MOLECULAR MODELING, NMR-SPECTROSCOPY, AND CONFORMATIONAL-ANALYSIS OF 3',4'-ANHYDROVINBLASTINE

The assignment of the proton spectrum of 3',4'-anhydrovinblastine is r eported. Assignments are made for several protons for which only appro ximate assignments were available previously. Homonuclear TOCSY and RO ESY 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'-anh ydrovinblastine in which the 21-methyl of the 20/21 ethyl group of the vindoline (lower) portion is in proximity to the H14' and 16'-NH reso nances of the cleavamine. In a Monte Carlo search, the global minimal energy structure was oriented with the 16-methoxyl group oriented towa rd the H14' and 16'-NH resonances. Two other structures, the second an d tenth lowest in energy, 0.2 Id and 8 kJ higher in energy, respective ly, brought the 21-methyl group in proximity to the H14' and 16'-NH re sonances in a fashion consistent with the ROESY data. The preferred so lution conformation of 3',4'-anhydrovinblastine is consistent with the reported solution conformation of vinblastine.