β-Peptides: Synthesis by Arndt-Eistert homologation with concomitant peptide coupling. Structure determination by NMR and CD spectroscopy and by X-ray crystallography. Helical secondary structure of a β-hexapeptide in solution and its stability towards pepsin

Authors

  • Dieter Seebach,

    Corresponding author
    1. Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Zentrum, Universitätstrasse 16, CH–8092 Zürich
    • Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Zentrum, Universitätstrasse 16, CH–8092 Zürich
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  • Mark Overhand,

    1. Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Zentrum, Universitätstrasse 16, CH–8092 Zürich
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    • Postdoctoral research fellow, ETH-Zürich, 1995.

  • Florian N. M. Kühnle,

    1. Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Zentrum, Universitätstrasse 16, CH–8092 Zürich
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    • Part of the projected dissertation of F.N.M.K.

  • Bruno Martinoni,

    1. Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Zentrum, Universitätstrasse 16, CH–8092 Zürich
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  • Lukas Oberer,

    1. Präklinische Forschung, Sandoz Pharma AG, CH–4002 Basel
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  • Ulrich Hommel,

    1. Präklinische Forschung, Sandoz Pharma AG, CH–4002 Basel
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  • Hans Widmer

    1. Präklinische Forschung, Sandoz Pharma AG, CH–4002 Basel
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Abstract

The β-hexapeptide (H-β-HVal-β-HAla-β-HLeu)2-OH (2) was prepared from the component L-β-amino acids by conventional peptide synthesis, including fragment coupling. A cyclo-β-tri- and a cyclo-β-hexapeptide were also prepared. The β-amino acids were obtained from α-amino acids by Arndt-Eistert homologation. All reactions leading to the β-peptides occur smoothly and in high yields. The β-peptides were characterized by their CD and NMR spectra (COSY, ROESY, TOCSY, and NOE-restricted modelling), and by an X-ray crystal-structure analysis. β-Sheet-type structures (in the solid state) and a compact, left-handed or (M) 31 helix of 5-Å pitch (in solution) were discovered. Comparison with the analogous secondary structures of α-peptides shows fundamental differences, the most surprising one at this point being the greater stability of β-peptide helices. There are structural relationships of β-peptides with oligomers of β-hydroxyalkanoic acids, and dissimilarities between the two classes of compounds are a demonstration of the power of H-bonding. The β-hexapeptide 2 is stable to cleavage by pepsin at pH 2 in H2O for at least 60 h at 37°, while the corresponding α-peptide H-(Val-Ala-Leu)2-OH is cleaved instantaneously under these conditions. The implication of the described results are discussed.

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