Dihydrothebainone

EtOH) methiodide, m.p. 273°. To be distinguished from the better-known dihydrothebainol, m.p. 138-142°, [a] ° — 46-2°, prepared by reducing dihydrothebainone with sodium amalgam (Speyer and Siebert ). 

Dihydrothebainone-A-5 6-methyl enolate, CjaHjjOjN, m.p. 164-165-5°, [a] ° — 115-7° (EtOH). Cold N/HCl converts it into dihydrothebainone hydrochloride. The isomeric dihydrothebainone-J-6 7-methyl enolate is formed on catalytic hydrogenation of phenolic dihydrothebaine. It has m.p. 127-8°, [a] ° — 8° (EtOH) and yields dihydrothebainone on acid hydrolysis. ... 

Thebainone methyl enolate. CuHjjOjN. This possible intermediate in the hydrogenation of thebaine to dihydrothebainone-J-5 6-methyl enolate (see above) has m.p. 154-6°, [a] ° -f 9-6° (EtOH). ... 

Most of the dihydrothebainone produced from thebaine is former under mild conditions of hydrogenation and probably not via dihydro thebaine, but by way of thebainone methyl enolate and dihydrothebainone A-5 6-methyl enolate as described above. 

A further anomaly in nomenclature is thebainol, the name applied to the substance formed by the alkaline reduction of metethebainone, and which was at first believed to be formed by reduction of the carbonyl group, but which Gulland and Robinson proved to be a ketone. It is isomeric with dihydrothebainone referred to above, and has been re-named dihydrom tathebainone (Schopf). The interrelationships of these substances are shown by the following formulae —... 

Thebainone (Schopf), CigHjjOgN. This substance, which must be distinguished from Pschorr s thebainone (metothebainone of Schopf (see p. 248) ), is formed, along with the latter in the reduction of thebaine by stannous chloride in hydrochloric acid, and was isolated by Schopf and Hirsch. Its prior isolation by Pschorr, as confirmed by Morris and Small, has been referred to already. It crystallises with 0-5 HjO, has m.p. 151-2°, yields a hydriodide, m.p. 258-9°, methiodide, m.p. 223°, and an oxime, m.p. 185-6°. On catalytic hydrogenation it yields dihydrothebainone (LI), and can be degraded to 3 4 6-triacetoxyphenanthrene, m.p. 165-7°. On this basis formula (XLIX) is assigned to it. The mechanism of the formation of codeinone, thebainone and mefathebainone from thebaine is discussed by Schopf and Hirsch. ... 

Dihydrothebainone, CigHagOgN, produced by the hydrogenation of thebaine in acetic acid in presence of palladium as catalyst, has m.p. 138-43°, — 72-5° (Schopf) gives a hydriodide, m.p. 262-3° (Freund) ... 

Since dihydrothebainone is also formed by hydrogenation of thebainone (Schopf and Hirsch i), and as Schopf and Pfeifer have shown that 1 5-dibromodihydrothebainone, on treatment with alkali, is converted into. 1-bromodihydrocodeinone by formation-of the C -C oxygen bridge, and this, on catalytic hydrogenation, yields dihydrocodeinone (LIII, p. 246), the constitution of which has been demonstrated by Schopf (p. 244), there can be little doubt that dihydrothebainone is represented by (LI). Schopf and Winterhalder have also isolated as an oxime (m.p. 228°, [a] °° — 115-8°) an e.pidihydrothebainone, which is regarded as the epimeride of dihydrothebainone. 

Steric hindrance around an allylic function will diminish its hydrogenolysis as access of the function to the catalyst surface is impeded. Reduction of 5-methylthebaine (32) proceeds smoothly over Pd-on-C in ethanol at 1 atm to afford 5-methyldihydrothebaine (33), whereas reduction of thebaine itself is less clean and gives dihydrothebainol, dihydrothebainone, and dihydro-thebaine (/b). 

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... 

Thebaine has been shown to react with lithium dimethylcuprate to give 7/j-methyldihydro- -thebaine (97),187,188 acid hydrolysis of which gives 7-methyl-thebainone-A (98) and its B/c-trans-isomer, which can be catalytically reduced to 7a- and 7/ -dihydrothebainone (99) and their B/c-trans-isomers. The la- and 7/j-dihydrothebainones are also obtained by the action of lithium dimethylcuprate on dihydrothebaine and on dihydrocodeinone enol acetate and subsequent hydrolysis of the products.187 The phenol (97) can be converted into the... 

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. 

Barton(29) devised a biomimetic route to thebaine (3), dihydrothebainone (13), and thus morphine following observations of Battersby.(30,3l) The alkaloid salutaridine (19) was derived from (+)-reticuline (18) by a low-yielding (0.03%) regioselective para-ortho phenolic coupling reaction according to Scheme 2.3. By the use of thallium tristrifluoracetate, Schwartz(32) improved yields to up to 23%. 

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 ... 

For many years it was assumed that bromination occurred at C-5 as well as at C-l, and this assumption appeared to be endorsed by the ease of cyclization of B/C cis compounds relative to their B/C trans isomers. In the former the alicyclic bromine was ideally located for displacement by the phenoxide anion. However, Bentley 54 had suggested, without experimental evidence, that C-7 appeared to be the more likely site of C-ring bromination. Once isolation of B/C cis and B/C fraas-dihydrothebainone and dihy-... 

Gates and Helg(102) established earlier that /3-thebainone (47, R = H) (B/C trans) could be readily inverted under both acid (HOAc) and base (NaOEt) conditions to give predominantly dihydrothebainone (48, R. = H) (B/C cis), which was separated from the mixture in a pure yield of 60%. In addition, /3-thebainone 2,4-dinitrophenylhydrazone is subject to quantitative conversion to the B/C cis isomer in warm acetic acid within 6 h. 

Sawa and co-workers(36) elegantly and unambiguously related the naturally occurring (+)-morphinan, sinomenine (53), and dihydrothebainone... 

Aromatic ring reduced morphinans and isomorphinans have been reported/52 Birch reduction of 3-methoxy- N-methylmorphinan (61a) and the corresponding isomorphinan (61b) gave the respective l,2,3,4-tetrahydro-3-oxo-derivatives (62a and 62b) together with small amounts of the desoxo compounds 63a and 63b. The morphinan and isomorphinan precursors (60a and 60b) were derived from (58)(53) or dihydrothebainone (59), according to Scheme 3.8. In the RTF test, no significant activity was observed for 62a or 62b. 

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). 

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