Protopine alkaloids biosynthesis

TANAHASHI, T., ZENK, M.H., Elicitor induction and characterization of microsomal protopine-6-hydroxylase, the central enzyme in benzophenanthridine alkaloid biosynthesis. Phytochemistry, 1990,29,1113-1122. 

Although in P. somniferum and Sinomenium acutum the biosynthesis of the morphinane bases can be carried out with (+)-reticuline as starting material, these bases and also protopine (101a) cannot be obtained biosyn-thetically in satisfactory yield from (+)-tembetarine chloride (reticuline methochloride). Similar results were obtained with D. spectabilis (683). Important intermediates of the biosynthesis between tetrahydroprotober-berine and protopine alkaloids are the compounds of the dihydroprotopine type (102), which were prepared in high yield by partial synthesis with cyanogen bromide (von Braun method) (684). The biosynthesis of pro topine alkaloids is also discussed in Section III,N. 

M. Rueffer and M.H. Zenk, S-Adenosyl-L-methionine (S)-7,8,13,14-Tetra-hydroberberine-cis-N-methyltransferase, a branch point enzyme in the biosynthesis of benzophenanthridine and protopine alkaloids. Tetrahedron Lett. 

Pharmacological Activity Other Biological Activity Protoberberidine Alkaloids Biosynthesis Biological Activity Protopine Alkaloids Benzophenanthridine Alkaloids Phthalideisoquinoline Alkaloids Rhoeadane Alkaloids Dibenzopyrrocoline Alkaloids Pavine and Isopavine (Argemone) Alkaloids Cularine Alkaloids Bisbenzylisoquinoline Alkaloids Biological Activity... 

The benzophenanthridine skeleton is encountered in approximately 30 alkaloids, principally of the family Papaveraceae (Cordell, 1978a). In contrast to the biosynthesis of protopine alkaloids, phenanthridine alkaloids are synthesized in the cytoplasm (Hartmann, 1991). This type of system arises from a protoberberine precursor by fission of the C-6-N bond and recyclization. The biogenetic sequence leading to chelidonine (80) biosynthesis in Chelidonium majus has been supported by feeding experiments with multiply-labeled (-t-)-reticuline [(5)-reticuline] (20) and with labeled stylopine (79) (Fig. 32.25) (Hutchinson, 1986 Sim ek, 1985 Tanahashi and Zenk, 1988). (5)-Z-V-Methylstylopine and protopine (60) have been shown to be metabolites in this pathway. Reticuline is oxidatively cyclized to ( —)-scoulerine (72). Formation of two methylenedioxy groups results in the formation of stylopine (79) (Hartmann, 1991). 

Barton DHR, Cohen T (1957) In Festschrift Dr A Stoll, Birkhauser, Basel, p 117 Barton DHR, Kirby GW, Taylor JB, Thomas GM (1963) Phenol oxidation and biosynthesis, part VI. The biogenesis of amaryllidaceae alkaloids. J Chem Soc 4545—4558 Barton DHR, Hesse RH, Kirby GW (1965) Phenol oxidation and biosynthesis, part VIII. Investigations on the biosynthesis of berberine and protopine. J Chem Soc 6379-6389 Barton DHR, Bracho RD, Potter CJ, Widdowson DA (1974) Phenol oxidation and biosynthesis, part XXIV. Origin of chirality in the erythrinan system and derivation of the lactone rings of a- and ]3-erythroidine. J Chem Soc Perkin Trans 1 2278-2283 Basmadjian GP, Paul AG (1971) The isolation of an O-methyltransferase from peyote and its role in the biosynthesis of mescaline. Uoydia 34 91-93 Basmadjian GP, Hussain SF, Paul AG (1978) Biosynthetic relationships between phenethylamine and tetrahydroisoquinoline alkaloids in peyote. Lloydia 41 375-380 Battersby AR, Binks R, Francis RJ, McCaldin DJ, Ramuz H (1964) Alkaloid biosynthesis, part IV. 1-Benzylisoquinolines as precursors of thebaine, codeine and morphine. J Chem Soc 3600-3610... 

The protoberberine alkaloids (5-75) play important roles as precursors in the biosynthesis of a variety of related isoquinoline alkaloids such as protopine, phthalideisoquinoline, spirobenzylisoquinoline, rhoeadine, inde-nobenzazepine, secoberbine, and benzo[c]phenanthridine alkaloids. Chemical transformations of protoberberines to these alkaloids are particularly interesting and exciting from the biogenetic viewpoint and further from ready availability of starting protoberberines in nature or synthesis. 

The probability63 that (69) lies along the pathway to protoberberine and derived alkaloids, between scoulerine (65) and stylopine (70), has been supported by the observation that tritiated (69) is a precursor for protopine (73), and also for corynoline (78).64 Evidence previously obtained for the intermediacy of the metho-salt of stylopine [as (71)] in the biosynthesis of chelidonine (62)63 and protopine (73)63,65 has been affirmed, and it is apparently the a-form (71) and not the /3-form that is involved. [The authors are mistaken in assuming that ( —)-stylopine has the R-configuration at C-14 cf. ref. 63]. 

Study70 of the biosynthesis of the closely related alkaloid rhoeadine (83) confirms that the formation of the skeleton common to this alkaloid and (82) involves compounds of the types (80) and (81), in this case (71) and protopine (73) (for interlocking evidence on protopine biosynthesis see above). 

Figure 2.7 Biosynthesis of protopine and the benzophenanthridine alkaloids. STS, stylopine synthase SNMT, stylopine N-methyltransferase DBOX, dihydrosanguinarine oxidase SanR, sanguinarine reductase.

Tani and Tagahara also studied the biosynthesis of rhoeadine and reported that in P. rhoeas this alkaloid arises from a-stylopine methochloride (58n) via protopine. jS-Stylopine methochloride does not participate in this biosynthesis (740). 

Takao N, Iwasa K, Kamigauchi M, Sugiura M (1976) Studies on the alkaloids of papaveraceous plants XXV. Biosynthesis of the alkaloids of Corydalis incisa Pers. and Chelidonium majus L. Incorporation of tetrahydroberberines, N-methosalts of tetrahydroprotoberberines and protopine. Cliem Pharm Bull 24 2859-2868... 

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