Asymmetric Synthesis of Allene Compounds

The asymmetric synthesis of allene compounds centres on the controlled construction of axial chirality distributed over a cumulated diene framework. Such chiral allenes represent versatile intermediates in the preparation of natural products, pharmaceuticals and agrochemicals, owing to their unique geometry and reactivity. Traditional approaches have relied on pre-functionalised propargylic substrates undergoing nucleophilic substitution or metal-catalysed rearrangements, while modern strategies increasingly exploit radical pathways, photoredox activation and dual-catalysis schemes to access highly substituted targets with excellent enantioselectivity. Key challenges include suppressing racemisation of the non-rigid allene axis, achieving broad substrate scope under mild conditions and integrating sustainable catalysts. Recent advances have demonstrated that combination of light-driven processes with earth-abundant metals, or judicious ligand design in copper and chromium systems, can deliver tetrasubstituted and exocyclic allenes in high yield and enantiomeric excess. Mechanistic insights from computational studies and kinetic experiments now guide rational catalyst development, enabling practical, scalable routes to both simple and functionally dense allenes with precise stereochemical control.

Research from Nature Portfolio

Recent studies have introduced a photoredox/cobalt-catalysed protocol for regio-, diastereo- and enantio-selective propargylation of aldehydes via propargyl radicals. This method transforms racemic propargylic carbonates into homopropargyl alcohols with broad functional group tolerance and high stereoconvergence. Mechanistic analysis and density functional theory reveal the radical nature of the stereocontrolling step and the origin of enantioinduction. In parallel, the merger of photoredox and chromium catalyses has enabled an asymmetric three-component 1,4-dialkylation of 1,3-enynes to produce chiral allenols, featuring simultaneous control of axial and central chirality under redox-neutral conditions. Additionally, a copper(I)-catalysed intramolecular reductive coupling of 1,3-enynes to cyclohexadienones provides optically pure exocyclic allenes bearing cis-hydrobenzofuran and related frameworks in excellent yield, diastereo- and enantioselectivity.

Asymmetric Synthesis of Allene Compounds publication trend

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

Technical terms

Axial chirality: Stereochemical feature arising from restricted rotation about a cumulene axis, resulting in non-superimposable enantiomers. 1,3-Enyne: Conjugated alkyne-alkene substrate commonly employed in allene synthesis via difunctionalisation. Photoredox catalysis: Visible-light-driven electron transfer process enabling radical generation under mild conditions. Propargylic carbonate: Activated alkyne precursor bearing a carbonate leaving group used for nucleophilic substitution and radical reactions. B(MIDA) moiety: Boron unit masked by a N-methyliminodiacetate ligand that modulates reactivity and prevents over-isomerisation of allenes.

References

1. Photoredox cobalt-catalyzed regio-, diastereo- and enantioselective propargylation of aldehydes via propargyl radicals. Nature Communications (2023).
2. NHC‐Au‐Catalyzed Isomerization of Propargylic B(MIDA)s to Allenes and Double Isomerization of Alkynes to 1,3‐Dienes. Advanced Science (2024).
3. Decarboxylative 1,4-carbocyanation of 1,3-enynes to access tetra-substituted allenes via copper/photoredox dual catalysis. Chemical Science (2021).
4. Asymmetric 1,4-functionalization of 1,3-enynes via dual photoredox and chromium catalysis. Nature Communications (2022).
5. Copper(I)-catalyzed diastereo- and enantio-selective construction of optically pure exocyclic allenes. Nature Communications (2020).
6. Rapid Asymmetric Synthesis of Disubstituted Allenes by Coupling of Flow‐Generated Diazo Compounds and Propargylated Amines. Angewandte Chemie International Edition (2017).