From anhydrovinblastine

The question of the possible artifactual nature of leurosine (11) was examined by Kutney and co-workers (229) using a cell-free preparation at pH 6.3. After a 3-hr incubation, a 22% yield of leurosine (11) was formed from anhydrovinblastine (8), and when anhydrovinblastine (8) was incubated with horseradish peroxidase in the presence of HjOj, leurosine (11) was formed in 65% yield. 

The diols (15 / )- and (15 S)-hydroxyleurosidine, and the four 15 -hydroxy-compounds derived from deoxyleurosidine and deoxyvinblastine, have been prepared by standard procedures from anhydrovinblastine for pharmacological evaluation.122... 

Further investigations have been carried out into the direct preparation of 5 -nor-alkaloids from parent alkaloids of the vinblastine group.141 The 7 -chloro-indolenines (328) and (329) derived from anhydrovinblastine and leurosine fragment in the presence of silver fluoroborate to give, after re-cyclization, the 5 -nor-bases (330) and (331). In the formation of (328) and (329), some chlorination also occurs at position 12, and this can, under appropriate conditions, form the major reaction. Products similar to (330) and (331) were also obtained from the analogous reactions with anhydrovincristine and leuroformine. 

Whether leurosine, Catharine, and their congeners are true alkaloids, or artefacts derived from anhydrovinblastine, the fact remains that the aerial oxidation of anhydrovinblastine is a facile process which does not need to be enzyme-mediated, and a further examination of this reaction has revealed that all the alkaloids of the vinblastine group are produced. The oxidations were performed in acetonitrile solution, and in one experiment, conducted at 26 for 48 hours, the composition of the alkaloid mixture obtained was roughly similar to the relative abundances of the dimeric alkaloids isolated from Catharanthus species. In the oxidation the lone electrons on Nb are presumably involved, since anhydrovinblastine Nb-oxide is inert towards oxidation by air, and while the presence of moisture promotes the reaction, oxygen from the water is not incorporated into the oxidized alkaloids. On the basis of the available evidence, a mechanism, shown in truncated form in Scheme 37, was proposed for the oxidative transformation of anhydrovinblastine into the various alkaloids iso-lated. "°... 

The synthesis of Catharine (250), " to which catharinine was initially believed to be closely related, has in fact been achieved by a process which involves the fission of ring D of the velbanamine component of leurosine (249). This conversion was first reported as a result of the accidental over-oxidation that occurred in the preparation of leurosine from anhydrovinblastine by means of t-butyl hydroperoxide in the presence of trifluoroacetic acid. The by-product in this reaction was initially regarded as the 21-lactam related to leurosine, but it has now been recognised as Catharine, and can be prepared equally well by oxidation in the absence of acid (Scheme 41) a radical mechanism appears to be involved. In view of this facile conversion under oxidising conditions, the status of Catharine as a bona fide natural product is open to question. Indeed, the status of leurosine itself as an alkaloid has been questioned, in view of the ease with which anhydrovinblastine is oxidised to leurosine, even in the absence of specific oxidising agents. For example, anhydrovinblastine is oxidised to leurosine if not stored in an inert atmosphere, and the conversion is even more rapid in solution, particularly in the presence of adsorbents such as silica or alumina. A conversion of 40% has been observed after only 72 hours at room temperature. In view of these results it is perhaps not surprising that anhydrovinblastine has not been isolated from any Catharanthus species examined to date. 

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