Erythrina alkaloids 3-Erythroidine

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. 

Since that time dramatic advances have been made in our understanding of the biosynthetic pathways to these alkaloids, almost entirely as a result of 14C-labeled feeding experiments. In an early study 113) [2-14C]tyrosine (34) was found to be incorporated equally at C-8 and C-10 of /J-erythroidine (60), a type of Erythrina alkaloid always believed (114) to arise from aromatic-type compounds. This observation was regarded as a strong piece of evidence in favor of Scheme 32. 

In the course of investigating Erythrina alkaloids, treatment of / -erythroidine (186) with phosphoric acid gave a rearranged demethoxy derivative, apo-/J-erythroidine (77), which was isomerized on alumina to give isoapo-/ -erythroidine (187) (50JA2062). Compound 77 is of interest because of its own physiological activity. A synthesis is described in Section IV,A,2. 

The remarkable curariform activity of the Erythrina alkaloids has been discussed in earlier volumes of this series and a review has been published (41). More recent comparison of the activity of dihydro- -erythroidine with standard curare agents such as [Pg.513]

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). 

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." ... 

Although the first of the Erythrina alkaloids was isolated in 1937 (12), it is only recently that the exact ring-systems and the relationship between the aromatic and erythroidine types have been elucidated. Prelog and collaborators (95, 96) proved that the aromatic Erythrina alkaloids are represented by XIX. This is probably the basic ring-system for all of the... 

Erythrina alkaloids except erythroidine. Boekelheide and coworkers (97) have shown that erythroidine and its derivatives are represented by XX-XXII. Boekelheide (97) suggested a biogenetical relationship between /3-erythroidine and the aromatic Erythrina alkaloids. 

These results led to the postulation of the spirocyclic erythrinane skeleton and this was confirmed by synthesis of the parent nucleus by Belleau (1953). The structures of the two lactonic alkaloids (3) were also elucidated by Boekelheide (1960) and coworkers, who recognised their close structural identity to the other aromatic erythrina alkaloids (1) the lactonic alkaloids also underwent an apo -type rearrangement under drastic acidic conditions. Subsequently the structures of both the aromatic and lactonic alkaloids were confirmed by X-ray crystallography of erythra-line hydrobromide (Nowacki and Bonsma 1958) and of the erythroidines (Hanson 1963). The spiro centre was shown to have the same configuration in all the erythrina alkaloids by use of optical rotatory measurements (Weiss and Ziffer 1963, Beecham 1971). 

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... 

In our own studies in Cardiff we have also isolated 8-oxo-a- and j3-erythroidine (4a) and (4b) (Chawla et al. 1982) from E.herteroana as well as 8-oxo-erysodine from E.tahitensis (Chunchatprasert 1983) it thus seems likely that 8-oxo- analogues of many of the other dienoid alkaloids are also likely to be found accompanying the parent alkaloid, albeit in small amounts. However, the relatively high polarity makes them less amenable to GC-MS and only 8-oxo-i3-erythroidine (4b) has been detected by GC, presumably because the derivatization of the lactone residue by the silylat-ing reagent makes it much more volatile. (The TMS derivative of 3-erythroidine itself has the shortest retention time of all the Erythrina alkaloids we have studied so far). 

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. 

Boar RB, Widdowson DA (1970) Mass spectra of the Erythrina Alkaloids - A novel fragmentation of the spiran system. J Chem Soc (B) 1591-1595 Boekelheide V (1960) In Manske RHF, Holmes HL (eds) The alkaloids, chap 11. Erythrina alkaloids. Academic Press, London New York, pp 201-227 Boekelheide V, Grundon MF (1953) A characterisation of a-Erythroidine. J Am Chem Soc 75 2563-2568... 

Boekelheide V, Weinstock J, Grundon MF, Sauvage GL, Agnello EJ (1953) The structure of l3-Erythroidine and its derivatives. J Am Chem Soc 75 2550-2554 Carmack M, McKusick BC, Prelog V (1951) Erythrina Alkaloide Dber das Apo-Erysodin und das Apo-Erythralin. Helv Chim Acta 34 1601-1609... 

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... 

Erythraline, K7 Erythrina alkaloids, K7 Erythristemine, K7 Erythritol, Cl Erythroaphins, YIO a-erythroidine, K7 jS-erythroidine, dihydro-, K7 ]3-erythroidine, j3-tetrahydro-,... 

The erythrina alkaloids form a widely distributed family that lately has received considerable attention as a result of their unique tetracychc skeleton and biological activities. Erythrocarine (46) [27, 28], erythravine (50) [29], and (-l-)-jS-erythroidine (59) [30] are three members of this family that have been synthesized with metathesis as a key step. The molecular structures of erythrocarine, found in the seeds of Erythrina carihaea, and erythravine, isolated from Erythrina cochleata, are related. As a result, the total syntheses independently proposed by, respectively, Mori et al. and Hatakeyama et al. proceeded via the comparable intermediates 45 and 49, respectively, as shown in Scheme 2.11. Ene-yne 45 was synthesized in a number of steps. This substrate was subjected to HCl, followed by [Ru]-I catalyst (10mol%) to induce a tandem enyne-RCM process to yield the acetylated natural product in a quantitative conversion as a 1 1 mixture of diastereoisomers. After... 

The efficient approach to erythravine paved the way for a second erythrina alkaloid [(- -)-/l-erythroidine (56)] synthesis by Hatakeyarna et al. This alkaloid was found in several species of the Erythrina genus and was synthesized in 26 linear steps as depicted in Scheme 2.12. Starting from 54, tandem ene-yne RCM of the isomeric mixture 55 underwent cyclization with [Ru]-I catalyst (10mol%) to... 

The beanlike seeds of the trees and shrubs of the genus Erythrina, a member of the legume family, contain substances that possess curare-like activity. The plants are widely distributed in the tropical and subtropical areas of the American continent, Asia, Africa, and Australia, but apparently they are not used by the natives in the preparation of arrow poisons. Of 105 known species, the seeds from more than 50 have been tested, and all were found to contain alkaloids with curariform properties. Erythroidine, from E. americana, was the first crystalline alkaloid of the group to be isolated. It consists of at least two isomeric alkaloids, a and P-erythroidine both are dextrorotatory. Most experimental and clinical study has centered on the b form because it is more readily obtainable in pure state. P-Erythroidine is a tertiary nitrogenous base. Several hydrogenated derivatives of p-erythroidine have been prepared of these, dihydro-P-erythroidine has been studied most carefully and subjected to clinical trial. Conversion of P-erythroidine into the quaternary metho salt (p-erythroidine methiodide) does not enhance, but rather almost entirely, abolishes its curariform activity this constitutes a notable exception to the rule that conversion of many alkaloids into quaternary metho salts results in the appearance of curare-like action. 

The alkaloids and certain of their derivatives from some 28 species of Erythrina have been examined pharmacologically. The most effective of the group, /3-erythroidine and dihydro-/3-erythroidine, have been examined the most extensively. The results of the investigations are summarized in Table 3. 

The first crystalline pharmacologically active alkaloid was isolated from Erythrina americana mentioned above (7) and was called ery-throidine. This name had already been used by Altamirano referring, however, to the unknown constituents of the plant (774). Further analytical investigations revealed the material isolated to be a mixture of isomeric alkaloids, which were subsequently named a- and /3-erythroidines (14 and 225, see Figs. 2 and 4). 

Folkers K, Major RT (1937) Isolation of Erythroidine, an Alkaloid of Curare Action, from Erythrina americana Mill. J Am Chem Soc 59 1580... 

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