Phenethylisoquinoline biosynthesis

Cephalotaxus Alkaloids.—Preliminary results indicate that the homo-Erythrina alkaloid schelhammeridine (52) derives from phenylalanine and tyrosine by way of a phenethylisoquinoline precursor [as (53)].52 Previous evidence for the biosynthesis of the related alkaloid cephalotaxine (54), obtained with tyrosine labelled in the side-chain, has indicated a different pathway which involves two molecules of this amino-acid.53 Recently, however, tyrosine labelled in the aromatic ring was examined as a cephalotaxine precursor and was found54 to label ring A of (54) almost exclusively, i.e. only one unit of tyrosine is used for biosynthesis. This is obviously inconsistent with the previous evidence and the early incorporations are... 

Although biosynthesis of the phenethylisoquinoline alkaloids has not yet been studied in full, that of androcymbines, homoaporphines, and homoerythrinans has been examined by work with radioactive tracers. In this section tracer experiments as well as hypothetical biogenetic routes in the synthesis of the phenethylisoquinoline alkaloids are discussed. 

In view of the importance of the isoquinoline system in biosynthesis it is surprising that so little effort has been devoted in the past to the biosynthesis of the basic ring system. No doubt the success of this investigation in the peyote cactus will stimulate further work in other systems. It is likely that the normal pattern will involve condensation of a phenethylamine with the appropriate pyruvic acid. However, reference has already been made to ipecoside (27) (Scheme 3) in which the isoquinoline system is formed by condensation of the phenethylamine with an aldehyde [secologanin]. Presumably the corresponding aldehyde, rather than a pyruvic acid, will be found to serve as precursor for the phenethylisoquinolines,3 5 and also for the isoquinoline alkaloids of the Lophophora cactus such as lopho-cerine (66). 

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...

The "homo-Erythrina alkaloid schelhammeridine (24) appears to be derived, as expected, from a phenethylisoquinoline/" After some initial doubt the evidence for the biosynthesis of the related base cephalotaxine (25) has been deduced to be consistent with it too being a modified phenethylisoquinoline/ ... 

Biosynthesis The concomitant occurrence of C. a. and homoerythrina alkaloids indicates a common biosynthesis. Both types of alkaloids are derived from 1-phenethylisoquinoline with (see phenethyltetrahydroi-soquinoline alkaloids) ring A originating from tyrosine and ring B from phenylalanine. The acid components, e. g., harringtonic, isoharringtonic, and deoxyharring-tonic acids are derived from leucine. 

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. 

A possible pathway of the biosynthesis of Cephalotaxus alkaloids is shown in Fig. 5.2.13 (120). A similarity has been pointed out between this scheme and that of Erythrina alkaloids (Sect. 5.2.2.5.T). The starting open-ring intermediate in the present case is phenethylisoquinoline, instead of benzylisoquinoline for the Erythrina alkaloids. On this basis, homoerythrinan-type alkaloids are also called phenethylisoquinoline-type alkaloids. 

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... 

The manifold possibilities for the elaboration of structurally intriguing natural products via the aforementioned oxidative aryl-aryl coupling reactions emphasize the importance of phenolic coupling reactions in the biosynthesis of tyrosine-derived alkaloids. This important reaction not only plays a significant role in the biosynthesis of benzyltetrahydroisoquinoline alkaloids but also for the construction of phenethylisoquinoline alkaloids and Amaryllidaceae constituents, discussed in the following sections. 

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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