Amino acid derived chiral thioureas: design, synthesis and applications as NMR resolving agents for enantioselective recognition

Abstract

A new class of chiral thiourea derivatives derived from amino acids have been developed that harness the dual influence of strong hydrogen bonding and stereogenic amino acid scaffolds. Both unsymmetrical (UTU) and symmetrical (STU) amino acid-based thioureas were synthesized and evaluated as molecular receptors for chiral analytes using NMR spectroscopy. These receptors exhibit efficient binding with both acidic and neutral substrates through supramolecular interactions, enabling enantiodiscrimination readily detected by ¹H and ³¹P NMR analysis. Structure–function relationships were investigated by varying the amino acid substituents and functional groups, with mandelic acid serving as a model substrate. The match–mismatch binding effect was further supported by 1D NOESY experiments and computational studies. Notably, an unexpected isomerization was observed during the synthesis of STUs from amino acid methyl esters; the mechanistic rationale was elucidated through single-crystal X-ray crystallography. The scope of enantiodiscrimination was further extended to a broad range of analytes, including chiral carboxylic acids, phosphoric acid derivatives, dihydropyrimidinones, sulfoxides, N-Boc amino alcohols and proton pump inhibitors such as Omeprazole and Rabeprazole. These findings establish amino acid based chiral thioureas as versatile receptors for molecular recognition and enantiodiscrimination of diverse substrates.