Thiourea Derivative of 2-[(1 R)-1-Aminoethyl]phenol: A Flexible Pocket-like Chiral Solvating Agent (CSA) for the Enantiodifferentiation of Amino Acid Derivatives by NMR Spectroscopy

Abstract

Thiourea derivatives of 2-[(1R)-1-aminoethyl]phenol, (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol, (1R,2R)-(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol, and (R)-1-phenylethanamine have been compared as chiral solvating agents (CSAs) for the enantiodiscrimination of derivatized amino acids using nuclear magnetic resonance (NMR) spectroscopy. Thiourea derivative, prepared by reacting 2-[(1R)-1-aminoethyl]phenol with benzoyl isothiocyanate, constitutes an effective CSA for the enantiodiscrimination of N-3,5-dinitrobenzoyl (DNB) derivatives of amino acids with free or derivatized carboxyl functions. A base additive 1,4-diazabicyclo[2.2.2]octane(DABCO)/N,N-dimethylpyridin-4-amine (DMAP)/NBu₄OH) is required both to solubilize amino acid derivatives with free carboxyl groups in CDCl₃ and to mediate their interaction with the chiral auxiliary to attain efficient differentiation of the NMR signals of enantiomeric substrates. For ternary systems CSA/substrate/DABCO, the chiral discrimination mechanism has been ascertained through the NMR determination of complexation stoichiometry, association constants, and stereochemical features of the diastereomeric solvates.

Figure 1

CSA structures.

Figure 2

Chemical structures of derivatives 5–17 (DNB = 3,5-dinitrobenzoyl, TFA = trifluoroacetyl, DMB = 3,5-dimethoxybenzoyl).

Figure 3

¹H NMR (600 MHz, CDCl₃, 25 °C) spectral regions corresponding to the aliphatic methine protons of (R,S)-5 in 1-TU/DABCO/5 (1:1:1) mixtures: [5] = 60 mM (a), 30 mM (b), and 15 mM (c), in the 1-TU/DABCO/5 (2:1:1) mixture ([5] = 15 mM) (d), and in the DABCO/5 (1:1) mixture ([5] = 30 mM) (e).

Figure 4

¹³C{¹H} NMR (150 MHz, CDCl₃, 25 °C) spectral regions corresponding to carboxy (C-d) and amide (C-b) carbonyl carbons, C-NO₂ (C-c), and aliphatic methine (CH) of 5, 6, 12, and 16 (30 mM) in the presence of 1 equiv of 1-TU and 1 equiv of DABCO for 5 and 6. *Resonance of CSA.

Figure 5

Stoichiometry determination based on ortho (▲) and para (●) protons of the DNB group for the (S)-5/1-TU/DABCO complex.

Figure 6

Representation of the three-dimensional (3D) structure of 1-TU according to ROE data.

Figure 7

Representation of the interaction model between 1-TU and (S)-5 (left) or (R)-5 (right) in the presence of DABCO (green sphere) according to NMR data with a black skeleton for 5.