New Methodology For The Generation Of Ortho-quinone Methides: Application To The Synthesis Of Cannabinoids.

Abstract

Two general approaches for the generation of orthoquinone methides are described. These methods involve oxidations of ortho-substituted phenols and the 1,4-elimination of ortho-hydroxybenzylic alcohol derivatives. 2- (3*R)-3,7-Dimethyl-1-trimethylsilyloxy-6-octenyl -3-methoxy-5(n-pentyl)-1-trimethylsilyloxybenzene undergoes regiospecific 1,4-desilylation-elimination to an incipient ortho-quinone methide that is trapped in a stereocontrolled intramolecular Diels-Alder reaction to enantiospecifically produce hexahydrocannabinols. In addition, ortho-hydroxybenzyl alcohols of this type undergo acid-catalyzed dehydration to form ortho-quinone methides which are trapped in the same manner to yield cannabinols. Attempts to synthesize (DELTA)('9)-tetrahydrocannabinol methyl ether directly from an ortho-quinone methide intermediate resulted in the formation of chromene products. The DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) oxidation of 2- (Z)-3,7-dimethyl-2,6-octadienyl -5-(n-pentyl)-3-methoxyphenol gave a high yield of cannabichrome methyl ether. Demethylation afforded cannabichromene, a naturally-occurring cannabinoid. The fluoride-induced desilylations of 2- (Z)-3,7-dimethyl-1-hydroxy-2,6-octadienyl -3-methoxy-5-(n-pentyl)-1-trimethylsilyloxybenzene resulted in chromene production. These results are attributed to the electrocyclic closure of the incipient cisoid ortho-quinone methide species. In an attempt to synthesize optically-active cannabinoids functionalized at the C-9 and C-10 positions, four chiral neral derivatives were made. However, (2*S,3*S)-3,7-dimethyl-2,3-epoxy-6-octen-1-al, (4*S,5*S)-3-phenyl-4-carboxaldehyde-5-methyl-5-(4-methyl-3-pentenyl)-2-oxazolidinone, (2*R,3*R)-3,7-dimethyl-2-hydroxy-3-(N-methylanilino)-6-octen-1-al and (4*R,5*R)-3-phenyl-4-methyl-3-pentenyl-5-carboxaldehyde-2-oxazolidinone all failed to undergo the desired condensation reaction with various aryl anions.