<i>Diels‐Alder</i> 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

Abstract

Abstract 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. 1 H 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 1 H NMR and single‐crystal X‐ray analysis. Compound 12 showed morphine‐like activity in the PPQ assay.