Vincoside lactam

A limited number of alkoyl-glucoalkaloids have been reported in the literature so far. The first specimen of this class of compounds to be isolated was rubescine (43), which was found in Adina rubescens (64). More recently another esterified vincoside lactam, rhynchophine (44), was extracted from the leaves of Uncaria rhynchophylla, a member of the tribe Cinchoneae (65). Thus, chemotaxonomic correlations again tend to raise the question whether Pauridiantha should not join, along with Adina and Uncaria, the tribe Naucleae. 

Pathway D implies rotation around the C-14-C-15 bond, followed by lac-tamization. Vincoside lactam is the precursor of esterified derivatives, e.g., rubescine found in Adina (Naucleae) and rhynchophine found in Uncaria (Cinchoneae). These compounds are alkoyl-glucoakaloids, as are lyalosidoferine and lyalosidosinapine found in Pauridiantha (Urophylleae). 

The difference in stability of vincoside and strictosidine as the free bases was quite marked. Aqueous sodium carbonate at room temperature rapidly converted the former into vincoside lactam (50 or 52) mp 201-202° [a]D-118° (MeOH), whereas the latter remains unaffected. In order to obtain strictosidine lactam (strictosamide) (50 or 52) [a]D - 75° (MeOH) it was found necessary to heat the reaction mixture at 70° for a considerably longer time. Since then, both these transformation products have been isolated from natural sources—vincoside lactam from A. rubescens (9) and strictosidine lactam from R. stricta (24) and N. latifolia (3). One notable difference between the epimers was that strictosidine lactam tetraacetate (51 or 53) displayed one acetate signal in its NMR spectrum at anomalously high field (t8.78), a characteristic not shared by the vincoside derivative. 

Considerable efforts have been made in the synthesis of the Strychnos angustiflora alkaloids reviewed last year. A photochemical cyclization lies at the heart of a neat synthesis " of angustidine (85a) (Scheme 13). 18,19-Dihydroangustine (85b) has been prepared from vincoside lactam tetra-... 

Studies on strictosamide (27a) from Rhazya stricta (which may be an artefact for it is formed from strictosidine under mild conditions) and vincoside lactam (27b) have also been adduced in support of the revised formulations. 

Vincoside lactam (27b), isolated from Adina rubescens, was converted (Scheme 7) " into a triol (30). Corynantheine (31) was degraded to a triol (32) which proved to be enantiomeric with the major vincoside lactam degradation product (30). 

Rubescine, also from A. rubescens, is the 3,4-dihydroxycinnamate of vincoside lactam, where the extra acyl residue is at the 3-position of the glucose unit. 

From the leaves of Uncaria rhynchophylla, a glycoindole alkaloid, rhyn-chophine, has been isolated along with vallesiachotamine, vincoside lactam, and strictosamide (2). 

Vincoside is converted by mild base (conditions which do not affect isovincoside) into a lactam (42a). Isovincoside gave a corresponding compound (42b) on more vigorous basic treatment. This difference in reactivity can be rationalised in terms of the assigned C(3)-stereochemistry for the two precursors, since models indicate that fewer non-bonded interactions exist in the lactam (42a), and by implication in the transition state leading to it, than in the isomeric lactam (42b). 

The C-3 epimeric lactams [as (154)] were proposed as potential intermediates after vincoside/isovincoside, and in support the lactam (154), synthesized from radioactive isovincoside (153), was found to be an efficient precursor for camptothecin (155) the epimeric lactam formed from radioactive vincoside (142) was only incorporated to an insignificant extent. These results stand in contrast to those for the terpenoid indole alkaloids where vincoside but not isovincoside has been found to be a biosynthetic intermediate. 

The interpretation should find the explanation of the following facts 1. The coupling reaction with biogenic amines is selective, if it is at all, in favour of the 3R or 1R epimer (R series), and the selectivity could be increased (especially in the vincoside series) by increasing the bulkiness of the ligand attached to N-4 (or N-2). 2. The A -benzyl oxotryptamine derivative gave the ester (35-78b) as main product, the oxotryptamine derivative the (3R-19) lactam. 3. The lactamization of the ester alkaloids is much faster in the R series, than in the S series. 4. The neo compounds are formed in smaller amount than the normal products. 

The first factor is the structure of the transition state from the most probable ester educt (e. g. strictosidine and vincoside) to the tetrahedric intermedier of the lactamization (Fig. (16)). Concerning the educts, the most probable C-14 conformer of strictosidine was proved by NMR measurements to be Sll, that of vincoside was prognosed according to Table (lb) to be Rll. The conformation of the tetrahedric intermediates as products should be close to that of the appropriate lactams, i. e. S31 and R12. In the R series, both Rll and R12 are favoured conformers, and the transition from Rll to R12 can pass a single favoured eclipsed... 

Because 1-methyl vincoside and its dihydro derivative were spontaneously lactamized, for studies of the subsequent cyclization their aglucones (3i -93a)=(3/ -4-debenzyl-96a) and (3i -93b)=(3i -4-debenzyl-96b) were prepared in situ by catalytic hydrogenolysis of their benzyl derivatives (3i -96a) and (3i -96b). 

In the vincoside series the reactivity order of the functional groups can be summarized as follows. The preferred nucleophilic site is N-4 over N-l and 0-17 over 0-21 (C-18 has an intermediate position in the natural series). The preferred electrophile is C-19 over C-21 and C-17 in the natural series, and C-21 over C-17 in the dihydro series. C-22 is the preferred electrophile only in the vincoside series when lactamization preceded the deglucosylation. However, it seems from the work of De Silva and co-workers [53] that in the strictosidine series, in which the lactamization is slow, the preferred electrophile is C-17 over the others. 

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