Asymmetric Dearomatization in Organic Synthesis

Dearomatization transforms planar aromatic compounds into three-dimensional cyclic frameworks, enabling rapid access to molecular architectures that are otherwise difficult to assemble. Asymmetric dearomatization employs chiral catalysts—ranging from organocatalysts and phosphoric acids to transition-metal complexes and photocatalysts—to overcome the high stability of aromatic systems while exerting precise stereochemical control. Key advances include divergent reaction pathways that furnish multiple stereoisomers from a single substrate by tuning temperature, catalyst enantiomer or reagent structure. Such strategies have been applied in the concise synthesis of natural products, drug-like scaffolds and agrochemicals, where three-dimensional shape and stereochemical purity are critical to bioactivity. Recent mechanistic insights into radical, polar and energy-transfer activation modes have broadened substrate scope to heteroarenes, phenols and indoles, highlighting the field’s capacity to unite diversity-oriented synthesis with late-stage functionalisation. Ongoing efforts focus on expanding catalyst design, enhancing enantioselectivity in challenging substrates and integrating photochemical and electrochemical approaches to further streamline access to complex, enantioenriched molecules.

Research from Nature Portfolio

Recent studies have demonstrated the asymmetric dearomatization of phenols via chiral phosphoric acid catalysis, achieving divergent intermolecular (3 + 2) cycloadditions and alkylation pathways to furnish cyclohexadienones and tetrahydroindolones bearing all-carbon quaternary stereogenic centres. Control of reaction temperature enables chemo-divergence, while catalyst enantiomer sequencing affords stereo-divergent access to all possible stereoisomers. Another milestone involves a photocatalytic N-centered radical cascade, wherein visible-light-driven iridium(III) catalysis triggers sulfonamidyl radical intermediates for carboamination/dearomatization cascades of arenes. The room-temperature, base-assisted process converts simple aromatics into 1,4-cyclohexadiene-fused sultams with high regioselectivity, showcasing the power of photochemical activation in asymmetric dearomatization.

Asymmetric Dearomatization in Organic Synthesis publication trend

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

Technical terms

Dearomatization: The chemical transformation of an aromatic system into a non-aromatic or partially saturated cyclic structure.

Catalytic Asymmetric Dearomatization (CADA): A dearomatization process mediated by chiral catalysts to induce enantioselectivity in the product.

Enantioselectivity: The preferential formation of one enantiomer over its mirror image in a chiral reaction, quantified by enantiomeric excess.

Heteroarene: An aromatic ring containing at least one atom other than carbon, such as nitrogen, oxygen or sulfur.

References

1. Photochemical dearomative skeletal modifications of heteroaromatics. Chemical Society Reviews (2024).
2. Catalytic asymmetric dearomatization of phenols via divergent intermolecular (3 + 2) and alkylation reactions. Nature Communications (2023).
3. Diversity‐Oriented Catalytic Asymmetric Dearomatization of Indoles with o‐Quinone Diimides. Advanced Science (2023).
4. Arene dearomatization through a catalytic N-centered radical cascade reaction. Nature Communications (2020).
5. Recent advances in the dearomative functionalisation of heteroarenes. Chemical Science (2022).