Ajmaline compounds

Ajmaline (intravenously only) and its orally applicable propyl-substituted prodrug prajmaline are classified as class IA drugs, but due to their long dissociation time constant can also be considered as class IC compounds. 

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... 

A-Acyliminium ions are versatile intermediates for synthesis of nitrogenous compounds, particularly alkaloids [154]. The conjugate system is very electrophilic such that it can be intercepted by various donors including carbonyl compounds and jt-systems. In comparison with a,p-unsaturated ketones the replacement of the a-carbon with a nitrogen atom accentuates the reactivity of these species. Ingenious applications of the JV-acyliminium ions include service to synthesis of corydaline [155], lycoramine [156], quebrachamine [157], and ajmaline [158], to name a very few. 

The increase in heart muscle excitability induced by some natural quinuclidine derivatives (quinidine, ajmaline), suggesting pharmacological activity of some synthetic quinuclidine compounds and the possibility of using quinuclidines as catalysts for production of polymers,17 stimulated further interest in the ring system. 

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. 

Upon hydrogenation (30) of voachalotine, the ethyl formed is in the same configuration as in ajmaline, which stands in contrast to the course of the(hydrogenation evinced by deoxysarpagine itself. The nature of the iV-methyl in voachalotine has been thoroughly studied by physical methods and compared with many model compounds (64). 

R. serpentina cell cultures, raucaffricine levels amounted to 1.2 g/L medium, whereas ajmaline levels reached only 0.3 g/L medium (Schtibel et al, 1986). It is interesting to note that raucaffricine is a fypical constituent of R. cajfra, but has not been isolated from other Rauvolfia species. However, in Rauvolfia cell cultures the compound is found in all species tested, with a maximum yield in R. serpentina. In other words, under these growth conditions, the pathway to ajmaline appears to have become deregulated. 

The number of known ajmaline structures sensu stricto) has grown markedly in recent years to a present count of 77 (compounds 1 - 77). Some of these might be artefacts and a few structures have not been convincingly determined vide in/m). In addition, seven bisindole alkaloids (compounds 78 84) containing at least one monomeric ajmalan unit have been isolated, increasing the total number to 84 (77 + 7). 

The first enantiospecific total synthesis of (+)-ajmaline [(+)-17] was developed by Cook et al. 161). D-(+)-Tiyptophan methyl ester (126) was converted enantiospecifically, via intermediate 127, to the optically active )-N -benayltetracyclic ketone (-) 107, which was then transformed into the ot,P-unsaturated aldehyde (-)-128. When compound (-)-128 was stirred with 3-bromo-4-hq>tene in die Barbier Grignard process conditions the 1,4-addition products 129a,b... 

For a long time, the van Tamelen synthesis of ajmaline (17) via the "deoxyajmalal system" was authoritative in the field. However, in contrast to van Tamelen and Oliver, Lounasmaa and Hanhinen 163) were unable to detect a spontaneous "biogenetic-type cyclization", and were unable to cyclize compound 138 (or similar ones) to the "deoxyajmalal ring system" (138 -> 139 -> 140) (Scheme 7). 

The mass spectra of ajmaline type alkaloids can be divided into three main groups namely, ajmaline (17) and similar compounds widi a H-2P orientation, ajmalidine (15) and other compounds with a 17-keto group, and compounds with a H-2a configuration [e.g. quebrachidine (36)]. For the general features of the mass spectra of ajmaline alkaloids, and the determination of structures with the aid of mass spectra, see Refs. 198-202. 

Ajmaline, because of its availability and facile transformations, remains the compound of choice as a convenient material for partial synthetic work. The continuing study of its biosynthesis is beginning to bear fruit and it is now certain that the hydroaromatic moiety of this type I base (f) is derived from a terpenoid percursor (4). 

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