Aporphines biogenesis

Kupchan and his colleagues were the first to use vanadium oxytrifluoride in trifluoroacetic acid (VOF3-TFA) for the oxidation of tetrahydrobenzylisoquinolines in the synthesis of aporphines and related alkaloids. This significant development has allowed the ready preparation of a variety of aporphines in high yield, and has also provided an insight into possible modes of aporphine biogenesis in plants. 

The pseudobenzylisoquinoline alkaloids are fairly widespread in nature, being found among members of Berberidaceae, Annonaceae, Fumariaceae, and Ranunculaceae. The biogenesis of the pseudobenzylisoquinoline alkaloids assumes their formation from protoberberinium salts by C-8—C-8a bond scission in a Baeyer-Villiger-type oxidative rearrangement to produce the enamides of type 73 and 74. These amides may be further biotransformed either to rugosinone (76) type alkaloids by hydrolytic N-deformylation followed by oxidation or to ledecorine (75) by enzymatic reduction. These transformations were corroborated by in vitro studies (80-82). It is suggested that enamide seco alkaloids may be precursors of aporphine alkaloids (80), on one hand, and of cularine alkaloids (77), on the other. 

All aporphine-benzylisoquinoline dimers so far isolated from Thalictrum species have identical configurations, suggesting common biogenesis (545). Rules for predicting the configurations of Thalictrum bisbenzylisoquinoline alkaloids have been derived the sole exception is isothalidezine (170), which may be formed by epimerization via an iminium salt of the major co-occurring alkaloid thalidezine (53) (538). 

A useful and timely supplementary listing of new aporphines, oxoaporphines, phenanthrenes, and 4,5-dioxoaporphines has appeared.1 The alkaloids of Glaucium species, which include several aporphines and oxoaporphines, have been tabulated2 and a general discussion of the chemistry and biogenesis of isoquinoline alkaloids, including the aporphines, has been presented.3... 

A similar scheme may be advanced for the biogenesis of thebaine [xv] as shown below [xm] -> [xv], but in this case the isoquinoline precursor [xm] has an arrangement of substituents not found elsewhere in nature (neither of the two corresponding aporphine types occur naturally), and also for its formation would require two dissimilar fragments, namely 3 4-dihydroxyphenylacetaldehyde and /3-(2 3 dihydroxy-phenyl)-ethylamine. 

In continuation of their chemical investigation of peptide alkaloids obtained from Zizyphus amphibia (see Vols. 3 and 4 of these Reports), Tschesche and coworkers have elucidated the structures of the new amphibines F (40), G (41), and H (42) by the established spectroscopic and degradative methods. Amphibine I (43), an alkaloid of obvious mixed biogenesis, has been isolated from Z. am-phibia. Interestingly, the aporphine base (—Fnuciferine was also obtained from this species. 

Azafluoranthene and Tropoloisoquinoline Alkaloids Aporphine Alkaloids Biogenesis Biological Activity Aristolactams and Aristolochic Acid Eupomatia Alkaloids Proaporphine Alkaloids... 

Fig. 32.14. Biogenesis of aporphine alkaloids such as bulbocapnine and glaucine (modified from Geissman and Grout, 1969).

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. 

It is clear that additional work with labeled precursors is required before a complete picture of the biogenesis of aporphines can be formulated. 

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). 

As a goieral example of the biogenesis of aporphines. Scheme 5 shows the biogenesis of magnoflorine based on mechanistic considerations. The chemistry of the aporphines has been extoirively reviewed (33-37). 

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