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Synthesis 2008(15): 2381-2390  
DOI: 10.1055/s-2008-1067171
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Dimeric Building Blocks for Solid-Phase Synthesis of α-Peptide-β-Peptoid Chimeras

Gitte Bonkea, Line Vedela, Matthias Wittb, Jerzy W. Jaroszewskia, Christian A. Olsen*a, Henrik Franzyk*a
a Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Fax: +45(3533)6040; e-Mail: hf@farma.ku.dk;
b Bruker Daltonik GmbH, Fahrenheitstraße 4, 28359 Bremen, Germany
Further Information

Publication History

Received 11 December 2007
Publication Date:
08 July 2008 (online)

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Abstract

Recently, a novel type of antimicrobial and proteolytically stable peptidomimetic oligomers having an α-peptide-β-peptoid chimeric backbone was reported. The present paper describes efficient protocols for the preparation of a wide range of dimeric building blocks, displaying different types of side-chains, for use in solid-phase synthesis (SPS) of libraries of this type of oligomers. The β-peptoid monomers were obtained by microwave-assisted aza-Michael additions to acrylic esters. Subsequent solution-phase peptide coupling with suitably protected α-amino acids afforded dimeric intermediates. Even sluggish peptide couplings, involving sterically hindered N-alkyl-β-alanines or amino acids with bulky side-chains, gave high yields on multigram-scale when using microwave (MW) irradiation. Protecting group and side-chain manipulations were performed as one-pot solution-phase procedures to afford ten different building blocks in good to excellent yields. Finally, the efficiency of SPS oligomerization of a representative dimer was demonstrated by preparing 10- to 16-residue homomers and by the assembly of four different building blocks to give a diversely functionalized octamer.

Key words

peptides - peptoids - Michael addition - solid-phase synthesis - microwave irradiation

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