Molecular modeling, NMR spectroscopy, and conformational analysis of 3′,4′-anhydrovinblastine

The assignment of the proton spectrum of 3′,4′-anhydrovinblastine is reported. Assignments are made for several protons for which only approximate assignments were available previously. Homonuclear TOCSY and ROESY spectra were utilized in conjunction with HMQC and HMBC spectra in making the assignment. Correlations in the ROESY spectrum suggested a preferred conformation of the cleavamine (upper) portion of 3′,4′-anhydrovinblastine in which the 21-methyl of the 20/21 ethyl group of the vindo-line (lower) portion is in proximity to the H14′ and 16′-NH resonances of the cleavamine. In a Monte Carlo search, the global minimal energy structure was oriented with the 16-methoxyl group oriented toward the H14′ and 16′-NII resonances. Two other structures, the second and tenth lowest in energy, 0,2 kJ and 8 kJ higher in energy, respectively, brought the 21-methyl group in proximity to the H14′ and 16′-NH resonances in a fashion consistent with the ROESY data. The preferred solution conformation of 3′,4′-anhy-drovinblastine is consistent with the reported solution conformation of vinblastine.