Complete assignment of1H and13C NMR spectra of vinflunine

Abstract

A new family of fluorinated Vinca alkaloids was synthesized in superacidic media. Superacidic media were obtained by mixing a strong Bronsted acid, such as anhydrous hydrogen fluoride, with a strong Lewis acid, such as antimony pentafluoride. Thus vinflunine was obtained when vinorelbine was treated in HF–SbF5 at −40 °C in the presence of a chlorinated solvent such as CH2Cl2, CHCl3 or CCl4. Vinflunine was characterized by superior in vivo activity to vinorelbine in preclinical tumor models. The chemical structure of vinflunine was been examined using NMR spectrometry. Taking into account the complexity of the NMR spectra, the total assignment of the 1H and the 13C spectra required experiments using homonuclear (1H–1H) and heteronuclear (1H–13C) correlations such as gradient-selected COSY (gs-COSY), double-quantum filtered COSY (DQFCOSY), heteronuclear multiple quantum-correlation spectroscopy (HMQC) and heteronuclear multiple bond correlation spectroscopy (HMBC). We also undertook a comparative structural analysis between vinflunine base and vinflunine ditartrate in acetone solution. The conformation of the vinflunine base molecule in acetone solution was studied with a NOESY experiment. The structure of vinflunine was thus determined without ambiguity, and its conformation was verified by a single-crystal x-ray diffraction study. The results indicated that the conformation in the solution state was analogous to that observed in the solid state. Copyright © 2001 John Wiley & Sons, Ltd.