Dihydrothebainone synthesis

Rice, K.C. (1980) Synthetic Opium Alkaloids and Derivatives. A Short Total Synthesis of (ib)-Dihydrothebainone, ( )-Dihydrocodeinone, and ( )-Nordihydrocodemone as an Approach to a Practical Synthesis of Morphine, Codeine, and Congeners. Journal of Organic Chemistry, 45, 3135-3137. 

Weller, D.D. 8c Rapoport, H. (1976) A Practical Synthesis of Codeine from Dihydrothebainone. Journal of Medicinal Chemistry, 19, 1171-1175. 

Codeine has also been prepared in 70% overall yield, again without purification of intermediate compounds, from dihydrothebainone (132) by the route (132) — (137) shown in Scheme 4. The initial product of the action of bromine and then alkali on dihydrothebainone is the 1,7-dibromo-derivative of dihydro-codeinone, which can be reduced to dihydrocodeinone (133). This may be converted into 7-bromodihydrocodeinone dimethyl ketal (136), which on treatment with potassium t-butoxide in DMSO at 120 °C is converted exclusively into thebaine, but at 60 °C the product is codeinone dimethyl ketal (137), which can be hydrolysed to codeinone (131).154 The process has obvious value in the possible synthesis of codeine via dihydrothebainone, for which a patent has been filed covering a process that proceeds from the reduced isoquinoline (138) 155 the conversion of A-formylnordihydrothebainone into dihydrothebainone by hydrolysis and reductive methylation and by ketalization, reduction, and hydrolysis has been reported.156... 

Elad and Ginsburg(27,28) approached the synthesis from the arylcy-clohexanone, 14, according to Scheme 2.2. The key cyclization, 16 — 17 occurred during ketalization, when in addition the 4-OMe group was demethy-lated. ( )-Dihydrothebainone (13) resulted from the pathway shown and this was resolved to the (-)-antipode with (+)-tartaric acid. This constitutes a synthesis of codeine and morphine following the final stages of Scheme 2.1. 

The closure of the 4,5-epoxide bridge during synthesis of compounds with structures related to morphine has been the subject of several investigations. Schopf 50,51 was the first to achieve the closure of dihydrothebainone (13) in high yield, by dibromination followed by debromination effected with alkali. When the corresponding isomorphinan-6-one (i.e., B/C trans-dihydrothebainone) was treated in a similar manner, cyclization was less efficient/52 This pathway was employed during early syntheses of both metopon<53) (74, Scheme 2.12) (p. 36) and morphine/5 ... 

Morphinans bearing a 6-oxygen function have proved to be a valuable source of precursors for the synthesis of natural opiates/53,55 58 Compounds such as dihydrothebainone (64, R = OMe R = H) may be derived from thebaine, whereas others are totally synthetic/8 ... 

A total synthesis of ( )-codeine also utilized the aziridinium salt 94 as a key intermediate, which was converted to 100 via epidihydrothebainone methyl ether (98) according to Evans s procedure. Specific ether cleavage reaction of 100 with NaSEt afforded dihy othebainone (101) in 100% yield. Since dihydrothebainone (101) had already been transformed into codeine (102), this synthesis constitutes a formal synthesis of 102 (Scheme 19). 

Three of the four methoxyl groups in dimethylsinomenol were believed to be located in the 3 4 6-positions of phenanthrene, owing to the degradation of sinomenine to derivatives of the optical antipode of dihydrothebainone (see below), and dimethylsinomenol was finally identified as 3 4 6 7-tetramethoxyphenanthrene by the following synthesis [12-14]. 

Eig. 1 shows a synthetic approach to the morphine structure made by Ginsburg, the correct stereo-chemical arrangement of the rings being ob. tained. The same synthesis is being carried out in the 3 4-dimethoxy series, the goal being the synthesis of dihydrothebainone. 

A second synthesis of Z-dihydrothebainone has been carried out by Ginsburg and Elad (378, 378a). Taken together with Gates and Tschudi s conversion of -dihydrothebainone to morphine, this may be considered another synthesis of the alkaloid itself. The path to dihydrothebainone followed by Elad and Ginsburg is quite different from that taken by Gates and Tschudi, but like the latter it involves an unusual reaction in the closure of the ethanamine chain. 

This now classic name reaction has over the decades proved amenable to both synthetic improvements and introduction of increased substitution,37 resulting in a formal synthesis of morphine itself, via dihydrothebainone, as reported in 1967.38 The same approach was almost simultaneously reported by Morrison, Waite, and Shavel39 (vide infra) and adapted in a later practical synthesis by Rice.35 Further related examples of Grewe-type approaches are summarized in Section 4 of this review. 

Short total synthesis of dihydrothebainone, dihydrocodeinone and nordihydrocodeinone... 

Recently, Rapoport et al. described a new synthesis of oripavine and thebaine, a practical synthesis of codeine from dihydrothebainone, and the conversion of thebaine to codeine (yield 85% from thebaine) (497, 498). The transformation of thebaine into codeine with sulfonyl hydrazine and later with methyl hypobromite was reported by Krausz (yield 70%) (499) (Scheme 16). 

Rice KC (1980) Synthetic opium-alkaloids and derivatives - a short total synthesis of (-1-/—)-dihydrothebainone, (+/—)-dihydrocodeinone, and (-f/—)-nordihydrocodeinone as an approach to a practical synthesis of morphine, codeine, and congeners. J Org Chem... 

Scheme 13.45. Representation of a high-yield synthesis of racemic dihydrothebainone. The product was subsequently converted to thebaine, codeine, and morphine (see Scheme 13.46). After Rice, K. /. Org. Chem., 1980,45,3135.

The synthesis devised by Kenner Rice (vide supra) (Scheme 13.45) was actually directed toward dihydrothebainone since the conversion of that intermediate to... 

Chemical procedures most frequently applied to the synthesis of morphinans are illustrated on Figs, 3 ajnd 4, showing the total synthesis of (-)-N-methylmorphinan (12) (Henecka 1953a, Schmidhammer et al. 1982), the ketomorphinan (13) (Henecka 1953a) and a partial synthesis of reversed" (-)-dihydrothebainone (Brossi et al. 1982). 

Lie TS et al. (1978a) Chemistry of opium alkaloids, part XI. Synthesis of racemic and chiral codeine and morphine via the dihydrothebainones. Reel Trav Chim Pays-Bas Belg 98 419-420... 

Razdan RK, Portlock DE, Dalzell HC, Malmberg C (1978) Synthesis of fi-dihydrothebainone. J Org Chem 43 3604-3606... 

Vecchietti y, Casagrande C, Gerrari G (1976) Ocobotrine and 14-episinomenine, new trans-mor-phinane alkaloids ofOcotea brachybotra. Tetrahedron Lett 1631-1633 Weller DD, Rapoport H (1976) A practical synthesis of codeine from dihydrothebainone. J Med Chem 19 1171-1175... 

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