Erythroidine alkaloids

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. 

In view of the fact that the conversion of tertiary into quaternary base other hand, hydrogenation in this series ma have 110 effect on activity (cf. erythraline and its dihydro-derivative ery thramine) or may enhance it (cf. -erythroidine and its dihydride) or mai diminish it (cf. erythramine and its dihydride). 

Soto-Hernandez, M. and Jackson, A. H. 1993. Studies of alkaloids in foliage of Erythrinia berteroana and E. poeppigiana detection of 3-erythroidine in goats milk. Phytochemical Analysis, 4 97-99. 

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 pharmacological properties of P-erythroidine and its dihydro derivative are very similar to those of d-tubocurarine and therefore need not be described in any detail. The two compounds differ from curare in three important respects, namely, less potent paralytic action on neuromuscular junctions, briefer duration of paralysis, and oral efficacy. Indeed, gastrointestinal absorption of the alkaloids is so rapid and complete that the difference between effective oral and subcutaneous doses is rather small. Dihydro-P-erythroidine is longer acting than P-erythroidine and about six times as active. Similar to curare, P-erythroidine and its dihydro derivative are antagonized at the neuromyal junction by anticholinesterases such as neostigmine. 

There are rarely more than eight alkaloids present in a species, and the possibility of the same GC retention time is not normally a problem. In cases where overlap has been observed it has proved possible to identify both components from the mass spectrum of the mixture. The crude alkaloid extracts are treated with trimethylsilyldiethylamine to form volatile TMS derivatives of the hydroxylated components. The presence of a free phenolic or hydroxyl group is then detected by an ion with m/e 73 [(CH3)3Si+]. Positional isomers [e.g., erysovine (5) and erysodine (7)] are resolved although a- and /1-erythroidine are not. The presence of fi-erythroidine (60) can be estimated since it shows some enol content under the silylation conditions and gives rise to a monotrimisyl derivative with m/e 345 (15). 

The insecticidal alkaloid cocculolidine (61), a lower homolog of /5-erythroidine (60) (see Fig. 4), was mentioned in the previous review (7) where its isolation from C. trilobus DC was reported. It has now been isolated from C. carolinus DC, a species native to the Southeastern United States (69). 

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. 

Alkaloids of the erythroidine type have not yet been synthesized, but the parent ring system has been obtained (148) by the method summarized in Scheme 43. 

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 above syntheses of the parent spiroamine system establish the skeleton of the aromatic alkaloids. A synthesis of a derivative of jS-erythroidine (III) with the intact spiro skeleton, achieved in Boekel-heide s laboratory (15), provides similar confirmation for the lactonic alkaloids. 

All of the aromatic alkaloids (except for erythratine) and -erythroi-dine possess two asymmetric carbon atoms—the spiro carbon (C-5) and the carbon substituted by methoxyl (C-3). a-Erythroidine has an additional center of asymmetry at C-12. Chemical, spectroscopic, and crystallographic methods have been used to assign relative and absolute configurations at the asymmetric centers. 

No determination of absolute configuration of any of the aromatic alkaloids by X-ray methods or direct chemical correlations has been made. One way in which this might be accomplished would be to interrelate one of them wdth the erythroidines, but attempts (23) to convert both groups to a common degradation product have not been successful. 

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). 

With the aid of decoupling experiments and the INDOR technique, it was possible to define completely the structure and stereochemistry of erythristemine (1) with the exception of the configuration at C-11." In order to obtain the latter information, recourse was taken to A-ray analysis on the 2-bromo-4,6-dinitrophenolate salt of (1). This constitutes a new method and may be applicable elsewhere. Details of the structural and stereochemical elucidation of the interesting insecticidal alkaloid (2), which may be regarded as a ring-D degraded erythroidine structure, have appeared. ... 

Eight known bases were isolated from this plant, namely, erysopine, erythraline, erythramine, erysodine, erysotrine, erythratine, N,N-dimethyltryptophan, and hypaphorine. In addition three alkaloids, not previously known to occur naturally, were isolated, namely, N-norprotosinomenine (CigHaiO N hydrochloride, mp 242-244° [a] +18°) (74), protosinomenine (picrolonate, mp 172-174°) (75) which was methylated to laudanosine (mp 83-85°), and j8-erythroidine (76) (92). 

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 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. 

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. 

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