Tetrasubstituted Chiral Calix[4]arene Platform for Tunable Chiroptical Detection of d / l -Amino Acids

Abstract

Detection of amino acid chirality is important for biomedical applications, yet the direct recognition of underivatized d/l-amino acids remains challenging because of their subtle stereochemical differences. Herein, we report a pair of upper-rim tetrasubstituted chiral Schiff-base calix[4]arenes, R-C4A and S-C4A, in which four configurationally identical phenylglycinol-derived side arms form an intrinsically chiral chromophore array around the calixarene rim. The hosts translate amino-acid-dependent host-guest interactions into tunable circular dichroism (CD) signals, enabling the direct differentiation of underivatized d/l-amino acids. Among the amino acids examined, Proline, Phenylalanine, and Tryptophan produce the most pronounced chiroptical responses. Aromatic amino acids and Proline induce CD changes in opposite directions, indicating that side-chain aromaticity, backbone rigidity, and binding geometry govern the reorganization and coupling of the upper-rim chromophores. A linear correlation between the CD response and the enantiomeric excess of Proline further enables quantitative analysis of its enantiomeric composition. Spectroscopic investigations, together with solvent- and metal-ion-dependent modulation, confirm that the chiroptical responses originate from interaction-driven conformational reorganization of the Schiff-base side arms. This work establishes an adaptive chiral chromophore-array strategy for direct and solvent-tunable chiroptical detection of d/l-amino acids.