Version française

Saturday 29 November 2008

GIOVANELLI Emerson

Alternative strategies for the synthesis of vinflunine.


University : Paris XI Orsay

Jury :

  • Président : D. Aitken
  • Rapporteurs : B. Langlois, F. Guerritte
  • Examinateurs : E. Doris, P. Hellier
  • Directeur de thèse : B. Rousseau

Summary

Vinflunine is a fluorinated derivative of a dimeric Vinca alkaloid, which should be on the market soon, due to its outstanding anticancer properties. Its synthesis is carried out in three steps by Pierre Fabre Laboratories via biomimetic coupling of two monomeric subunits, catharanthine and vindoline, extracted from the Madagascan periwinkle; gem-difluorination in superacidic medium of the resulting dimer, anhydrovinblastine; and cycle contraction. Nevertheless, the superacidic medium is very hard to handle and causes the loss of half of anhydrovinblastine, which is a very highly-valued product. Noticing that only the part of the dimer originating from the catharanthine moiety is modified during superacidic fluorination, the biomimetic coupling between vindoline and the gem-difluorinated derivative of catharanthine has been envisaged as an alternative for the synthesis of vinflunine. Gem-difluorocatharanthine has been prepared by two methods, each based on various and unprecedented functionalizations of natural catharanthine. However, the study of the coupling between difluorocatharanthine and vindoline showed the concomitant hydrolysis of the fluorinated group. To prevent this and to access diverse fluorinated analogues of dimeric alkaloids, the synthesis and coupling of difluorocatharanthine derivatives have been performed. The results acquired, offer very promising prospects towards the preparation of vinflunine and other fluorinated dimers. Finally, the mechanism of superacidic fluorination has also been studied and better understood, using two dimers obtained through coupling between catharanthine derivatives and vindoline.

Key words : Alkaloids, Madagascar preiwinkle, catharanthine, vinfunine.