Preparation of Phosphonic Acid Analogues of Proline and Proline Analogues and Their Biological Evaluation as δ-Pyrroline-5-carboxylate Reductase Inhibitors.

Racemic 1-hydroxy-3-butenyl-, 3-chloro-1-hydroxypropyl-, and 3-bromo-1-hydroxypropylphosphonate and the corresponding ()-enantiomers obtained by lipase-catalyzed resolution of the respective racemic chloroacetates were subjected to functional group manipulations. These comprised ozonolysis, Mitsunobu reactions with hydrazoic acid and -hydroxyphthalimide, alkylation of hydrazine derivative, removal of phthaloyl group followed by intramolecular substitution, and global deprotection to deliver the racemates and ()-enantiomers (ee 92-99% by chiral high-performance liquid chromatography) of pyrrolidin-2-yl-, oxazolidin-3-yl-, oxazolidin-5-yl-, pyrazolidin-3-yl-, and 1,2-oxazinan-3-ylphosphonic acids. These phosphonic acids were evaluated as analogues of proline and proline analogues for the ability to inhibit γ-glutamyl kinase, δ-pyrroline-5-carboxylate synthetase, and δ-pyrroline-5-carboxylate reductase. Only the latter enzyme was inhibited by two of them at concentrations exceeding 1 mM.