Diastereoisomeric Derivatization and Liquid Chromatographic Analysis of N-(Phenylsulfonyl)-2-phenylglycine Aldose Reductase Inhibitors

Abstract

A series of (S)- and (R)-N-(phenylsulfonyl)-2-phenylglycines are synthesized as potential inhibitors of the enzyme aldose reductase. In vitro analysis of these compounds reveals that the S-enantiomers are more potent than the corresponding R-enantiomers and that the difference in potencies between enantiomeric pairs is dependent on the nature of the ring substituent. To ensure that the enantioselectivity observed does not reflect varying degrees of racemization during the synthesis of the N-(phenylsulfonyl)-2-phenylglycines, the enantiomeric purity of these products is determined by HPLC after chiral derivatization. Each 2-phenylglycine inhibitor is derivatized with R-alpha-methylbenzylamine, and the resulting diastereomers are analyzed using reversed and normal achiral stationary phases. Reversed-phase methods with C18 or phenyl stationary phases and solvent mixtures of acetonitrile or methanol in water do not provide satisfactory resolution of the diastereomers. However, normal-phase analyses with a silica stationary phase and mixtures of methanol, ethanol, or acetonitrile in chloroform provide good separations with relatively short analysis times. The normal-phase analyses demonstrate that a single diastereomeric amide forms from each N-(phenylsulfonyl)-2-phenylglycine product, establishing that these compounds do not racemize during synthesis.