Synthesis of Rotationally Restricted Tetrahydrocannabinol Ethers
Two rotationally restricted tetrahydrocannabinol (THC) ethers were synthesized to test the concept that the psychopharmacological activity of cannabinoids derives, in part, from the orientation of the lone pairs of electrons of the phenolic hydroxyl oxygen. These compounds, 0,2-propano-A6-THC (3) and 0,lO-methano-Ag-THC (12), lock the orientation of the lone pairs of electrons toward and away from the cyclohexene ring, respectively, by restricting bond rotation through the formation of cyclic ethers. The synthesis of 3 was achieved by alkylation of the phenolic oxygen of A8-THC (1) with 3-bromo-1-propanol followed by cyclodehydration in the presence of phosphorus pentoxide. The synthesis of 12 was achieved from a sequence of reactions that involved the cyclization of a chloroformate in a modification of the Darzens acylation of olefins. Thus, treatment of AS-THC with phosgene in the presence of NJV-dimethylaniline afforded A9-THC chloroformate. Subsequent intramolecular cycloaddition of the chloroformyl moiety to the Ag-unsaturation in the presence of AlC1, afforded the corresponding 0-chloro ester 9. Treatment of 9 with lithium aluminum hydride gave 10-(hydroxymethy1)-AS-THC (10). Compound 12 and 10-methylene-A8-THC (11) were obtained as a readily separable mixture by treatment of 10 with 3 mol of tosyl chloride in pyridine. I3C NMR and IH NMR spectral assignments were made. A model study of the TiC14-mediated cleavage of the MEM ether of phenol demonstrated generation of the phenoxymethyl cation.
Seltzman HH, Hsieh YA, Pitt CG, Reggio PH. 1991. Synthesis of rotationally restricted tetrahydrocannabinol ethers. J Org Chem 56(4):1549-53.