Synthesis of the Major Mammalian Metabolites of THCV

Abstract

A simple synthesis of the major oxidized metabolites in mammalian tissues of (−)-Δ 9 -tetrahydrocannabivarin (THCV) (1) has been accomplished by kinetic studies of allylic oxidation using SeO 2 on botanically derived THCV with the aim to yield primary and secondary allylic alcohols concurrently. This synthetic approach led to the preparation of numerous THCV derivatives, including two new compounds, 8α-hydroxy-Δ 9 -tetrahydrocannabivarin (2) and 8β-hydroxy-Δ 9 -tetrahydrocannabivarin (3), and the known compounds 11-hydroxy-Δ 9 -tetrahydrocannabivarin (4) and Δ 9 -tetrahydrocannabivarin-11-oic acid (5), without affecting the C-10a stereogenic center in the natural precursor and without formation of tricyclic dibenzopyran derivatives. This simple synthetic methodology could be useful to investigate the pharmacological role of THCV metabolites at, among others, the endocannabinoid CB1 and CB2 receptors for which THCV reportedly acts as respectively a neutral antagonist and partial agonist.