Codeinone reduction

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. ... 

Biotransformations of morphinan alkaloids have been reported for plant, fungal, and mammalian enzymatic systems with emphasis on rather specific reactions such as the reduction of ketones, N- and O-demethylation, and perox-idative transformations. Furuya et al. used immobilized tissue culture cells of Papaver somniferum to accomplish the selective reduction of codeinone (135) to codeine (136) (207) (Scheme 30). Suspension cultures of a well-established cell line of P. somniferum were grown for one week as a source of cell mass for immobilization in calcium alginate. The cells continued to live in the alginate matrix for 6 months maintaining their biological activity. The reduction of co-... 

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. 

Acyldihydrocodeinones (146) were made in a similar manner. The 8/3-(trans-1 -oxo-2-butenyl)- and 8/3-benzoyl derivatives were prepared from protected acyl lithium cuprates, and the 8/3-methylcarbonyl- (146) from the lithium bis(a-ethoxyvinyl) cuprate with codeinone, followed by mild hydrolysis of the intermediate, 147. Preparation of 8/3-t-alcohols may be achieved from 147 after reduction of the ring carbonyl, treatment with an appropriate alkyl lithium to 148, and oxidation back to a ketone, 149. 

Lenz R, Zenk MH. Stereoselective reduction of codeinone, the penultimate enzymic step during morphine biosynthesis in Papaver somniferum Tetrahedron Lett. 1995 36 2449-2452. UnterUnner B, Lenz R, Kutchan TM. Molecular cloning and functional expression of codeinone reductase. Plant J. 1999 18 465-475. 

Morphine and related alkaloids are specific to the genus Papaver (Berberidaceae), although the antipodal series of alkaloids is distributed in the Menisperma-ceae. Early in the biosynthesis of morphine, an inversion at C-1 of (5)-reticuline occurs, followed by ortho-para benzylic coupling to afford salutaridine. Stereospecific reduction and cyclization-elimination affords the 4,5-Ether bridge and thebaine. The dominant pathway from this point involves neopinone, codeinone, codeine, and morphine. Again, most of the enzymes in this sequence were isolated and characterized by Zenk s group (Fig. 30). 

Catalytic hydrogenation of codeine proceeds rapidly with saturation of the 7 8 double bond and formation of dihydrocodeine [m, R = OH] [267-9], also obtainable by the electrolytic reduction of codeine [270], the catalytic reduction of neopine [xm] [271], the methylation of dihydromorphine [272], and the catalytic reduction of dihydro-codeinone [xiv] [273]. By the latter method the optical antipode of dihydrocodeine may be prepared from the sinomenine series [274-5] (see Chap. XXVII). Both enantiomorphs can be demethylated to the corresponding dihydromorphines [269, 274-5]. Dihydrocodeine methyl ether is identical with tetrahydrothebaine [276-8] (see Chap. XIII). 

Dihydrodesoxycodeine-D [xm], the only non-phenolic dihydro-desoxycodeine, can be prepared by the catalytic hydrogenation of a-chlorocodide [rv] [29], /3-chlorocodide [v, It = Cl] [7, 29], bromocodide [v, R = Br] [29], and desoxycodeine-C [ix] hydrochloride [6], It has also been reported to be formed by catalytic reduction of codeinone oxime [xlii] hydrochloride [30]. Dihydrodesoxycodeine-D methine [xlhi] results from Hofmann degradation of the methiodide [7], and a substance that is presumably the dihydromethine [xliv] is obtained by catalytic reduction of a-chlorocodeimethine [xlv] [26]. 

As i/j-codeinone contains a 6 7-double bond and is in effect an allylic ether it can, like -codeine, give both phenolic and non-phenolic products on reduction. 

Hydrogenation in neutral or weakly acid solution with a palladium catalyst affords tetrahydro-i/r-codeinone [xxix] [7, 28] which is further reduced by sodium and alcohol to tetrahydro-i/r-codeine [xxx], the latter being obtained directly from i/r-codeinone by sodium and alcohol reduction. In no case do derivatives of allo-[Pg.171]

Speyer and Rosenfeld on reduction of 14-bromocodeinone [xxn] with sodium hydrosulphite obtained an amorphous halogen-free base that was converted by hot alkali to a crystalline, ketonic, tertiary base Cx8H2i03N that they suggested was dihydro-i/ -codeinone [40], but its properties do not agree with those of the latter [7] and its nature remains obscure. 

Sodium amalgam reduction proceeds with opening of the cyclic ether and reduction of the carbonyl group, giving dihydrothebainol-A, identical with that prepared in the same way from dihydrothebainone [33] and epimeric with that obtained by the catalytic reduction of codeinone [3]. 

The phenolic substance previously stated to be formed when codeinone is allowed to stand in hydrochloric acid, to have the composition Cl8Ha04N [3], and to be phenolic has now been identified as 8-hydroxy-dihydrocodeinone [B], which is formed from codeinone by the addition of a molecule of water to the double bond. Reduction of [B] catalytically or with lithium aluminium hydride affords 8-hydroxydihydrocodeine G], which is not oxidized by periodates, thus eliminating formula [D] for the parent ketone. 

Thebainone-A [v] results from thebaine or codeinone when these bases are reduced with stannous chloride and concentrated hydrochloric acid under conditions different from those required for the preparation of metathebainone, which nevertheless is formed at the same time in small amount [1]. (A small amount of a by-product m.p. 156-158° C. was also obtained during one reduction of thebaine [1].) Thebaine hydrochloride and stannous chloride in acetic acid at 160° C. yield methebenine [1] (see Chap. XXV). 

Catalytic hydrogenation of dihydrothebainone affords the alcohol dihydrothebainol-B [xxxn] [11], which also results from the catalytic reduction of codeinone [ii] [33] (see Chap. X). The optical antipode of this compound has been prepared in the sinomenine series [34-35], and the C-14 epimer by the catalytic reduction of /3-dihydrothebainone [36],... 

The C-6 epimer of dihydrothebainol-B results from the sodium amalgam [35, 37] and sodium and liquid ammonia [38] reduction of dihydrothebainone [ix], and the sodium amalgam reduction of dihydro-codeinone [xxxm] [34] it is also obtained as a by-product during the electrolytic reduction of dihydrothebainone [39]. Its optical antipode, desmethoxydesoxydihydrosinomeninol, has been prepared from sinomenine [34-35, 40-42]. 

That 14-hydroxy- and 14-bromocodeinonehave the morphine skeleton intact is demonstrated by the reduction of the latter with ferrous hydroxide to codeinone [vm] and catalytically to dihydrocodeinone [8, 13], and its conversion to 14-hydroxycodeinone oxime on treatment with hydroxylamine [8-9]. 

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