ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 5, pp. 1079–1084. © Pleiades Publishing, Ltd., 2017. 1079 Cyclopropyl-Containing Sulfonyl Amino Acids: Exploring the Enantioseparation Through Chiral Ligand-Exchange Chromatography 1 R. Sardella a , F. Ianni a , L. Pucciarini a , M. Marinozzi a , S. S. Zlotskii b , and B. Natalini a * a University of Perugia, Department of Pharmaceutical Sciences, Via del Liceo 1, Perugia, 06123 Italy b Ufa State Petroleum Technological University, ul. Kosmonavtov 1, Ufa, Bashkortostan, 450062 Russia *e-mail: benedetto.natalini@unipg.it Received March 16, 2017 Abstract—In the scope of a broader study focused on glutamate receptors regulators, we have been engaged in synthesis, analysis and pharmacological characterization of rigid analogues of glutamic acid. These compounds exhibited the bioisosteric replacement of the distal carboxylic group with the sulfonic one. Besides the sophisticated synthetic approach, we targeted preparation of a series of cyclopropyl-containing sulfonyl amino acids and development of a chromatographic enantioselective method suitable for distinguishing and quantifying the resulting isomers. Due to chelating ability, the chiral ligand-exchange chromatography (CLEC) was used for diastereo- and enantioseparation of the synthesized compounds. The CLEC-based enantio- separation was achieved by using a chiral mobile phase (CMP) system with N,N-dimethyl-(S)-phenylalanine [(S)-DMP] as the chiral selector. Only one of the investigated enantiomeric pairs was undiscriminated with the employed CLEC–CMP system which, very importantly, produced the simultaneous diastereo- and enantioseparation of two compounds of the series. Furthermore, the large α and R S values computed for three enantiomer pairs could be a good basis for a successful scale-up to a semi-preparative level. Keywords: cyclopropyl, sulfonyl amino acids, chiral ligand-exchange chromatography 1 The text was submitted by the authors in English. INTRODUCTION It is widely accepted that chemical behavior of cyclopropane ring is quite similar to that of olefinic double bond. From a stereochemical point of view, while the double bond generates two diastereomers, cyclopropane containing two chiral carbon atoms can exhibit four diastereomers. Consequently, in case of functional groups directly linked or closely related to the three-membered ring involved in receptor recogni- tion, a more detailed configurational exploration of the interacting receptor surface becomes possible. Such stereochemical ability is one of the major features that induced a vast array of papers demon- strating potential of compounds with the cyclopropyl fragment in medicinal chemistry. Recently there were published a review [1] on pre- clinical/clinical drug molecules containing the cyclo- propane fragment and some papers on achievements in modulatory activity [2–6]. The results of our long lasting study of cyclopropyl-containing compounds, their synthesis and analysis, and pharmacological characterization of rigid analogs of glutamic acid are presented in the publications [7–15]. Cyclopropyl-containing sulfonyl amino acids have received limited attention [16], to the best of our knowledge. Such compounds exhibit two main charac- teristic features, the rigid carbon skeleton and the bioisosteric replacement of the distal carboxylic group with the sulfonic one [17]. The challenging task was chromatographic enantioresolution of the resulting racemates of a series of cyclopropyl-containing sul- fonyl amino acids in the course of developing analytical protocols for preparative scale-up or for assessment of the optical purity in case of enantio- selective synthesis. Compounds 1–7 contain different linkage of either sulfonic acid or amino acid moiety with the cyclo- propane ring (see the table). Due to their chelating ability, the chiral ligand-exchange chromatography DOI: 10.1134/S1070363217050309