Synthesis of β‐Peptides with β‐Helices from New C‐Linked Carbo‐β‐Amino Acids: Study on the Impact of Carbohydrate Side Chains

The design and synthesis of β-peptides from new C-linked carbo-β-amino acids (β-Caa) presented here, provides an opportunity to understand the impact of carbohydrate side chains on the formation and stability of helical structures. The β-amino acids, Boc-(S)-β-Caa(g)-OMe 1 and Boc-(R)-β-Caa(g)-OMe 2, having a D-galactopyranoside side chain were prepared from D-galactose. Similarly, the homo C-linked carbo-β-amino acids (β-hCaa); Boc-(S)-β-hCaa(x)-OMe 3 and Boc-(R)-β-hCaa(x)-OMe 4, were prepared from D-glucose. The peptides derived from the above monomers were investigated by NMR, CD, and MD studies. The β-peptides, especially the shorter ones obtained from the epimeric (at the amine stereocenter Cβ) 1 and 2 by the concept of alternating chirality, showed a much smaller propensity to form 10/12-helices. This substantial destabilization of the helix could be attributed to the bulkier D-galactopyranoside side chain. Our efforts to prepare peptides with alternating 3 and 4 were unsuccessful. However, the β-peptides derived from alternating geometrically heterochiral (at Cβ) 4 and Boc-(R)-β-Caa(x)-OMe 5 (D-xylose side chain) display robust right-handed 10/12-helices, while the mixed peptides with alternating 4 and Boc-β-hGly-OMe 6 (β-homoglycine), resulted in left-handed β-helices. These observations show a distinct influence of the side chains on helix formation as well as their stability.