Synthesis of 7‐substituted 6‐demethoxythebaines and Diels‐Alder reaction of 7‐methoxy‐5β‐methyl‐6‐demethoxythebaine (chemistry of opium alkaloids, part XLI)

Abstract

AbstractMesylation of 7‐acetoxyneopine (4), followed by reductive cleavage of the acetyl group gave 6α‐O‐mesyl‐7α‐hydroxyneopine (6), in which the hydroxyl group was protected as a methoxymethoxy group. Elimination of the mesyl ester yielded 7‐(methoxymethoxy)‐6‐demethoxythebaine (7). For the 5β‐methyl analogue, we started from 6‐O‐acetyl‐7α‐hydroxy‐5β‐methyl‐neopine (5), which was converted into 9 via hydroxyl protection as a methoxymethoxy group and removal of the acetyl group. Mesylation and elimination gave 7‐(methoxymethoxy)‐5β‐methyl‐6‐demethoxythebaine (10). Hydrolysis of 7 and 10 afforded the salutaridine analogue 11 and 5β‐methyl‐6‐deoxyneopin‐7‐one (12), which were easily converted into the 7,7‐dimethoxy‐6‐deoxyneopine analogues 13 and 14. Elimination of methanol from 14 yielded the desired diene 15. Diels‐Alder reaction of 15 with ethyl acrylate yielded exclusively the 8β‐substituted 6β,14β‐ethenomorphinan 16, due to α‐face approach. Cycloaddition of diene 15 with maleic anhydride gave the 6α, 14α‐ethenoisomorphinan 17 and the 6β,14β‐ethenomorphinan 18 in a ratio of 5: 4. The outcome of the Diels‐Alder reactions is discussed in relation to the substituents at the 5β‐ and 7‐positions combined with an asynchronous cycloaddition mechanism.