Synthesis and Conformational Behaviors of Unnatural Peptides Alternating Chiral and Achiral α,α‐Disubstituted α‐Amino Acid Units

Abstract

AbstractThe development of peptidomimetics to modulate the conformational profile of peptides has been extensively studied in the fields of biological and medicinal chemistry. However, large‐scale synthesis of peptidomimetics with both an ordered sequence and a controlled secondary structure is highly challenging. In this paper, the framework of peptidomimetics has been designed to be alternating an achiral α,α‐disubstituted α‐amino acid unit and a chiral α‐methylphenylalanine unit. The polymers are synthesized via invented Ugi reaction‐based polycondensation technique. The chiral higher‐order structures of the alternating peptides are evaluated mainly through circular dichroism (CD) spectroscopy. The UV–Vis and CD spectra of the polymers in three solvents are systematically measured at various temperatures. The anisotropic factors of CD (gCD) values are calculated to know the chiroptical response. The results indicate the characteristic conformational behaviors. In a polar solvent, the hydrogen bonds between the N‐H group of MePhe unit and the C=O of α,α‐diphenylglycine unit outweigh the intraresidue hydrogen bonds in α,α‐diphenylglycine unit, leading to the formation of a prevailing preferred‐handed 310‐helical conformation. On the other hand, in a less polar solvent, the intrachain hydrogen bonds switch to intraresidue hydrogen bonds in α,α‐diphenylglycine unit, which make the polymer adopting a prevailing extended planar C5‐conformation.