Direct Synthesis of Noroxymorph­one from Thebaine: Unusual Ce^IV Oxidation of a Methoxydiene‐Iron Complex to an Enone‐γ‐Nitrate

Abstract

Noroxymorphone was prepared from thebaine in seven operations. The key steps involved the successive N‐ and O‐demethylations of an iron tricarbonyl complex of thebaine followed by the unusual ceric ammonium nitrate oxidation of the methoxydiene moiety to the corresponding enone‐γ‐nitrate during the decomplexation of the iron tricarbonyl functionality.

TEMPO‐Mediated Electrochemical N‐demethylation of Opiate Alkaloids

“…[2][3][4] These opiate therapeutic agents are typically synthesized from 1 a or 2 a, which are converted to oxycodone 7 a or oxymorphone 8 a through C14 hydroxylation and hydrogenation, before N-demethylation and subsequent functionalization. [1,[3][4][5][6] However, 1 a is preferred over 2 a as starting compound due to its considerably higher natural abundance. [3,7] The most challenging step in the reaction sequence, from natural opiates to opiate-like therapeutics, is the selective N-demethylation of the highly functionalized morphinan structure.…”

Synthesis of Nororipavine and Noroxymorphone via N- and O-Demethylation of Iron Tricarbonyl Complex of Thebaine

“…In the course of the investigation of iron decomplexation with ammonium cerium(IV) nitrate (CAN), we have discovered that decomplexation performed with five equivalents of CAN furnished 80% yield of nitrate ester 29 (Scheme 6). 39 This unprecedented formation of a nitrate ester from the methoxydiene provided an opportunity for the preparation of noroxymorphone without relying on TMANOmediated decomplexation, considered to be the bottle neck of nororipavine synthesis (vide supra).…”

“…The mechanism for the formation of the nitrate ester may be postulated as shown in Scheme 7 and previously reported in the preliminary communication. 39 Hydrogenation of nitrate ester 29 in ethyl acetate, somewhat sluggish because of the steric hindrance at C-14, provided hydroxy ketone 28, whose acid-catalyzed hydrolysis furnished the desired noroxymorphone 30 in good yield. 39 Hydrogenation under milder conditions (3% wt.…”

“…39 Hydrogenation of nitrate ester 29 in ethyl acetate, somewhat sluggish because of the steric hindrance at C-14, provided hydroxy ketone 28, whose acid-catalyzed hydrolysis furnished the desired noroxymorphone 30 in good yield. 39 Hydrogenation under milder conditions (3% wt. Pd/C, paste; 60% moisture) in methanol afforded a very polar compound 33, identified by X-ray crystallographic analysis…”

“…This result was recently reported in a preliminary communication. 39 All solvents were used as obtained unless otherwise stated. Thebaine was purchased from Tasmania Alkaloids and from MD Pharm.…”