Synthesis of a tetracyclic, conformationally constrained analogue of Δ-THC

A tetracyclic, conformationally constrained analogue of Δ⁸-THC (2) has been synthesized in which a two carbon bridge exists between C2 and C2′. Two conceptually related syntheses of 2 are described, both of which employ 5,7-dimethoxy-4-oxo-1,2,3,4-tetrahydronaphthoic acid (11) as starting material. This substrate was converted to 5,7-dimethoxy-2-propyl-1,2,3,4-tetrahydronaphthalene (7) and its 4-keto derivative (18). Demethylation of 11 and 18 provided the corresponding resorcinols, which were condensed with trans-p-menthadienol to afford cannabinoid 2, and a keto derivative (20). LiAlH₄/AlCl₃ reduction of 20 provided 2. Cannabinoid 2 has relatively low affinity for the cannabinoid brain receptor (K_i = 703 ± 98nM).