Introducing the Chiral Constrained α‐Trifluoromethylalanine in Aib Foldamers to Control, Quantify and Assign the Helical Screw‐Sense**

Abstract

Oligomers of α-aminoisobutyric acid (Aib) are achiral peptides that adopt 3 10 helical structures with equal population of left-and right-handed conformers. The screwsense preference of the helical chain may be controlled by a single chiral residue located at one terminus. 1 H and 19 F NMR, X-ray crystallography and circular dichroism studies on new Aib oligomers show that the incorporation of a chiral quaternary α-trifluoromethylalanine at their N-terminus induces a reversal of the screw-sense preference of the 3 10 -helix compared to that of a non-fluorinated analogue having an lα-methyl valine residue. This work demonstrates that, among the many particular properties of introducing a trifluoromethyl group into foldamers, its stereo-electronic properties are of major interest to control the helical screw sense. Its use as an easy-to-handle 19 F NMR probe to reliably determine both the magnitude of the screw-sense preference and its sign assignment is also of remarkable interest.

A Chiral 19F NMR Reporter of Foldamer Conformation in Bilayers

“…The strength of the screw-sense preference of a given controller is often presented as an inferred helical excess (h.e. 0 ), which corresponds to the helical excess adjacent to the controller at the foldamer N-terminus. , Phe induces a moderate h.e. 0 in the closest part of the helix (−52% for l , +52% for d ), whereas αMeVal (+68% for l , −68% for d ) and (αMeVal) 2 (+95% for l , −95% for d ) are stronger inducers of h.e.…”

“…0 of +80. 21 The (R)-1-(trifluoromethyl)ethylamido ((R)-TFEA) reporter (Figure 1a, in green) was designed with this isosteric relationship in mind; it was hoped any intrinsic helical preference would be diminished by attachment to the C-terminus. 22 Both enantiomers of the amine are commercially available, which will allow the effect of phospholipid chirality to be probed (Figure 1c).…”

“…reported that stereoselectively replacing a single methyl on Aib with CF 3 provides a residue (( S )-TfmAla) that acts as an N-terminal controller for Aib foldamers, producing a significant h.e. 0 of +80 . The ( R )-1-(trifluoromethyl)­ethylamido (( R )-TFEA) reporter (Figure a, in green) was designed with this isosteric relationship in mind; it was hoped any intrinsic helical preference would be diminished by attachment to the C-terminus .…”

Proteolytically Stable Diaza-Peptide Foldamers Mimic Helical Hot Spots of Protein–Protein Interactions and Act as Natural Chaperones

“…To our knowledge, a positive band near 225 nm has been reported in β/γ-peptides displaying 13-helix 36,37 or Aib foldamers showing right-handed 3 10 -helix, 38,39 or in natural polyproline type-II helix (PPII), but it is generally accompanied by a negative signal near 205 nm. In our case, PPII was excluded because this positive cotton effect was only very modestly reduced at high temperature, slightly increased under high concentration of urea, and stable under CaCl 2 conditions (Figures S11−S13, Supporting Information).…”

“…Furthermore, a shift of the negative band toward 200 nm for the CD spectrum of 11 in ACN (Figure S14, Supporting Information) is in accordance with an increased population of helical con- formation, as found for 13-helix in β/γ-peptides 36,37 or 3 10helix in poly-Aib. 38,39 Thus, although CD analysis could not well define the structure of the azapeptides, it proved useful in selecting compounds 7 and 11, showing the more pronounced helical structure, for further analysis using FTIR, NMR, and MD. In FTIR analysis, the amide I band (1600−1700 cm −1 ) mainly originating from the peptide backbone CO stretching vibrations 44 was deconvoluted to distinguish between the individual secondary structure types.…”