THC Syntheses

After identification of A9-THC as the major active compound in Cannabis and its structural elucidation by Mechoulam and Gaoni in 1964 [66], a lot of work was invested in chemical synthesis of this substance. Analogous to the biosynthesis of cannabinoids, the central step in most of the A9-THC syntheses routes is the reaction of a terpene with a resorcin derivate (e.g., olivetol). Many different compounds were employed as terpenoid compounds, for example citral [67], verbenol [68], or chrysanthenol [69]. The employment of optically pure precursors is inevitable to get the desired (-)-trans-A9-THC. 

Chapter 5 THC Syntheses Water Soluble Derivatives of Cannabinoids... 

But all work on the stereospecificity of caimabinoid action had been done with (+) THC synthesized according to a procedure published by our group based on commercial a-pinene. And we knew that commercial pinene is not stereochemically pure, and therefore would lead to stere-ochemically impure products. Hence, the lack of stereospecificity could be due to the presence of varying amounts of the active (-) stereoisomer in the presumed pure (+) isomer. So we repeated the synthesis with stereochemically pure (+) a-pinene and tested the (-t) THC produced. It had no (-) THC-like activity, as expected. Then we evaluated the activity in the 11-hydroxy-dimethylheptyl series. As mentioned earlier (-) HU210, is very potent — at least 100 times more than THC. Its enantiomer, (-t) HU211, turned out to be many thousands of times less active than HU210 in a wide series of tests done in collaboration with my friends Billy Martin, Toby Jarbe, and Allyn Hewlett. The stereochemical hurdle was thus overcome. (For a review on the cannabinoid stereochemistry and biological activity, see Mechoulam et al., 1992). 

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