Flat, C^α,β‐Didehydroalanine Foldamers with Ferrocene Pendants: Assessing the Role of α‐Peptide Dipolar Moments

Abstract

The foldamer field is continuously expanding as it allows to produce molecules endowed with 3D-structures and functions never observed in nature. We synthesized flat foldamers based on the natural, but non-coded, C α,β -didehydroalanine α-amino acid, and covalently linked to them two ferrocene (Fc) moieties, as redox probes. These conjugates retain the flat and extended conformation of the 2.0 5 -helix, both in solution and in the crystal state (X-ray diffraction). Cyclic voltammetry measure-ments agree with the adoption of the 2.0 5 -helix, characterized by a negligible dipole moment. Thus, elongated α-peptide stretches of this type are insulators rather than charge conductors, the latter being constituted by peptide α-helices. Also, our homo-tetrapeptide has a N-to-C length of about 18.2 Å, almost double than that (9.7 Å) of an α-helical αtetrapeptide.

Flat, Ferrocenyl‐Conjugated Peptides: A Combined Electrochemical and Spectroscopic Study

“…This condition is dramatically diverging from that observed in α‐ or‐3 10 ‐helical peptides, where the amide C=O groups align along the helix axis and generate important macro‐dipoles. In our recent contribution [8c] we have shown that the 2.0 5 ‐helix has indeed a negligible dipole moment, thus confirming the relevance of this feature in promoting electron/charge transfer in helical peptides. In that contribution we appended two ferrocene (Fc) probes to the ends of flat peptides, as we previously did with 3 10 ‐helical peptides [11] .…”

“…In the amide A region (Figure 2A and 2 C) the band at about 3440 cm −1 is due to the stretching of C‐terminal amide N−H, not involved in H‐bonds. The intense band at about 3385 cm −1 , that encompasses all other amide NH, has the typical frequency of the intra ‐residue (C 5 conformation) H‐bond observed in ΔAla peptides [8a,c,13] . In addition, in all peptides this frequency is unchanged, because the intra‐residue H‐bonds in the 2.0 5 ‐helix do not interconnect with residues that precede or follow.…”

“…In that contribution we appended two ferrocene (Fc) probes to the ends of flat peptides, as we previously did with 3 10 ‐helical peptides [11] . However, we did not observe communication between the two Fc moieties, [8c] at variance from the case where the intervening peptides are 3 10 ‐helices [11]…”

“…In the present work, we expect both conditions to be insignificant because we used, as in Ref. [8c], the naturally occurring, C α,β ‐didehydroalanine (ΔAla) residue, [12] known to promote the 2.0 5 ‐helix [8a,c,13] . Again, we relied on Fc as electrochemical probe as its derivatives are stable in solution and in air and preserve their redox characteristics even when chemically modified [14] .…”

“…Again, we relied on Fc as electrochemical probe as its derivatives are stable in solution and in air and preserve their redox characteristics even when chemically modified [14] . Also, Fc already proved to be a reliable probe in studies involving peptides [6b,f,h,m,8c,11,15] …”