Erythrina alkaloids biosynthesis

A new synthesis of bis(2-arylethyl)amines (7), required in connection with studies in Erythrina alkaloid biosynthesis, may have general applicability (c/. Scheme 1). 

Early experiments on Erythrina alkaloid biosynthesis carried out by Leete and Ahmad (1966) confirmed that tyrosine is a precursor of the erythroidines and that a symmetrical intermediate is involved. Several speculative schemes for Erythrina... 

The last review in this series (7) covered the literature to the end of October, 1966. At that time 10 Erythrina alkaloids were known, and the structures and stereochemistries of most of them had been established. The total synthesis of erysotrine had been described by Mondon s group in a preliminary communication (2), but nothing was known about the biosynthesis of these alkaloids, although some speculations had been reported. 

The biosynthesis of the unusual Erythrina alkaloids such as isococculi-dine (36), cocculidine (54), and cocculine (56) proceeds (119,120) from ( + )-... 

The studies of the biosynthesis of erythrina alkaloids got off to a false start. In a beautiful experiment, A. I. Scott and colleagues showed49,50 that the whole erythrina skeleton could be constructed in one simple phenolate coupling radical reaction. 

The dibenzazonines are intermediates in the biosynthesis of Erythrina alkaloids (72). Several biogenetic routes have been proposed to explain the formation of dibenzazonines in plants. 

Scheme 31). The biogenetic pathway shown in Scheme 31 has been proved to be operative for the biosynthesis of Erythrina alkaloids, at least when starting from norprotosinomenine, which was efficiently incorporated into erythraline (76) (Scheme 32). 

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 dienone (34), a proposed intermediate in the biosynthesis of Erythrina alkaloids, has been obtained by the phenolic oxidative coupling reaction of the norprotosinomenine derivative (33) with potassium ferricyanide in the presence... 

There is sound evidencethat the biosynthesis of Erythrina alkaloids, e.g. erythraline (105), proceeds by the novel pathway shown in Scheme 7. New evidence" of a negative kind supports the previously established role of (S)-N-norprotosinomenine (102) as an intermediate in the biosynthesis of these alkaloids. 

New investigation of bisbenzylisoquinoline biosynthesis is welcome (see ref. 32 also this Report, p. 16). Although aporphine alkaloids are the simplest developments of the benzylisoquinoline skeleton, their biosynthesis need not, as several examples show, be simple. It has, however, been found that the biosynthesis of boldine and isocorydine is straightforward. Further detail has been repor-ted on the biosynthesis of Erythrina alkaloids, which were established to be modified benzylisoquinolines some time ago. Further detail on the biosynthesis of morphine (23) and related alkaloids continues to be published. Of particular R. B. Herbert, in ref. 9, p. 11. 

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/ ... 

In the formulation of (88) and (89), the point at which loss occurs of the oxygen atom, expected to be at C-16, is of considerable interest and relevance to the biosynthesis of Erythrina alkaloids in general. Consideration of the pathway deduced for bases like erythraline (84), as shown in Scheme indicates two... 

Due to the increasing attraction and rapid extension in this field the Erythrina alkaloids have been regularly reviewed concerning occurrence, structure, analytic and spectral properties, biosynthesis, total synthesis, and biological activities covering the literature up to 1997. The most important reviews are cited in Refs. 18-24. 

The present contribution will give a brief classification of the Erythrina alkaloids, a compilation of new alkaloids isolated from 1997 to 2004 covering source, structure, analytical/spectral data, a new pathway of their biosynthesis, an overview of all the synthesis strategies hitherto known for the erythrinane alkaloids including several approaches to the homoerythrinane group, and finally a short review of their biological activities. 

Barton DHR, Boar RB, Widdowson DA (1970) Phenol Oxidation and Biosynthesis. Part XXI. The Biosynthesis of the Erythrina Alkaloids. J Chem Soc C 1213... 

Maier HU, Rddl W, Deus-Neumann B, Zenk MH (1999) Biosynthesis of Erythrina Alkaloids in Erythrina crista-galli. Phytochemistry 52 373... 

Gervay JE, McCtqtraF, Money T, Sharma GM (1966) Phenol Oxidation. A Model for the Biosynthesis of the Erythrina Alkaloids. J Chem Soc Chem Commun 142... 

Maier, U.H. Rodl, W. Deus-Neumann, B. Zenk, M.H. Biosynthesis of Erythrina alkaloids in Erythrina crista-galli. Phytochemistry, 1999, 52, 373-382. 

Franck, B. Teetz, V. Model reactions for the biosynthesis of Erythrina alkaloids. Angew. Chem., 1971,10,411-412. 

Erythrina alkaloids. (S)-iV-Norprotosinotnenine is the specific precursor of the Erythrina alkaloids (Fig. 285). It is assumed that by oxidative coupling (C 2.3.1). intermediate I is formed, which by a further rearrangement yields intermediate II. Erysodienone, a key product in the biosynthesis of the other alkaloids of this group, is probably derived from the quinone III. 

It is of chemotaxonomic interest that the bases cocculine and cocculidine, which closely resemble some of the Erythrina alkaloids, have been isolated from Cocculus species (Menispermaceae). The recent isolation from C. trilobus of coccutrine, an apparent relative of protostephanine, as reflected by the ring-A oxygenation pattern, suggests that the dibenzazonines are not an end point in alkaloid biosynthesis. 

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). 

Actually there are no good definitions of alkaloids (Bate-Smith and Swain, 1966) since each one is either too narrow or too broad. Even in the restricted Winterstein and Trier definition, at least five alkaloid families exist that can be derived from different amino acids consequently, there is a need to establish the proper biosynthetic pathways to permit the application of the alkaloid character to chemotaxonomy, It has been mentioned above that canadine (berberidine) may be found in plants of six partially unrelated botanical families. This fact is not surprising when considered in relation to the biochemical investigations of canadine biosynthesis. Many reactions are necessary to convert tyrosine into canadine consequently, one might even wonder why the distribution of this alkaloid is so limited. In contrast, other plants (and even some that produce canadine) can produce many alkaloids that are derived from tyrosine but have a marked difference in structure. Tyrosine serves as the key precursor of alkaloids of the isoquinoline type, but other types of alkaloids, such as colchicine and the Amaryllidaceae and the Erythrina alkaloids, may be synthesized from this amino acid. The nucleus of an alkaloid molecule can arise from different precursors thus the indole nucleus in Erythrina alkaloids arises from tyrosine, while in brucine it comes from tryptophan (Figure 1.5). The alkaloids cinchonamine and cinchonine differ in that cinchonamine has an indole nucleus, while cinchonine (like quinine) has a quinoline nucleus however, they exist in a precursor-product relationship (that is, the quinoline type is derived from the indole type in a one-step reaction). 

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. 

The biosynthesis of these novel pyridine analogues of the dienoid Erythrina alkaloids is of considerable interest and it seems likely that they arise by a variant of the pathway leading to the lactonic alkaloids a- and jS-erythroidine (cf. Fig. 5). Thus oxidative ring openings of the C16-C17 bond of erysovine (lb) followed by amination could afford erymelanthine directly. 

Barton DHR, James R, Kirby GW, Turner DW, Widdowson DA (1966) Constitutions of Ery-thratine and Erysodine and the Biosynthesis of Erythrina alkaloids. Chem Commun 294-295... 

Barton DHR, Potter CJ, Widdowson DA (1974) Phenol oxidation and biosynthesis, part XXIII. On the benzyltetrahydroisoquinoline origins of the Erythrina alkaloids. PCS Perkin I 347 -352... 

Leete E, Ahmad A (1966) Biosynthesis of the Erythrina alkaloids. The incorporation of Tyrosine 2-C into Erythroidines. J Am Qiem Soc 88 4722-4727... 

In many of the isoquinoline alkaloids the tetrahydroisoquinoline skeleton is clearly seen as part of the stmcture, in others it is somewhat obscured, e.g. chelidonine (76) (Sect. 3.4), and in still others, e.g, colchicine (77) (Sect. 4), which is a phen-ethylisoquinoline, and the Erythrina alkaloids (Sect. 3.3) severe modification in the course of biosynthesis has obliterated any suggestion of an isoquinoline moiety. 

The structures of the Erythrina alkaloids, e.g. erythraline (61), suggest an unusual biosynthesis. But these alkaloids, it turns out, are modifications of the benzyliso-quinoline skeleton, and so the unusual biosynthetic steps are confined to the later stages of biosynthesis. 

It is interesting to note the use made of the dienone (41) = (57) in the biosynthesis of both Erythrina alkaloids of the Leguminosae and ihe Dicentra aporphine alkaloids of the Papaveraceae. 

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