Arylindoles via Atroposelective Cyclization of Ynamides Catalyzed by Chiral Brønsted Acids.

An unprecedented example of a chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler reaction of N-arylindoles is reported. Highly enantioenriched N-aryl-tetrahydro-β-carbolines with C-N bond axial chirality are obtained via dynamic kinetic resolution. The hydrogen bond donor introduced on the bottom aromatic ring, forming a secondary interaction with the phosphoryl oxygen, is essential to achieving high enantioselectivity. A wide variety of substituents are tolerable with this transformation to provide up to 98 % ee. The application of electron-withdrawing group-substituted benzaldehydes enables the control of both axial and point stereogenicity. Biological evaluation of this new and unique scaffold shows promising antiproliferative activity and emphasizes the significance of atroposelective synthesis.

Sunjung Park

Papers

Catalytic and Enantioselective Control of the C–N Stereogenic Axis via the Pictet–Spengler Reaction