Structure of cyclic nucleoside phosphonate ester prodrugs: an inquiry.

The configuration at phosphorus in cyclic (S)-HPMPC (1, cidofovir) and (S)-HPMPA (2) phenyl ester (5 and 6, respectively) diastereomers ((R(p))-5, (R(p))-6, (S(p))-6) was determined by X-ray crystallography and correlated to their (1)H and (31)P NMR spectra in solution. (R(p))-5 and (R(p))-6 have chair conformations with the nucleobase substituent equatorial and the P-OPh axial. Perhaps surprisingly, (S(p))-6 is (a, a) in the crystal and exists largely as an equilibrium of (a, a)/(e, e) conformers in chloroform or acetonitrile.