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.

The thermal degradation of cannabichromene (CBC, 3) is dominated by cationic reactions and not by the pericyclic rearrangements observed in model compounds. The rationalization of these differences inspired the development of a process that coupled, in an aromatization-driven single operational step, the condensation of citral and alkylresorciniols to homoprenylchromenes and their in situ deconstructive annulation to benzo­[c]­chromenes. This process was applied to a total synthesis of cannabinol (CBN, 5) and to its molecular editing.

Cannabitwinol (CBDD, 3), the second member of a new class of dimeric phytocannabinoids in which two units are connected by a methylene bridge, was isolated from a hemp (Cannabis sativa L.) industrial extract. The structural characterization of cannabitwinol, complicated by broadening of 1H NMR signals and lack of expected 2D NMR correlations at room temperature, was fully carried out in methanol-d 4 at −30 °C. All the attempts to prepare CBDD by reaction of CBD with formaldehyde or its iminium analogue (Eschenmoser salt) failed, suggesting that this sterically congested dimer is the result of enzymatic reactions on the corresponding monomeric acids. Analysis of the cannabitwinol profile of transient receptor potential (TRP) modulation evidenced the impact of dimerization, revealing a selectivity for channels activated by a decrease of temperature (TRPM8 and TRPA1) and the lack of significant affinity for those activated by an increase of temperature (e.g., TRPV1). The putative binding modes of cannabitwinol with TRPA1 and TRPM8 were investigated in detail by a molecular docking study using the homology models of both channels.

Bergamot (Citrus bergamia) is cultivated in Southern Italy almost exclusively to produce the prized essential oil, a top note in several perfumes. The juice of bergamot, until recently poorly studied, is the object of a growing scientific interest due to its claimed activity to treat metabolic syndrome. The aim of this investigation was a detailed characterization of bergamot juice polyphenolic fraction (BPF) based on a UPLC-DAD-MS analysis complemented by preparative chromatographic separations, followed by NMR characterization of the isolated compounds. The combination of these techniques efficiently covered different classes of secondary metabolites, leading to the identification of 39 components, several of which had never been reported from bergamot. One of them, bergamjuicin (35), is a new flavanone glycoside, whose structure has been determined by MS and NMR techniques. The reported results could provide a guide for future routine analyses of BPF, a material of great nutraceutical and industrial interest.

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