Synthesis of (+/-)-11-Nor-9-carboxy-Δ9-tetrahydrocannabinol: New Synthetic Approaches to Cannabinoids

Article abstract of DOI:10.1021/jo00004a027

A completely regioselective synthesis of (+/-)-11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol (1), a principal human metabolite of Δ⁹-tetrahydrocannabinol (2), has been carried out in seven steps and 14percent overall yield from apoverbene (9) and the bis-MOM ether of olivetol.Condensation of 9 with the aryllithium derived from the bis-MOM ether of olivetol gives an unstable tertiary allylic alcohol that undergoes oxidative rearrangement to give enone 42.Reaction of 42 with acid results in hydrolysis of the MOM ethers and cyclization to benzopyranone 21.Conversion to MOM ether 39 followed by Li/NH3 reduction and trapping of the enolate with N-phenyltriflimide gives vinyl triflate 40 plus the isomer with a cis ring fusion.Palladium-catalyzed carboxylation, hydrolysis of the MOM ether, and separation from cis acid 41 gives pure 1.Model experiments employing unsubstituted resorcinol derivatives that lead to ester 27 are described, as are a number of alternative approaches to acid 1.