Syntheses and Properties of Oligo-l-leucines Containing α-Aminoisobutyric Acid Residues. The Novel Strategy for Solubility Improvement in Helical Oligopeptides Based on the Restriction of the Values of the Backbone Dihedral Angles φ and ψ of α-Aminoisobutyric Acid Residues

Abstract

Abstract In order to provide a succinct demonstration of the usefulness of a new strategy for solubility improvement in protected peptide fragments included in α-helical regions of proteins, model oligo(Leu)s containing Aib or Ala residues were prepared by stepwise elongation and fragment condensation methods. The peptides prepared were the following: Boc–(Leu3–Aib)n–OBzl, Boc–(Leu4–Aib)n–OBzl, and Boc–(leu3–Ala)nOBzl (n=1–3). Carboxyl component peptides having Aib residues at the C-terminals smoothly reacted with amino component peptides in high yields with no care of racemization due to the absence of chiral centers in Aib residues. As expected, peptides containing Aib residues have high solubility in moderate- and high-polar organic solvents and are easily purified by recrystallization from aqueous ethanol. This is in remarkable contrast with the result that the octa- and dodecapeptides containing Ala residues are barely soluble or insoluble in these solvents. Conformational analyses by IR spectroscopies indicated that Boc–(Leu3–Aib)n–OBzl and Boc–(Leu4–Aib)n–OBzl (n=2 and 3) had helical conformations (310- or α-helices) in dichloromethane, whereas Boc–(Leu3–Ala)n–OBzl (n=2 and 3) had fully developed β-sheet structures in the solid state. The high solubility of the peptides containing Aib residues is explained by the observation that replacement of Cα hydrogen atoms with methyl groups greatly disturbs β-sheet structures, promoting helical folding in peptides. The implications of the new findings for the chemistry of peptides and proteins containing α,α-disubstituted α-amino acid residues is also discussed by building up a CPK model of an α-helical structure.