Morphine biogenesis

Although this isoquinoline at first bears little structural resemblance to morphine (108), careful rearrangement of the structure (A) shows the narcotic to possess the benzylisoquinoline fragment within its framework. Indeed, research on the biogenesis of morphine has shown that the molecule is formed by oxidative coupling of a phenol closely related to papaverine. 

A new approach to the problem of the biogenesis of the morphine alkaloids has recently been made by SohOpf and kindly disclosed to the... 

If this theory of the biogenesis of the morphine alkaloids is correct, the cell must be capable of preventing formation of an o-quinone on enzymatic oxidation of [xxxvi], and it seems probable that such an oxidation will only be achieved by the use of an enzyme system. 

Since it is known that quaternary salts give better yields of phenolic oxidative coupling products than do tertiary bases, when oxidised with one-electron transfer agents in the laboratory, the possible role of reticuline methochloride (tembetarine chloride) in the biogenesis of more complex alkaloids has been examined. The labelled salt has been found to be very poorly incorporated into morphine, sinomenine, and protopine. 

The chemistry of natural products encompasses their isolation, structure elucidation, partial and total synthesis, elucidation of their biogenesis, and the biomi-metic synthesis of N. p. Major breakthroughs in analysis were, e.g., the structural clarifications of morphine, lignin, insulin, estrones, and cholesterol as well as the elucidation of the biosyntheses of terpenoids, morphine, penicillin, chlorophyll, and vitamin B 2. Major advances in synthetic chemistry were, e.g., the total syntheses of camphor, hemin, quinine, saccharose, tropine, stryehnine, chlorophyll, vitamin B 2, erythromycin, taxol and palytoxin. Numerous N. p. of the so-ealled ehiral pool are used as starting materials for the synthesis of optically active compounds or serve (in the form of their derivatives) as catalysts for enantioselective syntheses. 

Fig. 32.20. Biogenesis of morphine (modified from Geissman and Grout, 1969).

The idea that the opium alkaloid morphine is a modified benzyliso-quinoline provided the key to the structure 6.152) for the alkaloid twisting of the benzylisoquinoline skeleton into that shown for reticuline (6.127) in (6.148) illustrates this relationship and suggests a possible biogenesis. This was later proved correct in the course of a study which is one of the classics of alkaloid biosynthesis. In the first experiments ever to be carried out with complex plant-alkaloid precursors, [1- C]- and [S- Cj-norlaudanosoline [as (6.123) were fed to opium poppies [99, 100]. They were found to label morphine (6.152), codeine (6.153) and thebaine (6.151) specifically, thus establishing that these alkaloids are indeed benzylisoquinoline derivatives. The key intermediate [101] proved to be reticuline (6.148). Both (R) and (5)-isomers were utilized, the latter by way of (6.155) [101, 102] which allowed its conversion into (i )-reticuline (6.148), the correct intermediate, with the same configuration as the three opium alkaloids [as (6.151). ... 

That tyrosine plays a role in the biogenesis of several types of benzylisoquinoline alkaloids results from its incorporation to the hydrophen-anthrene bases (thebaine, codeine, morphine) and to the benzylisoquino-lines papaverine, narcotine, and narcotoline w hen the generally labeled amino acid was fed to P. somniferum 219). 

On the other hand, evidence was accumulating showing that the two aromatic units derived from tyrosine were not identical in the step of condensation leading to the benzylisoquinoline structure. This had already been pointed out by Rapoport et al. (223) in a study on the distribution of the radioactivity in the morphine isolated from P. somni-ferum grown in an atmosphere of labeled carbon dioxide. Similar conclusions were reached in an investigation of the biogenesis of hydrastine in Hydrastis canadensis L. fed with labeled tyrosine, where the ratio of the radioactivity of the two carbon atoms representative of the original tyrosine molecules indicated unequal incorporation (224). 

The existence of a different metabolic pathway for each unit became more evident when labeled dopamine (CLIII) was used as precursor of hydrastine. Only one unit was incorporated it formed the isoquinoline moiety of the alkaloid (225), a specific type of incorporation which was also found in the biosynthesis of morphine (226), chelidonine (227), and berberine (228) when the base was fed to the proper plants. Although dopamine has not been experimentally tested in the biogenesis of papaverine it is an acceptable hypothesis that it will be incorporated following the same pattern as with the other alkaloids. 

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Barton DHR, Kirby AJ, Kirby GW (1968) Phenol oxidation and biosynthesis, part XVII. Investigation on the biosynthesis of sinomenine. J Chem Soc (C) 929-936 Battersby AR (1963) Tilden lecture. The biosynthesis of alkaloids. Proc Chem Soc 189-200 Battersby AR, Francis RJ (1964) Alkaloid biosynthesis, part V. Experiments on opium alkaloids using 3,4-dihydroxyphenethylamine. J Chem Soc 4078-4080 Battersby AR, Harper BIT (1958) Biogenesis of morphine. Chem Ind London 1958 364 Battersby AR, Harper BJT (1960) Rate studies on the incorporation of tyrosine into morphine, codeine and thebaine. Tetrahedron Lett 27 21-24 Battersby AR, Binks R, Harper BJT (1962) Alkaloid biosynthesis, part II. The biosynthesis of morphine. J Chem Soc 3534-3544... 

Kiippers FJEM, Salemink CA, Bastart M, Paris M (1976) Alkaloids of Papaver bracteatum Presence of codeine, neopine and alpinine. Phytochemistry 15 444-445 Leete E (1959) The biogenesis of morphine. J Am Chem Soc 81 3948-3951 Leete E, Murrill JB (1964) The incorporation of dopamine into chelidonine and morphine. Tetrahedron Lett 147-151... 

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