NMR AND MOLECULAR MODELING STUDY OF THE CONFORMATIONS OF TAXOL AND OF ITS SIDE-CHAIN METHYLESTER IN AQUEOUS AND NONAQUEOUS SOLUTION

The conformations of the antimitotic agent taxol and its side chain methyl ester have been studied by NMR-spectroscopy and molecular modeling in hydrophobic (CDCl3) and hydrophilic (water, d6-DMSO) solvents. For the side chain methly ester (4), the coupling constant J(H2'-H3') changes from approximately 2 Hz in chloroform to approximately 5 Hz in d6-DMSO or water : d6-DMSO, 1 : 1 (v/v). The conformational equilibrium for 4 thus shifts from one favoring conformers with a gauche <H-C2'-C3'-H> torsion angle (chloroform), to one predominantly of conformers having this torsion angle anti. In the case of taxol, J(H2'-H3') changes from 2.7 Hz in CDCl3 to approximately 8 Hz in water, water - sodium dodecyl sulfate (SDS) and/or d6-DMSO. Again, gauche conformations are implicated in chloroform but molecular modeling suggests the anti conformer 27 to be dominant in aqueous media and in d6-DMSO. No nuclear Overhauser effects (nOe's) between the side chain and the taxane ring-system are observed in chloroform solution. In water and/or d6-DMSO, however, nOe's between the side chain (Ph3' and H2') and the OAc4 methyl group are detected.