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Chemistry (Weinheim an der Bergstrasse, Germany)
Oct 23, 2024;30 (59): e202402637.

Unraveling the Source of Self-Induced Diastereomeric Anisochronism in Chiral Dipeptides.

Fabio Spiaggia, Federica Aiello, Luca Sementa, Jean-Marc Campagne, Renata Marcia de Figueiredo, Gloria Uccello Barretta, Federica Balzano
Author Information
  1. Fabio Spiaggia: Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124, Pisa, Italy. ORCID
  2. Federica Aiello: Institute for Chemical and Physical Processes (IPCF), National Research Council (CNR), Via G. Moruzzi 1, 56124, Pisa, Italy. ORCID
  3. Luca Sementa: Institute for Chemical and Physical Processes (IPCF), National Research Council (CNR), Via G. Moruzzi 1, 56124, Pisa, Italy. ORCID
  4. Jean-Marc Campagne: ICGM, Univ Montpellier, CNRS, ENSCM, 34296, Montpellier, France. ORCID
  5. Renata Marcia de Figueiredo: ICGM, Univ Montpellier, CNRS, ENSCM, 34296, Montpellier, France.
  6. Gloria Uccello Barretta: Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124, Pisa, Italy. ORCID
  7. Federica Balzano: Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124, Pisa, Italy. ORCID
PMID: 39128878 DOI: 10.1002/chem.202402637

Abstract

Mastering of analytical methods for accurate quantitative determinations of enantiomeric excess is a crucial aspect in asymmetric catalysis, chiral synthesis, and pharmaceutical applications. In this context, the phenomenon of Self-Induced Diastereomeric Anisochronism (SIDA) can be exploited in NMR spectroscopy for accurate determinations of enantiomeric composition, without using a chiral auxiliary that could interfere with the spectroscopic investigation. This phenomenon can be particularly useful for improving the quantitative analysis of mixtures with low enantiomeric excesses, where direct integration of signals can be tricky. Here, we describe a novel analysis protocol to correctly determine the enantiomeric composition of scalemic mixtures and investigate the thermodynamic and stereochemical features at the basis of SIDA. Dipeptide derivatives were chosen as substrates for this study, given their central role in drug design. By integrating the experiments with a conformational stochastic search that includes entropic contributions, we provide valuable information on the dimerization thermodynamics, the nature of non-covalent interactions leading to self-association, and the differences in the chemical environment responsible for the anisochronism, highlighting the importance of different stereochemical arrangement and tight association for the distinction between homochiral and heterochiral adducts. An important role played by the counterion was pointed out by computational studies.

Keywords

Computational chemistry Dimerization Molecular recognition NMR spectroscopy Self-assembly

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Grants

  1. PRA_2022-2023/Università di Pisa
  2. ANR-18-CE07-0038-01/Agence Nationale de la Recherche
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