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. 2024 Mar 15;29(6):1319.
doi: 10.3390/molecules29061319.

A Thiourea Derivative of 2-[(1 R)-1-Aminoethyl]phenol as a Chiral Sensor for the Determination of the Absolute Configuration of N-3,5-Dinitrobenzoyl Derivatives of Amino Acids

Federica Aiello  1 , Alessandra Recchimurzo  2 , Federica Balzano  2 , Gloria Uccello Barretta  2 , Federica Cefalì  2
Affiliations

A Thiourea Derivative of 2-[(1 R)-1-Aminoethyl]phenol as a Chiral Sensor for the Determination of the Absolute Configuration of N-3,5-Dinitrobenzoyl Derivatives of Amino Acids

Federica Aiello et al. Molecules. .

Abstract

In the exploration of chiral solvating agents (CSAs) for nuclear magnetic resonance (NMR) spectroscopy designed for the chiral analysis of amino acid derivatives, notable advancements have been made with thiourea-CSAs. 1-TU, derived from 2-[(1R)-1-aminoethyl]phenol and benzoyl isothiocyanate, is effective in the enantiodifferentiation of N-3,5-dinitrobenzoyl (N-DNB) amino acids. In order to broaden the application of 1-TU for configurational assignment, enantiomerically enriched N-DNB amino acids were analyzed via NMR. A robust correlation was established between the relative position of specific 1H and 13C NMR resonances of the enantiomers in the presence of 1-TU. 1,4-Diazabicyclo[2.2.2]octane (DABCO) was selected for the complete solubilization of amino acid substrates. Notably, the para and ortho protons of the N-DNB moiety displayed higher frequency shifts for the (R)-enantiomers as opposed to the (S)-enantiomers. This trend was consistently observed in the 13C NMR spectra for quaternary carbons bonded to NO2 groups. Conversely, an inverse correlation was noted for quaternary carbon resonances of the carboxyl moiety, amide carbonyl, and methine carbon at the chiral center. This observed trend aligns with the interaction mechanism previously reported for the same chiral auxiliary. The configurational correlation can be effectively exploited under conditions of high dilution or, significantly, under sub-stoichiometric conditions.

Keywords: NMR; chiral solvating agents; chirality; enantiodiscrimination; sense of nonequivalence.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Structures of 1-TU, DABCO, and N-DNB amino acids 1–9.
Scheme 1
Scheme 1
Synthesis of 1-TU and amino acid derivatives 1–9.
Figure 2
Figure 2
1H NMR (600 MHz, CDCl3, 25 °C) spectral regions corresponding to N-DNB protons of (S)-enantiomerically enriched mixtures of substrates 1–7 (15 mM) in the presence of 2 equiv of 1-TU and 1 equiv of DABCO and of (R)-enantiomerically enriched mixtures of substrates 8 and 9 (7.5 mM) in the presence of 4 equiv of 1-TU and 2 equiv of DABCO.
Figure 3
Figure 3
1H NMR (600 MHz, CDCl3, 25 °C) chemical shifts (ppm) of (S)-ortho (●), (R)-ortho (●), (S)-para (×), and (R)-para (×) protons in progressively diluted (S)-enantiomerically enriched mixtures of 6 in the presence of 2 equiv of 1-TU and 1 equiv of DABCO.
Figure 4
Figure 4
Left: 1H NMR (600 MHz, CDCl3, 25 °C) spectral regions corresponding to ortho-protons of (S)-enantiomerically enriched mixtures of 4 (2.5 mM) and 6 (1 mM) in the presence of 2 equiv of 1-TU and 1 equiv of DABCO, and of (R)-enantiomerically enriched mixture of 9 (1 mM) in the presence of 4 equiv of 1-TU and 2 equiv of DABCO. Right: 1H NMR (600 MHz, CDCl3, 25 °C) spectral regions corresponding to ortho-protons of (S)-enantiomerically enriched mixtures of 4 and 6 (15 mM) in the presence of 1-TU (3 and 1 mM, respectively) and DABCO (15 mM) and of (R)-enantiomerically enriched mixture of 9 (7.5 mM) in the presence of 1-TU (1.5 mM) and DABCO (15 mM).
Figure 5
Figure 5
13C{1H} NMR (150 MHz, CDCl3, 25 °C) spectral regions corresponding to carboxylic (green), amidic (blue), C-NO2 (purple) and methine (red) carbons of (S)-enantiomerically enriched mixtures of substrates 1–7 (15 mM) in the presence of 2 equiv of 1-TU and 1 equiv of DABCO and of (R)-enantiomerically enriched mixture of 8 (7.5 mM) in the presence of 4 equiv of 1-TU and 2 equiv of DABCO. * indicates 1-TU resonance.
Figure 6
Figure 6
Schematic representation of the interaction between 1-TU and (R)-/(S)-amino acid derivative.
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