Vincristine first synthesis

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

Procarbazine, an antineoplastic agent (2 to 4 mg/kg/day for the first week) in combination with other antineoplastic agents (MOPP regimen—nitrogen mustard, vincristine, procarbazine, prednisone), is indicated in the treatment of stage III and IV Hodgkin s disease. Procarbazine inhibits the synthesis of protein RNA and DNA (see also Figure 15). 

After their discovery, the Vinca alkaloids became the first natural anticancer agents to be clinically used, and they are still an indispensable part of most curative regimens used in cancer chemotherapy nowadays. On the other hand, the plant producing these alkaloids, C. roseus, has become one of the most extensively studied medicinal plants. The levels of vincristine and vinblastine in the plant revealed to be extremely low and, for pharmaceutical production, approximately half a ton of dry leaves is needed to obtain 1 g of vinblastine [4]. This feet stimulated intense investigation in alternative methods for the production of vinblastine and vincristine, namely chemical synthesis and plant cell cultures. However, chemical synthesis showed not to be viable due to the high number of transformations involved, and the anticancer alkaloids were never detected in cell cultures, which express alkaloid metabolism very poorly [5, 6]. The biosynthetic pathway of terpenoid indole alkaloids in C. roseus has also been intensively studied with the objective of developing a manipulation strategy to improve the levels of the anticancer alkaloids in the leaves of the plant [5, 7-10]. 

The modified Polonovski reaction first used in [19] and later called the Potier-Polonovski reaction, resulted in the formation of an iminium dimer which, after reduction with NaBELt, yielded a-3 ,4 -anhydrovinblastine, Fig. (2). Thus, this was the first dimeric Vinca alkaloid with the natural configuration to be synthesized. This method allowed, subsequently, the development of approaches to the synthesis of other natural dimerics like vinblastine, vincristine, leurosidine and leurosine [110-114], and more recently, to the semisynthetic vinorelbine and vinflunine [16, 22]. 

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