Syntheses and CD-Spectroscopic Investigations of Longer-Chain β-Peptides: Preparation by Solid-Phase Couplings of Single Amino Acids, Dipeptides, and Tripeptides

The synthesis and CD-spectroscopic analysis of eleven water-soluble β-peptides composed of all-β³ or alternating β²- and β³-amino acids is described. Different approaches for the efficient syntheses of longer-chain β-peptides (>9 residues) were investigated. They were synthesized on solid phase with Fmoc-protected amino acids or Fmoc-protected di- or tripeptide fragments (assembled using solution-phase synthesis). The use of preformed fragments significantly increased the purity of the crude peptides and facilitated purification. Especially, the use of Fmoc-protected β²/β³-dipeptides for the synthesis of a ‘mixed' β²/β³-nonapeptide proved to be remarkably effective, yielding the crude peptide in 95% purity and without detectable epimerization of the β²-amino acid residues. This is a significant improvement over previously reported procedures for the solid-phase synthesis of β-peptides, and foreshadows that the field of β-peptide research will now switch from synthesis to the design and study of complex functional ‘β-proteins'.