Synthesis of 6, 14‐ethenoisomorphinans and 6, 14‐ethenomorphinans based on Diels‐Alder adducts of 6‐demethoxythebaine and 6‐demethoxy‐β‐dihydrothebaine; pharmacology of the isomorphinans (Chemistry of Opium Alkaloids, Part XIX)

Two different types of Diels‐Alder additions to morphinan‐6, 8‐dienes have been found. 6‐Demethoxythebaine (2) yielded ethyl 4, 5α‐epoxy‐3‐methoxy‐N‐methyl‐6, 14‐ethenoisomorphinan–7α‐carboxylate (3) with ethyl acrylate, in analogy to the reaction with thebaine. The ester 3 was converted into the alcohol 4, of which the 3‐methoxy ether was hydrolyzed to yield 5. Similarly, 2 gave the 7α‐acetyl‐6, 14‐ethenoisomorphinan 7 with methyl vinyl ketone. The latter compound was converted into 4 using methylmagnesium iodide. With propylmagnesium bromide, 7 afforded four compounds; two are new etorphine analogues (8 and 9), to which we were able to assign the absolute configuration; the other two are the Grignard reduction products 10 and 11. When the 4, 5α‐epoxy bridge of 2 is first opened, the Diels‐Alder reaction with methyl vinyl ketone proceeds from the other side of the diene system yielding the 7β‐acetyl‐6, 14‐ethenomorphinan 6, which belongs to a novel class of rigid morphinans. Preliminary pharmacological screening of 5, 8 and 9 showed these compounds to be potent agonists.