The Oxidation of Phytocannabinoids to Cannabinoquinoids.

Spurred by a growing interest in cannabidiolquinone (CBDQ, HU-313, ) as a degradation marker and alledged hepatotoxic metabolite of cannabidiol (CBD, ), we performed a systematic study on the oxidation of CBD () to CBDQ () under a variety of experimental conditions (base-catalyzed aerobic oxidation, oxidation with metals, oxidation with hypervalent iodine reagents). The best results in terms of reproducibility and scalability were obtained with λ-periodinanes (Dess-Martin periodinane, 1-hydroxy-1λ,2-benziodoxole-1,3-dione (IBX), and SIBX, a stabilized, nonexplosive version of IBX). With these reagents, the oxidative dimerization that plagues the reaction under basic aerobic conditions was completely suppressed. A different reaction course was observed with the copper(II) chloride-hydroxylamine complex (Takehira reagent), which afforded a mixture of the hydroxyiminodienone and the halogenated resorcinol . The λ-periodinane oxidation was general for phytocannabinoids, turning cannabigerol (CBG, ), cannabichromene (CBC, ), and cannabinol (CBN, ) into their corresponding hydroxyquinones (, , and , respectively). All cannabinoquinoids modulated to a various extent peroxisome proliferator-activated receptor gamma (PPAR-γ) activity, outperforming their parent resorcinols in terms of potency, but the iminoquinone , the quinone dimers and , and the haloresorcinol were inactive, suggesting a specific role for the monomeric hydroxyquinone moiety in the interaction with PPAR-γ.