Two novel cannabinoid model compounds, (3 R, 4 R)-dl @)-tetrahydrocannabinol-5"-oic acid (22) and 4" (R, S)-methyl-(3 R, 4 R)-d1(6)-tetrahydrocannabinol-5"-oic acid (23) were synthesized by acid-catalyzed condensation of (+)-truns-p-mentha-2,8-dien-l-o1 (1) with the substituted resorcinols 18 and 19 obtained by a Wittig reaction between 3,5-bis (benzy1oxy)benzaldehyde (7) and methyl 4-bromobutanoate (10) or methyl 4-bromo-2 (R, 5')-methylbutanoate (11) resp. with subsequent hydrogenation. The resulting methyl esters 20 and 21 were hydrolyzed to give acids 22 and 23.In the course of our investigation of structure-activity relationships in the cannabinoid series we described the synthesis, properties and biotransformation of the non-psychotropic cannabinoid (3 R , 4 R)-d1(7)-tetrahydrocannabinol [l] [2]. We now wish to report on the synthesis of two novel cannabinoid model compounds, (3 R, 4 R)-d~f6)-tetrahydrocannabinol-5"-oic acid (22) (= ~l~(~)-THC-5"-oic acid) and 4" (R, S)-methyl-(3 R, 4 R)-Al (6)-tetrahydrocannabinol-5"-oic acid (23) ( = 4"methyl-d1 (6)-THC-5"-oic acid). Both compounds are derivatives of d1(6)-THC (3), one of the psychotropic principles of the drug hashish. Being mainly interested in acid 23 where the full aliphatic C5 side chain of the parent compound is retained, acid 22 was prepared to elaborate the synthesis of 23. Both methyl esters 20 and 21 and the acids 22 and 23 are now investigated for psychotropic activity after intraventricular injection in the cat3).The general stereospecific pathway to (3 R , 4R)-d1 @)-THC (3) and its derivatives consists according to Petrzilka et al. [3] in the acid-catalyzed reaction of (+ )-trans- ') Part 1: see [I].
2,
3,Part of the thesis of I.F. In two double blind studies the esters 20 and 21 at doses of 10 and 20 mg resp. (spiked cigarettes, total lung delivery 2 mg 20 and 4 mg 21) could not be distinguished from placebo. 0018-019X/80/8/2508-07$01.00/0 0 1980 Schweizerische Chemische Ciesellschaft