Acid-catalysed terpenylations of olivetol in the synthesis of cannabinoids

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Abstract
Examination of the toluene-p-sulphonic acid-catalysed reaction of (1S,2S,3R,6R)-(+)-trans-car-2-ene epoxide with olivetol shows that, inconsistently with the accepted mechanism, (3R,4R)-(–)-o- and -p-cannabidiols are produced as well as (3R,4R)-(–)-Δ1-and Δ6-tetrahydrocannabinols. Evidence is now presented that, as in Petrzilka's reaction employing chiral p-mentha-2,8-dien-1-ols, the reacting species is the delocalised (4R)-p-mentha-2,8-dien-1-yl cation (9). Similar terpenylation using (1S,3S,4R,6R)-(+)-trans-car-3-ene epoxide shows that besides the reported (–)-Δ6-THC, o- and p-cannabidiols, Δ1-THC and Δ4,8-iso-THC can also be produced. The nature of the products, the chirality, and the characteristics of the reaction implicate again the delocalised cation (9). Its formation via Kropp-type rearrangement is excluded and a pathway leading to (4R)-p-mentha-2,6,8-triene, which on protonation gives (9), is proposed. Protonated on C-8, the triene can be trapped and isolated as (4R)-p-mentha-2,6-dien-8-ol. The latter, made in (±)-form from citral, proved to be an excellent terpenylating agent for producing cannabinoids. Terpenylation of olivetol by the pinanes (1S,4S,5S)-(–)-cis-verbenol and (1R,5S,7R)-(+)-cis-chrysanthenol is compared. A major drawback of the latter is partial racemisation which occurs in the verbenone–chrysanthenone isomerisation during its photochemical preparation. Whilst Δ1-THC cannot be directly obtained from verbenol, its tertiary allylic cation permits a much higher yielding terpenylation than the secondary cation from chrysanthenol.

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