Probing the Helical Secondary Structure of Short-Chain β-Peptides

Authors

  • Dieter Seebach,

    Corresponding author
    1. Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule, ETH-Zentrum, Universitätstrasse 16, CH–8092 Zürich
    • Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule, ETH-Zentrum, Universitätstrasse 16, CH–8092 Zürich
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  • Paola E. Ciceri,

    1. Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule, ETH-Zentrum, Universitätstrasse 16, CH–8092 Zürich
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    • Part of the master's thesis of P.E.C., University of Pavia, Italy, carried out at ETH-Zürich 1995/1996 as part of the ERASMUS cooperation programme.

  • Mark Overhand,

    1. Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule, ETH-Zentrum, Universitätstrasse 16, CH–8092 Zürich
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    • Postdoctoral research fellow, ETH-Zürich, 1995/1996, financed by a ‘Bundesstipendium der Eidgenössischen Stipendienkommission für Ausländische Studierende’. New Address: c/o Prof. Dr. J.H. van Boom, Gorlaeus Laboratoria, Rijks Univesiteit Leiden, Einsteinweg 55, Postbus 9502, NL–2300 RA Leiden.

  • Bernhard Jaun,

    1. Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule, ETH-Zentrum, Universitätstrasse 16, CH–8092 Zürich
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  • Dario Rigo,

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

    1. Sandoz Pharma AG, Preclinical Research, CH–4002 Basel
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  • Ulrich Hommel,

    1. Sandoz Pharma AG, Preclinical Research, CH–4002 Basel
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  • René Amstutz,

    1. Sandoz Pharma AG, Preclinical Research, CH–4002 Basel
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  • Hans Widmer

    1. Sandoz Pharma AG, Preclinical Research, CH–4002 Basel
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  • Dedicated to Professor Teruaki Mukaiyama, a dear friend and revered colleague on the occasion of his 70th birthday

Abstract

Structural prerequisites for the stability of the 31 helix of β-peptides can be defined from inspection of models (Figs. 1 and 2): lateral non-H-substituents in 2- and 3-position on the 3-amino-acid residues of the helix are allowed, axial ones are forbidden. To be able to test this prediction, we synthesized a series of heptapeptide derivatives Boc-(β-HVal-β-HAla-β-HLeu-Xaa-β-HVal-β-HAla-β-HLeu)-OMe 13–22 (Xaa = α- or β-amino-acid residue) and a β-depsipeptide 25 with a central (S)-3-hydroxybutanoic-acid residue (Xaa = –OCH(Me)CH2C(O)–) (Schemes 1 3). Detailed NMR analysis (DQF-COSY, HSQC, HMBC, ROESY, and TOCSY experiments) in methanol solution of the β-hexapeptide H(-β-HVal-β-HAla-β-HLeu)2-OH (1) and of the β-heptapeptide H-β-HVal-β-HAla-β-HLeu-(S,S)-β-HAla(αMe)-β-HVal-β-HAla- β-HLeu-OH (22), with a central (2S,3S)-3-amino-2-methylbutanoic-acid residue, confirm the helical structure of such β-peptides (previously discovered in pyridine solution) (Fig.3 and Tables 1–5). The CD spectra of helical β-peptides, the residues of which were prepared by (retentive) Arndt-Eistert homologation of the (S)- or L-α-amino acids, show a trough at 215 nm. Thus, this characteristic pattern of the CD spectra was taken as an indicator for the presence of a helix in methanol solutions of compounds 13–22 and 25 (including partially and fully deprotected forms) (Figs.4–6). The results fully confirm predicted structural effects: incorporation of a single ‘wrong’ residue ((R)-β-HAla, β-HAib, (R,S)-β-HAla(α Me), or N-Me-β-HAla) in the central position of the β-heptapeptide derivatives A (see 17, 18, 20, or 21, resp.) causes the CD minimum to disappear. Also, the β-heptadepsipetide 25 (missing H-bond) and the β-heptapeptide analogs with a single α-amino-acid moiety in the middle (13 and 14) are not helical, according to this analysis. An interesting case is the heptapeptide 15 with the central achiral, unsubstituted 3-aminopropanoic-acid moiety: helical conformation appears to depend upon the presence or absence of terminal protection and upon the solvent (MeOH vs. MeOH/H2O).

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