Phenethylisoquinoline precursor

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 the phenethylisoquinoline alkaloids represent a wide diversity of chemical types, it appears nevertheless that they share a common origin from the 1-phenethylisoquinoline precursor, and that their biosyntheses parallel the formation of analogous alkaloids from... 

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,... 

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). 

Tyrosine was indeed found to be a precursor for cephalotaxine (122) but the labelling pattern precluded a phenethylisoquinoline intermediate. Thus [3- C]tyrosine gave cephalotaxine with 68% of the activity at C-16 and 32% at C-9 (Scheme 14), whereas [2- C]tyrosine labelled C-17 to the extent of 37% with no label at C-2 or C-3. It is to be noted that both samples of tyrosine were incorporated to similar extents and yet the expected correlation of activity between C-16 and C-17 is poor. This was attributed to some scatter of the label from C-2 of tyrosine. [l- CjTyrosine was only incorporated at a very low level and the activity appeared to be scattered. The results clearly implicate two molecules of tyrosine with loss of the carboxy-functions in a novel pathway to cephalotaxine. A scheme which is consistent with these results has been tentatively advanced (Scheme 15). This hypothesis is capable of further testing, which is in progress. 

Homoaporphines and Homoproaporphines.—A new homoaporphine from C. cornigerum is CC-24 (219). Photolysis of the appropriate bromotetrahydro-phenethylisoquinolines can lead to racemic multifloramine (218), kreysigine (220), or 0-methylkreysiginone (221). In each of these syntheses the bromine is situated either at C-8 or at C-2 of the tetrahydrophenethylisoquinoline precursor. ... 

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... 

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. 

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