γ-Peptides Forming More Stable Secondary Structures than α-Peptides: Synthesis and helical NMR-solution structure of the γ-hexapeptide analog of H-(Val-Ala-Leu)2-OH

Authors

  • Tobias Hintermann,

    1. Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich
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    • Part of the projected Ph. D. theses of T. H. and K. G., ETH-Zürich.

  • Karl Gademann,

    1. Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich
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    • Part of the projected Ph. D. theses of T. H. and K. G., ETH-Zürich.

  • Bernhard Jaun,

    1. Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich
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  • 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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  • Dedicated to Professor E. J. Corey on the occasion of his 70th birthday

Abstract

For a comparison with the corresponding α- and β-hexapeptides H-(Val-Ala-Leu)2-OH (A) and H-(β-HVal-β-HAla-β-HLeu)2-OH (B), we have now prepared the corresponding γ-hexapeptide 1 built from the homochirally similar (S)-4-aminobutanoic acid, (R)-4-amino-5-methylhexanoic acid, and (R)-4-amino-6-methylheptanoic acid. The precursors were prepared either by double Arndt-Eistert homologation of the protected amino acids Boc-Val-OH, Boc-Ala-OH, and Boc-Leu-OH (Schemes 1 and 2), or by the superior route involving olefination/hydrogenation of the corresponding aldehydes (Boc-valinal, Boc-alaninal, and Boc-leucinal; Scheme 3). Conventional peptide-coupling methodology (EDC/HOBt) furnished the γ-hexapeptide 1 (through the intermediate γ-di- and γ-tripeptide derivatives 911). Analysis of NMR measurements in (D5)pyridine and CD3OH solution (COSY, TOCSY, HSQC, HMBC, ROESY) reveals that the γ-hexapeptide 1 adopts a right-handed helical structure ((P)-2.61 helix of ca. 5-Å pitch, containing 14-membered H-bonded rings) which is to be compared with the left-handed helix of the corresponding β-peptide B ((M)-31 helix of 5-Å pitch, 14-membered H-bonded rings) and with the familiar right-handed, so-called α-helix of α-peptides ((P)-3.61 helix of 5.4-Å pitch, 13-membered rings). Like the helix sense, the helix dipole reverses when going from α-, (N + → C) to β-(C + → N) to γ-peptides (N + → C). The surprising difference between the natural α-, and the analogous β- and γ-peptides is that the helix stability increases upon homologation of the residues.

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