Design of a “New Motif” with β-Amino Acids and α-Aminoxy Acids: Synthesis of Hybrid Peptides with 12/10-Helix

Hybrid peptides are prepared from a C-linked carbo-β-amino acid ester (R-β-Caa) and an α-aminoxy acid (R-Ama) derived from S-lactic acid. Extensive NMR (in CDCl3 solution), CD, and MD studies on the tetra- and hexapeptides led to identification of robust 12/10-mixed helices. The dipeptide repeat having an R-β-Caa and an R-Ama thus provides a “new motif” to realize a 12/10-mixed helix, for the first time, in oligomers containing R-Ama. To understand the impact of side chains in the mixed helix formation, R-β-Caa/Ama (with no substitution in Ama) and S-β-hAla/R-Ama oligomers were investigated. NMR studies revealed the existence of 12/10-helices in these hybrid peptides, and the side chains of monomers were found to have a profound influence on their stabilities. These observations imply that the propensity of β-amino acid to prefer a mixed 12/10-helix governs the structural behavior in these peptides. The structural consequences of the lone-pair repulsion between nitrogen and oxygen atoms result in a new and interesting structural motif which behaves like “pseudo” β32-peptides in generating 12/10-mixed helices.