Friedel-Crafts alkylation of resorcinols with ( S)- cis-verbenol and subsequent cyclization allows the construction of the tetrahydrodibenzopyran core of (-)-Δ-THC which is also found in other natural products in one step. Using a benzofuryl substituted resorcinol, followed by diastereoselective hydroboration and oxidative or reductive workup, directly provides (-)-machaeriol B and D in 42% and 43% overall yields. Bromoresorcinol as a coupling partner delivers Br-THC that can be applied for late-stage diversification by Suzuki-Miyaura cross-coupling to readily access (-)-Δ-THC analogues.
A two-step synthesis of para (−)-Δ 8 -THC-OTf that can be used as building block for late-stage introduction of side chains to the tetrahydrodibenzopyran core of THC by cross-coupling chemistry is presented. No protecting groups are needed, and (−)-Δ 8 -THC-OTf can be cross-coupled to access derivatives bearing pharmacologically interesting side chains such as benzoyl units, sterically demanding groups, aromatic chains, and alkenyl groups. This approach allowed an efficient fourstep synthesis of (−)-Δ 8 -THC from commercial materials.Cannabis sativa L. contains more than 70 cannabinoids 1 of which the main psychoactive compound (−)-Δ 9 -THC was identified in 1964 by Gaoni and Mechoulam, 2 and more than 20 years later the cannabinoid receptors CB 1 and CB 2 were discovered. 3 Since CBs are involved in many different physiological processes, 4 understanding the structure−activity relationship of THC plays an important role in drug development. Under acidic conditions, (−)-Δ 9 -THC isomerizes to its thermodynamically more stable double bond isomer (−)-Δ 8 -THC (Figure 1). Although the Δ 8 isomer is less
Mycotoxins are secondary plant metabolites that have been found to cause severe diseases in humans and livestock. Exposure can take place on a daily basis since mycotoxins can be found not only in food, animal food, and dietary supplements but also in materials used in buildings. For this work, the Alternaria toxins alternariol (AOH) and alternariol methyl ether (AME) are chosen as representatives for this relevant compound class and are investigated regarding their oxidative phase I metabolism using a combination of electrochemical (EC) oxidation and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). This previously established method has been proven to be a valuable tool for the electrochemical simulation of certain phase I metabolic reactions. A comparison of the electrochemically generated products with those formed during microsomal incubation demonstrates the potential of the method for the successful prediction of the main phase I metabolic reactions of mycotoxins. It can thus find use as a supportive method in the elucidation of the metabolic pathways of various mycotoxins.
(−)-Δ-9-tetrahydrocannabinol ((−)-Δ-9-THC) is the main psychoactive constituent in cannabis. During phase I metabolism, it is metabolized to (−)-11-hydroxy-Δ-9-tetrahydrocannabinol ((−)-11-OH-Δ-9-THC), which is psychoactive, and to (−)-11-nor-9-carboxy-Δ-9-tetrahydrocannabinol ((−)-Δ-9-THC-COOH), which is psychoinactive. It is glucuronidated during phase II metabolism. The biotransformation of (−)-Δ-9-tetrahydrocannabinol-glucuronide ((−)-Δ-9-THC-Glc) and (−)-11-nor-9-carboxy-Δ-9-tetrahydrocannabinol-glucuronide ((−)-Δ-9-THC-COOH-Glc) is well understood, which is mainly due to the availability of commercial reference standards. Since such a standardized reference is not yet available for (−)-11-hydroxy-Δ-9-tetrahydrocannabinol-glucuronide ((−)-11-OH-Δ-9-THC-Glc), its biotransformation is harder to study and the nature of the glucuronide bonding—alcoholic and/or phenolic—remains unclear. Consequently, the aim of this study was to investigate the biotransformation of (−)-11-OH-Δ-9-THC-Glc in vitro as well as in vivo and to identify the glucuronide by chemically synthesis of a reference standard. For in vitro analysis, pooled human S9 liver fraction was incubated with (−)-Δ-9-THC. Resulting metabolites were detected by high-performance liquid chromatography system coupled to a high-resolution mass spectrometer (HPLC-HRMS) with heated electrospray ionization (HESI) in positive and negative full scan mode. Five different chromatographic peaks of OH-Δ-9-THC-Glc have been detected in HESI positive and negative mode, respectively. The experiment set up according to Wen et al. indicates the two main metabolites being an alcoholic and a phenolic glucuronide metabolite. In vivo analysis of urine (n = 10) and serum (n = 10) samples from cannabis users confirmed these two main metabolites. Thus, OH-Δ-9-THC is glucuronidated at either the phenolic or the alcoholic hydroxy group. A double glucuronidation was not observed. The alcoholic (−)-11-OH-Δ-9-THC-Glc was successfully chemically synthesized and identified the main alcoholic glucuronide in vitro and in vivo. (−)-11-OH-Δ-9-THC-Glc is the first reference standard for direct identification and quantification. This enables future research to answer the question whether phenolic or alcoholic glucuronidation forms the predominant way of metabolism.
Further investigation of 2D NMR data of compound 5b revealed that the structures of compounds 4 and 5a−c in Scheme 3 were misassigned. Scheme 3. One-Step Synthesis of ortho-(−)-Δ 8 -Br-THC and Subsequent Suzuki−Miyaura Cross-Coupling Provide ortho-(−)-Δ 8 -THC Derivatives with Different Side Chains The scheme is corrected by changing the side chains of the (−)-Δ 8 -THC derivatives 5a−c and of the bromo substituent of precursor Br-THC (4) to the ortho position on the tetrahydrodibenzopyran core. The wrong assignment was based on a literature report published by Dethe et al. in 2015 describing a similar BF 3 •OEt 2 catalyzed Friedel−Crafts reaction of 1-bromo-3,5-dihydroxybenzene with a monoterpenoid derivative. 1 The authors suggested para-(−)-Δ 9 -Br-THC as the product. In a recent publication, also Trauner and Carreira mentioned significant differences in NMR spectra of their and the Dethe para-(−)-Δ 9 -Br-THC compound. 2The corrected Supporting Information containing exemplary 2D-NMR data of compound 5b to proof the ortho substitution has been provided. The authors sincerely apologize for any inconvenience this may have caused.
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