Naturally Occurring Bisindole Alkaloids from Catharanthus

Naturally Occurring Bisindole Alkaloids from Catharanthus 

The relatively high yield of vinblastine from Catharanthus extracts and the remarkable biological activity of this alkaloid render this compound a natural choice for structural modification. Vinblastine is subject to attack by electrophilic reagents at a number of sites (Fig. 6), but by careful selection of reagents and conditions it is possible to operate in this structurally complex theater with considerable selectivity. Potentially electrophilic sites are, in some cases, immune from electrophilic attack. 

As a substrate for chemical modification, vincristine (2) represents much more challenge. The extracted yield of 2 from Catharanthus is approximately 10% that of 1, making this compound a much scarcer substrate (42). Furthermore, the chemical lability of the N-1 formyl bond is extreme under a variety of conditions. The preparation of compounds in this series is usually accomplished by performing the requisite functional group interconversions with compounds bearing an N-1 methyl and reserving the oxidation of this methyl for the last step. 

Leurosine (3) represents a useful entry for the synthesis of compounds in which the stereochemistry at C-4 is inverted (43,44). The reactivity patterns exemplified by vinblastine (1) are also present in the chemistry 

Modifications of the Upper Half (Velbanamine Portion) of Bisindole 

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IV. Naturally Occurring Bisindole Alkaloids from Catharanthus... 

The chemical reactivity of N-6 (or N ), directed entirely by the basicity of this atom, is controlled by the nature and stereochemistry of the substituents at C-4 (vide supra). Oxidation of N-6 occurs under mild conditions in several naturally occurring bisindole alkaloids. Thus, treatment of a dichloromethane solution of leurosine (4) with m-chloroperben-zoic acid at -20°C for 4 hr gives the N -oxide (15) in greater than 90% yield after preparative reversed-phase chromatography (46). Leurosine A/ -oxide has also been isolated from Catharanthus roseus and should therefore be considered a naturally occurring bisindole (50). The analogous conversion of vinblastine (1) to its A/ -oxide (16) proceeds under similar conditions but requires longer exposure to the peraeid (24 hr) (5/) 3, 4 -anhydrovinblastine is converted to its N -oxide (17) in 10 min at 0°C... 

The 4-acyl derivatives of 4-deacetylvinblastine (98) are among the earliest semi-synthetic compounds prepared in exploring the medicinal chemistry of the bisindole alkaloids from Catharanthus. By 1965, the clinical utility of vinblastine (1) and vincristine (2) was firmly established, and the naturally occurring congeners leurosine (3) and leurosidine (4) had been well characterized with respect to their experimental antitumor activity. Since these compounds were substantially less active in animal tumor... 

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