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

ABSTRACT

The 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.