Pauson-Khand Reaction Strategies in Natural Product Synthesis
Summary
The Pauson–Khand reaction is a cornerstone in modern synthetic chemistry for the rapid assembly of cyclopentenone cores via a formal [2+2+1] cycloaddition of an alkyne, an alkene and carbon monoxide under transition-metal catalysis. Traditionally mediated by cobalt carbonyl complexes, recent advances have extended catalysis to rhodium, palladium and other metals, unlocking improved reactivity, regioselectivity and stereocontrol. Intramolecular variants enable the construction of densely functionalised polycyclic frameworks, while intermolecular processes facilitate modular access to diverse cyclopentenones. Strategic tuning of ligands, substrate design and reaction parameters has led to enantioselective protocols, the incorporation of heteroatom tethers and the exploitation of polar substituents for enhanced selectivity. These developments have been instrumental in total syntheses of terpenes, alkaloids and other architecturally complex natural products, where the cyclopentenone motif often serves as a platform for further ring expansions, oxidations and cascade sequences. Computational studies have elucidated key transition states and energy profiles, guiding the design of chiral catalysts and expanding substrate scope to challenging 1,1-disubstituted alkenes and fluoroalkylated enynes. Across diverse targets, the Pauson–Khand reaction remains uniquely attractive for the convergent assembly of cyclopentanoid frameworks with precise control over stereochemistry and functionality.
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Pauson-Khand Reaction Strategies in Natural Product Synthesis publication trend
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Technical terms
Pauson–Khand reaction: A transition-metal-catalysed formal [2+2+1] cycloaddition of an alkyne, an alkene and CO to form cyclopentenones.
Cyclopentenone: A five-membered cyclic enone that serves as a versatile scaffold in organic synthesis.
Enyne: A molecule containing both an alkene and an alkyne functionality, typically separated by a tether.
Enantioselectivity: The preferential formation of one enantiomer over the other in a chiral reaction.
Metallacycle: A cyclic organometallic intermediate formed by coordination of unsaturated substrates to a metal centre.
References
- Enantioselective Rhodium‐Catalyzed Pauson–Khand Reactions of 1,6‐Chloroenynes with 1,1‐Disubstituted Olefins. Angewandte Chemie International Edition (2023).
- Systematic Parameter Determination Aimed at a Catalyst-Controlled Asymmetric Rh(I)-Catalyzed Pauson–Khand Reaction. ACS Catalysis (2024).
- Evolution of Pauson-Khand Reaction: Strategic Applications in Total Syntheses of Architecturally Complex Natural Products (2016–2020). Catalysts (2020).
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