500-MHz proton NMR studies of the medium-dependent conformational preference of prostaglandin F2 alpha analogues.

The complete assignments of the 1H NMR spectra of 2-10 mM D2O solutions of prostaglandin F2 alpha (PGF2 alpha), its C-15 epimer, and analogues bearing a gem-dimethyl group at C-16 or C-17 are presented. PGF2 alpha and its 1,9- and 1,15-lactones were similarly studied in CDCl3 solution. The assignments follow from extensive scalar decoupling and difference NOE spectra and the examination of a specifically deuterated analogue. These studies also define the conformation (including cyclopentane pseudorotational preference) from C-5 through C-16 in each system. The macrolides show little or no conformational freedom at C-4----C-1, but extensive rotational averaging occurs in the terminal portions of both side chains in the monocyclic compounds. The conformational features so determined are contrasted to those seen in crystal structures and those postulated to occur upon binding to PGF2 alpha-recognizing receptors. The NMR data run counter to the DeTitta hypothesis that changes in the orientation of the C-13,14 pi-bond nodal plane relative to the cyclopentane ring and the C-15-O bond are recognition determinants at PGF2 alpha-specific receptors and account for the medium-dependent chiroptical spectral changes previously reported.