Efficient Access to Enantiopure γ4‐Amino Acids with Proteinogenic Side‐Chains and Structural Investigation of γ4‐Asn and γ4‐Ser in Hybrid Peptide Helices. Issue 48 (21st October 2013)

• Record Type: Journal Article
• Authors: Jadhav, Sandip V.; Misra, Rajkumar; Singh, Sumeet K.; Gopi, Hosahudya N.
• Is Part Of: Chemistry. Volume 19:Issue 48(2013)
• Page Start: 16256
• Page End: 16262
• Publication Date: 2013-10-21
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201302732
• Languages: English
• ISSNs: 0947-6539

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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<sup>4</sup>‐amino acids are less studied than their β‐counterparts. However, recent investigations reveal that γ<sup>4</sup>‐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<sup>4</sup>‐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<sup>4</sup>‐residues, starting from the benzyl esters (COOBzl) of <italic>N</italic>‐Cbz‐protected (<italic>E</italic>)<italic>‐</italic>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<sup>4</sup>‐amino acids (γ<sup>4</sup>‐Val, γ<sup>4</sup>‐Leu, γ<sup>4</sup>‐Ile, γ<sup>4</sup>‐Thr(O<italic>t</italic>Bu), γ<sup>4</sup>‐Tyr, γ<sup>4</sup>‐Asp(O<italic>t</italic>Bu), γ<sup>4</sup>‐Glu(O<italic>t</italic>Bu), and γ‐Aib) reveals that these amino acids adopted a helix favoring <italic>gauche</italic> conformations along the central C<sup>γ</sup>C<sup>β</sup> bond. To study the behavior of γ<sup>4</sup>‐residues with functional side chains in peptide sequences, two short hybrid γ‐peptides <bold>P1</bold> (Ac‐Aib‐γ<sup>4</sup>‐Asn‐Aib‐γ<sup>4</sup>‐Leu‐Aib‐γ<sup>4</sup>‐Leu‐CONH<sub>2</sub>) and <bold>P2</bold> (Ac‐Aib‐γ<sup>4</sup>‐Ser‐Aib‐γ<sup>4</sup>‐Val‐Aib‐γ<sup>4</sup>‐Val‐CONH<sub>2</sub>) were designed, synthesized on solid phase, and their 12‐helical conformation in single crystals were studied. Remarkably, the γ<sup>4</sup>‐Asn residue in <bold>P1</bold> facilitates the tetrameric helical aggregations through interhelical H bonding between the side‐chain amide groups. Furthermore, the hydroxyl side‐chain of γ<sup>4</sup>‐Ser in <bold>P2</bold> is involved in the interhelical H bonding with the backbone amide group. In addition, the analysis of 87 γ<sup>4</sup>‐residues in peptide single‐crystals reveal that the γ<sup>4</sup>‐residues in 12‐helices are more ordered as compared with the 10/12‐ and 12/14‐helices.</p> </abstract>