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

Abstract

Hybrid peptides are prepared from a C-linked carbo-beta-amino acid ester (R-beta-Caa) and an alpha-aminoxy acid (R-Ama) derived from S-lactic acid. Extensive NMR (in CDCl 3 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-beta-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-beta-Caa/Ama (with no substitution in Ama) and S-beta-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 beta-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" beta (3),beta(2)-peptides in generating 12/10-mixed helices.

Peptidomimetics via modifications of amino acids and peptide bonds

“…164 Tetra-and hexa-hybrid peptides of a-aminoxy acids and carbo-b-amino provided robust 12/10-mixed helices. 165 Scheme 6 Preparation of azadepsipeptides through activated formats.…”

Investigation and folding pattern of l-ido and d-gluco peptides by EASY ROESY NMR and X-ray

“…9 Peptides containing diverse furanoid and pyranoid sugar b-amino acids have shown a wide variety of structural pattern such as helices, 1,3,10-16 turns 17,18 and other secondary structures. 4,13,17,19,20 In particular furanoid sugar b-amino acids have been shown to play a crucial role in the formation of different helices in hybrid peptides. 1,3,[10][11][12][14][15][16]21 Furanoid sugar b-amino acids also form several distinct secondary structures in cyclic tetra and pentapeptides.…”

Conformational Studies on Peptides of α‐Aminoxy Acids with Functionalized Side‐Chains

“…[59][60][61] Because of the repulsion between the lone pair of electrons of the nitrogen and oxygen atoms, the backbones of a-aminoxy acids are more rigid, and so they can form stable secondary structures in solution. [60][61][62][63][64][65][66][67][68][69] We have reported previously that when an a-aminoxy acid having a nonpolar side chain is incorporated into a peptide backbone, strong eight-membered-ring intramolecular hydrogen bonds (the N-O turn) could be induced between the adjacent residues. [59][60][61][62][63] Furthermore, oligomers of homochiral a-aminoxy acids that have hydrophobic side chains can form 1.8 8 helical conformations (or a twisted 2 8 helix with two residues per helical turn) in nonpolar solvents.…”