NUCLEAR OVERHAUSER EFFECT SPECTROSCOPY (NOESY) AND DIHEDRAL ANGLE MEASUREMENTS IN THE DETERMINATION OF THE CONFORMATION OF TAXOL IN SOLUTION

The 300 MHz H-1-NMR and 75 MHz C-13-NMR spectral assignments of taxol were made with the aid of APT and DEPTGL 1-D spectra and COSY, HETCOR, and NOESY 2-D spectra. In addition to being useful for spectral line assignments, the cross-peaks in the phase-sensitive NOESY spectrum were also used to estimate the distances between protons located on adjacent ring systems of taxol by measuring the volume integration of the cross-peaks. Key dihedral angles of taxol were also estimated using a Karplus-type equation that takes into account the heteroatom substitution on the adjacent carbon atoms. Using the proton-proton distances and the dihedral angles as a guide, molecular mechanics energy minimization molecular modeling was used to arrive at a structure of taxol that was consistent with the NMR data. While the X-ray data for taxol was not available, the NMR data and the molecular modeling results were compared to the X-ray data for taxotere, a close structural analog of taxol that has slightly more biological activity. The NMR and molecular modeling data indicate that the structure of taxol in solution had a general "U"-shape that was very similar to the crystal structure of taxotere, except that in solution the ends of the "U" were closer together than found in the crystal structure.