The Voacanga Alkaloids

Plants of the Voacanga genus have given rise to four groups of bases apart from the iboga type represented by voacangine, voacristine, and 

The indolic nitrogens were excluded as points of attachment based on the recognition of signals in the NMR-spectra of a number of derivatives characteristic for two indole N—H groups (actually one of these at 7.78 ppm was hydrogen bonded to the 10-methoxyl). 

The NMR-spectrum of voacamine revealed only six aromatic protons and additional data which provided an important clue as to the nature 

The initial mass spectra were not in agreement with this proposal but it turned out that what was being measured was the transmethylated pyrolytic product, voacamine methine (molecular ion m/e 722 4, calc. 718). Once the transmethylating methoxycarbonyl groups were removed the expected molecular ions were obtained. The full papers (45, 48) are worth reading for what they have to teach concerning this difficulty. 

A partial synthesis of voacamine (and voacamidine, XXVI) was carried out by condensing voacangine and vobasinol in refluxing 1.5% methanolic hydrochloric acid 45, 49). This vinylogous Mannich type condensation (Chart VI) has an analogy in the known dimerization of 1-hydroxy-1,2,3,4-tetrahydrocarbazole 45, 50). 

This alkaloid is a member of the sarpagine group, and its structure was readily derived by simple transformations (58) which, among others, 

Voacorine [voacaline (54)] C45-46H54-56N4O7 273 -42° 2 COOMe, OMe, NMe TJVa 5 MeO-indole acid yields no voacangine (61) o(53), p(56) 

Conoduramine (C41-42H5O--52N4O0) 215-217 (foaming) -77° 2 COOMe, OMe, no NMe UV ftJ voacorine d(14) 

The structure of callichiline, apart from recognition of its chromo-phoric moiety which must include the carbonyl and methoxy groups, is practically unknown it has no W-methyl and is apparently not identical with any of the other indole alkaloids (about a dozen) with the same UV-spectra. If the functional group analyses are correct, biogenetic considerations would suggest that the formula be revised to C21H22-24N2O3. 

The mode of biosynthesis of none of these alkaloids is known but, in the case of the iboga group, some guesses have been made (39, 63, 64), all of which start from the amino acids, tryptophan and dihydroxy-phenylalanine, and involve a fission of the latter s aromatic ring. A more sophisticated approach (65), starting from precursors of the aromatic amino acids, namely shikimic and prephenic acids, is apparently not in agreement with recent work on other indole alkaloids (66). The genesis of most indole alkaloids appears to stem from tryptophan and three 

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From a pharmacological point of view, the Voacanga alkaloids are relatively nontoxic, rapidly eliminated, and of no great interest (68). The reported potent cardiotonic properties (9, 54, 69) of some of these alkaloids have apparently not withstood the test of time (52). 

The first reported preparation of a binary alkaloid of the vinblastine type came from the efforts of J. Harley-Mason and Atta-ur-Rahman 15,16). In accord with a proposal for the synthesis of vinblastine-type alkaloids (77), their synthetic strategy was based on a coupling reaction previously developed by G. Biichi et al. for the synthesis of Voacanga alkaloids (75), as shown in Scheme 1. There, acid-catalyzed ionization... 

In the Voacanga series, conodurine and voacamine are among the alkaloids of Peschiera laeta,62 and the symmetrical dimer 12,12 -bis-ll-hydroxycoronaridine (245) occurs in the leaves of Bonafousia tetrastachya.149... 

Under this heading are collected the alkaloids from the plants given in Table I, with the exception of the iboga bases already considered and those dealt with under Voacanga alkaloids. 

Gonopharyngia durissima has afforded iboga bases, two dimeric alkaloids discussed under Voacanga alkaloids, and a trace of a base, alkaloid E, mp 191°-193°, pif a 7.26, UV-maxima at 210 and 305 mp, which differed from the other isolates in having no carbonyl absorption in the IR-spectrum (14). Gonopharyngia pachysiphon, in contrast to C. durissima, has yielded only steroidal bases (45). 

Isolation of the stereospecific strictosidine s)mthase (STS) and formation of strictosidine with the 3a-(S) configuration proved conclusively that this was the natural precursor of the terpenoid indole alkaloids. Strictosidine occurs naturally in Rhazya stricta and the synthase has been isolated from a number of other species Amsonia salicifolia, A. tabemaemontam, Catharanthus pusillus, C. roseus, Rauvolfia verticillata, R. vomitoria, R. serpentina, Rhazya orientalis and Voacanga africana. The enzyme has been purified to homogeneity from R. serpentina (Hampp and Zenk, 1988). A comparison of the activity of STS from C. roseus roots, the only portion of the plant to contain ajmalicine, with that present in plant cell cultures producing the same alkaloid demonstrated that the plant cell cultures are far more metabolically active (Ziegler and Facchini, 2008). 

The total alkaloids in Voacanga seeds ranged from 0.2% to 1.5% (Table 11). Highest content of alkaloids were found in samples 7 (1.2%) and 8 (1.5%). 

In the past decades, many stndies were condncted and reported that focused on the identification of the wide array of V. africana alkaloids and the main ergot alkaloids have been isolated. With the improvement of the isolation procedures many minor components have been identified (Table IV). Voacanga alkaloids have been isolated from leaves, seeds (mature and inmature), tmnk and root bark (Table IV). 

Table V. Voacanga Alkaloids Reported in Other Speeies of the Apoeyaneeae Family...

Among the natural products that can be isolated from Voacanga species, it is the alkaloids which account for the wide range of pharmacological activies and thus medicinal uses. For instance, the bisindole alkaloid amataine isolated from Voacanga exhibited cytotoxicity effects in vitro and conld be nsed in chemotherapy as cytotoxic gronp 44). 

Some of the most difficult structural problems in the indole alkaloid field are associated with the bisindole alkaloids of the vobtusine type. Since 1955, vobtusine has been isolated on numerous occasions, often in large quantities, from the Apocynaceae species Callichilia, Conopharyngia, Rejoua, and Voacanga A correct molecular formula could only be determined by high-resolution mass spectrometry. In 1966 a partial structure was proposed for the alkaloid and later in the same year a complete structure was put forward. An unambiguous structural proof is, however, still lacking. The difficulty arises from the complete resistance of the alkaloid and its derivatives to cleavage, in contrast, for example, to the dimers of the voacamine and vinblastine types. Non-cleavable dimers occur also in calabash-curare but in these cases chemical correlation with cleavable alkaloids has been possible (see Section 2, p. 209). To date no bisindole alkaloid related to vobtusine has been found which can be split into monomeric units. 

Details of the Czech group s chiroptical studies of the Iboga and Voacanga alkaloids, summarized previously, " have now been published. ... 

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