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

The conformations of the antimitotic agent taxol and its side chain me thyl ester have been studied by NMR-spectroscopy and molecular modelin g in hydrophobic (CDCl3) and hydrophilic (water, d6-DMSO) solvents. Fo r the side chain methly ester (4), the coupling constant J(H2'-H3') ch anges from approximately 2 Hz in chloroform to approximately 5 Hz in d 6-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'-C 3'-H> torsion angle (chloroform), to one predominantly of conformers h aving this torsion angle anti. In the case of taxol, J(H2'-H3') change s 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 conf ormer 27 to be dominant in aqueous media and in d6-DMSO. No nuclear Ov erhauser effects (nOe's) between the side chain and the taxane ring-sy stem are observed in chloroform solution. In water and/or d6-DMSO, how ever, nOe's between the side chain (Ph3' and H2') and the OAc4 methyl group are detected.