DACH-Based Chiral Sensing Platforms as Tunable Benzamide-ChiralSolvating Agents for NMR Enantioselective Discrimination

Chiral discrimination is an indispensable tool that has pivotal importance in the assignment of absolute configuration and determination of enantiomeric excess in chiral compounds. A series of enantiomerically pure <i>trans</i>-1,2-diaminocyclohexane (<i>trans</i>-DACH)-derived benzamides were first synthesized by simple chemical steps, and 14 variated derivatives <b>6a–6n</b> have been assessed as NMR chiral solvating agents (CSAs) for discrimination of the signals of mandelic acid (MA) in ¹H NMR analysis. The highly efficient chiral recognition of CSA <b>6e</b> on different substrates, including MAs, carboxylic acids, amino acid derivatives, and phosphoric acids (32 examples), was expanded via ¹H, ¹⁹F, and ³¹P NMR spectroscopy. The quality of enantiodiscrimination was evaluated by means of the enantioresolution parameter <i>R</i>_s. Single-crystal X-ray analysis of three derivatives <b>6c</b>, <b>6e</b>, and <b>6h</b> helped to understand enantiomeric recognition for the promising NMR analysis. Interestingly, the NMR signals of nonequivalent protons between the <i>R</i> and <i>S</i> configurations were completely opposite in the presence of CSA <b>6e</b> and its stereoisomer, which can be utilized to establish a straightforward method for the configuration assignment of diverse hydroxy acid substrates.