Codeinones

The three alkaloids concerned, morphine, codeine and thebaine, all behave as tertiary bases. Morphine contains two hydroxyl groups of which one is phenolic and the other a secondary alcohol group. On methylation of the phenolic hydroxyl codeine results. On oxidation, codeine is transformed into codeinone by conversion of the secondary alcohol group into a carbonyl group, and when thebaine is boiled with A-sulphuric acid for a few minutes, it is hydrolysed into codeinone and methyl sulphate, and in other ways thebaine has been shown to contain two methoxyl groups. That the relationship between the three alkaloids is close may be illustrated by the following slightly extended formula —... 

Codeine is therefore a methyl ether of morphine, whilst thebaine is a methyl ether of an enolic form of codeinone. There has been much discussion as to the function of the third or indifferent oxygen in the three alkaloids, and its nature has only been disclosed by a study of degradation products. 

Thebenine, CjgHjgOgN. This secondary amine, which differs by CHj in empirical composition from thebaine, is formed by the action of hot dilute hydrochloric acid on thebaine or codeinone, but not -codeinone, which does, however, yield triacetylthebenine and ethanolmethylamine... 

Morphothebaine, CigHigOgN. This tertiary base results from th( action of hydrochloric acid on thebaine at 80-90° in closed vessels, or ii a similar manner from codeinone. It forms colourless crystals, whicl become tinted green or blue when kept, m.p. 197° (dec.), [a]p ° — 130 (EtOH). The base furnishes a characteristic acid hydrochloride, Bg. 3HC1 colourless needles, m.p. 254-5°, which is converted by water or alcohol t< the normal hydrochdoride, B. HCl, minute needles, m.p. 256-60°. Th(... 

Mechanisms for the change of thebaine into thebenine have been suggested by Freund and Speyer, i i Gulland and Robinson and Schopf and Borkowsky and for the conversion of thebaine (or codeinone) into morphothebaine by the same authors and in addition by Gulland and Robinson and Wieland and Kotake. f ... 

Codeinone, CjaHijOgN. This ketone (XLVII) corresponds to the secondary alcohol codeine and its stereoisomeride wocodeine. It may be prepared by oxidising codeine with potassium permanganate in acetone or with potassium dichromate in dilute sulphuric acid and in various other ways. Codeinone can be reduced to codeine electrolytically or by chemical methods. It crystallises from alcohol in prisms, m.p. 185-6, [a]J, ° — 205° (EtOH). The hydrochloride, B. HCl. HjO, has m.p. 179-80°, picrate, m.p. 205°, methiodide, B. CHjI. 2H2O, m.p. 180°. 

EtOH). On catalytic hydrogenation, codeinone is reduced to dihydro-codeinone. ... 

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. ... 

Thehaine stands at the other end of the series from morphine and is a convulsant poison rather than a narcotic (see table, p. 261). Hildebrandt states that it excites the reflexes of cold-blooded animals but in dogs it exerts a narcotic and anti-emetic effect resembling that of morphine rather than that of chloromorphide. The alkaloid is scarcely used in medicine as such, but is a primary material for the preparation of certain of the modern morphine derivatives, such as hydroxydihj dro-codeinone and methyldihydromorphinor.e. 

Nor-codeinon-dimethylacetal3 2,59 g (7,3 mMol) N-Cyan-nor-codeinon-dimethylacetal werden in 150 m/ abs. THF gclost und unter trockenem Stickstoff zu einer Suspension von 1,5 g (40 mMol) Lithiumalanat in 150 ml THF getropft. Man erhitzt 3 Stdn. unter RiickfluB, laBt 12 Stdn. bei 20° stehen, versetzt mit 20 ml Essig-saure-athylester, danach mit 35 ml ges. Kalium-natrium-tartrat-Losung, dampft die organ. Phase i. Vak. ein und kristallisiert den Riickstand aus Ather/Petrolather Ausbeute 1,81 g(75% d.Th.) F 117-118"(aus Ather/Petrolather). 

Durch Trametes sanguined laBt sich auch (+)-Codeinon selektiv stereospezifisch zum (+)-Dihydro-isocodein reduzieren1 ... 

Gates, M. (1953) The Conversion of Codeinone to Codeine. Journal of the American Chemical Society, 75, 4340 341. 

Fig. 10.6 Reaction catalyzed by codeinone reductase (COR), the penultimate step in morphine biosynthesis.

The peptide sequences obtained for codeinone reductase aligned well with the amino acid sequences for 6 -deoxychalcone synthase (chalcone reductase) from alfalfa, Glycerrhiza, and soybean. Knowledge of the relative positions of the peptides allowed for a quick RT-PCR based isolation of cDNAs encoding codeinone reductase from P. somniferum. The codeinone reductase isoforms are 53 % identical to chalcone reductase from soybean.25 By sequence comparison, both codeinone reductase and chalcone reductase belong to the aldo/keto reductase family, a group of structurally and functionally related NADPH-dependent oxidoreductases, and thereby possibly arise from primary metabolism. Six alleles encoding codeinone... 

With a morphine biosynthetic gene in hand, we believed we could begin to address the question why only P. somniferum produces morphine, while other Papaver species such as P. rhoeas, P. orientale, and P. bracteatum do not. Unexpectedly, we found that the codeinone reductase transcript was present to some degree in all four species investigated. A review of the literature revealed no alkaloids reported in P. rhoeas for which codeinone reductase should participate in the synthesis. Similarly, P. orientale accumulates the alternate morphine biosynthetic precursor oripavine, but codeinone reductase is not involved in the biosynthesis of oripavine, acting instead after this alkaloid along the biosynthetic pathway to morphine.22 P. bracteatum produces the morphine precursor thebaine as a major alkaloid. As for oripavine in P. orientale, codeinone reductase would act in P. bracteatum after thebaine formation on the pathway to morphine. It appears, therefore, that the reason that P. rhoeas, P. orientale, and P. bracteatum do not produce morphine is not related to the absence of the transcript of the morphine biosynthesis-specific gene codeinone reductase. The expression of codeinone reductase may simply be an evolutionary remnant in these species. 

Fig. 10.8 Selected cDNAs isolated in recent years that encode enzymes involved in the biosynthesis of various classes of isoquinoline alkaloids. 6-OMT, norcoclaurine 6-0-methyltransferase 23 CYP80A1, berbamunine synthase 19 CYP80B1, (S)-A-methylcoclaurine 3 -hydroxylase 20 CPR, cytochrome P-450 reductase 29 4 -OMT, (5)-3 -hydroxy-A-methylcoclaurine 4 -0-methyltransferase 30 BBE, berberine bridge enzyme 12 SalAT, salutaridinol 7-O-acetyltransferase 28 COR, codeinone reductase.25...

---