Biosynthesis of morphine

One step in the biosynthesis of morphine is the reaction of dopamine with p-hydroxyphenylacetaldehyde to give (S)-norcoclaurine. Assuming that the reaction is acid-catalyzed, propose a mechanism. 

Morphine and codeine biosynthesis (Samuelsson, 1999 Herbert et al., 2000 Novak et al., 2000) Studies on the biosynthesis of morphine have been carried out mainly on cell cultures mainly of Coptis japonica and species of Thalictrum. Two enzymes (tyrosine decarboxylase and phenolase) catalyze the formation of dopamine from one molecule tyrosine. Dopamine is also the key intermediate in the biosynthesis of mescaline. 

Scheme 27 Biosynthesis of morphine conversion of dopamine to mescaline.

Papaver Alkaloids.—Biosynthesis of morphine (36) occurs, in Papaver somniferum, through reticuline (33) by way of thebaine (35). The sequence from (35) to (36) involves, inter alia, two O-demethylations, with that at the methoxy-group at C-6 occurring first.1,2 Confirmation that the other methoxy-group is not demethylated first in this Papaver species obtains from the failure to detect oripavine (37), which is found in other Papaver species, as a natural constituent of P. somniferum. The experiment involved attempted isolation of radioactive (37), using inactive alkaloid as carrier, following a feeding experiment with radioactive reticuline (33).37... 

Oripavine 3-ethyl ether (38), an unnatural analogue of thebaine (35), was found to be metabolized to morphine 3-ethyl ether and to morphine (36). The efficiency of the conversion was comparable to that of natural biosynthesis. (For an examination of other unnatural compounds as substrates for the enzymes of the biosynthesis of morphine alkaloids, see Vol. 4, p. 15.)... 

Scheme 1. Biosynthesis of morphine in plants. Metabolic conversions marked by asterisks are highly stereoselective.

Figure 2.8 Biosynthesis of morphine via the conversion of (S)-reticuline to (R)-reticuline, salutaridine and thebaine. SalS, salutaridine synthase SaIR, salutaridine reductase THS, thebaine synthase COR, codeinone reductase.

Total synthesis of morphine is difficult, but analogs lacking the dihydrofuran ring are accessible (8) from 1-benzylisoquinolines, in analogy with the biosynthesis of morphine, to... 

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). 

Scheme 3. Biosynthesis of morphine, a, Oxidative coupling b, reductive cleavage.

The stereochemical relationship between (— )-reticuline and morphine during biosynthesis has already been dealt with in connection with the promorphinane bases (52). The intermediates of the biosynthesis of morphine have the same R-configuration on the tertiary C-9 atom to which nitrogen is attached. Consequently, the biosynthesis of morphine proceeds along the following pathway (see Scheme 3) ... 

P. somniferum) in this biosynthetic pathway is still obscure. InP. somni-ferum the biosynthesis of morphine can also proceed from (+ )-reticuline provided that this compound is first transformed into (— )-reticuline. The biosynthesis is, however, impossible (via thebaine) from ( + )-reticuline methochloride (52). 

Oxidative phenol coupling (4, 499-500). Schwartz and Mami have effected oxidative para-ortho coupling of the benzyltetrahydroisoquinoline alkaloid (1) to (2) with TTFA in CH2CI2 ("78 to 20°, overnight) in 23% yield. This oxidative coupling is involved in the biosynthesis of morphine alkaloids, but it has... 

Figure 12.15. Biosynthesis of morphine from (. )-reticuUne. Reprinted with permission from Chou and Kutchan (1998) ".

New investigation of bisbenzylisoquinoline biosynthesis is welcome (see ref. 32 also this Report, p. 16). Although aporphine alkaloids are the simplest developments of the benzylisoquinoline skeleton, their biosynthesis need not, as several examples show, be simple. It has, however, been found that the biosynthesis of boldine and isocorydine is straightforward. Further detail has been repor-ted on the biosynthesis of Erythrina alkaloids, which were established to be modified benzylisoquinolines some time ago. Further detail on the biosynthesis of morphine (23) and related alkaloids continues to be published. Of particular R. B. Herbert, in ref. 9, p. 11. 

Morphinan Alkaloids.—Extensive research on the biosynthesis of morphine (51) and related alkaloids in Papaver somniferum has allowed a detailed description of the pathway from the amino-acid tyrosine through reticuline (44), thebaine (46), and codeine (50) to morphine (51) (Scheme The incorporation of (R)-... 

Battersby, A. R. and D. M. Foulkes, Alkaloid biosynthesis. Part VIII Use of optically active precursors for investigations on biosynthesis of morphine alkaloids, J. Chem. Soc., 3323-3332 (1965). 

As shown in Schemes 13.40 and 13.41, the biosynthesis of morphine (via thebaine and codeine) has been shown to involve the conversion of tyrosine (Tyr, Y) into... 

The existence of a metabolic channel wonld be in line with the regnlatory independence of the enzymes of the morphinane branch from the general benzylisoqninohne biosynthesis. A well known expression of this phenomenon is the intimate link between lacticifer development and biosynthesis of morphine dedifferentiated, cultured cells of opium poppy do not prodnce... 

FIGURE 25.6 An abbreviated pathway for the biosynthesis of morphine from two molecules of tyrosine. The individual steps are explained in more detail in the text. 

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