The Oxidation of Phytocannabinoids to Cannabinoquinoids

Spurred by a growing interest in cannabidiolquinone (CBDQ, HU-313, 2 ) as a degradation marker and alledged hepatotoxic metabolite of cannabidiol (CBD, 1 ), we performed a systematic study on the oxidation of CBD ( 1 ) to CBDQ ( 2 ) 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 5 -periodinanes (Dess-Martin periodinane, 1-hydroxy-1λ 5 ,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 11 and the halogenated resorcinol 12 . The λ 5 -periodinane oxidation was general for phytocannabinoids, turning cannabigerol (CBG, 18 ), cannabichromene (CBC, 10 ), and cannabinol (CBN, 19 ) into their corresponding hydroxyquinones ( 20 , 21 , and 22 , 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 11 , the quinone dimers 3 and 23 , and the haloresorcinol 12 were inactive, suggesting a specific role for the monomeric hydroxyquinone moiety in the interaction with PPAR-γ.