Part I: the synthesis of C3 heteroadamantyl cannabinoids; Part II: the synthesis of C3 heteroaroyl cannabinoids

Abstract

Part I: The total synthesis of fourteen C9 hydroxyhexahydrocannabinol analogs, with heteroadamantyl moieties incorporated into the aliphatic side chain at C3, is described. The key steps in the synthesis were the condensation of persilylated phloroglucinol with diacetates derived from nopinone, the TMSOTf mediated formation of the dihydropyran ring, selective triflation at C3, stereoselective reduction at C9, palladium catalyzed cyanation, and Suzuki cross coupling of a vinyl pinacol boronate. Binding affinities of the analogs towards the cannabinoid receptors CB1 and CB2 were determined by in vitro assays. All analogs showed at least micromolar affinity for the receptors, while the C9 β-hydroxy 2-oxaadamantyl analog had the highest affinity for CB2 (Ki = 18.5 nM) and showed a slight preference for CB2 over CB1. Molecular modeling of the analogs showed that the presence of a carbonyl or methylene linker at C1' drastically increases the pharmacophoric space resulting in decreased binding affinity. PART II: The total synthesis of nineteen β-hydroxyhexahydrocannabinol analogs, with heteroaroyl moieties introduced at C3, is described. The key steps in the synthesis were the carbonylative Stille between the aryl triflate and heteroaroyl stannanes, addition of heteroaryl groups to the aromatic aldehyde, and protecting group removal with TMSBr. Binding affinities of the analogs towards the cannabinoid receptors CB1 and CB2 were determined by in vitro assays and all analogs showed at least micromolar affinity for the receptors, with the 3-benzothiophene (Ki = 34.2 nM), 3-trifluoromethylphenyl (Ki = 45.8 nM) and 3-indole (Ki = 60.4 nM) analogs being most potent.