14-Hydroxy codeinone

The TPP-sensitized photo-oxidation of thebaine 101 as ammonium salts (entries ii and iii) affords the endoperoxide 104 and the 14-hydroxy-codeinone 105, stereoselectively and in high yields. Instead, product 103 is the main product under neutral conditions and its formation has been rationalized via an endoperoxide intermediate 102 that undergoes oxidation at the nitrogen atom (Sch. 61) [103]. 

The oxidation of thebaine with manganic acetate first gives [xvi], which on hydrolysis with 20 per cent, hydrochloric acid affords after three minutes at 100° C. the dihydroxyketone [xvrr], and 14-hydroxy-codeinone [xvm] after twenty minutes [98]. The 14-substituted codeinones are discussed in Chapter XVIII. 

The only recorded instance of the dehydration of a 14-hydroxy -codeinone derivative is that recorded by Schopf and Borkowsky, who claimed to have dehydrated 14-hydroxydihydrothebainone methine to [xxxvii] [34], Now [xxxvn] has the structure assigned to thebainone-B methine obtained by the hydrolysis of dihydrothebaine- methiodide [xxxvm] and /3-dihydrothebaine methine [xxxix] [35], and whereas thebainone-B methine can be hydrogenated to /3-dihydrothebainone... 

Buckett WR (1964) The relationship between analgesic activity, acute toxicity and chemical structure in esters of 14-hydroxy codeinone. J Pharm Pharmacol 16 68T-71T... 

An improved rapid procedure for the preparation of normorphine and norcodeine by A/-demethylation with phenyl chloroformate followed by hydrazine has been reported.An efficient synthesis of N-cyclobutylmethylnoroxymorphone (naltrexone) from thebaine, via 14-hydroxy-codeinone, has been described,as have preparations of A/-tetrahydrofurfuryl-noroxymorphone and of N-s-alkyl- and N-t-alkyl-normorphines. ° N-Demethylation and O-de-ethylation of 3-O-ethylmorphine by rat hepatic microsomes has been observed.A patent has been published covering the... 

However, subsequent work by the same investigators [83] on hydroxy-codeinone [xliii] indicated that this compound does not contain the system —CO—CH2-— but that dihydrohydroxycodeinone [xliv] does, facts best explained by postulating the presence of the system... 

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...

The other factor that may determine the type of cell death is the chemical structure of inducing agents [14]. We have recently found that u,(>-unsaluraled ketones such as 4,4-dimethyl-2-cyclopenten-l-one, a-methy-lene-y-butyrolactone, 5,6-dihydro-2H-pyran-2-one [15], codeinone [16], and morphinone [17] and a-hydroxylketones such as 3,3,3-trifluoro-2-hydroxy-1-phenyl-1-propanone induced caspase-independent cell death [18], induced vacuolization or autophagosome formation engulfing organelles, but without induction of apoptosis markers. 

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. 

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]. 

Thebainone, 7,S-Didehydro-4-hydroxy-3-meth-oxy-l7-nteihvlmorphinan-6-one thebainone-A. C.gHj.NO, mol wt 299 36. C 72.21%, H 7.07%, N 4.68%, O 16.03%. Prepn from thebaine. codeinone Or 0-ethylthiocodide Morris, Small, J. Am. Chem. Soc. 56, 2159(1934). Earlier references and discussion of structure Small, Lutz, Chemistry of the Opium Alkaloids, U.S. Public Health Reports Suppt. No. 103, Washington (1932). About anomalies in nomenclature and difference from metathebaioone see Henry. Plant Alkaloids (London, 1939) p 249. Description of all thebainones K. W. Bentley, The Chemistry of I he Morphine Alkaloids (Oxford, 1954) p 219-... 

Scheme 1. Biosynthesis of the benzylisoquinoline alkaloids berberine, morphine, and sang-uinarine. Enzymes for which corresponding molecular clones have been isolated are shown in bold. Abbreviations 4 OMT, 3 -hydroxy-A-methylcoclaurine 4 -0-methyltransferase 60MT, norcoclaurine 6-0-methyltransferase 70MT, reticuline 7-0-methyltransferase BBE, berberine bridge enzyme CFS, cheilanthifoline synthase CNMT, coclaurine A-methyltransf-erase COR, codeinone reductase CYP719A1, canadine synthase CYP80A1, berbamunine synthase CYP80B1, A-methylcoclaurine 3 -hydroxylase DBOX, dihydrobenzophenanthri-dine oxidase DRR, 1,2-dehydroreticuline reductase DRS, 1,2-dehydro reticuline synthase MSH, A-methylstylopine 14-hydroxylase NCS, norcoclaurine synthase P6H,...

Fig. 8.6 Biosynthetic pathway for benzylisoquinoline alkaloid (BIA) biosynthesis in plants. TYDC tyrosine/dopa decarhoxylase, 60MT norcoclaurine b-O-methyltransfoase, 40OMT 30-hydroxy-Af-methylcoclaurine 40-O-methyltransferase, OMT ITl O-methyltransferase II-l, CYP80A1 berbamunine synthase, CYP80B1 (Si-N-methylcoclaurine 30-hydroxylase, btaber-ine bridge enzyme, SOMT scoulerine iV-methyltransferase, COR codeinone rednctase (Adopted from Ref. [3])...

Figure 4.2 Biosynthesis of benzylisoquinoline alkaloids. Enzyme abbreviations TYDC, tyrosine/dopa decarboxylase NCS, norcoclaurine synth lse 60MT, norcoclaurine 6-O-methyltransferase 4 OMT, 3 -hydroxy-/V-methylcoclaurine 4 -0-methyltransferase CYP80A, berbamunine synth lse CYP80B, N-methylcoclaurine 3 -hydroxylase BBE, berberine bridge enzyme SOMT, scoulerine 9-0-methyltransferase CYP719A, (S)-canadine synthase SAT, salutaridinol 7-O-acetyltransferase COR, codeinone reductase.

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