Erythrina alkaloid structure

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 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... 

Cocculine (C17H21N02) and cocculidine (ClgH23N04) were isolated from C. laurifolius in 1950 (77) but escaped mention in previous reviews of this treatise because only a partial structure, unrelated to the Erythrina alkaloids, had been advanced (78). On the basis of the spectroscopic properties of the alkaloids and their Hofmann degradation products, structures 56 and 54 (without stereochemistry) were proposed for cocculine and cocculidine, respectively (79) however, a different group (80) proposed structures 69 and 70, respectively, on the basis of similar evidence. The... 

A related alkaloid coccutrine (C18H23N03) was isolated from C. trilobus (60) and structure 52 established spectroscopically, with the positions of the aromatic hydroxyl and methoxyl groups being defined by X-ray analysis. Coccutrine is the only example of an Erythrina alkaloid containing an oxygen function at C-17. 

Continued examination of the pharmacologically interesting species C. laurifolius, particularly by Singh et al. (55, 56, 70- 72, 74) has led to the isolation of more Erythrina alkaloids that have structures related to cocculine (56) and cocculidine (54). Coccuvine (C17H19N02) and coccuvinine (C18H2IN02) were found to be of the 1,6-diene type (56, 72) and the structures 16 and 14, respectively, were established on the basis of spectroscopic evidence and chemical interconversions. Methylation of coccuvine (16) (see... 

Only two normal Erythrina alkaloids have been isolated from Cocculus species, dihydroerysodine (47) (75) and dihydroerysovine (44), the latter recently from C. trilobus (57). Neither alkaloid has been found in Erythrina species. The structure 44 for dihydroerysovine was deduced from the spectroscopic evidence and by methylation using diazomethane to give the known dihydroerysotrine (38). The positions of the aromatic substituents were determined by detailed NMR experiments using NOE and INDOR techniques (see Section II,C,2d). 

Many Erythrina alkaloids possess curare-like action. Alkaloidal extracts from different parts of Erythrina species have been used in indigenous medicine, particularly in India (176). Many pharmacological effects, including astringent, sedative, hypotensive, neuromuscular blocking, CNS depressant, laxative, and diuretic properties, have been recorded for total alkaloid extracts, although not all these properties can be associated with the ery-thrinane structure alone (38, 177, 178). 

Two analogues of Erythrina alkaloids that lack the aromatic ring have been synthesized, for use in studies of structure-biological activity relationships.17... 

In 1957, at the time of writing the previous review of the Erythrina alkaloids in this series 1), the structures of the major alkaloids had only recently heen elucidated. Preliminary reports had appeared of syntheses of the parent skeleton which confirmed the unusual spiroamine framework of these alkaloids. Little chemical evidence was available concerning the stereochemistry, though an X-ray study had confirmed the structure and shown the relative configuration of erythraline, one of the aromatic subgroup. 

Cocculolidine, an alkaloid with striking insecticidal properties isolated from the leaves of Cocculus trilohus DC, has recently been isolated and assigned the structure (XCIV) of a lower homolog of -erythroidine 50). The degradation reactions reported closely parallel those of /3-erythroidine. This makes the second report of Erythrina alkaloids in Cocculus species, dihydroerysodine having been isolated earlier from C. laurifolius 51). 

Schelhammeridine.—Schelhammeridine (37), a major alkaloid of Schelhammera pedunculata, is structurally related to the Erythrina alkaloids, e.g. erythraline (38),... 

A new erythrina alkaloid, erythroculine, from Cocculus laurifolius has been shown to have the structure (167). The ester group may be reduced with lithium aluminium hydride and the acetyl ester of the resulting alcohol on treatment with cyanogen bromide affords the hindered diphenyl (168), with loss of hydrogen bromide and methanol. This on reduction to the secondary base, N-methylation, and successive Hofmann degradations affords an olefin that may be oxidised to the tricarboxylic acid (169).The base represents a novel structure in having the additional carbon atom linked to the ring system. 

Erythrina Alkaloids.—Although a small number of new alkaloids have been discovered, most of these show interesting structural features. Erysotrine has been obtained for the first time from a natural source Erythrina suberosa Roxb.). Erythroculine is the first case of an Erythrina alkaloid which bears a methoxy-carbonyl-substituent at C-15. ... 

Cephalotaxine Alkaloids.— The structures of this group have been elucidated mainly by n.m.r. and mass spectroscopyand confirmed by an X-ray crystallographic analysis.This class of compounds, exemplified by cephalotaxine (23), bears an intriguing resemblance to the Erythrina alkaloids and may be derived by a dienol-phenol rearrangement, a bond migration, and reduction from the partially reduced form of a recognised precursor (22). The first step has ample in vivo and in vitro precedent in related alkaloid series. 

The enol-lactam (30), which has occupied a central role in the synthesis of Erythrina alkaloids, has been converted in an unprecedented reaction into the dimeric isomers [31 C(6)-a-0] and [31 C(6)-/ -OJ.15 This reaction may be effected in benzene, pyridine, or acetic acid solution in the presence of lead tetra-acetate. The structures of the products were elucidated by spectral and chemical means. As enol ethers, these compounds were found to exhibit surprising stability to mineral acids. However, catalytic reduction of [31 C(6)-a-OJ under neutral conditions gave the starting enol-lactam (30) and the 7/Miydroxylactam (32 RJ = OH, R2 = R3 = H). The dimer [3 l C(6)-/i-0] yielded only compound (32 R1 = OH, R2 = R3 = H). Similarly, sodium borohydride reduction of the dimer mixture in hot isopropanol led to cleavage products (32 R1 = OH, R2 = R3 = H)and(32 RJ = R3 = H, R2 = OH). Besides the dimeric products, compound (32 R1 + R2 = O, R3 = OAc) was also isolated from the lead tetraacetate oxidation in low yields. Attempts to discover conditions for the formation of preparative amounts of (32 R1 + R2 = O, R3 = OAc), a compound of more potential usefulness for alkaloid synthesis, were fruitless. The other question of interest, whether or not the trans-dimer [31 C(6)-/i-0] could be converted into a monomeric trans-erythrinane system, remains to be answered. 

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). 

It appears that the combined g.c.-m.s. method for analysis of crude natural product mixtures can be improved by using it in conjunction with high-resolution field-ionization m.s. studies. ° Such studies on the crude mixture from E. princeps (formerly known as E. lysistemon) have allowed the tentative structural assignments of several new Erythrina alkaloids. ... 

Erysodienone (1 R = H), a compound previously unknown in Nature, has been isolated from Erythrina lithosperma. The isolation of erybidine (2) from E. xbidwilli Lindl. is of biogenetic interest. Its structure was determined by spectral studies, Hofmann degradation, and synthesis from erysodienone (1 R = H). This species has been shown previously to elaborate Erythrina alkaloids. 

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. 

Because of their unique structures and their biological activities there has been much interest in the total synthesis of Erythrina alkaloids. Thus numerous synthesis approaches to the tetracyclic framework, mainly to... 

Fig. 4. Chemical structures of several Erythrina alkaloids with special pharmacological properties (c/. pages 26-27)...

The present review summarizes the work of the last fifty years in the field of the synthesis of Erythrina alkaloids and structurally related compounds. Their unique structure has attracted the attention of the synthesis chemists over a period of more than half a century until now. The numerous efforts devoted to the construction of the tetracyclic spiroamine framework have certainly led to original and impressive results, but with regard to today s standard and especially to an adequate supply of the promising compounds for a systematic pharmacological examination the total efficiency of their preparation yet leaves wishes in many cases. 

Not only because of their attractive structure, but also of their pharmacological potential, mainly that of the pure compounds, the synthesis of the Erythrina alkaloids will remain an important goal challenging the synthesis chemists in the forthcoming years. It is hoped, that this review along with the powerful arsenal of modem synthesis methods can stimulate the development of new efficient strategies to the Erythrina alkaloids and possibly to related new active agents. 

The methanol extract of E. herbacea flowers was subjected to the conventional extraction and isolation procedures for alkaloids. A new Erythrina alkaloid, 10-hydroxy-ll-oxoerysotrine (29), was isolated together with five known compounds. The structure of the new compound was elucidated on the basis of its spectral data, including 2-D NMR and mass spectra (MS). The new compound is a rare C-10 ox ygenated Erythrina alkaloid [49]. 

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