Grant from the Association pour la Recherche sur le Cancer (ARC), France
β2- and β3-Peptides with Proteinaceous Side Chains: Synthesis and solution structures of constitutional isomers, a novel helical secondary structure and the influence of solvation and hydrophobic interactions on folding†
Article first published online: 25 OCT 2004
Copyright © 1998 Verlag GmbH & Co. KGaA, Weinheim
Helvetica Chimica Acta
Volume 81, Issue 5-8, pages 932–982, 1998
How to Cite
Seebach, D., Abele, S., Gademann, K., Guichard, G., Hintermann, T., Jaun, B., Matthews, J. L., Schreiber, J. V., Oberer, L., Hommel, U. and Widmer, H. (1998), β2- and β3-Peptides with Proteinaceous Side Chains: Synthesis and solution structures of constitutional isomers, a novel helical secondary structure and the influence of solvation and hydrophobic interactions on folding. HCA, 81: 932–982. doi: 10.1002/hlca.19980810513
Partially mentioned in preliminary communications  and in a review article .
- Issue published online: 18 APR 2005
- Article first published online: 25 OCT 2004
- Manuscript Received: 19 JAN 1998
Enantiomerically pure β-amino-acid derivatives with the side chains of Ala, Val, and Leu in the 2- or 3-position (β2- and β3-amino acids, resp.), as well as with substituents in both the 2- and 3-positions (β2,3-amino acids, of like-configuration) have been prepared (compounds 8–17) and incorporated (by stepwise synthesis and fragment coupling, intermediates 24–34) into β-hexa-, β-hepta-, and β-dodecapeptides (1–17). The new and some of the previously prepared β-peptides (35–39) showed NH/ND exchange rates (in MeOH at room temperature) with τ1/2 values of up to 60 days, unrivalled by short chain α-peptides. All β-peptides 1–7 were designed to be able to attain the previously described 31-helical structure (Figs. 1 and 2). CD Measurements (Fig. 4), indicating a new secondary structure of certain β-peptides constructed of β2- and β3-amino acids, were confirmed by detailed NMR solution-structure analyses: a β2-heptapeptide (2c) and a β2,3-hexapeptide (7c) have the 31-helical structure (Figs. 6 and 7), while to a β2/β3-hexapeptide (4) with alternating substitution pattern H-(β2-Xaa-β3-Xaa)3-OH a novel, unusual helical structure (in (D5)pyridine, Fig. 8; and in CD3OH, Figs. 9 and 10) was assigned, with a central ten-membered and two terminal twelve-membered H-bonded rings, and with CO and NH bonds pointing alternatively up and down along the axis of the helix (Fig. 11). Thus, for the first time, two types of β-peptide turns have been identified in solution. Hydrophobic interactions of and hindrance to solvent accessibility by the aliphatic side chains are discussed as possible factors influencing the relative stability of the two types of helices.