Phenethylisoquinoline colchicine

Nasreen, A. Gundlach, H. Zenk, M.H. Incorporation of phenethylisoquinolines into colchicine in isolated seeds of Colchicum autumnale. Phytochemistry 1997, 46, 107-115. 

Phenethylisoquinoline alkaloids are classified into six major alkaloid groups based on structural differences, namely, simple 1-phenethyliso-quinoline (1), homomorphinandienone (2), bisphenethylisoquinoline (3), homoproaporphine (4), homoaporphine (5), and homoerythrina alkaloids (6). These alkaloids are related to the benzylisoquinoline alkaloids such as morphinandienone, bisbenzylisoquinoline, proaporphine, apor-phine, and erythrina alkaloids. Although colchicine and its derivatives also belong to the phenethylisoquinoline alkaloids group, these alkaloids are not included in this review as they have been reviewed earlier 1). 

Androcymbine may be derived from phenethylisoquinoline 68 by phenol oxidation. The derivation of colchicine from phenethylisoquinoline precursors 67 and 68, which were formed from 65 and 66,... 

Colchicine.—It is clearly established that ring a and carbons 5, 6, and 7 of colchicine (5) arise from phenylalanine by way of cinnamic acid. Beyond cinnamic acid the next known intermediate is a phenethylisoquinoline it is not as yet known whether reduction of the double bond in cinnamic acid occurs before or after construction of the isoquinoline ring. 

An important clue to the actual biosynthetic pathway was the discovery that androcymbine (CXVII R = H) occurs along with colchicine-type compounds in A. melanthioides 2, 47). The similarity of CXVII to CXVI was striking, as was the fact that CXVII (R = H) has the same absolute stereochemistry as colchicine [47, 68). This suggested that a 1-phenethylisoquinoline structure might be involved in the biosynthesis of colchicine. This hypothesis, as well as a detailed pathway to colchicine (see Fig. 2), has been brilliantly demonstrated by Battersby and coworkers 68, 69) in recent tracer experiments. 

Fig. 2. Battersby, A. R.. et al. Reproduced from Alkaloid biosynthesis. Part XVIII. Biosynthesis of colchicine from the 1-Phenethylisoquinoline system. J. C. S. Perkin Trans. I, 1741 (1972), by kind permission of the Editor...

Alkaloids are not limited to those natural products which are basic in character. For example, colchicine isolated from Colchicum autumnale (Ldiaceae) and used for the treatment of gout, etc. is not basic because the nitrogen atom in the molecule is present in a neutral amide group. However, the biosynthetic precursor of colchicine is autumnaline, a typical, basic phenethylisoquinoline alkaloid. Therefore any compound derived from such an intermediate should be classified as an alkaloid. 

Autumnaline is a phenethylisoquinoline alkaloid, and possesses an additional Cj unit compared with the benzylisoquinoline alkaloids. Autumnaline, postulated to be the biosynthetic precursor of colchicine, was isolated from Colchicum cornigerutn (Colchicaceae) [4]. O-methylandrocymbine is formed through the intramolecular -oxidative phenolic coupling... 

Alkaloid anti-inflammatory agent autumnaline colchicine Colchicum double haploid elicitors in vitro culture phenethylisoquinoline polyploid... 

The crucial test for the hypothesis lay in the examination of compounds of type 6.171) and 6.173) as colchicine precursors. In the event [119-121], 0-methylandrocymbine 6.172) was a spectacularly good precursor for colchicine. The phenethylisoquinoline 6.171), called autumnaline, was also clearly implicated in biosynthesis only the (5)-isomer of autumnaline, with the same absolute configuration as colchicine is involved, and oxidative coupling of this base occurs in a para-para sense rather than the alternative, ortho-para. Results of other experiments, together with those discussed here, led to the pathway illustrated in Scheme 6.34. 

Of singular value in unravelling the biosynthesis of colchicine (77) was the idea that this alkaloid could be derived from the androcymbine skeleton and was therefore a modified phenethylisoquinoline. A reasonable way of transforming the androcymbine skeleton into that of colchicine would be to begin by forming the hydroxy-derivative (82). Homoallylic ring expansion and subsequent minor modification would yield colchicine (77) (Fig. 13). 

Battersby AR, Herbert RB, McDonald E, Ramage R, Qements JH (1972b) Alkaloid biosynthesis, part XVni. Biosynthesis of colchicine from the 1-phenethylisoquinoline system. J Chem Soc Perkin Trans 1 1741-1746... 

Phenethylisoquinoline alkaloids constitute another important group of tyrosine-derived secondary metabolites. This class of natural products with colchicine (54) as most prominent member is obtained when aldehyde 43 is employed in a condensation reaction with dopamine, followed by a Pictet-Spengler cyclization reaction. The difference to benzyltetrahydroisoquinoline alkaloids is an additional carbon between the tetrahydroisoquinoline core and the aromatic ring. As outlined in Scheme 12.9, aldehyde 43 is derived from phenylalanine (42) via intermediary formation of 4-hydroxycinnamaldehyde. The formation of the tetrahydroisoquinoline system 44 from dopamine (4) and 4-hydroxydihydrocinnamaldehyde (43) is followed... 

Several genera of the Liliaceae plant family have been identified to produce the secondary metabolite autumnaline (45), which also serves as key intermediate in the biosynthesis of a variety of phenethylisoquinoline alkaloids (see Schemes 12.9 and 12.10). Colchicine (54), derived from autumnaline (45) via a remarkable ring-expanding rearrangement, is the most prominent member of this class of tyrosine-derived alkaloids. 

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