Diels‐Alder reaction of 6‐demethoxy‐β‐dihydrothebaine with methyl vinyl ketone using microwave heating; preparation and pharmacology of 3‐hydroxy‐α,α, 17‐trimethyl‐6β,14β‐ethenomorphinan‐7β‐methanol, a novel deoxygenated diprenorphine analogue (chemistry of opium alkaloids, part XXV

Diels‐Alder reaction of 6‐demethoxy‐β‐dihydrothebaine 6 with methyl vinyl ketone (3‐buten‐2‐one) yielded, in a 3:2 ratio, (+)‐7β‐acetyl‐3‐methoxy‐17‐methyl‐6β,14β‐ethenomorphinan‐4‐ol (7) and the novel (+)‐8β‐acetyl‐3‐methoxy‐17‐methyl‐6β,14β‐ethenomorphinan‐4‐ol (8). Performing the reaction in a microwave oven resulted in a faster and cleaner reaction. 1H NMR and mass spectra of 8 were studied and the structure was finally established by single‐crystal X‐ray analysis of its 4‐O‐phenyl ether 13. In contrast to thebaine and 6‐demethoxythebaine, the cyclo‐addition reaction of 6‐demethoxy‐β‐dihydrothebaine with methyl vinyl ketone occurred at the α‐face of the diene system. Ullmann reaction of 7 with bromobenzene, followed by Grignard reaction with methylmagnesium bromide and removal of the phenoxyl group using sodium in liquid ammonia, afforded the tertiary alcohol 11. O‐Demethylation of 11 by potassium hydroxide in boiling glycol, using microwave heating, afforded (+)‐3‐hydroxy‐α,α,17‐trimethyl‐6β,14β‐ethenomorphinan‐7β‐methanol 12. The structure of 12 was confirmed by 1H NMR and single‐crystal X‐ray analysis. Compound 12 showed morphine‐like activity in the PPQ assay.