Synthesis of cannabinoids carrying ω-carboxy substituents: the cannabidiols, cannabinol and Δ1- and Δ6-tetrahydrocannabinols of this series

Abstract

A convenient synthesis of methyl 5-(3,5-dihydroxyphenyl)pentanoate adaptable for isotopic side-chain labelling is reported. Using acid-catalysed terpenylations involving (1S,4R)-(+)-trans-p-menthadienol, conditions for making (3R,4R)-o-and p-cannabidiols, (3R,4R)-Δ¹-THC's, (3R,4R)-Δ⁶-THC's and cannabinol in ω-carboxylated or methoxycarbonylated formats are described. Multigram amounts of the thermodynamically labile (3R,4R)-Δ¹-THC-ω-ester, readily convertible to the ω-acid, were made: the acid is a mammalian and microbial metabolite of Δ¹-THC and is of interest for membrane studies as well as for spin-labelling and radioimmunoassay purposes. A convenient synthesis of (2E,4E)-5-(3,5-dihydroxyphenyl)penta-2,4-dienoate allows its conversion into the crystalline Δ⁶-THC analogue having a conjugated dienoic esterside chain. Chromatographic information is tabulated for esters of the ω-carboxy cannabinoid series along with data for esters of the naturally occurring Ar-carboxylated cannabinoid series made synthetically in earlier work.