Cannabidiol as the Substrate in Acid-Catalyzed Intramolecular Cyclization

Abstract

The chemical reactivity of cannabidiol is based on its ability to undergo intramolecular cyclization driven by the addition of a phenolic group to one of its two double bonds. The main products of this cyclization are Δ9-THC (trans-Δ-9-tetrahydrocannabinol) and Δ8-THC (trans-Δ-8-tetrahydrocannabinol). These two cannabinoids are isomers, and the first one is a frequently investigated psychoactive compound and pharmaceutical agent. The isomers Δ8-iso-THC (trans-Δ-8-iso-tetrahydrocannabinol) and Δ4(8)-iso-THC (trans-Δ-4,8-iso-tetrahydrocannabinol) have been identified as additional products of intramolecular cyclization. The use of Lewis and protic acids in different solvents has been studied to investigate the possible modulation of the reactivity of CBD (cannabidiol). The complete NMR spectroscopic characterizations of the four isomers are reported. High-performance liquid chromatography analysis and 1H NMR spectra of the reaction mixture were used to assess the percentage ratio of the compounds formed.

Synthetic Strategies for Rare Cannabinoids Derived from Cannabis sativa

“…Cannabinol (CBN or CBN-C 5 , 6a ), which differs from Δ 9 -THC ( 4a ) only by an aromaticity of the ring in the terpene moiety of the cannabinoid, has been shown to have higher receptor-binding affinity for CB1 than CB2. , The first preclinical studies of this biphenyl compound for the treatment of wide-angle glaucoma and Epidermolysis bullosa have shown some promising results. ,, This rare cannabinoid has been synthesized via aromatization of THC-C 5 ( 4a ) . However, Razdan et al found that not all isomers with a THC scaffold can convert into CBN-C 5 .…”

Total Synthesis of (−)‐Cannabidiol‐C4

“…Therefore, other possible reactions were considered, avoiding the use of acidic conditions, as cyclization of the substrate to THC-derivative isomers would be induced. [31] The use of a large excess of sodium ethanethiolate (EtSNa) in dry DMF at 140 °C in a sealed tube led to some encouraging results. By monitoring the reaction progression by HPLC, it was evident that the removal of the first methyl proceeded smoothly, but the second was more difficult.…”

“…Although many procedures report the use of methylmagnesium iodide (MeMgI) as a successful protocol for the demethylation of CBD, [16,27–30] no acceptable results have been obtained with this method. Therefore, other possible reactions were considered, avoiding the use of acidic conditions, as cyclization of the substrate to THC‐derivative isomers would be induced [31] . The use of a large excess of sodium ethanethiolate (EtSNa) in dry DMF at 140 °C in a sealed tube led to some encouraging results.…”

Cannabis Vaping: Existing and Emerging Modalities, Chemistry, and Pulmonary Toxicology

“…The ring-closing reaction to Δ 9 -THC is accompanied by the double-bond isomerization to Δ 8 -THC, which also occurs under acid catalysis, and generation of the latter may be favored by longer reaction times. The use of CBD as a substrate for the synthesis of other cannabinoids has been recently reviewed, and additional products that may result from these processes have been described. , Crude online guides exist for this synthesis, and it has been suggested that some Δ 8 -THC CEC manufacturers do not include a postreaction purification step, potentially resulting in traces of sulfuric acid, hydrochloric acid, trifluoroacetic acid, or p -toluenesulfonic acid . One analysis by the U.S. Cannabis Council found that a majority of CEC products tested contained Δ 9 -THC concentrations far in excess of the 0.3% Δ 9 -THC required to not meet the DEA’s definition “marijuana extract” and were also contaminated with residual solvents and heavy metals .…”