Alkaloids Erythrina

Erythrina Alkaloids.—The Erythrina alkaloids, c.g. erythraline (103), have been shown to be artful variations on the benzylisoquinoline theme. They arise from the benzylisoquinoline (S)-N-norprotosinomenine (100) via the dibenzazonine (101) and erysodienone (102).  

Recent results have shown that only (—)-erysodienone, which has the (5S)-chirality of the natural alkaloids, is a precursor for erythraline (103) and a- and -erythroidine (106). The conversion of (S)-N-norprotosinomenine (100) into (5S)-erysodienone (102), it is apparent, involves, formally at least, an inversion of chirality. However, the chirality of (100) may well be lost in vivo for it was found that the biosynthetic intermediate (101) prepared by chemical reduction from chiral erysodienone underwent very rapid racemization at room temperature. 

Further experiments have established the aromatic Erythrina alkaloids as precursors for the lactonic bases (106). [17- H]Erysodine [as (104)], [14,17- H2]erysopine [as (105)], and ( )-[l,17- H2]erysodienone [as (102)] were incorporated satisfactorily into a- and /S-erythroidine (106) degradation of the material obtained after feeding [17- H]erysodine established that the label was confined to C-17. This is the expected labelling site and the absence of scrambling is established.  

The biosynthesis of betalains provides a rare example of the cleavage of an aromatic ring in higher plants. The conversion of alkaloids of the type (103) into (106) provides another these results do not allow definition of the manner in which ring cleavage occurs since both intra-diol (C-15—C-16) and extra-diol (C-16—C-17) cleavage may lead to loss of C-16 and retention of tritium at C-17 as observed. 

The relationships of C. laurifolius alkaloids were studied, with the following results (88) was reversibly converted into (89), and a similar relationship was found for (89) and (90) the retention of label from the 7-methoxy-group of (81) in (89) indicates that (89) precedes (90) in biosynthesis. 

Study of the biosynthetic interrelationships of alkaloids in C. laurifolius has shown that, up to and beyond (80), the reactions involved are demethylation as well as dehydrogenation and oxygenation.22 

Further experiments have been carried out in which (85)—(88) were tested as precursors for each other.23 It appears that (85) and (86) are interconvertible and that (87) and (88) are formed after (85), i.e., the O-methyl group in (85) is retained from an early stage of biosynthesis (88) is readily reduced to (87) in vivo. 

Alkaloid distribution in C. harringtonia in relation to age has been noted. Physiological stress (pruning) was found to cause hydrolysis of cephalotaxine esters. Environmental factors also caused hydrolysis and, in addition, oxidation of cephalotaxine (85) to 11-hydroxycephalotaxine and of two other alkaloids to epoxy-derivatives.24 

Esters of cephalotaxine (85) that are found in Cephalotaxus species are exemplified by deoxyharringtonine (89), isoharringtonine (90), and harring-tonine (91). The acyl portion (92) of deoxyharringtonine (89) derives from the amino-acid leucine. The results published previously in preliminary form (cf. Vol. 8, p. 13) are now available in full.25 Additional information is that (92) serves as a specific precursor for the acyl portions of (91) and (90) and that (93) is not involved in the biosynthesis of the latter. Results of an examination of (89) as a possibly intact precursor for (91) were inconclusive.25 

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). 

The pathway [97, 98] must involve a symmetrical intermediate because [2- C]tyrosine [as 6.94) gave ) -erythroidine 6.147) with equal labelling of C-8 and C-10, and more importantly because A -[4 -m Ao 9 - C]norprotosinomenine [as 6.1%) gave erythraline 6.144) with equal labelling of methoxy- and methylenedioxy-groups. 

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 

From Erythrina crystagalli cv. Maruba deiko, erythraline, erythrinine, and ery-thratine were isolated (77). Examination by TLC demonstrated that these alkaloids are present in all heartwood, bark, and roots. Many other Erythrina alkaloids have been isolated from plants of the genus Erythrina (Leguminosae), but most have been obtained from leaves and fruits. 

The biogenesis of the Erythrina alkaloids (15, 40, 65, 107) has been studied by using labeled precursors a proposed general scheme is shown in Fig. 5.2.12. 

It is interesting to note that a member of the Erythrina alkaloids, dihydroery-sodine, was isolated (0.003%) from a Menispermaceae, Cocculus laurifolius (158). 

The detection of Al-nororientaline and orientaline (62) in a number of Erythrina species suggested that they might be involved in the elaboration of Erythrina alkaloids. In the event neither tritiated (+ )-N-nororientaline nor tritiated D. H. R. Barton, C. J. Potter, and D. A. Widdowson, J.C.S. Perkin /, 1974, 346. 

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As -erythroidine and its hydrides appear to be important curarising agents in the erythrina series it is convenient to tabulate at this stage the threshold curarising potencies of these alkaloids and to add for comparison the curarising potencies of the other free erythrina alkaloids. Similar tables are given later for the liberated and combined (p. 390) alkaloids. 

Combined Erythrina Alkaloids. The sources of the liberated alkaloids (see above) are now known to be, at least in two cases, the sulphur-containing alkaloids erysothiopine and erysothiovine, which are esters of sulphoacetic acid, HOOC. CHj. SOj. OH, identified as the aniline salt, m.p. 187-9° with erj sopine and erysovine respectively. The sources of erysodine and erysonine have not yet been isolated. These combined alkaloids arc believed to be sulphonic esters, of the type HO. OC. CHj. SOj. 0. R, where R is the alkaloidal residue. ... 

Alkaloids of Curare Curine, Tubocurarine, Protocuridine, Calabash-curare I, etc., including Erythrina alkaloids Alkaloids of Ipecacuanha. ... 

The sequential process consisting of palladium-catalyzed alkylation and the intramolecular Michael addition of nitro compound provides a nitrocyclohaxane derivative, which is a good precursor for synthesis of Erythrina alkaloids (Eq. 4.131).179... 

On route to the Erythrina alkaloid 3-dimethoxyerythratidinone, Wang and Padwa encountered the interesting acid catalyzed rearrangement of lactam 151 to the tetracyclic hydroxyindole 153 via the lactone 152 <060L601>. 

Oxidative caibon-carbon bond formation from laudanosine derivatives generally favours a 6-membered ring. Severe steric constraints result in exceptions to this rule. Oxidation of the bridged ether derivative 34 results in carbon-carbon bond formation to form a 5-membered ring product and this process has been used for one stage in the synthesis of erythrina alkaloids [138]. Some of the morphinadie-none system is also formed, in spite of the steric constraint imposed by the ether-bridge. 

Erythrina alkaloids, possessing curare-like activity, are a large class of natural products found in Erythrina plants (Leguminosae). In a study towards construction of the erythrina skeleton, disfavored 5-endo-trig cyclizations were achieved by Ikeda et al. by BusSnH-mediated radical cyclization of an //-vinylic a-chloroacetamide to give five-membered lactams... 

Demethoxyerythratidinone (10), one of the simplest of the erythrina alkaloids, was isolated in 1973 by Barton et al. from Erythrina lithosperma [14]. A concise approach to such Erythrina alkaloids using a disfavored 5-endo-trig radical cyclization mediated by nickel powder was described by Zard and coworkers [15]. A-Alkenyl trichloroacetamide 7 was... 

Scheme 2. Nickel powder promoted 5-endo-trig radical cyclization in erythrina alkaloid synthesis...

Erythrina Alkaloids.—AT-Norprotosinomenine (74) is known to be a key precursor for Erythrina alkaloids (cf. Vol. 8, p. 10 Vol. 9, p. 16 ref. 2), and its unique role compared to isomeric isoquinolines has been confirmed for coccuvine (80) in Cocculus laurifolius.22 The incorporation of JV-norprotosinomenine (74) [the (+)-(S)-isomer is preferred] was with loss of the O-methyl group at C-7 and complete retention of the 4 -0-methyl group, measured relative to a secure internal tritium marker. The results for coccuvine (80) show that no symmetrical intermediate is involved, unlike, e.g., for erythraline. Consequently the same biosynthetic route is not followed. Plausibly this route could be (74) —> (75) — (76) - (77) (Scheme 7). The unsymmetrical intermediate... 

The biosynthetic pathway suggested for cephalotoxine (Scheme 8) includes intermediates whch are homologous with those for Erythrina alkaloids (see above). It depends in part on the fact that homo-Erythrina alkaloids co-occur naturally with those having the cephalotaxine skeleton. 

A new abnormal Erythrina alkaloid, obtained from the leaves of Cocculus laurifolius, was assigned the structure isococculine (7) on the basis of spectral and chemical studies.7... 

The dibenzazonine (13), related to a biosynthetic precursor of the Erythrina alkaloids, has been prepared in 35% yield by the intramolecular nickel-promoted coupling of the bis-(2-phenylethyl)amine (14), which in turn was obtained from the commercially available (3-methoxyphenyl)acetic acid by a conventional series of reactions.16... 

The regular team of authors reviews the whole of the alkaloid literature for the year and a two-year coverage of Erythrina alkaloids is included. 

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. 

In the intervening 13 years the subject has expanded dramatically over 60 compounds are now classified as Erythrina alkaloids, and the structures of most of these have been deduced from a combination of mass spectral fragmentation analysis, H-NMR spectral interpretations, and chemical correlations with alkaloids of known structures. Some unusual alkaloids have been obtained from certain Cocculus species and a new, as yet small, subgroup, the Homoerythrina alkaloids, has been recognized. The biosynthetic pathway from tyrosine through the aromatic bases to the ery-throidines has been elucidated, and some significant advances have been made in methods of total synthesis. Reviews of the Erythrina alkaloids since 1966 have appeared (3-6). 

The Erythrina alkaloids are conveniently divided into two main structural groups the 1,6-diene group and the Al(6)-alkene group (see Fig. 1). The biogenetically important alkaloid erysodienone cannot be classified in this way. 

There are now over 60 Erythrina alkaloids of known structure 1-61 (see Figs. 2-4) and several more, the structures of which are yet to be assigned (12). The alkaloids occur in species of Erythrina (Leguminosae), a genus of wide distribution in tropical parts of the world, and in species of Cocculus... 

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