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

TY - JOUR

T1 - Dimeric Building Blocks for Solid-Phase Synthesis of α-Peptide-β-Peptoid Chimeras

AU - Seigan, Gitte Bonke

AU - Vedel, Line

AU - Matthias, Witt,

AU - Jaroszewski, Jerzy W.

AU - Olsen, Christian Adam

AU - Franzyk, Henrik

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1055/s-2008-1067171

DO - 10.1055/s-2008-1067171

M3 - Journal article

SN - 0039-7881

VL - 2008

SP - 2381

EP - 2390

JO - Synthesis

JF - Synthesis

IS - 15

ER -