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 λ5-periodinanes (Dess-Martin periodinane, 1-hydroxy-1λ5,2-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 λ5-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.
The Oxidation of Phytocannabinoids to Cannabinoquinoids / Caprioglio, D.; Mattoteia, D.; Pollastro, F.; Negri, R.; Lopatriello, A.; Chianese, G.; Minassi, A.; Collado, J. A.; Munoz, E.; Taglialatela-Scafati, O.; Appendino, G.. - In: JOURNAL OF NATURAL PRODUCTS. - ISSN 0163-3864. - 83:5(2020), pp. 1711-1715. [10.1021/acs.jnatprod.9b01284]
The Oxidation of Phytocannabinoids to Cannabinoquinoids
Lopatriello A.;Chianese G.;Taglialatela-Scafati O.
Penultimo
Conceptualization
;
2020
Abstract
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 λ5-periodinanes (Dess-Martin periodinane, 1-hydroxy-1λ5,2-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 λ5-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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
