Aporphine alkaloids biosynthesis

A key role for dienones, e.g. [6.133) and [6.137), in aporphine alkaloid biosynthesis is apparent. Their importance is emphasized by their natural occurrence. One such is crotonosine [6.141) formed... 

Aporphine Alkaloids.—A study on the biosynthesis of boldine previously published in preliminary form and reviewed73 is now available in full74 without the addition of essentially new information. 

Minami et al. (2008) succeeded to express the genes of scoulerine and mag-noflorine biosynthesis (NCS, CNMT, 40MT, BBE) to produce scoulerine and the aporphine alkaloid magnoflorine in recombinant . coli and S. cerevisiae. 

Barton and Cohen (48) were the first to suggest the seminal idea that dienones could be intermediates in the biosynthesis of aporphine alkaloids from benzylisoquinolines, since such dienones could rearrange to the aporphine nucleus either through a dienone-phenol or a dienol-benzene rearrangement as shown in the scheme on the following page. 

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... 

By analogy with the biosynthesis of several aporphine alkaloids (33-35) the homoaporphines could arise naturally by way of homoproaporphines 78a and 78b or by direct coupling of the diphenolic isoquinoline 77a. 

The aporphine alkaloids have been previously reviewed in this series and there has also been published a summarizing report (450). Therefore, only a tabulation (Table VI) of those bases which were isolated from the Papaveraceae and their photochemical synthesis, the characteristic Pellagri reaction, the physicochemical data, and the biosynthesis are given. 

The biosynthesis of aporphine alkaloids takes the course—laudanoso-line, norlaudanosoline, reticuline, or orientaline—by means of phenolic oxidation via the cyclohexadienone proaporphine (27, 28, 39, 40, 47, 49, 65, 66, 68, 69,147,148,150, 229, 231, 240, 250, 275, 349, 445, 451, 512) after dienone-phenol or dienol-benzene rearrangement, as described in more detail in the preceding section. The foregoing results, considered as a whole (39,49), provide good evidence that isothebaine is biosynthesized in P. orientale along the following pathway ... 

Similar to proaporphine bases which are intermediates in the biosynthesis of the aporphine alkaloids, the promorphinanes, having a cyclohexadienone ring D, form an intermediate in the biosynthesis of the morphinane alkaloids. They also arise from benzyltetrahydroisoquino-line bases by phenolic oxidation. The first known alkaloid of this group was salutaridine (36) (first isolated from Groton salwtaris) (see Scheme 3) which in all probability is identical with the already known floripavine... 

Aporphine Alkaloids.—The biosynthesis of the proaporphine and aporphine alkaloids of Croton sparsiflorus has been investigated and found to be unexceptional. Thus [2- C]tyrosine was found to be a precursor for crotsparine (74), crotsparinine (75), and sparsiflorine (76). Moreover, labelled ( )-coclaurine (77), but not ( )-isococlaurine (78), was found to give radioactive alkaloids. Coclaurine was also shown to be present in C. sparsiflorus by means of a trapping experiment using [2- C]tyrosine and inactive coclaurine radioactive coclaurine was isolated at the end of the experiment. 

The methylation pattern of boldine (79) might have been taken to indicate a biosynthetic pathway similar to that of the aporphine alkaloids of Dicentra but the above results clearly refute this idea. The change in the methylation pattern from reticuline (82) to boldine (79) is not apparently due to methyl migration for ( )-[6-0 CH3,l- H]reticuline [as (82)] was incorporated with loss of 64% of the labelsimilar results have been obtained in the related case of crotonosine biosynthesis. ... 

The biosynthesis of the aporphine alkaloids in P. sommferum has been studied (258, 259, 456, 465). In 1911, Gadamer postulated that the biosynthesis of the aporphine alkaloid glaucine (24h) proceeds via the simple benzyltetrahydroisoquinolines (466). Later, this hypothesis was experimentally confirmed, but some of the problems remained unresolved owing to the inadequate technique employed then. Recently, some authors have returned to this problem (152,258,259,467). By addition of N—CH3 labeled reticuline to a nutrient solution it was shown that, from the thus... 

In the light of established pathways to aporphine alkaloids (see p. 15) study of the biosynthesis of glaucine (6) and related bases in Dicentra eximia might have been expected to yield orthodox results. On the contrary, however, a novel pathway was unearthed which implicates dienone intermediates of quite un-... 

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. 

New investigation of bisbenzylisoquinoline biosynthesis is welcome (see ref. 32 also this Report, p. 16). Although aporphine alkaloids are the simplest developments of the benzylisoquinoline skeleton, their biosynthesis need not, as several examples show, be simple. It has, however, been found that the biosynthesis of boldine and isocorydine is straightforward. Further detail has been repor-ted on the biosynthesis of Erythrina alkaloids, which were established to be modified benzylisoquinolines some time ago. Further detail on the biosynthesis of morphine (23) and related alkaloids continues to be published. Of particular R. B. Herbert, in ref. 9, p. 11. 

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 unusual structures of the Erythrina alkaloids, e.g. erythraline 6.144), suggest an unusual biogenesis. Although the later steps of biosynthesis are unusual, the first key intermediate is surprisingly a benzylisoquinoline A-norprotosinomenine 6.136) (5 -isomer), which is involved along with a dienone [as 6.137) = 6.142) in the biosynthesis of both erythraline and some aporphine alkaloids (see above). 

The biosynthesis of aporphine alkaloids iUustrates splendidly this hypothesis of phenol oxidative coupling most of the possible ways of joining two aromatic residues have been observed. The results obtained show that a pathway is in general not... 

To isolate and examine the enzymes involved in aryl-aryl coupling in these examples and to compare their properties with the enzymes involved in similar coupling in the biosynthesis of, e.g., aporphine alkaloids must surely be a most worthwhile project. 

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. 

Battersby AR, Brocksom TJ, Ramage R (1969) Further studies on the synthesis and biosynthesis of isothebaine. J Chem Soc Chem Commun 464-465 Battersby AR, McHugh JL, Staunton J, Todd M (1971) Biosynthesis of the apparently directly coupled aporphine alkaloids. J Chem Soc Chem Commun 985-986 Battersby AR, Herbert RB, Pijewska L, Santavy F, Sedmera P (1972a) Alkaloid biosynthesis, part XVII. The structure and chemistry of androcymbine. J Chem Soc Perkin Trans 1 1736-1740... 

M. Shamma and H. Guinaudeau, Tetrahedron 40, 479S (1984). Biosynthesis of aporphinoid alkaloids. In addition to monomeric alkaloids, discusses proaporphine- and aporphine-benzyliso-quinoline dimers, dimeric oxidized aporphines, and types derived by catabolism of benzyliso-quinoline-derived dimers. 

We may safely assume that phenanthrene alkaloids with a 2-dimethylamino side chain derive from quaternary aporphinium salts by in vivo Hoffmann elimination. These phenanthrene alkaloids may later be oxidized to the corresponding A -oxides or methylated to give trimethyl 2-(l-phenanthryl)ethylammonium salts. Far more intriguing is the biosynthesis of phenanthrene alkaloids with a 2-monomethylaminoethyl side chain, for which we have four examples A -nor-atherosperminine (13), noruvariopsine (14), secoglaucine (15), and secophoebine (16). One possibility would be direct elimination after protonation of the nitrogen of an aporphine. This transformation would have some similarity to the formation of 167 by acid treatment of 166 18). 

Although the biosynthesis of all the phenethylisoquinoline alkaloids has not yet been studied in full, that of androcymbine and homo-aporphine has been examined by tracer work. In this section tracer experiments as well as hypothetical biogenetic routes in the synthesis of the phenethylisoquinoline alkaloids are discussed. 

The biosynthesis of cularine alkaloids (239) by phenolic oxidation also proceeds via the dienone compound (Scheme 4) similar to the aporphine or morphinane alkaloids. 

Scheme 13) this may not be the case for aporphines with substituents in positions 1,2,10, and 11 [corytuberine type (25e)]. Because of steric factors these aporphines are more likely to be produced via a dienone proaporphine intermediate followed by a dienone-phenol rearrangement. In the second work, the same authors report that orientaline was detected in the opium poppy by an isotope-dilution method based on its biosynthesis from norlaudanosoline (7p) (258). Administration of labeled orientaline (7s) revealed that in P. somniferum this alkaloid was not a precursor of isoboldine (24c), and the experimental results provided no evidence for a pathway involving norprotosinomenine (7t) this route is, however, very likely for P. orientate and P. bracteatum (Scheme 13). 

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. 

In conclusion, oxidized cularine alkaloids might be formed by reactions analogous to those occurring in aporphine biosynthesis (73), according to the following general sequence ... 

The final steps shown in Scheme 4 include oxidative phenol coupling (65, 64,75) and other reactions analogous to those which occur during tqroiphine biosynthesis (74, 76). In addition to the final products (13 and 6) indicated in Scheme 4, any of the other phenanthroindolizidine alkaloids so far isolated could be produced by simple modifications of the scheme similar to those that take place in the biogenesis of aporphines. It is interesting that in spite of the apparent synunetry in substitution pattern of rings A and B of tylophorine (13), they are formed by separate pathways from phenylalanine and tyrosine, respectively. 

The appropriate time in the biosynthesis for the methylation reaction to occur and, of course, the correct position of the methyl group in the molecule, have important influences on modifying the skeleton. This is particularly true for the isoquinoline skeleton, especially in alkaloids of the morphine and aporphine groups (see p. 204 for structures). Methylation is considered to be a type of detoxication reaction. Thus Pohm (1966) has observed that in seedlings of Cytisus laburnum with removed cotyledons, cultivated in appropriate feeding solution, addition of small amounts of cytisine was inhibitory, whereas 50 times as much methylcytisine had no effect. Moreover, it seemed that methylcytisine acted as a type of antagonist toward cytisine. Generally methylation is considered to diminish the reactivity of a compound (Mothes, 1965, 1966). 

---