NMR and molecular modeling study of the conformations of taxol and of its side chain methylester in aqueous and non-aqueous solution.

Abstract

The conformations of the antimitotic agent taxol and its side chain methyl ester have been studied by NMR-spectroscopy and molecular modeling in hydrophobic (CDCl 3) and hydrophilic (water, d 6-DMSO) solvents. For the side chain methyl ester ( 4), the coupling constant J H2′-H3′ changes from ≈2 Hz in chloroform to ≈5 Hz in d 6-DMSO or water : d 6-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 CDCl 3 to ≈8 Hz in water, water - sodium dodecyl sulfate (SDS) and/or d 6-DMSO. Again, gauche conformations are implicated in chloroform, but molecular modeling suggests the anti conformer 27 to be dominant in aqueous media and in d 6-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 d 6-DMSO, however, nOe's between the side chain (Ph3′ and H2′) and the OAc4 methyl group are detected.