Phenethylisoquinoline derivative

An approach to the cephalotaxine skeleton, based upon the presumed biogenetic route, has been reported (164) and involves the oxidation of the 1-phenethylisoquinoline derivative (260) with VOF3 (Scheme 54). Alkaline cleavage of the dienone (261) gave 262 which, as the hydrochloride salt, was reduced 263. A-trifluoroacetylation followed by O-methylation yielded 264 which, after hydrogenolysis to 265, was oxidized with potassium ferricyanide to give the dienone (266). 

Lilaceae also contain 1-phenethylisoquinoline alkaloids, it was suggested [82) that the homoerythrina derivatives are biosynthesized along a pathway analogous to that followed by the Erythrina alkaloids themselves (Scheme 35). Some preliminary results from feeding experiments (121) support this view ( )-[2-14C]tyrosine causes specific labeling of C-8 in 77a. 

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... 

The isoquinoline alkaloids are the second largest group of alkaloids, numbering about 6000, and can be viewed as five subgroups—the simple tetrahydroisoquinolines, the benzylisoquinolines, the phenethylisoquinolines, the Amaryllidaceae alkaloids, and the monoterpene isoquinolines. In addition, there are a number of simple phenethylamine derivatives, including ephedrine (originally from Ephedra species, but now synthesized) and pseudoephedrine, used for asthma and nasal... 

Extensive tracer experiments show that tropolone alkaloids of the species Colchicum are derived from the I-phenethylisoquinoline system (73) by way of the dienone O-methylandrocymbine (16) (56). These findings, when combined with results of the earlier work (57), support the sequence shown. 

Tracer experiments suggest that schelhammeridine (78) of the species Schelhammera is derived from the 1-phenethylisoquinoline 75 by way of the dibenz[r//]azecine 76a and dienone 77 (59). 

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,... 

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. 

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. 

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). 

The steps which lie between phenylalanine and tyrosine on the one hand and the first identified phenethylisoquinoline (81) are not completely understood but dopamine (4) is an intermediate derived from tyrosine, and cinnamic acid is an intermedi-... 

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. 

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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