Stereoselective Synthesis and Structural Confirmation of All Four 8-Hydroxyhexahydrocannabinol Stereoisomers

Hexahydrocannabinol (HHC), a hydrogenated derivative of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), is a semi-synthetic cannabinoid marketed as an alternative to Δ⁹-THC. Its hydroxylated metabolite, 8-hydroxyhexahydrocannabinol (8-OH-HHC), exists as four stereoisomers: (6a<i>R</i>,8<i>R</i>,9<i>R</i>,10a<i>R</i>), (6a<i>R</i>,8<i>S</i>,9<i>S</i>,10a<i>R</i>), (6a<i>R</i>,8<i>S</i>,9<i>R</i>,10a<i>R</i>), and (6a<i>R</i>,8<i>R</i>,9<i>S</i>,10a<i>R</i>). 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 Δ⁸-THC with BH₃·THF followed by oxidation predominantly produced <i>anti</i>-isomers (6a<i>R</i>,8<i>R</i>,9<i>R</i>,10a<i>R</i>) and (6a<i>R</i>,8<i>S</i>,9<i>S</i>,10a<i>R</i>) in moderate yields, along with small amounts of <i>syn</i>-isomer (6a<i>R</i>,8<i>S</i>,9<i>R</i>,10a<i>R</i>), suggesting an atypical mechanistic pathway. In contrast, <i>syn</i>-isomers (6a<i>R</i>,8<i>S</i>,9<i>R</i>,10a<i>R</i>) and (6a<i>R</i>,8<i>R</i>,9<i>S</i>,10a<i>R</i>) were accessed via epoxidation of Δ⁸-THC acetate using <i>m</i>CPBA and subsequent reduction with NaBH₃CN/BF₃·OEt₂, 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.