2020
DOI: 10.1021/acs.jnatprod.9b01284
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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… Show more

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Cited by 42 publications
(33 citation statements)
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“…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).…”
Section: Resultsmentioning
confidence: 99%
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“…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).…”
Section: Resultsmentioning
confidence: 99%
“…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.…”
Section: Introductionmentioning
confidence: 99%
“…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.…”
Section: Methodsmentioning
confidence: 99%
“…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.…”
Section: Methodsmentioning
confidence: 99%