The C-linked carbo-beta-peptides, oligomers of a new class of C-linked carbo-beta3-amino acids, have been shown to generate mixed 12/10 and 10/12 helices. The design involves use of "alternating chirality" of the epimeric (at the amine center) monomers to control the stability of these helices. The observation of stable 12/10 helix in a tripeptide and 10/12 helix in a tetrapeptide is unprecedented.

New classes of alpha/gamma- and beta/gamma-hybrid peptides have been synthesized with novel 12/10- and 11/13-mixed helical patterns, respectively. The alpha/gamma-peptides were derived from the dipeptide repeats with alternating arrays of l-Ala and gamma-Caa((l)) (C-linked carbo-gamma-amino acid from d-mannose), which generated a new 12/10-mixed helix, for the first time, without a beta-amino acid. The beta/gamma-peptides made from an alternating arrangement of beta-Caa((x)) (C-linked carbo-beta-amino acid) and gamma-Caa((x)) (C-linked carbo-gamma-amino acid from d-xylose), on the other hand, resulted in an unprecedented 11/13-helix. The secondary structures in these peptides have been ascertained from detailed NMR studies, and CD spectroscopy and molecular dynamics investigations provided additional support for the structures derived.

No abstract

Ein neuer Dreh: Die α/β‐Hybriddipeptid‐Wiederholungseinheiten, die aus alternierenden C‐verknüpften Carbo‐β3‐aminosäuren und L‐Ala‐Resten hergestellt wurden, tendieren stark zur Bildung gemischter Helices und liefern bislang unbekannte rechtsgängige 11/9‐ und 9/11‐Helixstrukturen (siehe Bild).

Synthetic oligomers of b-amino acids, that is, b-peptides, [1] are amongst the most studied class of molecules in foldamer chemistry. Changes in their substitution pattern generate a variety of interesting structural features in these molecules, [2][3][4][5] which have thus begun to prove immensely useful in bioactive peptide mimicry.[6] Amongst the various peptide secondary structures, mixed helices are unique to b-peptides. These structures contain intertwined 12 and 10-membered Hbonded rings and are unprecedented in a-proteins. Seebach et al. [4a] were the first to demonstrate the existence of righthanded 12/10 mixed helical structures in b-peptides with alternating b 2 and b 3 residues. Kessler and co-workers [4b] have reported such structures in mixed peptides containing constrained f-sugar amino acid and b-hGly repeats. We recently reported [7] the formation of both 10/12 and 12/10 right-handed helices by b-peptides derived from C-linked carbo-b 3 -amino acids (Caa) with "alternating chirality." Although a variety of helical structures have been discovered in b-peptides, no reports have been published in this active area of research that describe left-handed mixed helices. Several natural proteins [8] have been found to contain small fragments of left-handed helices, most of which occur in or near an active or binding site and are thus likely to be of functional importance. Herein, we report the design, synthesis, and structural study of "mixed b-peptides" with right-handed and novel left-handed mixed (10/12 and 12/10) helical structures. These peptides are derived from alternating epimeric Clinked carbo-b 3 -amino acids [9] (1 or 2; Scheme 1) and b-hGly units.Our previous study revealed that Caa 1 occupies an energetically unfavorable position in the carbo-b-peptides 3 and 4, [7] although robust mixed helical structures were formed by these peptides. We envisaged a new design intended to provide more conformational freedom and relieve steric strain [10,11] through the inclusion of alternating Caa (1 or 2) and b-hGly residues. Mixed b-peptides 5-12 (5/6 and 7/8 with Caa 2 and 1 at the N terminus, respectively; 9/10 and 11/12 with b-hGly at the N terminus) were prepared by conventional procedures (1-ethyl-3(3-dimethylaminopropyl)carbodiimide, 1-hydroxy-1H-benzotriazole) and differences in the conformational behavior of the various peptides were studied. We anticipated that Caas 1 and 2 would define the conformational behavior of b-hGly in 5-12 (Scheme 1).Structural studies on these peptides were carried out by using NMR and CD spectroscopic techniques. The 1 H NMR spectra of 5 and 6 in CDCl 3 show well-resolved backbone proton signals, as well as low-field NH resonances (NH(2)-NH(3) for 5; NH(2)-NH(5) for 6), which indicate the involvement of these NH groups in H bonding. This bonding was further confirmed by solvent titration studies.[12] The coupling constants 3 J CaH/CbH of the peptides (> 10 Hz or < 5 Hz) clearly demonstrate the predominance of a single conformation about the CaÀCb bond (single q valu...