Total Synthesis of Natural Products via Cycloaddition Reactions
Summary
Total synthesis of natural products via cycloaddition reactions brings together strategic bond construction with the precision of pericyclic processes to assemble complex molecular frameworks from simple precursors. Cycloaddition reactions—characterised by the concerted formation of cyclic structures through the interaction of unsaturated partners—enable the generation of multiple bonds and stereocentres in a single operation, enhancing step economy and molecular complexity. Within this domain, Diels–Alder cycloadditions and their variants have been instrumental in forging six-membered rings, while [2+2+2] cyclotrimerisations, [4+2] and [3+2] processes extend the repertoire to aromatic and heterocyclic targets. Advances in catalyst design, notably in transition-metal and organocatalytic systems, have broadened substrate scope and permitted enantioselective control. Moreover, inverse electron demand strategies exploit electron-rich dienophiles and electron-poor dienes to access otherwise challenging substitution patterns. The concerted nature of cycloaddition underpins predictable stereochemical outcomes, critical for the total synthesis of bioactive terpenes, alkaloids and polyketides. Contemporary research emphasises tandem and cascade cycloaddition sequences, integrating theoretical insights to fine-tune reactivity and selectivity. The global significance of this field extends to sustainable synthesis, enabling efficient routes to pharmacologically relevant scaffolds and natural product analogues through environmentally benign protocols.
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Total Synthesis of Natural Products via Cycloaddition Reactions publication trend
The graph below shows the total number of articles in total synthesis of natural products via cycloaddition reactions across all publications each year (not limited to Nature Index journals).
Technical terms
Cycloaddition reaction: A pericyclic process in which two or more unsaturated components combine to form a cyclic adduct in a concerted fashion.
Diels–Alder reaction: A [4+2] cycloaddition between a conjugated diene and a dienophile to form a six-membered ring.
Inverse electron demand: A cycloaddition variant where an electron-poor diene reacts with an electron-rich dienophile to invert normal polar interactions.
Cyclotrimerisation: A [2+2+2] cycloaddition that joins three unsaturated units, typically alkynes, to generate aromatic rings.
Dienophile: An electron-deficient unsaturated molecule that reacts with a diene in cycloaddition reactions.
References
- Collective Synthesis of Illudalane Sesquiterpenes via Cascade Inverse Electron Demand (4 + 2) Cycloadditions of Thiophene S,S‑Dioxides. Journal of the American Chemical Society (2022).
- Regioselective [2 + 2 + 2] Alkyne Cyclotrimerizations to Hexasubstituted Benzenes: Syntheses of Fomajorin D and Fomajorin S. The Journal of Organic Chemistry (2024).
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