Ajmaline alkaloids derivatives

Sarpagine (75) and deoxysarpagine (76) have only fleeting effects on the blood pressure and the pressor amines. Voachalotine, like ajmaline, has some cardiotonic properties (77). Akuammidine is inactive in bird malaria (78). The alkaloids derived from Vinca species are probably... 

Several cardenolide derivatives of ajmaline alkaloids have been synthesised and tested for their anti-arrhythmic activity. iV(,-(Strophanthidin-3 -yloxycarbonyl mediyl)ajmalinium chloride (167) was found to be one of die most potent of these (210). 

During the recent decades, attempts were made to detect novel biological and pharmacological activities of alkaloids from the genus Rauvolfia. The results demonstrated that ajmaline and derivatives interact with ion... 

The 3-hydroxyajmaline derivatives [e.g. herbamine (85) and herbadine (86) (4)], which exist, in part, in the 2-acylindolenine form, and thus behave in a different manner, are not included in this review (Scheme 1). The various alkaloids of the seco ajmalinoid type [e.g. rhazicine (87), isoihazicine (88) and sandwicoline (89) (4)] are also excluded from the present review (Figure 3). In addition, some doubtful compounds of unknown structures (e.g. sandwicensine and ajmaiinine), which have persisted in earlier lists of ajmaline alkaloids (i), have been rejected. 

During the enantiospecihc total synthesis of ajmalin-related alkaloids, (-)-suaveoline and (-)-raumacline, N-debenzylation of the hydrochloride salt of the alkaloids was performed with 10% Pd/C (0.12 mol Pd/mol compound) in absolute EtOH at room temperature and 1 atm of hydrogen for 1 or 2 hours. When this catalytic debenzylation was performed, however, using 10% Pd/C (0.28 mol Pd/mol compound) in MeOH for 5 hours, N-methyl derivatives were produced in good yield (Scheme 4.91).339,340... 

Terpenoid Indole Alkaloids.—Important recent work has defined strictosidine (97) as a key intermediate in the biosynthesis of terpenoid indole alkaloids with both 3a- and 3/3-configurations. Some of this work, published earlier in preliminary form (cf. Vol. 9, p. 18), is now available in a full paper.26 In addition to those alkaloids examined earlier, strychnine, gelsemine, vincadifformine, isoreserpiline, aricine, isoreserpinine, and ajmaline have been shown to derive from strictosidine (data are also included for ajmalicine, for catharanthine, and for vindoline which had been reported earlier). 

The arbitrary classification of Rauwolfia alkaloids (91) is simplified here, and it is slightly different from a recent arrangement (92). The Rauwolfia alkaloids can all be regarded as yohimbinoid derivatives as shown in Chart I, viz. the yohimbines (all yohimbine isomers) 18-hydroxyyohimbines (reserpine-type alkaloids) ring E heterocycles and their anhydronium analogs (ajmalicine, serpentine) ajmaline-type (which includes sarpagine) and compounds of unknown constitution. 

The pair corynantheine-corynantheidine plays an important role in that a number of alkaloids of other structural types can be transformed into derivatives of either of this pair. The configuration a of C-15,H can thus be assigned to ajmaline (CXIII) because it can be transformed into two isomers of CXV, one of which on further transformation yields a tetracyclic derivative (CXV) related to corynantheidine (75). The same sequence of reactions applied to isoajmaline (epimeric at C-20 with ajmaline) gives a derivative of corynantheine (75). Sarpagine (CXVI)... 

By contrast, main fragments of alkaloids of the epiajmaline type are also formed from the piperidine part of the molecule. The difference in the fragmentation behavior of the epimers was explained157 by assuming that in ajmaline-type alkaloids the hydrogen in position 2 is shifted to C-17, producing an indole derivative which is now cleaved, (264)—>[265] ... 

Several carboline-derived alkaloids have been studied using 2D NMR methods, the first in 1995 was ajmaline (89) [107[. Long-range couplings for... 

The biosynthetic pathway for ajmaline in R. serpentina is one of the best-characterized terpenoid indole alkaloid pathways. Much of this progress has been detailed in a recent extensive review (78). Like all other terpenoid indole alkaloids, ajmaline, an antiarrhythmic drug with potent sodium channel-blocking properties (79), is derived from deglycosylated strictosidine (Fig. 2c). 

After deglucosylation, the pathway proceeds through a 4,21-Dehydrogeissoschizine derivative to ajmalicine (an a-Blocking spasmolytic agent, used for tinnitus and cranial trauma with an ergot derivative). If cyclization occurs between C-17 and C-18, the yohimbine nucleus is produced, whose derivatives include the Rauvolfia alkaloids reserpine and resdnnamine (antihypertensive activity). Ajmaline, formerly used as an antiarrythmic, also occurs in Rauvolfia species, and several of the enzymes in the pathway have been isolated. Recent considerations suggest that the C-16-C-5 bond may be formed before the N-4-C-21 bond (Fig. 38). 

Ajmaline and its derivatives, prajmalium bitartrate (rINN A-propylajmaline), lorajmine (rINN chloroacetylajma-line), detajmium bitartrate (rINN), and diethylaminohy-droxypropylajmaline, are Rauwolfia alkaloids. Their use is restricted by serious adverse effects, such as neutropenia and cardiac dysrhythmias, which have been reviewed (1). Other adverse effects include dizziness, headache, and a sensation of warmth after intravenous injection. 

Sarpagine-Ajmaline-Picraline Group. (+)-Quebrachidine (142) is one of the minor alkaloids of the root bark of Cabucala striolata, and of the stem and root bark of C. torulosa, which also contains (-)-vincamajine (143). O-Trimethoxy-cinnamoylvincamajine (144), a known alkaloid, and six new vincamajine derivatives, have been extracted from the aerial parts of Alstonia lanceolifera. Three of the new alkaloids are 10-methoxy-3,4,5-trimethoxycinnamoylvincamajine (145), 10-hydroxy-3,4,5-trimethoxycinnamoylvincamajine (146), and 10-methoxyvinca-majine (147) the other three alkaloids are suspected to be the trimethoxybenzoyl... 

The intensity of the search for new alkaloids of the ajmaline type will certinly not abate. The research on cell culture methods to prepare gmaline alkaloids is likely to continue. So far, however, the alkaloid content in cultured cells has almost always been low. For the future, we can expect the production of ajmaline derivatives by gene transfer techniques. 

Hie first, by Lounastnaa and Hanhinen, updates an area of indole alkaloids which has been neglected in the series for over 30 years, namely, the ajmaline group of alkaloids, where numerous advances in chemistry and biosynthesis have been made recently. The second chapter by Michael reports on the progress made in a vast area of alkaloid chemistry, those alkaloids with either an indolizidine or a quinolizidine nucleus derived from plant, marine animal, and fungal sources. 

Of the 12 alkaloids belonging to this group occurring in Sri Lankan flora, 11 were encountered in Alstonia macrophylla Wall, of the family Apocynaceae, and the remaining alkaloid was isolated from Taberrtaemon-tana divaricata (L.) Br. ex Roem et Schult. of the same family. Six of the alkaloids were found to be new. Vincamajine (101) and its new derivative, 19-hydroxyvincamajine (102), are two alkaloids of the ajmaline subgroup present in A. macrophylla (82). The structure of 102 was elucidated with the aid of IR, H NMR, and low-resolution MS data. A. macrophylla also... 

The presence in alstonerine of the ring E functions was deduced from the IR and NMR spectra, and on this basis a structural relationship with alstonisine (alkaloid C) (54) from the same plant or with alstophylline (53) was suspected. This was substantially supported by a comparison of the mass spectrum of alstonerine with that of the ajmaline degradation product 55 the two mass spectra were virtually identical except for the upward displacement by 14 mass units of the molecular ion of alstonerine (52) (M 336) and a small peak at m/e 267 derived from it compared with the molecular ion of 55 (M+ 322) and a fragment ion at m/e 253. 

Oxidation of 3,3-disubstituted indoline derivatives (121) with 5 equiv of H202 H2NC0NH2 complex in the presence of a catalytic amount of Na2W04 (82b) also affords the A a-hydroxyoxindole derivatives (118) in moderate yield (84a). By applying this procedure, the synthesis of a new humantenine-type alkaloid, 20-hydroxydihydrorankinidine (26), starting from ajmaline (66) was achieved (84b). 

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