Alkaloids of the Papaveraceae

The following groups of alkaloids occur in the plant family of the Papaveraceae benzylisoquinoline, cularine, aporphine, proaporphine, morphine, protoberberine, protopine, narceine, benzophenanthridine, phthalide-isoquinoline, rhoeadine, papaverrubine, pavine, isopavine and ochotensimine. Many of these alkaloid groups are formed by one genus only, whereas others occur in many genera and even in plants of other families. Alkaloids of all these groups must thus be taken into considera- 

Borke et al. [31] ( chromatostrip technique [104]) and Mariani and Mariaiu-Marelli [129] in their studies of opium alkaloids, were the first to draw attention to the advantages of TLC over other analytical methods, including PC. The method really developed only after Stahl [227] had introduced standardised conditions and apparatus for separation in 1956. 

Ikram et al. [94] describe the separation of morphine, codeine, papaverine and thebaine on a loose alumina layer (Merck), using three solvents. Papaverine and narcotine cannot always be separated satisfactorily and this has led to the use of two-dimensional TLC [99, 176]. With xylene-butanone-methanol-diethylamine (40 + 60 + 6 + 2) in a one-dimensional procedure on activated silica gel G, Bayer [16] has recently succeeded in separating the following alkaloids narcotine hi / 74, papaverine 59, thebaine 45, codeine 26, morphine 12. The problem of the papaverine-narcotine separation has thus been solved. 

Stahl and Jork [229 c] have critically compared the numerous solvents already quoted in the literature, with a view to introducing TLC into pharmacopoeia procedures and to identifying crude opium and opium preparations. 

The standard method was used on silica gel GF254 layers, with uniform external conditions. The fluorescence-quenching zones of the six best known opium alkaloids could be visualised with concentrated sulphuric acid, which yielded differentiating, colours. Thebaine alone was visible in the cold, as a yellow spot. 10 jxg amounts on heating 10 min at 150° C gave the colours morphine, violet narceine, brown violet codeine, reddish blue thebaine, light violet papaverine, grey and narcotine, pale red. 

---

The pavine and isopavine alkaloids of the Papaveraceae have been discussed in Vols. 4, 10, 12, and 17 of this treatise (2-5), and only brief references have been made to occurrences outside this botanical family. Individual chapters have been devoted to the pavine and isopavine alkaloids in the two books by Shamma (6,7), covering developments until 1977, and also in Rodd s Chemistry of Carbon Compounds (8), published in 1978. A listing of naturally known pavines and isopavines up to 1975, with references to physical and spectral data, appeared in Kametani s Chemistry of the Isoquinoline Alkaloids 9,10). A more recent compilation by Gozler and co-workers 11) has covered references to mid-1982. Relevant literature has also been summarized regularly in Vols. I-XIII of Spe-... 

The structures of rhoeadine-isorhoeadine represent a new type of skeleton in alkaloids. The occurrence of rhoeadine-papaverrubine alkaloids was observed in all of the thus far examined sections of the genus Papaver. Their common occurrence leads to the assumption that a biogenetical relationship to the other alkaloids of the Papaveraceae exists. They greatly resemble the phthalideisoquinoline alkaloids. With this in... 

Scheme 20. The interrelationship of some alkaloids of the papaveraceae (the C atoms of reticuline, I, marked by dots and arrows, show the possible linkage during the formation of the derivatives II-XV). a = Oxidative coupling b = reductive cleavage R = H or CH3.

Studies of the isolation and the constitution of alkaloids of the Papaveraceae family have led to the investigation of the effect of various types of drying on the quantity of alkaloids in the leaves of Macleaya (Bocconia) microcarpa (52), the stability of some Papaver alkaloids (in different solvents) to sunlight (294), the accumulation of alkaloids in the latex of the Papaveraceae (243), the site of origin of the alkaloids in the studied plants (295, 296), the different geographical zones (297, 298), the time after flowering (299), and the seasonal variations in the content of the individual groups of alkaloids, particularly in P. somniferum (300). 

S)-(+)-reticuline (20) and orientaline (25). The alkaloids of the Papaveraceae and Fumariaceae can be subdivided into several constitutional types (Fig. 3), viz., simple isoquinolines, benzylisoquinolines, pavines, isopavines, cularines, proaporphines, aporphines, promorphinanes, morphinanes, protoberberines, retroprotoberberines, secoberbines, benzophenanthridines, protopines, phthali-deisoquinolines, secophthalideisoquinolines, indenobenzazepines, spirobenzyl-isoquinolines, and rhoeadines. 

Allocryptopine (thalictrimine) is a strong myocontractile agent in mice, and is apparently less toxic than the indole alkaloid brevicolline. The pharmacology of protopines and other alkaloids of the Papaveraceae has been thoroughly covered up to 1972 in Ref. 11. 

Slavik J, Slavikova L 1956 Alkaloids of the Papaveraceae. VIII. Glaucium corniculatum Curt. Chem Listy 50 969-974... 

It is interesting to note the use made of the dienone (41) = (57) in the biosynthesis of both Erythrina alkaloids of the Leguminosae and ihe Dicentra aporphine alkaloids of the Papaveraceae. 

In collaboration with Dr. Margaret Roberts of the University of London, we recently learned that latex also contains miUimolar concentrations of dopamine, a fraction of which occurs in the same, relatively dense vacuoles that are rich in alkaloids (Roberts et al. 1983). Dopamine is an essential intermediate in the biogenesis of the alkaloids of the Papaveraceae (Shamma and Moniot 1978, Spenser 1969). Dopamine, which is formed from tyrosine, condenses with different carbonyl derivatives in Pic-tet-Spengler reactions to afford simple tetrahydroisoquinolines that can then give rise to a diverse array of alkaloids. Considerable evidence exists to suggest that the chirality of the tetrahydroisoquinoline alkaloids influences their transformation. It appears that morphinan alkaloids are formed from (-)-R-reticuline, whereas most other alkaloids including sanguinarine are derived from (+)-S-reticuline (Battersby et al 1965, 1975, Wilson and Coscia 1975, Borkowski et al. 1978, Brossi 1982). 

The first occurrence of an isopavine alkaloid outside the Papaveraceae was demonstrated when (—)-thalisopavine (30) was found in Thalictrum dasycarpum (53). The proposed structure was verified through spectral analyses and total synthesis (53). Methylation yielded (—)-0-methylthalisopavine (26), which was later synthesized as a racemate (77). (—)-0-Methylthalisopavine was discovered in Papaver radicatum some years later (78), so this represents another case of synthesis preceding natural occurrence. 

The family of the Papaveraceae includes 31 genera and approximately 700 species (2). The alkaloids contained therein are derivatives of the 1-benzyltetrahydroisoquinoline alkaloid reticuline (1). For the classification and chemical data of the described alkaloids (3-5) as well as for the pharmacodynamic properties of morphine and codeine (6, 7) see reviews. Some pharmacological aspects have been dealt with by Shamma (5) and Krueger et al. (8). 

II. Structure, Pharmacological, and Toxicological Properties of the Papaveraceae Alkaloids... 

Chapter 5. The Pharmacology and Toxicology of the Papaveraceae Alkaloids V. Preininger... 

The protoberberine alkaloids are widely distributed, occurring in at least eight botanical families. They occur most frequently in the various genera of the Papaveraceae but are also well represented in the Berber-aceae, Menispermaceae, Ranunculaceae, Rutaceae, and Annonaceae families. Table I shows the additional plant sources of the protoberberines that have been reported since the appearance of the last review in Volume IV. 

Reviews have appeared on the distribution and systematic significance of alkaloids of the Rutaceae and of the Papaveraceae and on the taxonomic significance of benzyltetrahydroisoquinoline-derived alkaloids in particular. The isolation of alkaloids from plants in the Soviet Union has been discussed. In addition to continued alkaloid screening studies, surveys encompassing detection of alkaloids have been carried out on plants from Argentina, India, and Morelos State, Mexico. ... 

In view of the tremendous progress in the investigation of the alkaloids of the plant family Papaveraceae, it seemed desirable to bring up to date the chapters dealing with this problem which were published earlier in this series. In this connection, mention should be made that sufficient data have been accumulated to make it profitable to undertake bio-genetic and chemotaxonomic studies. 

The finding that the majority of the Papaveraceae alkaloids arise from the benzylisoquinoline precursors reticulme, orientaline, and probably norlaudanosoline, by phenolic oxidation 30, 40,137,148, 35S), has... 

A classification of the known alkaloids based on the individual tribes, genera, and sections (Table I) shows that all the investigated genera contain protoberberine, protopine, and benzophenanthridine alkaloids of the sanguinarine and chelerythrine type 195). There was also observed a frequent occurrence of the aporphine alkaloids. In the plant family Papaveraceae, the aporphine alkaloids having oxygen substituents in position C-8 are absent. None of these groups of alkaloids can be used for chemotaxonomic purposes. The enzymes which synthesize them are therefore ubiquitous for the whole family Papaveraceae. 

The genus Papaver differs substantially from other members of the Papaveraceae by the presence of rhoeadine-papaverrubine alkaloids and the genera Oorydalis, Dicentra and probably P )wana which, in addition to the common benzylisoquinoline alkaloids contained in this family, are also able to synthesize some alkaloids having an additional CH3 group (13-methyltetrahydroprotoberberine audits natural derivatives— see p. 384, and 13-methylprotopine—see p. 391). 

Alkaloid isolation work is summarized in Table 7. Callus tissues from eleven species of the Papaveraceae (e.g. Macleaya cordata), known as sources of protopines, did... 

A number of reviews on various aspects of QBA have been published. The principal information can be found in the two books on isoquinoline alkaloids by Shamma [1,2] and the reviews by Santavy [3,4] and Simanek [5] in The Alkaloids series. A highly valuable review of the physical and spectral data and the occurence of the 88 benzophenanthridine alkaloids has been compiled by the Shamma group [6], Preininger has summarized the distribution of QBA in plant species of the Papaveraceae and Fumariace-ae families [7]. A review by Dostal and Potacek specifically devoted to the in vitro nucleophilic conversions of QBA appeared in 1990 [8], Surveys on the biological activities [9-11] and biosynthetic formation [12,13] of these alkaloids have been published. Well-designed reviews of the syntheses of the QBA are also available [14-16]. Hanaoka and Mukai presented a treatise on the biomimetic syntheses of the benzophenanthridines from the protoberberines in volume 14 of the Studies in Natural Products Chemistry series [17]. Quite recently, a book by Bentley treating isoquinoline alkaloids also involved benzophenathridines [18]. 

---