Asymmetric Synthesis of Axially Chiral Compounds

Axial chirality arises when restricted rotation about a molecular axis generates enantiomeric conformers known as atropisomers. Such stereochemical motifs are ubiquitous in biaryls, heterobiaryls and other scaffold classes, and they underpin the function of numerous chiral ligands, organocatalysts and bioactive compounds. Asymmetric synthesis of axially chiral compounds encompasses strategies that impose stereochemical control during bond formation or induce resolution of racemic mixtures. Key approaches include metal-catalysed asymmetric C–H activation, organocatalytic atroposelective cycloadditions and N-heterocyclic carbene (NHC)-mediated annulations. Recent advances have emphasised mild reaction conditions, broad substrate scope and high enantiomeric excess, thereby facilitating access to underexplored scaffolds such as N–N and non-biaryl atropisomers. These methodologies are instrumental in drug discovery, enabling precise modulation of molecular conformation and target selectivity, and in the fabrication of bespoke chiral ligands for asymmetric catalysis.

Research from Nature Portfolio

Innovations in organocatalysis have enabled direct construction of N–N atropisomers with contiguous axial and central chirality. A catalytic oxidative NHC-promoted cycloaddition furnishes axially chiral pyrroles and indoles bearing vicinal stereocentres in high enantioselectivity and yield, demonstrating the utility of DFT-guided mechanism design. In parallel, a carbene-catalysed protocol achieves atroposelective synthesis of axially chiral styrenes by selective 1,4-addition to acetylenic acylazolium intermediates followed by stereocontrolled protonation. This strategy overcomes the low rotational barrier of alkene-aryl axes, delivering styrene derivatives with excellent E/Z and enantiomeric ratios and valuable functional handles for further elaboration.

Asymmetric Synthesis of Axially Chiral Compounds publication trend

The graph below shows the total number of articles in asymmetric synthesis of axially chiral compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Atropisomerism: Conformational chirality arising from restricted rotation about a bond.

Axial chirality: A stereochemical feature where chirality is defined by an axis rather than a stereocentre.

Atroposelective synthesis: A strategy that selectively forms one atropisomer over its mirror image.

N-Heterocyclic carbene (NHC): A nucleophilic organocatalyst that activates substrates via formation of acylazolium intermediates.

Chiral phosphoric acid: A Brønsted acid catalyst bearing axial chirality, used to induce enantioselectivity in organic transformations.

Enantiomeric excess (ee): A measure of the purity of an enantiomer in a chiral mixture, expressed as a percentage.

References

1. Organocatalytic diastereo- and atroposelective construction of N–N axially chiral pyrroles and indoles. Nature Communications (2024).
2. Carbene-catalyzed atroposelective synthesis of axially chiral styrenes. Nature Communications (2022).
3. Atropisomerism in the Pharmaceutically Relevant Realm. Accounts of Chemical Research (2022).
4. Asymmetric synthesis of N–N axially chiral compounds via organocatalytic atroposelective N -acylation. Chemical Science (2021).
5. Atroposelective Synthesis of Axially Chiral N‐Arylpyrroles by Chiral‐at‐Rhodium Catalysis. Angewandte Chemie International Edition (2020).