β‐Peptides: Synthesis by <i>Arndt‐Eistert</i> homologation with concomitant peptide coupling. Structure determination by NMR and CD spectroscopy and by X‐ray crystallography. Helical secondary structure of a β‐hexapeptide in solution and its stability towards pepsin

TLDR

β‑amino acids were generated from α‑amino acids via Arndt‑Eistert homologation. The β‑hexapeptide and related cyclo‑β‑peptides were assembled by conventional peptide synthesis with fragment coupling, and characterized by CD, NMR (COSY, ROESY, TOCSY, NOE‑restricted modelling) and X‑ray crystallography. Reactions proceeded smoothly with high yields, revealing β‑sheet structures in the solid state and a compact left‑handed (M)3₁ helix in solution, with β‑peptide helices exhibiting greater stability than α‑peptide analogues and the β‑hexapeptide remaining intact to pepsin at pH 2 for 60 h versus instantaneous cleavage of the α‑peptide.

Abstract

Abstract The β‐hexapeptide (H‐β‐HVal‐β‐HAla‐β‐HLeu) 2 ‐OH ( 2 ) was prepared from the component L ‐β‐amino acids by conventional peptide synthesis, including fragment coupling. A cyclo‐β‐tri‐ and a cyclo‐β‐hexapeptide were also prepared. The β‐amino acids were obtained from α‐amino acids by Arndt‐Eistert homologation. All reactions leading to the β‐peptides occur smoothly and in high yields. The β‐peptides were characterized by their CD and NMR spectra (COSY, ROESY, TOCSY, and NOE‐restricted modelling), and by an X‐ray crystal‐structure analysis. β‐Sheet‐type structures (in the solid state) and a compact, left‐handed or ( M ) 3 1 helix of 5‐Å pitch (in solution) were discovered. Comparison with the analogous secondary structures of α‐peptides shows fundamental differences, the most surprising one at this point being the greater stability of β‐peptide helices. There are structural relationships of β‐peptides with oligomers of β‐hydroxyalkanoic acids, and dissimilarities between the two classes of compounds are a demonstration of the power of H‐bonding. The β‐hexapeptide 2 is stable to cleavage by pepsin at pH 2 in H 2 O for at least 60 h at 37°, while the corresponding α‐peptide H‐(Val‐Ala‐Leu) 2 ‐OH is cleaved instantaneously under these conditions. The implication of the described results are discussed.