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1H NMR spectroscopy in the presence of Mosher acid to rapidly determine the enantiomeric composition of amino acid benzyl esters, chirons susceptible to easy racemization

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Abstract

Amino acid benzyl esters are very useful chiral synthons, whose enantiomeric purity needs to be carefully verified because of their susceptibility to easy racemization. Alternative to chiral HPLC, 1H NMR in the presence of a chiral solvating agent (CSA) can allow a more rapid and acceptably accurate determination of the enantiomeric composition, if explicit spectral non-equivalence of one or more protons of the analyte enantiomers is found. Here, we have studied the enantiodiscrimination of 13 amino acid benzyl esters by 1H NMR in the presence of (R)-Mosher acid and in different solvents proving that, for 5 of them (Ala, Pro, Glu, Met, Ser), efficient enantiodifferentiation can be achieved and ≤ 98% enatiomeric excesses accurately determined. Generally, as expectable, the best enantiodifferentiated proton was that on the amino acid stereogenic α-carbon, but also the spectral non-equivalence of methyl protons and of protons on the β-carbon and on the benzylic carbon could be exploited to distinguish the two enantiomers and to quantify the minor one. Structural feature favoring the amino acid ester enantiodiscrimination by the CSA seems to be low sterical hindrance at the amino acid β-carbon.

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Acknowledgements

The authors thank Mrs Donatella Nava for her excellent technical assistance in measuring NMR spectra on a Bruker Avance spectrometer at 600 MHz.

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Authors and Affiliations

  1. Dipartimento di Scienze Farmaceutiche, Sezione “Pietro Pratesi”, Università degli Studi di Milano, via Mangiagalli 25, 20133, Milan, Italy

    Cristiano Bolchi, Gabriella Roda & Marco Pallavicini

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  1. Cristiano Bolchi
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  2. Gabriella Roda
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  3. Marco Pallavicini
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Correspondence to Cristiano Bolchi.

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Bolchi, C., Roda, G. & Pallavicini, M. 1H NMR spectroscopy in the presence of Mosher acid to rapidly determine the enantiomeric composition of amino acid benzyl esters, chirons susceptible to easy racemization. Amino Acids 50, 1759–1767 (2018). https://doi.org/10.1007/s00726-018-2653-0

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