In search for new enantioselectivity profiles, the N-decyl-S-trityl-(R)-cysteine [C10-(R)-STC] was synthesized through a one-step procedure and then hydrophobically adsorbed onto an octadecylsilica surface to generate a stable chiral stationary phase for ligand-exchange chromatography (CLEC-CSP) applications. The CLEC analysis was carried out on underivatized amino acids, by using a Cu(II) sulphate (1.0 mM) containing aqueous eluent system. Most of the analysed compounds (34 out of 45) were enantiodiscriminated by the C10-(R)-STC-based CSP, with resolution factor (RS) values up to 8.86. Conformationally rigid and hydrophobic ligands often experienced the largest enantioselectivity effects. A high loadability emerged from the analysis of rac-NorVal (selected as prototype test compound): up to 20 mg/mL were efficiently enantioseparated with the CLEC-CSP. Two in-line hand-made cartridges filled with a strong cation-exchange resin allowed the effective catching of Cu(II) ions after the semi-preparative enantioseparation. The quantitative recovery of the rac-NorVal enantiomers was made possible by flowing through the cartridge a 5% (v) ammonia solution. The CLEC phase proved successful in the enantioselective analysis of a commercially available (S)-Leu containing tablet. Furthermore, in order to understand the molecular basis for a successful use of the C10-(R)-STC-based CLEC system, a descriptive structure-separation relationship study was performed. As a result, all compounds with a MEAN-QPlogS (a hydrophilicity descriptor) value lower than 0.373 can be most likely enantioseparated with the CLEC system under investigation. In the work, the numerous aspects complying with the principles of green chromatography are highlighted and discussed.