Abstract
The reaction of benzoyl isothiocyanate with (1R,2R)-1,2-bis(2-hydroxyphenyl)ethylenediamine afforded a new thiourea chiral solvating agent (CSA) with a very high ability to differentiate 1H and 13C NMR signals of simple amino acid derivatives, even at low concentrations. The enantiodiscrimination efficiency was higher with respect to that of the parent monomer, a thiourea derivative of 2-((1R)-1-aminoethyl)phenol, thus putting into light the relevance of the cooperativity between the two molecular portions of the dimer in a cleft conformation stabilized by interchain hydrogen bond interactions. An achiral base additive (DABCO or DMAP) played an active role in the chiral discrimination processes, mediating the interaction between the CSA and the enantiomeric mixtures. The chiral discrimination mechanism was investigated by NMR spectroscopy through the determination of complexation stoichiometries, association constants, and the stereochemistry of the diastereomeric solvates.
Highlights
Oftentimes, dramatic differences in the pharmacodynamics and pharmacokinetics of pure enantiomeric forms of therapeutic agents have increasingly brought to light the outstanding role of chirality and a generated great awareness of the need for rigorous and reproducible methods to properly identify and quantify stereoisomeric forms of chiral substrates, with a strong preference toward noninvasive methods involving minimum manipulative procedures, such as spectroscopic methods
Dimeric thiourea chiral solvating agent (CSA) BTDA is wellchannelled in this trend, constituting a new tweezer-like artificial receptor endowed with a very high enantiodiscriminating ability toward N-3,5-dinitrobenzoyl derivatives of amino acids
The CSA is able to anchor the enantiomeric substrates through a complex network of hydrogen-bond donor and hydrogen-bond acceptor interactions and to cap them using a pool of aromatic moieties, which exert relevant anisotropic effects and cause sensitive changes of the chemical shifts
Summary
Oftentimes, dramatic differences in the pharmacodynamics and pharmacokinetics of pure enantiomeric forms of therapeutic agents have increasingly brought to light the outstanding role of chirality and a generated great awareness of the need for rigorous and reproducible methods to properly identify and quantify stereoisomeric forms of chiral substrates, with a strong preference toward noninvasive methods involving minimum manipulative procedures, such as spectroscopic methods. Three main classes of chiral auxiliaries for NMR spectroscopy have been developed to this purpose, among which chiral solvating agents (CSAs)[1−4] stand out for their practicality of use, being mixed to the enantiomeric mixtures into the NMR tube without need for chemical derivatization and subsequent purification procedures. Design efforts are sometimes pursued to develop highly preorganized macrocyclic structures in favor of a pronounced enantiodiscriminating efficiency toward selected classes of chiral substrates, and more flexible structures could be preferred in view of enhancing the enantiodiscriminating versatility
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