Protoberberines from protopines

The alkaloids of the narcotine type can also be synthesized from benz[d]indeno(l,2-f ]azepine (133a) (698) (Scheme 45). Moreover, compound 133a forms a key substance for the synthesis of the tetrahydro-protoberberine (58), protopine (101), rhoeadane (154), and spiroben-zylisoquinoline (191) ring skeletons. The compounds 133a and 133b arise also by rearrangement from the spirobenzylisoquinoline, protoberberine, and 1-benzoylisoquinoline skeletons. Therefore, it is assumed that even in the plants it plays a key role in the formation and interconversion of the benzylisoquinoline alkaloids with 17 carbon atoms in the skeleton (Scheme 45). 

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. 

Nalliah et al. (202,203) developed a novel entry to protopine alkaloids from a protoberberine. 13-Oxotetrahydroberberine (ophiocarpinone) metho salt (291) was reduced with zinc in 30% acetic acid to afford a new type of the protopine analog 401 (Scheme 74) (202). On the other hand, 291 gave 13-oxoallocryptopine (402) via the hydroperoxide on exposure to air in the presence of sodium hydride and potassium iodide in dimethoxyethane (203). 

An indenobenzazepine skeleton was constructed from a protoberberine through C-8—N and C-14—N bond cleavage followed by formation of C-13—N and C-8—C-14 bonds via a protopine analog according to a bio-... 

The species of the genus Glaucium Toum. are characterized by the presence of aporphine and protopine alkaloids in addition to protoberberines and benzophe-nanthridines (Tables XVII and XVIII). Platonova et al. (110) isolated corydine (136) from G. squamigerum as the major alkaloid in addition to a smaller amount of protopine (309) and allocryptopine (310). In G. oxylobum, the major alkaloid was corydine together with protopine and allocryptopine (107). In contrast, Slavik et al. (108) isolated allocryptopine (310) and protopine (303) as the... 

Almost all of the studied plants have been found to contain protoberberines, protopines, and phthalideisoquinolines. The occurrence of aporphines and ben-zophenanthridines is frequent. The secoberbines have been isolated from C. incisa and C. ochotensis. The cularines, which are characteristic of some plants of the genus Corydalis, are also found in the genera Dicentra and Sarcocapnos. 

Fumaria chemically resembles Corydalis. Similarly, the genus Fumaria also contains protoberberines, protopines, and phthalideisoquinolines, and more frequently, secophthalideisoquinolines and spirobenzylisoquinolines. They also yield indenobenzazepines, which cannot be demonstrated in the genus Corydalis (Table LVI), but no aporphines and cularines, which have been isolated from the plants of the genus Corydalis. 

With the help of this N-methyltransferase the substrates for testing the hydroxylation reaction to the protopines were prepared (Fig. 3) from tetrahydro-protoberberines that had been labelled by reduction of the corresponding protoberberines with NaB H. ... 

Berberine or protoberberine alkaloids [such as stylopine (79)] may be converted into alkaloids of the protopine type (60) (Fig. 32.24) (Geissman and Crout, 1969 Hartmann, 1991). Highly specific microsomal cytochrome P-450-de-pendent enzymes from cells of Eschscholtzia californica (and other species of the Papaveraceae and Fumariaceae) introduce two methylenedioxy bridges into (5)-scoulerine (72) to form (5)-stylopine (79), which is, in turn, an important precursor of the protopine, phthalideisoquinoline, and benzophenanthridine groups (Hartmann, 1991). 

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). 

Among the 138 protoberberine alkaloids cited in the period covered by this review, a few are more widely distributed than the others. Berberine is the most cited alkaloid with 90 citations from plants of seven families and 20 genera, followed by protopine with 85 citations from plants of four families and 16 genera. The 138 different alkaloids were found in 741 citations. Thus, berberine alone appears in 12.1% of all the publications regarding protoberberine alkaloids. It is interesting to observe that 84 alkaloids (60.4% of the total) appeared only once in the review. 

Studies of plants from the section Argemonorhoeades show that these plants contain only a very few alkaloids including those of the protoberberine (5), rhoeadine (11), papaverrubine and protopine (3) types. These alkaloids are similar to those found in the section Orthorhoeades but they occur in markedly lower yields. 

Species of Glaucium are characterised by the presence of aporphine alkaloids in addition to the commonly occurring protopine (3), protoberberine (5) and benzophen-anthridine (6) alkaloids. In these respects, Glaucium resembles Papaver, Eschscholzia, Meconopsis mdRoemeria but it differs from the other genera of the Papaveraceae. 

Meconopsis comprises some 40 species which are mainly indigenous to China and the Himalayas. Protopine (3), protoberberine (5), benzophenanthridine (6), isopavine (13) and aporphine alkaloids (Fig. 2) have been isolated from a small number of species. Rhoeadine alkaloids, which are present in Papaver species, also occur in Meconopsis and their distribution appears to be limited to these two genera (Slavik and Slavikova 1977). The sole European representative, M. cambrica growing in England produces magnoflorine (4) as the major alkaloid, together with protoberberine (5), proaporphine (14) and promorphinan alkaloids (15) (Hemingway et al. 1981). 

Plants of the subfamily Hypecoideae differ chemotaxonomically from the plants of the subfamily Papaveroideae. Species of the genus Hypecoum contain secoberbine alkaloids (37-39) in addition to protopine (3), protoberberine (5) and benzophenanthridine (6) alkaloids. The presence of secoberbines (37-39) is indicative of a close relationship between Hypecoum and some species of Fumariaceae. 

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