Catharanthine biosynthetic precursor

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]. 

Within the natural products field, the investigation of complete biosynthetic pathways at the enzyme level has been especially successful for plant alkaloids of the monoterpenoid indole alkaloid family generated from the monoterpene gluco-side secologanin and decarboxylation product of tryptophan, tryptamine [3-5]. The most comprehensive enzymatic data are now available for the alkaloids ajmalicine (raubasine) from Catharanthus roseus, and for ajmaline from Indian Rauvolfia serpentina [6] the latter alkaloid with a six-membered ring system bearing nine chiral carbon atoms. Entymatic data exsist also for vindoline, the vincaleucoblastin (VLB) precursor for which some studies on enzymatic coupling of vindoline and catharanthine exist in order to get the so-called dimeric Catharanthus indole-alkaloids VLB or vincristine [7-9] with pronounced anti-cancer activity [10, 11]. 

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. 

It has been observed that labeled strictosidine [3] geis-soschizine [4] (80,85,86) stemmadenine [7] (86,87) and tabersonine [7b,9] (86-88) were all incorporated into both catharanthine [8] and vindoline [10] in Catharanthus roseus plants, indicating that these are the main precursors in the biosynthetic pathway to the Aspidosperma-lboga alkaloids. Other intermediates such as geissoschizine oxindole [5], preakuammicine [6] have been detected 28-40 hours after germination of c. roseus seeds (85,87,89) provided strong evidence for the formation of catharanthine [8] and vindoline [10] as presented in schemes I and ll. 

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