Vindoline Vinorelbine

If the C-15, C-16 bond is oxidatively cleaved, the secodine skeleton results (the proposed progenitor of the Aspidosperma and the iboga systems) through alternative Diels-Alder type cyclizations to afford tabersonine and catharanthine. The bisindole alkaloids of Catharanthus roseus reflect the union of vindoline and catharanthine to afford anhydrovinblastine modification affords the clinically significant alkaloids, vinblastine (VLB) and vincristine (VCR Fig. 39). The alkaloids, particularly VCR, are important as anticancer agents and have led to the development of the semisynthetic derivatives vindesine and vinorelbine (Fig. 40). Synthetic approaches are available to join the monomeric precursors. The enzymatically controlled sequence of reactions from tabersonine to vindoline has been elucidated. 

In 1975, Potier and collaborators proposed that, in planta, the dimeric vinblastine type alkaloids resulted from the coupling of catharanthine and vindoline and, in light of this hypothesis, they reported for the first time the chemical synthesis of a dimer with the natural configuration through a modified Polonovski reaction [18, 19]. This reaction resulted in the formation of an iminium dimer which, after reduction with NaBH4, yielded a-3 ,4 -anhydrovinblastine, Fig. (2), later proved to be the first dimeric biosynthetic precursor of vinblastine in the plant. The group of Potier investigated possible modifications of anhydrovinblastine and produced vinorelbine, Fig. (1), which was the first active derivative with an altered cleavamine (catharanthine) moiety [20, 21]. 

Vindoline and catharanthine are the last monomeric precursors of the dimeric anticancer alkaloids of C. roseus, and they are also the two major alkaloids accumulated in the leaves of the plant [106, 107], The study of the dimerization biosynthetic step stems in early work on the chemical synthesis of the dimeric alkaloids and it has involved much discussion. Moreover, the chemical dimerization reaction has industrial application in the synthesis of vinorelbine and vinflunine. Due to its potential regulatory importance for the production of the dimeric Vinca alkaloids in the plant, and to the much that is known about the chemical and biosynthetic reactions, the dimerization step will be presented in particular detail here. 

There have been several recent syntheses of anhydrovinblastine, stimulated in part by its role as a key intermediate in the synthesis of the anticancer drug, Navelbine (vinorelbine). Anhydrovinblastine has been prepared via an electrochem-ically mediated coupling of catharanthine (667) and vindoline (668). The oxidation of catharanthine on a platinum anode in MeCN-Et4NC104 at controlled potential (0.6 V vs. SCE) in the presence of vindoUne, gave, after in situ reduction with NaBH4, (16 5)- and (16. R)-anhydrovinblastine, in yields of 52 and 12%, respectively (Scheme 46) (459,460). 

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