Organic Chemistry

Helix-forming aliphatic homo-δ-peptides foldamers based on conformational restriction of cyclopropane

Authors

Abstract

Considerable effort has been directed toward developing artificial peptide-based foldamers. To date, however, detailed structural analysis of δ-peptide foldamers consisting of aliphatic δ-amino acids has not been reported. Herein, we rationally designed and stereoselectively synthesized aliphatic homo-δ-peptide foldamers forming a stable helical structure utilizing a chiral cyclopropane δ-amino acid as a monomer unit. Structural analysis of the homo-δ-peptides revealed that they form a stable 14-helical structure in solution. Furthermore, we successfully achieved X-ray crystallographic analysis of the homo-δ-peptides, showing their common right-handed 14-helical structures. The critical point is that the helical structures of these δ-peptides are theoretically predictable by calculations. This is the first example of aliphatic homo-δ-peptide foldamers forming a stable helical structure both in solution and crystal.

Version notes

Data of molecular dynamics (MD) simulations are added.

Content

Thumbnail image of Foldamer_220831_chemrxiv.pdf

Supplementary material

Thumbnail image of Foldamer_220831_SI_chemrxiv.pdf
Supporting Information
Figures S1–S10, Schemes S1–S6, Table S1, Summary of crystallographic data (Table S2), Synthetic procedures and characterization of compounds, Protocol of NMR structural calculation and MD simulation, and References
Thumbnail image of N-Ac-tetramer_11a.cif
X-ray crystal structure of N-Ac-tetramer 11a
X-ray crystallographic analysis showed that the tetramer has a right-handed helical structure, in which all the possible 14-membered-ring hydrogen bonds are observed as anticipated from the molecular design.