C1′-Azacycloalkyl Hexahydrocannabinols

We report the design, synthesis, and biological evaluation of a novel class of cannabinergic ligands, namely C1′-azacycloalkyl hexahydrocannabinols. Our synthetic approaches utilize an advanced common chiral intermediate triflate from which all analogues could be derived. Key synthetic steps involve microwave-assisted Liebeskind–Srogl C–C cross-coupling and palladium-catalyzed decarboxylative coupling reactions. The C1′-N-methylazetidinyl and C1′-N-methylpyrrolidinyl analogues were found to be high affinity ligands for the CB1 and CB2 cannabinoid receptors.