Anhydrovinblastine synthesis

Additionally, there had, for many years, been a vast synthetic effort underway aimed at the synthesis of the two monomeric units, where it was anticipated that the two units could be joined to form the vinblastine-type bisindole alkaloids. Coincidentally, as it transpired, 20 years of effort in the areas of synthesis and biosynthesis converged, at almost the same time, on the compound 3, 4 -anhydrovinblastine (8). 

The critical dependence of the stereochemical and regiochemical course of the modified Polonovski reaction on the oxygen functionality in the catharanthine derivative has been well exemplified in recent synthetic studies. Indeed, in the reaction that ultimately provided the first synthesis of anhydrovinblastine, a minor product proved to be the result of an alternative fragmentation of the catharanthine Nb-oxide derivative in which the 5,6-bond was cleaved [->(266)] and subsequent coupling of vindoline occurred at position 6, with formation of the dimeric species (267).159 When an attempt was made to couple the N-oxide of the lactone (238) with vindoline under Polonovski conditions, this type of coupling occurred exclusively, and the products were the lactone (268) (major product)163-165, the... 

Oxo-15,205 -dihydrocatharanthine (275a), prepared as described above, has been employed in a new synthesis of anhydrovinblastine (323). Stereospecific reduction of (275a), followed by acetylation and formation of the A -oxide, gave an... 

There are two especially relevant cases where Cp2TiCl-promoted epoxide deoxygenations have been demonstrated to conform to the requirements of selectivity, mildness, and wide functional group tolerance desirable in natural product synthesis the chemical correlation between cryptophycin-23 and cryptophycin-45 and the synthesis of anhydrovinblastine, the key intermediate in the synthesis of the anticancer drug Navelbine, from leurosine (Scheme 14) [91-93]. 

There are, however, a few examples in which the exclusive participation of peroxidase in the synthesis of natural bioactive alkaloids has been reported. These mainly concern the biosynthesis of some monoterpenoid indole alkaloids, especially the synthesis of a-3 ,4 -anhydrovinblastine (XLVII) [76],... 

C. roseus is, therefore, an amazing chemical factory, which produces more than 100 different monoterpenoid indole alkaloids, many of them possessing notable pharmacological activity [158-159]. The main alkaloids present in C. roseus plants are catharanthine, vindoline and a-3 ,4 -anhydrovinblastine. Ajmalicine and serpentine are also present in significant amounts in the plant [160-165]. Class III plant peroxidases have been involved in the synthesis of many of these monoterpenoid indole alkaloids. 

The Canadian group have also followed their synthesis of anhydrovinblastine (266) by studying the introduction of oxygen substituents to positions 15 and/or 20. Oxidation of anhydrovinblastine with t-butyl hydroperoxide afforded a moderate yield of leurosine following experience with other substrates in this reaction Kutney etal. formulate leurosine as the -epoxide, rather than the a-epoxide (258) favoured " by other workers. However, both formulations are at present tentative, and it will be intesting to note which one ultimately proves to be correct. 

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]. 

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. 

It would thus appear that the presence of an a-acetoxy-group at C-15 severely inhibits the fission of the 16,21-bond in the coupling reaction, since the isovinblastine O-acetate (258) was obtained in yields of only 6 and 4%, respectively, from (257) and (260). The effect of a /3 -acetoxy-group is less well defined Honma and Ban " report the formation of anhydrovinblastine (255), but only as the minor product of the reaction, whereas Kutney and Worth report the formation of (253) and (254), but in unspecified yield. For the synthesis of vinblastine derivatives the absence of a C-15 substituent, as in catharanthine and dihydro-catharanthine, seems preferable for example, catharanthine N-oxide was... 

Scheme 5 Total synthesis of vinblastine (117) by Boger and structure of anhydrovinblastine (126).

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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