A Supramolecular Extension of Mosher’s Method: Absolute Configuration Assignment of <i>N</i>-Amino Acid Derivatives via Bis-Thiourea Chiral Solvating Agent

A Supramolecular Extension of Mosher’s Method: Absolute Configuration Assignment of <i>N</i>-Amino Acid Derivatives via Bis-Thiourea Chiral Solvating Agent

The bis-thiourea chiral solvating agent (CSA) <b>BTDA</b> enables the NMR-based determination of absolute configuration in <i>N</i>-3,5-dinitrobenzoyl (DNB) amino acid derivatives without requiring covalent derivatization. A reliable trend of the sense of nonequivalence and a...

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Bibliographic Details
Main Authors: Virginia Rondinini, Federica Aiello, Federica Cefalì, Alessandra Recchimurzo, Gloria Uccello Barretta, Federica Balzano
Format: Article
Language:English
Published: MDPI AG 2025-07-01
Series:Molecules
Subjects:
CSA
NMR
absolute configuration
chiral analysis
ROESY
association constant
Online Access:https://www.mdpi.com/1420-3049/30/14/2930
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Summary:The bis-thiourea chiral solvating agent (CSA) <b>BTDA</b> enables the NMR-based determination of absolute configuration in <i>N</i>-3,5-dinitrobenzoyl (DNB) amino acid derivatives without requiring covalent derivatization. A reliable trend of the sense of nonequivalence and absolute configuration is found in both <sup>1</sup>H and <sup>13</sup>C NMR spectra. A dual-enantiomer approach, using (<i>R</i>,<i>R</i>)- and (<i>S</i>,<i>S</i>)-<b>BTDA</b>, generates diastereomeric complexes with the enantiopure substrate, and distinct spatial arrangements are reflected in consistent and interpretable Δδ values. The observed chemical shift differences correlate reliably with the stereochemistry of the chiral center and are further supported by ROESY (Rotating-frame Overhauser Enhancement SpectroscopY) experiments and binding constants’ measurements, confirming the formation of stereoselective non-covalent complexes. This methodology extends the logic of Mosher’s analysis to solvating agents and remains effective even in samples containing single pure enantiomers of the amino acid derivative. The <b>BTDA</b>-based dual-CSA system thus represents a robust, non-derivatizing strategy for stereochemical assignment by NMR, combining operational simplicity with broad applicability to DNB derivatives of amino acids with free carboxyl function.
ISSN:1420-3049

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