Abstract:
Cannabinol (CBN) is a minor cannabinoid that exhibits a broad range of medicinal activities without psychoactive effects. CBN derivatives have been typically synthesized from a terpenoid and a resorcinol derivative, through a multistep reaction including the Friedel-Crafts alkylation, cyclization, and aromatization. In this study, we envisioned that iodine could act as a Lewis acid catalyst and an aromatization agent. Consequently, we developed a one-pot iodine-mediated reaction between (1S,4R)-p-menthadienol and 5-(1,1-dimethylheptyl)resorcinol for the synthesis of 3-(1,1-dimethylheptyl)cannabinol (DMH-CBN). Various reaction parameters were evaluated, and the reaction yields were analyzed by quantitative 1H NMR. The optimized reaction conditions were found to be 1.5 and 1.0 equivalent of starting materials with 5.0 equivalents of iodine in toluene at refluxing temperature for 1 hr, giving DMH-CBN in 71% isolated yield. This reaction under the microwave-assisted condition gave the same product in 30% NMR yield. The same method could be applied to the synthesis of natural CBN from citral as an inexpensive terpenoid starting material and olivetol, providing the expected product in 22% isolated yield. Substrate scope investigation revealed that this one-pot iodine-mediated synthesis of CBN could produce 28–63% isolated yields of alkyl-substituted CBN derivatives, including the C3-unsubstituted CBN. This unsubstituted CBN reacted with 1.0 or 2.0 equivalents of N-bromosuccinimide to yield 4-bromo and 2,4-dibromo derivatives at 63% and 90% isolated yield, respectively. However, this condition was incompatible with resorcinols bearing electron-withdrawing groups, yielding no or very small amounts of the desired product. Some synthesized CBN derivatives were evaluated for their protective role in the epithelial barrier through the transepithelial electrical resistance (TER) assay. The results indicated that 2,4-diethyl CBN, 4-bromo, and 2,4-dibromo derivatives of C3-unsubstituted CBN showed better activities than natural CBN. This suggests that they could potentially serve as new candidates from the cannabinoid series, aiding in the resealing of tight junctions.
