Intramolecular Diels-Alder Chemistry for Natural Product Synthesis

Over recent decades, the intramolecular Diels–Alder reaction has emerged as a cornerstone transformation in the assembly of polycyclic frameworks characteristic of many natural products. By tethering a diene to a dienophile within the same molecule, this pericyclic process forges two carbon–carbon bonds in a single operation, imparting high levels of regio- and stereocontrol. The constrained geometry of the tether often enhances reaction rates and selectivity, enabling the rapid construction of complex ring systems such as cis-fused bicyclic and bridged motifs. This approach underpins total syntheses of alkaloids, terpenoids and polyketides, delivering multiple stereocentres with predictable configurations. Recent advances have extended the methodology to tandem and cascade sequences, merging intramolecular cycloaddition with subsequent functionalisation steps. Computational studies have elucidated key transition-state features, guiding the design of tethers and substituents to modulate activation barriers and diastereoselectivity. Moreover, the adoption of greener reaction media and room-temperature protocols has addressed sustainability concerns, increasing the appeal of intramolecular Diels–Alder chemistry in complex molecule synthesis.

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Intramolecular Diels-Alder Chemistry for Natural Product Synthesis publication trend

The graph below shows the total number of articles in intramolecular diels-alder chemistry for natural product synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Diene: A molecule containing two conjugated double bonds that participates in cycloaddition reactions.

Dienophile: A reactive alkene or alkyne that undergoes cycloaddition with a diene to form a six-membered ring.

Pericyclic reaction: A concerted transformation in which bonding changes occur through a cyclic reorganisation of electrons.

Stereoselectivity: The preferential formation of one stereoisomer when multiple configurations are possible.

References

1. Room Temperature Diels–Alder Reactions of 4-Vinylimidazoles. Molecules (2024).
2. Halogenation effects in intramolecular furan Diels–Alder reactions: broad scope synthetic and computational studies. Organic & Biomolecular Chemistry (2013).
3. Unusual Structure-Energy Correlations in Intramolecular Diels–Alder Reaction Transition States. Molecules (2014).
4. Sustainable tandem acylation/Diels–Alder reaction toward versatile tricyclic epoxyisoindole-7-carboxylic acids in renewable green solvents. Beilstein Journal of Organic Chemistry (2024).