Synthesis of a tetracyclic, conformationally constrained analogue of Delta(8)-THC

A tetracyclic, conformationally constrained analogue of Delta(8)-THC (2) ha s 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 mate rial. This substrate was converted to 5,7-dimethoxy-2-propyl- 1,2,3,4-tetra hydronaphthalene (7) and its 4-keto derivative (18). Demethylation of 11 an d 18 provided the corresponding resorcinols, which were condensed with tran s-p-menthadienol to afford cannabinoid 2, and a keto derivative (20). LiAlH 4/AlCl3 reduction of 20 provided 2. Cannabinoid 2 has relatively low affini ty for the cannabinoid brain receptor (K-i = 703 +/- 98 nM). (C) 1998 Elsev ier Science Ltd. All rights reserved.