Abstract
Hexahydrocannabinol (HHC), a hydrogenated derivative of Δ(9)-tetrahydrocannabinol (Δ(9)-THC), is a semi-synthetic cannabinoid marketed as an alternative to Δ(9)-THC. Its hydroxylated metabolite, 8-hydroxyhexahydrocannabinol (8-OH-HHC), exists as four stereoisomers: (6aR,8R,9R,10aR), (6aR,8S,9S,10aR), (6aR,8S,9R,10aR), and (6aR,8R,9S,10aR). However, the lack of reference standards has hindered pharmacokinetic and forensic studies. This work reports the first stereoselective synthesis and structural confirmation of all four 8-OH-HHC stereoisomers. Two strategies were employed: hydroboration-oxidation and epoxidation-reduction. Hydroboration of Δ(8)-THC with BH(3)·THF followed by oxidation predominantly produced anti-isomers (6aR,8R,9R,10aR) and (6aR,8S,9S,10aR) in moderate yields, along with small amounts of syn-isomer (6aR,8S,9R,10aR), suggesting an atypical mechanistic pathway. In contrast, syn-isomers (6aR,8S,9R,10aR) and (6aR,8R,9S,10aR) were accessed via epoxidation of Δ(8)-THC acetate using mCPBA and subsequent reduction with NaBH(3)CN/BF(3)·OEt(2), affording the desired products with moderate selectivity. Absolute configurations were confirmed by nuclear Overhauser effect spectroscopy (NOESY). These methods will facilitate future pharmacokinetic and forensic research and support the development of improved detection strategies.