NIS-Promoted Domino Electrophilic Cyclization of 2-Prenyl-2H-pyrans Toward iso-THC Related Systems.

Gurgone L.; Adessi T.; Huck J.; Pellegrinet S.; La-Venia A.; Riveira M. · The Journal of organic chemistry · 2026

**Background & Methods** This is a synthetic chemistry review describing a novel domino electrophilic cyclization reaction using N-iodosuccinimide (NIS) to promote cascade cyclization of prenylated 2H-pyrans. The synthetic strategy involves a two-step process: initial Knoevenagel/oxa-6π electrocyclization between 1,3-cyclohexanediones and citral to generate prenylated 2H-pyran intermediates, followed by NIS-promoted electrophilic cascade cyclization to form final products. **Key Findings** • The NIS-promoted domino reaction successfully generated iodo-substituted bridged-tricyclic systems with moderate to good yields, demonstrating efficient conversion of prenylated 2H-pyran substrates into complex heterocyclic frameworks. • The cyclization reaction proceeded with high regio- and diastereoselective control, indicating predictable and stereospecific formation of the desired tricyclic architectures with defined stereochemistry. • The resulting iodo-substituted products possess structural features related to tetrahydrocannabinol (THC) and iso-THC natural products, providing a practical synthetic methodology for constructing biologically active heterocyclic systems that may serve as precursors or analogues for cannabinoid research. **Dosage & Administration** Not reported. This is a synthetic chemistry study; dosage and administration parameters are not applicable. **Safety & Adverse Effects** Not reported. This study focuses on synthetic methodology and chemical transformations rather than biological safety or adverse effects in biological systems. **Evidence Quality** This review paper presents synthetic chemistry methodology rather than clinical or biological research. As a review article rather than original experimental data, the evidence quality is limited to the synthesis literature compiled and discussed by the authors. The study lacks clinical evaluation, biological testing, and in vivo/in vitro pharmacological validation. While the synthetic approach appears sound based on established organic chemistry principles and domino reaction strategies, direct applicability to cannabinoid research remains theoretical. The proximity to THC-related structures suggests potential future relevance for synthetic cannabinoid research, but no actual biological activity, safety profile, or therapeutic potential was evaluated. Further experimental validation and biological characterization would be necessary to establish clinical relevance.

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