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

Abstract

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 trans-1,2-diaminocyclohexane (trans-DACH)-derived benzamides were first synthesized by simple chemical steps, and 14 variated derivatives 6a–6n 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 6e 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 R_s. Single-crystal X-ray analysis of three derivatives 6c, 6e, and 6h helped to understand enantiomeric recognition for the promising NMR analysis. Interestingly, the NMR signals of nonequivalent protons between the R and S configurations were completely opposite in the presence of CSA 6e and its stereoisomer, which can be utilized to establish a straightforward method for the configuration assignment of diverse hydroxy acid substrates.