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Macrocycle Conformational Flexibility as a Key to Enantioselective Recognition
Tadeu Luiz Gomes Cabral1,2, Matthias Stein1, Claudio F Tormena2
1Molecular Simulations and Design Group, Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstrasse 1, Magdeburg 39106, Germany.
JACS Au
|July 30, 2026
Summary
This study reveals a chiral macrocycle
Area of Science:
- Organic Chemistry
- Supramolecular Chemistry
- Analytical Chemistry
Background:
- Enantiomer differentiation and absolute configuration assignment are crucial yet challenging in chemistry.
- Diffusion-ordered spectroscopy (DOSY) NMR with chiral resolving agents offers a promising avenue for enantiodiscrimination.
- Limitations persist in reliably assigning configurations and understanding the molecular basis of chiral recognition.
Purpose of the Study:
- To investigate the enantioselective differentiation of various chiral molecules using a novel chiral macrocycle (MAC).
- To elucidate the molecular mechanisms underlying the observed enantioselectivity through combined experimental and computational methods.
- To explore the role of macrocycle conformation in chiral recognition events.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy, including diffusion-NMR (DOSY) and ROESY experiments.
- Computational modeling, including conformational searches and analysis of complexation.
- Synthesis of a chiral macrocycle from N,N'-bis-(6-acylamino-2-pyridinyl)-isophthalamide units and BINOL derivatives.
Main Results:
- The chiral macrocycle (MAC) exhibited a stereopreference for (S)-enantiomers, indicated by lower diffusion coefficients.
- Computational modeling revealed that enantioselectivity is driven by a closed MAC conformation, not an open one.
- Temperature-dependent NMR and conformational searches confirmed an equilibrium between open and closed MAC conformers.
Conclusions:
- The observed enantiodifferentiation is accurately explained by the complexation of enantiomers with the closed MAC conformation.
- Macrocycle conformational flexibility is critical for chiral recognition and must be considered in receptor design.
- This study provides a framework for designing advanced chiral resolving agents for diffusion-NMR and computational analysis.
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