697. Alkaloid biosynthesis. Part IV. 1-Benzylisoquinolines as precursors of thebaine, codeine, and morphine

Battersby, Alan R.; Binks, Rachel M.; Francis, Rawle; McCaldin, D. J.; Ramuz, H.

doi:10.1039/jr9640003600

Cited by 78 publications

(34 citation statements)

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“…The initial reaction in isoquinoline biosynthesis has long [3] been assumed to be a condensation of two aromatic units, both derived from tyrosine, namely dopamine and 3,4-dihydroxyphenylacetaldehyde [4]. This scheme was later modified [5] where it was reported that condensation of dopamine with 3,4-dihydroxyphenylpyruvate wouldlead to an amino acid, norlaudanosoline-lcarboxylic acid, which in turn, by decarboxylation, would yield norlaudanosoline, the well-recognised precursor of papaver-alkaloids [6,7]. The intermediary nature of norlaudanosoline-1 -carboxylic acid was later claimed to be supported by in vivo [8] and in vitro [9,10] experiments.…”

Section: Introductionmentioning

confidence: 99%

(S)‐norlaudanosoline synthase: The first enzyme in the benzylisoquinoline biosynthetic pathway

et al. 1981

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Section: Introductionmentioning

confidence: 99%

(S)‐norlaudanosoline synthase: The first enzyme in the benzylisoquinoline biosynthetic pathway

et al. 1981

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“…NMR spectra: Varian EM-360 and Varian XL-100-15 instruments, chemical shifts as ppm (6) downfield from TMS. Mass spectra (MS): AEI MS 902 instrument (70eV, direct insertion).…”

Section: Methodsmentioning

confidence: 99%

Studies Aimed at the Synthesis of Morphine, IV: A New Approach to N‐Norreticuline Derivatives from Homoveratronitrile

Szántay

Dörnyei

Bogáts

et al. 1981

Archiv der Pharmazie

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Partial demethylation of homoveratronitrile (30) with Lewis acids affords a mixture of the isomeric monophenols 3b and 3c. Separation of the isomers offers a new approach to N-norreticuline (la) and its 6'-halogen derivatives lb,c. Untersucbungen zur Synthese von Morpbin, 4. Mitt.: Neuer Weg zur Synthese von N-NorretikulhDerivaten aus HomoveratronihilDie partielle Demethylierung von Homoveratronitril (3a) mit Lewis-Sauren gibt eine Mischung der isomeren Monophenole 3b und k. Die Trennung der Isomere offnet einen neuen Weg f i r die Synthese des N-Norretikulins (la) und seiner 6'-Halogen-Derivate lb,c.It is commonly assumed that the different reticuline and N-norreticuline derivatives play an important role in the biosynthesis*.') as well as in the synthetic appr~ach'.~) of morphine alkaloids. These compounds 1 are valuable intermediates for biomimetic synthesis of morphine type compounds as they proved to be proper starting materials in the formation of the morphinandienone structure via phenolic oxidative coupling.The synthesis of N-norreticuline and its derivatives has already been thoroughly investigatedc7). The I-benzyl-l,2,3,4-tetrahydroisoquinoline skeleton was generally obtained by Bischler-Napieralrki cyclization of the corresponding amide, whose phenolic hydroxy functions had formerly been protected. Brossi and coworkers were first to succeed in achieving the ring closure of Z I I amide, formed by direct condensation of 3-hydroxy-4-methoxyphenylacetic acid (413) and 4-hydroxy-3-methoxyphenylethylamine (S), with unprotected phenolic hydroxy groups. By subsequent NaBH, reduction la',') could be isolated. The two building blocks 4a and 5 of ZP amide were produced from isovanillin and vanillin, resp. (Formula s. p. 984).Our aim was to find a pathway in performing this economical synthesis of N-norreticuline starting from homoveratronitrile (3a), an inexpensive and easily available key-intermediate of industrial papaverine production, and furthermore, t o apply the method also to 6'-halogeno-N-norreticulines. It has been found that under appropriate conditions Lewis acids cleave only one of the two methoxy groups of homoveratronitrile (3a), thus furnishing a mixture of 3b and 3c in a ratio of about 1 : 1. Monodemethylation can be accomplished both in solution (AlCldnitrobenzene, BBrdCH,Cl,) and in heterogeneous media ('AlCldtoluene, benzene, chlorobenzene). The use of AlCl, in toluene is most preferable, e.g. when apphed in an amount of 1,&2 mole equivalents a distilled mixture of isomers, containing 45 % 3b and 55 % 3c (GC), was obtained in 80 % yield. Variation of the Lewis acids and the solvents hardly affected the total yield as well as the proportion of the two isomers.The separation of isomeric monophenols could be realized by fractionated crystallization or vacuum distillation on a highly effective column. The two components of the mixture have also been separated by a chemical method based on the different reactivities of 3b and 3c towards halogens. Due to the free para position of 3c excellent select...

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“…In the poppy plant, Papaver somniferum, the morphinetype alkaloid thebaine is biosynthesized from two molecules of L-tyrosine (10) by way of several intermediates, such as norcoclaurine, coclaurine (11,12), reticuline (13), and salutaridine (14). It has recently been shown that norcoclaurine and coclaurine are true precursors of reticuline and thebaine (11,12), though tetrahydropapaveroline (THP, norlaudanosoline) had long been assumed to be the precursor (15,16).…”

Section: Discussionmentioning

confidence: 99%

Identification of the convulsant opiate thebaine in mammalian brain.

Kodaira

Lisek²,

Jardine³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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The convulsant opiate thebaine, an intermediate of morphine biosynthesis, was purified from ovine brain to homogeneity by gel filtration and high-performance liquid chromatography (HPLC) monitored by a radioimmunoassay. The immunoreactive material behaved identically to standard thebaine in two HPLC systems and was confirmed to be thebaine by combined gas chromatography/mass spectrometry. To our knowledge, the presence of thebaine in mammalian tissue has not been demonstrated previously. Codeine and morphine were also found to exist in ovine brain. The presence of thebaine in ovine brain provides strong evidence that morphine and codeine, in various mammalian tissues, are of endogenous origin and actually biosynthesized from a precursor.Recent evidence has focused attention on the existence of endogenous opiate alkaloids in mammalian tissues (1-3). These molecules may then constitute a component of a unique regulatory pathway perhaps involving enkephalin, dynorphin, and endorphin, the more fully characterized opiate peptides. This notion is substantiated by the finding that the levels of two opiate alkaloids, morphine and codeine, are not static but rather undergo rapid alterations following physiological stimulation (3,4), whereas bioconversion of various opiate precursors can be demonstrated in vivo (1,5) or in vitro (5, 6). A critical issue is to establish whether any of these intermediates actually exists in brain and further to determine whether they have biological activity in their own right. We report here that one opiate, thebaine, a precursor in the biosynthesis of morphine and codeine that has convulsant properties, is present in ovine brain. METHODSMaterials. Ovine brains (from Colorado Lamb, Denver, CO) were used for the isolation of endogenous opiate alkaloids. (-)-Thebaine (Hoffmann-La Roche) crystallized from methanol was used for radioimmunoassay (RIA), highperformance liquid chromatography (HPLC), and gas chromatography/mass spectrometry (GC/MS) analysis as a standard. (-)-Codeine was from Merck. Morphine hydrochloride and '25I-labeled morphine (90-150 Ci/mmol; 1 Ci = 37 GBq)were from Hoffmann-La Roche. Other reagents were purchased from Baker or Sigma.RIA. A rabbit antiserum that was raised against 3-carboxymethylmorphine conjugated to bovine serum albumin (7) and 1251-labeled morphine as tracer were used in the RIA. The sensitivity of the assay to thebaine [IC50 = 0.58 + 0.04 pmol (mean ± SEM)] is about 1/10th that of morphine or codeine, both of which react equally well with the antiserum (6). The detectiori limit of the assay for thebaine is 0.08 pmol. With this level of sensitivity we were able to detect a thebaine-like compound during the purification steps.Extraction and Purification Procedures. For purification of thebaine-like immunoreactive (ir) compound from ovine brain, Iyophilized ovine brain (2000 g) was pulverized, defatted with two times 3 vol of methylene chloride, and dried. The defatted material was heated in 10 vol of 1 M acetic acid containing 10 mM HCl at 95-100'C ...

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697. Alkaloid biosynthesis. Part IV. 1-Benzylisoquinolines as precursors of thebaine, codeine, and morphine

Cited by 78 publications

References 0 publications

(S)‐norlaudanosoline synthase: The first enzyme in the benzylisoquinoline biosynthetic pathway

(S)‐norlaudanosoline synthase: The first enzyme in the benzylisoquinoline biosynthetic pathway

Studies Aimed at the Synthesis of Morphine, IV: A New Approach to N‐Norreticuline Derivatives from Homoveratronitrile

Identification of the convulsant opiate thebaine in mammalian brain.

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