Second-Generation Synthesis and Analytical Application of TBBA for Chiral Analysis of Amino Acids and Oligopeptides by 1 H and 19 F NMR Spectroscopy

A concise and efficient second-generation synthesis of 2-(2-(trifluoromethyl)-1H-benzodimidazol-1-yl)benzoic acid (TBBA) has been developed. The synthesis affording enantiomerically pure TBBA atropisomers was significantly streamlined through optical resolution by diastereomeric salt formation, enabling preparation on a 32 mmol scale. The applicability of TBBA as a chiral derivatizing agent in the solid-phase synthesis of amino acid derivatives was demonstrated, allowing determination of the absolute configuration and optical purity by 1H and 19F NMR spectroscopy. Furthermore, 19F NMR analyses were successfully carried out on a low-field benchtop NMR spectrometer, including samples dissolved in nondeuterated solvents.