Efficient Access to Enantiopure γ 4 ‐Amino Acids with Proteinogenic Side‐Chains and Structural Investigation of γ 4 ‐Asn and γ 4 ‐Ser in Hybrid Peptide Helices

Hybrid peptides composed of α‐ and β‐amino acids have recently emerged as new class of peptide foldamers. Comparatively, γ‐ and hybrid γ‐peptides composed of γ 4 ‐amino acids are less studied than their β‐counterparts. However, recent investigations reveal that γ 4 ‐amino acids have a higher propensity to fold into ordered helical structures. As amino acid side‐chain functional groups play a crucial role in the biological context, the objective of this study was to investigate efficient synthesis of γ 4 ‐residues with functional proteinogenic side‐chains and their structural analysis in hybrid‐peptide sequences. Here, the efficient and enantiopure synthesis of various N‐ and C‐terminal free‐γ 4 ‐residues, starting from the benzyl esters (COOBzl) of N ‐Cbz‐protected ( E ) ‐ α,β‐unsaturated γ‐amino acids through multiple hydrogenolysis and double‐bond reduction in a single‐pot catalytic hydrogenation is reported. The crystal conformations of eight unprotected γ 4 ‐amino acids (γ 4 ‐Val, γ 4 ‐Leu, γ 4 ‐Ile, γ 4 ‐Thr(O t Bu), γ 4 ‐Tyr, γ 4 ‐Asp(O t Bu), γ 4 ‐Glu(O t Bu), and γ‐Aib) reveals that these amino acids adopted a helix favoring gauche conformations along the central C γ C β bond. To study the behavior of γ 4 ‐residues with functional side chains in peptide sequences, two short hybrid γ‐peptides P1 (Ac‐Aib‐γ 4 ‐Asn‐Aib‐γ 4 ‐Leu‐Aib‐γ 4 ‐Leu‐CONH 2 ) and P2 (Ac‐Aib‐γ 4 ‐Ser‐Aib‐γ 4 ‐Val‐Aib‐γ 4 ‐Val‐CONH 2 ) were designed, synthesized on solid phase, and their 12‐helical conformation in single crystals were studied. Remarkably, the γ 4 ‐Asn residue in P1 facilitates the tetrameric helical aggregations through interhelical H bonding between the side‐chain amide groups. Furthermore, the hydroxyl side‐chain of γ 4 ‐Ser in P2 is involved in the interhelical H bonding with the backbone amide group. In addition, the analysis of 87 γ 4 ‐residues in peptide single‐crystals reveal that the γ 4 ‐residues in 12‐helices are more ordered as compared with the 10/12‐ and 12/14‐helices.