The Oxidation of Phytocannabinoids to Cannabinoquinoids

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 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.

Regiodivergent Synthesis of ortho‐ and para‐Cannabinoquinones

“…Cannabinoquinones are chemically unstable, and O-methylation was investigated as a stabilizing maneuver alternative to the aza-Michael addition/dehydrogenation strategy that led to the discovery of VCE004.8. [7] Two alkylation strategies were investigated, namely, the direct methylation of CBDQ (3a), the SIBX oxidation product of CBD, [9] or, alternatively, the SIBX oxidation of O-methyl CBD (1b), a natural constituent of cannabis. [12] Despite the use of the same iodane oxidant, the two strategies afforded a different quinone as the only reaction product (3b and 10, respectively) (Scheme 2).…”

“…After an initial and then faded excitement for the selective anti‐cancer activity of cannabinoquinoids, [ 3 ] interest was re‐kindled by the discovery of the immunomodulating properties of VCE.004.8 ( 9 ), [ 7 ] a 2‐aminoalkylderivative of cannabidiolquinone (CBDQ, 3a ) currently undergoing Phase II clinical development under orphan drug designation in EU and USA and fast track status in USA for systemic sclerosis, an autoimmune disease. [ 8 ] An improved and scalable synthesis of CBDQ ( 3a ) was developed using SIBX, [ 9 ] a non‐explosive formulation of the λ 5 ‐iodane iodoxybenzoic acid (IBX) as the oxidant, [ 10 ] while the electrochemical version of the oxidation of cannabinoids to cannabinoquinoids was investigated in the context of the development of a marijuana breathalyzer based on the formation of the quinone 7a from Δ 9 ‐THC ( 5a ). [ 11 ] These developments provided a rationale to systematically explore the chemical and biological space of cannabinoquinoids.…”

Isomeric O-methyl cannabidiolquinones with dual BACH1/NRF2 activity

“…O-Methyl para -cannabidiolquinone (Compound 2) : To a cooled (ice bath) solution of cannabidiolquinone ( Fig. 1 B (4)) (1.87 g, 5.69 mmol) [ 42 ] in DMF (19 mL), solid NaHCO 3 (0.95 g, 11.31 mmol) was added. After stirring for 10 min, methyl iodide (1.75 g, 28.11 mmol) was added, and the resulting mixture was stirred overnight at room temperature.…”

IsomericO-methyl cannabidiolquinones with dual BACH1/NRF2 activity

“…To a cooled (ice bath) solution of cannabidiolquinone (Fig. 1B (4)) (1.87 g, 5.69 mmol) [42] in DMF (19 mL), solid NaHCO 3 (0.95 g, 11.31 mmol) was added. After stirring for 10 min., methyl iodide (1.75 g, 28.11 mmol) was added, and the resulting mixture was stirred overnight at room temperature.…”