β²-amino acids in the design of conformationally homogeneous cyclo-peptide scaffolds

Abstract

Herein, we report studies on the influence of chiral β2- amino acids in the design of conformationally homogeneous cyclic tetrapeptide scaffolds. The cyclic α-tetrapeptide ryclo(-Phe-D-Pro-Lys-Phe-) (1) and its four mixed analogues, having one of the α-Phe replaced by either an (S)- or an (R)-β2hPhe residue (i.e., cyclo(-(R)- β2hPhe-D-Pro-Lys-Phe) (2a), cyclo(-(S)2hPhe-D-Pro- Lys-Phe-) (2b), cyclo(-Phe-D-Pro-Lys-(R)-β2hPhe-) (3a), and cyclo(-Phe-D-Pro-Lys-(R)-β2hPhe-) (3b)), were all synthesized through solid-phase procedures followed by solution-phase cyclization. Initially, all five cyclo-peptides were analyzed by1H NMR spectroscopic studies in different solvents and at variable temperatures. Subsequently, a detailed 2D NMR spectroscopic analysis of three of the mixed peptides in water was performed, and the information thus extracted was used as restraints in a computational study on the peptides' conformational preference. An X-ray crystallographic study on the side chain-protected (Boc) 2a revealed the solid-state structure of this peptide. The results presented herein, together with previous literature data on β3-amino acid residues, conclusively demonstrate the potential of β-amino acids in the design of conformationally homogeneous cyclic peptides that are homologous to peptides with known applications in biomedicinal chemistry and as molecular receptors. © 2006 American Chemical Society.