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Cyclic α,β-peptoid octamers with differing side chain patterns: synthesis and conformational investigation

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Abstract

The solution-phase synthesis and cyclisation of three α,β-peptoid octamers with differing side chain patterns is reported. One of these, compound C, showed a significantly greater resolution by NMR relative to the other two structurally related octamers. This observation was studied in detail by circular dichroism at a synchrotron light source to facilitate the correlation between the side chain patterns and conformational preference of these three peptoids. The X-ray crystal structure of cyclic octamer C, the first high-resolution structure for the α,β-peptoid backbone, was also obtained from methanol. Combined solid- and solution-phase studies allowed the identification of the N-2-(benzyloxy)ethyl side chain on the β-residue of the heterogeneous backbone as a key structural feature driving the increased conformational stability for octamer C.

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Abbreviations

CD:

Circular dichroism

COSY:

Proton–proton correlation experiment

DMAP:

4-Dimethylaminopyridine

DMF:

N,N-Dimethylformamide

EDC:

1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride

HATU:

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

HFIP:

1,1,1,3,3,3-Hexafluoroisopropanol

HMBC:

Heteronuclear multiple bond correlation experiment

HRMS:

High-resolution mass spectroscopy

HSQC:

Heteronuclear single quantum correlation experiment

IR:

Infrared

NMR:

Nuclear magnetic resonance

rt:

Room temperature

SI:

Supporting information

SRCD:

Synchrotron radiation circular dichroism

TFA:

Trifluoroacetic acid

TFE:

2,2,2-trifluoroethanol

THF:

Tetrahydrofuran

TLC:

Thin layer chromatography

UV:

Ultraviolet

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Acknowledgments

We gratefully thank the Carlsberg Foundation for a grant to TH and Aurélie Job and Bertrand Légeret (Clermont-Université, Laboratoire SEESIB) for HPLC and mass spectrometry analysis. AAE gratefully acknowledges the beam time awarded from the Diamond Light Source, UK for the circular dichroism beamline B23. We are greatly indebted to technical team of the “Plateforme de mesures de diffraction X” of the CRM2 (Université de Lorraine).

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Authors and Affiliations

  1. Medway School of Pharmacy, Universities of Kent and Greenwich at Medway, Central Avenue, Chatham Maritime, Kent, ME4 4TB, UK

    Emiliana De Santis & Alison A. Edwards

  2. Clermont-Université, Université Blaise Pascal, Laboratoire SEESIB, BP 10448, 63000, Clermont-Ferrand, France

    Thomas Hjelmgaard, Sophie Faure, Olivier Roy & Claude Taillefumier

  3. CNRS, UMR 6504, Laboratoire SEESIB, 63177, Aubière Cedex, France

    Thomas Hjelmgaard, Sophie Faure, Olivier Roy & Claude Taillefumier

  4. CRM2, Equipe Biocristallographie, UMR 7036 CNRS-UHP, Faculté des Sciences et Technologies, Université de Lorraine, BP 239, 54506, Vandoeuvre-lès-Nancy, France

    Claude Didierjean

  5. School of Science, University of Greenwich, Central Avenue, Chatham Maritime, Kent, ME4 4TB, UK

    Bruce D. Alexander

  6. Diamond Light Source Ltd., Diamond House, Harwell Science and Innovation Campus, Didcot, Oxfordshire, OX11 0DE, UK

    Giuliano Siligardi, Rohanah Hussain & Tamás Jávorfi

Authors
  1. Emiliana De Santis
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  2. Thomas Hjelmgaard
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  4. Olivier Roy
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  10. Alison A. Edwards
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  11. Claude Taillefumier
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Corresponding authors

Correspondence to Alison A. Edwards or Claude Taillefumier.

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De Santis, E., Hjelmgaard, T., Faure, S. et al. Cyclic α,β-peptoid octamers with differing side chain patterns: synthesis and conformational investigation. Amino Acids 41, 663–672 (2011). https://doi.org/10.1007/s00726-011-0887-1

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