Bis-Thiourea Chiral Sensor for the NMR Enantiodiscrimination of N -Acetyl and N -Trifluoroacetyl Amino Acid Derivatives.

A C2-symmetrical bis-thiourea chiral solvating agent (CSA), TFTDA , for NMR spectroscopy has been obtained by reacting (1 R ,2 R )-1,2-bis(2-hydroxyphenyl)ethylenediamine and 3,5-bis(trifluoromethyl)phenyl isothiocyanate. TFTDA shows remarkable propensity to enantiodiscriminate N -trifluoroacetyl ( N -TFA) and N -acetyl ( N -Ac) derivatives of amino acids with free carboxyl functions, with the co-presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as the third achiral additive, which is needed for substrate solubilization. TFTDA shows enhanced enantiodiscriminating efficiency in comparison with the corresponding monomeric counterpart, TFTMA , pointing out cooperativity between its two symmetrical entities. A wide range of amino acid derivatives have been efficiently enantiodiscriminated in CDCl 3 , with high enantioresolution quotients, which guarantee high quality in applications devoted to the quantification of enantiomers. High enantiodiscriminating efficiency is maintained also in diluted 5 mM conditions or in the presence of sub-stoichiometric amounts of CSA (0.3 equiv). The role of phenolic hydroxyls in the DABCO-mediated interaction mechanism between TFTDA and the two enantiomeric substrates has been pointed out by means of diffusion-ordered spectroscopy (DOSY) and rotating frame Overhauser effect spectroscopy (ROESY) experiments. A conformational model for both the CSA and its diastereomeric solvates formed with the two enantiomers of N -acetyl leucine has also been conceived on the basis of ROE data in order to give a chiral discrimination rationale.