Comparative conformational analysis of peptides based on the two Cα-tetrasubstituted, Cβ-branched, chiral α-amino acids (αMe)Dip and (αMe)Val †

Abstract

For the first time a number of terminally protected model peptides (to the pentamer level) of the sterically demanding α-amino acid C α -methyl,C α -diphenylmethylglycine, (αMe)Dip, in combination with either Ala or Gly residues, have been synthesized (by solution methods) and fully characterized. In a parallel synthesis the corresponding peptides based on the related α-amino acid C α -methyl,C α -isopropylglycine, (αMe)Val, have also been prepared. The results of a comparative conformational analysis, performed by using FTIR absorption, 1 H NMR, and X-ray diffraction techniques, favour the conclusion that, in contrast to the potent β-turn and 3 10 -helix promoter (αMe)Val, (αMe)Dip may induce either a folded or a fully extended conformation. These findings indicate that, despite the common C α -methylated and C β -branched features, (αMe)Dip and (αMe)Val are characterized by partially divergent conformational bias. † Experimental procedures for the synthesis of the new derivatives and peptides are available as supplementary data. For direct electronic access see http://www.rsc.org/suppdata/p2/a9/a909856i. See Instructions for Authors available via the RSC web page (http://www.rsc.org/ authors).The NMR spectra of the new derivatives and peptides are available as supplementary data from BLDSC (SUPPL. NO. 57694, pp. 16

Turn stabilization in short peptides by Cα‐methylated α‐amino acids

“…Bond lengths and bond angles are in general agreement with previously reported values for the benzyloxycarbonylamido24 and acetamido25 N‐terminal moieties, the ester group,26 the peptide unit,27, 28 and the Aib9, 29 Iva10, 30, 31 (αMe)Nva32 and (αMe)Val10, 33–36 residues.…”

New tools for the control of peptide conformation: the helicogenic Cα‐methyl, Cα‐cyclohexylglycine*

“…Furthermore, both l ‐( α Me)Val and l ‐( α Me)Chg residues tend to favour right‐handed turns and helices, in analogy with the stereopropensity of protein amino acids. However, these conformational conclusions are partially at variance with the known tendency of the aromatic ( α Me)Dip, also a C α ‐methylated, C β ‐trisubstituted residue, to extensively promote folded and fully extended structures to a remarkable extent (19). As this latter conformational versatility is shared by ( α Me)Phg, an aromatic, C α ‐methylated, C β ‐tetrasubstituted amino acid (20,21), the results described here confirm the hypothesis that it is the aromatic character and/or its related steric hindrance, not the degree of C β ‐substitution, that directs the structural bias of this class of C α ‐methylated α ‐amino acids.…”

“…Among the C α ‐methylated, C β ‐branched (C β ‐trisubstituted) α ‐amino acids only the preferred conformations of C α ‐methyl valine [( α Me)Val] (17,18) and C α ‐methyl, C α ‐diphenylmethylglycine [( α Me)Dip] (19) have been investigated. Despite their common chemical features the aliphatic ( α Me)Val and the aromatic ( α Me)Dip exhibit partially divergent conformational bias, in the sense that the former is a potent turn/helix promoter, while the latter may induce either a folded or a fully extended structure.…”

Amphipathic control of the 310‐/α‐helix equilibrium in synthetic peptides

“…However, the incorporation of high levels of C α ,C α ‐disubstituted glycines (e.g. α‐aminoisobutyric acid) into the sequence allows for the preparation of much shorter peptides with significant helical propensity (23,25,29–34). Peptides containing high levels of aliphatic C α ,C α ‐disubstituted glycines exhibit higher hydrophobic character than their proteinogenic counterparts and, as a result, spectroscopic studies have been limited to organic solvents such as dimethylsulfoxide (DMSO), methanol, 2,2,2‐trifluoroethanol (TFE) and acetonitrile.…”