Thebaine reduction

CjHj) picrate, m.p. 235° methiodide, m.p. 257°. To be distinguished from phenolic dihydrothebaine, m.p. 154° prepared by reduction of thebaine with sodium in alcohol. 

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. ... 

As in the case of the steroids, introduction of additional nuclear substituents yields morphine analogs of increased potency. The more important of these are derived from one of the minor alkaloids that occur in opium. Thebaine (14), present in crude opium in about one-tenth the amount of morphine, exhibits a reactive internal diene system that is well known to undergo various addition reactions in a 1,4 manner (e.g., bromination). Thus, reaction with hydrogen peroxide in acid may be visualized to afford first the 14-hydroxy-6-hemiketal (15). Hydrolysis yields the isolated unsaturated ketone (16). Catalytic reduction... 

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). 

Synthesis (Krauli (E. Merck), 1925, Juby et al., 1968, Ehrhart and Ruschig 1972) Thebaine is oxidized with hydrogene peroxide to 14-hydroxycodeinone (Bentley 1954, Hauser 1974), which is hydrogenated directly or via its oxime, or its bromination products to oxycodone. The reduction of 14-hydroxycodeinone can also be carried out with sodium hydrosulfite. Alternatively 14-hydroxycodeinone is prepared by oxidation of codeine. 

Details of the Diels-Alder addition of aromatic nitroso-compounds to thebaine to give adducts (117), the ring-opening of these to 14-hydroxylamino-compounds (118 R = OH), the reduction of these to 14-arylamino-compounds (118 R = H), and cyclization to (119) have been published.162 Dihydro-thebaine-< 4-phenyl ether (120 R = OPh) has been transformed into the benzylisoquinoline (121) by potassamide in liquid ammonia, but the same transformation could not be effected with the free phenol (120 R = H) or with the deoxy-compound (120 R = H).163... 

Thebaine has been converted into the 14-substituted compound (136 R = SCN) by treatment with (SCN)2, and this gives the ketal (136 R = OMe) when treated with methanol. The initial product (136 R = SCN) is hydrolysed to the codeinone by sodium bicarbonate, and reduction of this with lithium aluminium hydride gives 14-mercaptocodeine (137), which can be demethylated to 14-mercaptomorphine by boron trifluoride.166... 

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... 

The acetylation of morphine and of codeine by aspirin202 and the enzymatic hydrolysis of heroin203 and the reduction of codeinone204 have been studied. Dihydronorcodeine and dihydromorphine have been isolated from urine as metabolites of dihydrocodeine.205 Patents have been published covering the preparation of -(cyclopropylmethyOnormorphine,206 the conversion of thebaine into codeinone,207 and the preparation of nalorphine 6-sulphate.208 Salts of codeine and ethylmorphine with 5-carboxymethyl-2-thio-l,3-thiazan-4-one have been prepared.209 The circular dichroism210,211 and fluorescence characteristics212 of morphine and related bases have been studied. 

Conversion of (S)-reticuline to its ( )-epimer is the first committed step in morphinan alkaloid biosynthesis in certain species. 1,2-Dehydroreticuline reductase catalyzes the stereospecific reduction of 1,2-dehydroreticuline to (7 )-reticuline.39 Intramolecular carbon-carbon phenol coupling of (if)-reticuline by the P450-dependent enzyme salutaridine synthase (STS) results in the formation of salutaridine.40 The cytosolic enzyme, salutaridine NADPH 7-oxidoreductase (SOR), found in Papaver bracteatum and P. somniferum, reduces salutaridine to (7S)-salutaridinol.41 Conversion of (7S)-salutaridinol into thebaine requires closure of an oxide bridge between C-4 and C-5 by acetyl coenzyme A salutaridinol-7-0-acetyltransferase (SAT). The enzyme was purified from opium poppy cultures and the corresponding gene recently isolated (Fig.7.2).42,43 In the last steps of morphine... 

The morphinan-6-one (99), available from thebaine,<36,94,95) has been reacted with lithium dialkylcuprates to give 8/3-alkylmorphinan-6-ones(96) (100) (Scheme 3.14). Variation of the N-substituent was effected by standard procedures, and reductive removal of the carbonyl under Huang-Minlon conditions to 101 also caused some 3-O-demethylation. Similar pathways were used for isomorphinan-6-ones and isomorphinans (102). 

Redaction of thebaine. Thebaine (1) is reduced by potassium (2.3 equiv.) in liquid aminmonia to a 1 1 mixture of 2 and 3. Reduction under similar conditions but with calcium, lithium, or sodium gives only the nonconjugated diene 3. This... 

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