Vinblastine first synthesis

Polonoeski reaction (2, 7 5, 3). The first synthesis of the dimeric indole alkaloid vinblastine (4), used in the treatment of lymphomas, involved coupling of two indole units using a Polonovski reaction. Thus reaction of the N-oxide (1) and vindoline (2) with trichloroacetic anhydride afforded the quaternary im-monium compound (3), which was converted into (4) by standard methods (reduction with NaBH, rcacclylalion). ... 

The first synthesis of vinblastine was reported by Potier and coworkers more than a decade later and three more, again, after about another decade had passed. The syntheses all used a naturally occurring fragment (viz. vindoline) to complete the work. These works are worthy of study. However, a recent synthesis by Fukuyama and coworkers has captured the imagination and is reported below. 

The first reported preparation of a binary alkaloid of the vinblastine type came from the efforts of J. Harley-Mason and Atta-ur-Rahman 15,16). In accord with a proposal for the synthesis of vinblastine-type alkaloids (77), their synthetic strategy was based on a coupling reaction previously developed by G. Biichi et al. for the synthesis of Voacanga alkaloids (75), as shown in Scheme 1. There, acid-catalyzed ionization... 

The real breakthrough toward synthesis of vinblastine and, in fact, the first significant laboratory preparation of binary indole-indoline alkaloids with the natural C-16 -C14 PARF configuration, was due to the work of the Potier-Langlois team at Gif (38,39 for reviews, see Refs. 40 and 41), buttressed by results obtained by the Kutney group in Vancouver (42,43,44), and the efforts of Atta-ur-Rahman and associates in Karachi. Their basic idea, which relied on the biogenetic consideration that binary indole-indoline alkaloids are formed in plants by the union of vindoline... 

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-... 

The difficulties inherent in the synthesis of vinblastine, and in particular the generation of the natural stereochemistry at C-16, have been discussed by Atta-ur-Rahman, and the various possible synthetic approaches adopted up to mid-1976, which culminated in the first partial synthesis of vinblastine, have also been described.158... 

A total synthesis of vinblastine has not as yet been achieved. Methods of preparation involve making initial crude extracts from the periwinkle plant, followed by extraction at selected pH into organic solvents, and final separation of the complex mixture of alkaloids by column chromatography. Several methods have been devised since Noble, Beer, and Cutts1 first reported the isolation of vinblastine as the sulfate salt. A few are briefly described here. 

In view of the importance of vindoline (44) as a constituent of the oncolytic bisindole alkaloid vinblastine, methods for the synthesis of both vindorosine (43) and vindoline from members of the quebrachamine and vincadifformine groups have been extensively investigated. The first results... 

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]. 

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]. 

More recent work from Gross laboratory claims that at least some maternal mRNA s code for microtubule proteins, or, more correctly, for soluble proteins which, after partial purification by vinblastine precipitation, co-migrate on acrylamide gel electrophoresis with known microtubule proteins from sperm tails (Raff et ah, 1971, 1972). Although there is a pool of these microtubule proteins in the unfertilized egg it seems that this pool is maintained or supplemented (for the construction of such things as mitotic spindles and cilia) by continuous synthesis of the monomeric subunits from stored mRNA, starting from the first cleavage cycle. Hopefully, more detailed analysis of the relative rate of microtubule synthesis at different times after fertilization, in the absence of new RNA synthesis, will provide information about the way in which this particular maternal mRNA is utilized during development. 

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