Bulbocapnine biosynthesis

In contrast to the formation of isothebaine by a route involving a dienone, an alternative process is implicated in the biosynthesis of another aporphine alkaloid. Bulbocapnine (78) has been shown to be derived from reticuline (75). The methylation pattern of reticuline implies a direct ortho-ortho phenol coupling in which corytuberine (77) is the first alkaloid to be formed. Further experiments have been directed towards distinguishing this mode of coupling from an alternative pathway which involves hydroxylation of reticuline at C-6 and formation of bulbocapnine via a biologically unknown dienone type (76, Scheme... 

Aporphine Alkaloids.—Isothebaine (65) derives from orientaline (62) along a pathway which involves thedienone(63)and the dienol(64). The biosynthesis of the aporphine alkaloids of Dicentra eximia is quite different but dienone intermediates are also implicated. By comparison the biosynthesis of bulbocapnine (66) is simple, for the alkaloid arises directly from reticuline (67), in Corydalis cava, by ortho-ortho phenol oxidative coupling. 

In November 1950,1 studied the effect of bulbocapnine on rats, and published the results in the Archives of Neurology and Psychiatry. Bulbocapnine produces all of the motor manifestations of catatonic schizophrenia in human beings. The drug is an aporphine isoquinoline alkaloid that decreases dopaminergic activity in the brain, and inhibits tyrosine hydroxylase, the rate-limiting enzyme in the catecholamine biosynthesis. 

Biosynthesis A. a. are formed from phenolic tetrahy-drobenzylisoquinolines either by direct oxidative coupling or via dienones (proaporphines). The direct oxidative coupling can be either ortho-para (to isoboldine type) or ortho-ortho (to bulbocapnine type) . Lit, Eur. J. Pharmacol. 219,67-74(1992). PlantaMed. 57, 406ff. (1991). Biochem. Pharmacol. 43, 323-329 (1992). 

All that is required for the transformation of the benzylisoquinoline skeleton [as 6.123)] into that of the aporphines, e.g. bulbocapnine (5.729), is a single new bond. Clearly phenol oxidative coupling (N.B. see Section 1.3.1) is involved here, but there are several possible routes to a particular alkaloid. Interestingly examples of most of these possibilities have been found for the biosynthesis of one or more of the aporphine alkaloids, and in one case, that of boldine (5.757), biosynthesis takes a different course in two different plants. Methylation pattern in the alkaloid produced does not provide a reliable guide to the course of biosynthesis, as witness that of 6.131) in Scheme 6.25 [88]. The methylation pattern suggests a different pathway (see Scheme 6.27), which is followed in another plant. 

The simplest sequence of biosynthesis is found in the formation of bulbocapnine (32). Reticuline (25) is the immediate benzylisoquinoline precursor. Oxidative coupling ortho to each of the phenolic hydroxy-groups occurs to give (31) from which bulbocapnine (32) is then derived (Blaschke et al. 1974). 

---