Chelidonine biosynthesis

Protoberberine Alkaloids.—In the course of the bioconversion of the proto-berberine scoulerine (65) into chelidonine (62) and phthalide-isoquinolines, e.g. narcotine (63), C-13 becomes oxidized.61 Ophiocarpine (68), with a hydroxy-group at C-13, represents an intermediate stage in the modification of the protoberberine skeleton, and results62 of tracer experiments have shown that scoulerine (65) is also to be included in the biosynthesis of this alkaloid. Tetrahydro-protoberberine (67) is also a precursor, its incorporation indicating that C-13 hydroxylation is a terminal step. As for other protoberberine derivatives,63 nandinine (64) was not assimilated,62 and it follows then that (65) is probably converted into (67) by way of isocorypalmine (66). 

Using chirally tritiated samples of the protoberberine (67) it has been established that hydroxylation of (67) to give (68) occurs with loss of the 13-pro-R hydrogen atom, i.e. normal retention of configuration, and does not involve an enamine intermediate since tritium is not lost from C-14 during the course of this biotransformation.62 It is to be noted that similar results, associated with C-13, have been observed61 for narcotine (63) and chelidonine (62) biosynthesis, except that here the 13-pro-S proton is removed. 

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]. 

Stylopine, Chelidonine, and Related Alkaloids.—Full details have been published on a study of the biosynthesis of stylopine (71) and chelidonine (76) in Chelidonium majus. The original publications predate these reports so it is fitting that the work be summarized here. In any case some of the results are new and the work is notable for the rigour of its approach and the elegant application of tritium labelling as a probe for the course of the reactions involved. The results obtained with the R and S isomers of multiple labelled reticuline [as (67)] and scoulerine [as (68)] establish the biosynthetic sequence as (67) -> (68) (71) - (76) (-)-(5)-scoulerine was shown... 

Chelidonine [(66) p. 17] was long suspected as a protoberberine variant. The truth of this has been established by the results of a series of elegant experiments, which also defined the detail of biosynthesis, including the stereochemistry of the proton losses which occur during transformation of protoberberine into chelidonine (this Report, p. 16 see also ref. 30). Corydaline (19) is a methylated protoberberine, and investigation of its biosynthesis suggests an orthodox pathway. The corydaline skeleton appears in modified form in ochotensimine (20). ... 

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). 

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. 

In many of the isoquinoline alkaloids the tetrahydroisoquinoline skeleton is clearly seen as part of the stmcture, in others it is somewhat obscured, e.g. chelidonine (76) (Sect. 3.4), and in still others, e.g, colchicine (77) (Sect. 4), which is a phen-ethylisoquinoline, and the Erythrina alkaloids (Sect. 3.3) severe modification in the course of biosynthesis has obliterated any suggestion of an isoquinoline moiety. 

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