Enantiodifferentiation of Thiohydantoin Derivatives by NMR in the Presence of Chiral Solvating Agent: (1R,2S)-Ephedrine and Chiral Symmetrical and Unsymmetrical Thioureas

Abstract

2-Thiohydantoin derivatives, including different substitutions at N-1 and C-5 (5-methyl-, 5-isopropyl-, 1-acetyl-5-methyl-, and 1-acetyl-5-isopropyl-) (1–4, respectively), were synthesized by the known literature methods. In these synthetic pathways, it was reported that enantiomerically pure 2-thiohydantions were obtained in the absence of any solvent via the reaction of L-amino acids with thiourea (1&2) and via the reaction of L-amino acids with NH₄SCN and acetic anhydride (3&4). However, in this study, in contrary to the previous literature studies, racemic mixtures of 2-thiohydantoins were obtained although the same synthetic methods were used. The racemic nature of 2-thiohydantoin derivatives (1–4) was proved by using ¹H NMR analysis in the presence of (1R,2S)-(−)-ephedrine as a chiral auxiliary. In addition, the enantiomers of 3&4 were also resolved on chiral stationary phases by HPLC analyses. Furthermore, newly synthesized unsymmetrical chiral thioureas (S-1&S-2) and previously synthesized symmetrical ones (SS-3&SS-4) were used as chiral solvating agent (CSA) for the enantiodiscrimination of the thiohydantoins (5&6), previously reported. Optimal CSA/substrate ratios were determined for the best enantiodiscrimination.