A facile one-pot iodine-mediated synthesis of cannabinol and derivatives, and their intestinal epithelial barrier protective effect

Link:  https://doi.org/10.1016/j.tet.2024.134189

Title: A Facile One-pot Iodine-mediated Synthesis of Cannabinol and Derivatives, and their Intestinal Epithelial Barrier Protective Effect

Authors: Mongkonkorn Thanakorncharoenwit, Phanomsak Yukhet, Pichayapa Sukmak, Pawin Pongkorpsakol, Kriangsak Faikhruea, Chanat Aonbangkhen, Tanatorn Khotavivattana, Tirayut Vilaivan

Abstract:  

Cannabinol (CBN), an oxidation product of THC, is a minor cannabinoid that displays a wide range of medicinal properties with less psychoactive effects. Traditionally, CBN derivatives are synthesized from terpenoids and resorcinol derivatives using a complex multistep process, involving Friedel-Crafts alkylation, cyclization, and aromatization. In this study, we propose that iodine could serve as both a Lewis acid catalyst and an aromatization agent. As a result, a convenient one-pot iodine-mediated reaction between (1S,4R)-p-menthadienol and substituted resorcinol was developed. Various reaction parameters were explored, and the yields were assessed using quantitative 1 H NMR. The optimized conditions gave a 71 % isolated yield of 3-(1 ′ ,1 ′-dimethylheptyl) cannabinol (DMH-CBN) as a model substrate. Further investigation of the substrate scope demonstrated that this one-pot iodine-mediated synthesis could provide alkyl-substituted CBN derivatives in isolated yields ranging from 28 % to 63 %, including the C3-unsubstituted CBN, which could undergo bromination to give novel 4bromo and 2,4-dibromo derivatives in high yields. Citral was also successfully used in place of (1S,4R)-p-menthadienol as an inexpensive alternative starting material to give the natural CBN in 22 %. These newly synthesized CBN derivatives were studied for their protective effects on the intestinal epithelial barrier using the transepithelial electrical resistance (TER) assay, suggesting that the 2,4-diethyl, 4-bromo, and 2,4-dibromo derivatives of C3-unsubstituted CBN exhibited superior activity compared to natural CBN with low toxicity. This indicates their potential as novel candidates in the cannabinoid series, contributing to the anti-inflammatory activity.

Cite this: 

Thanakorncharoenwit, M.; Sukmak, P.; Faikhruea, K.; Yukhet, P.; Pongkorpsakol, P.; Aonbangkhen, C.; Khotavivattana, T.; Vilaivan, T. "A Facile One-pot Iodine-mediated Synthesis of Cannabinol and Derivatives, and their Intestinal Epithelial Barrier Protective Effect" Tetrahedron 2024, 165, 134189. https://doi.org/10.1016/j.tet.2024.134189