Position of Geminal Substitution of γ Amino Acid Residues Modulates Their Ability to Form Isolated Non‐Helical C 12 β‐turn Mimics

We have attempted the construction of isolated αγ non‐helical C 12 β‐turn mimics in Boc‐Val‐ D Pro‐γ x,x ‐Leu‐NHMe (x,x=2/2, 3/3, 4/4) peptides by the incorporation of differentially dimethyl substituted γ amino acid residues at the (i+2) position of the turn. Solution conformation was probed in detail using NMR and CD spectroscopy. Irrespective of the solvent polarity, peptide containing γ 2,2 amino acid residues failed to form the isolated tight β‐turn mimetic while peptides containing γ 3,3 and γ 4,4 residues successfully adopted isolated non‐helical C 12 β‐turn mimic structure. The conformations adopted in solution were corroborated with DFT calculations. Such difference in the stereochemical ability of these di‐substituted γ amino acid residues arose from the difference in position of the di‐substitution along the backbone of the residue. Thus prudent choice of the position of di‐substitution in ω amino acid residues might be used as a strong peptidomimetic handle to control the structural design and generate complex structures.