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

TL;DR

This paper describes the first synthesis of all four 8-hydroxyhexahydrocannabinol stereoisomers, enabling future pharmacokinetic and forensic studies.

Contribution

The first stereoselective synthesis and structural confirmation of all four 8-OH-HHC stereoisomers.

Findings

Hydroboration–oxidation produced anti-isomers with moderate yields and small amounts of syn-isomers.

Epoxidation–reduction provided syn-isomers with moderate selectivity.

NOESY confirmed the absolute configurations of the synthesized stereoisomers.

Abstract

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: (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 Δ8-THC with BH3·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 Δ8-THC acetate using mCPBA 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.

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