Convergent Solid-phase Peptide Synthesis Performed in a CHCl3-phenol Mixed Solvent: Synthesis of Amyloid β-peptides as Examples with a Difficult Sequence

Abstract

Convergent solid-phase peptide synthesis (CSPPS) involving the coupling of protected peptide segments on a solid support performed in a β-sheet disrupting solvent consisting of a mixture of CHCl3 and phenol (v/v, 3/1), proceeded smoothly without danger of epimerization or of significant phenyl ester formation with the carboxyl component when diisopropylcarbodiimide (DIC) was used in the presence of 1-hydroxy-7-azabenzotriazole (HOAt) or 6-chloro-1-hydroxybenzotriazole (Cl-HOBt). In particular, this synthetic strategy using the CHCl3 and phenol mixed solvent proved to be essential for coupling sparingly soluble segments even with difficult sequences. The present approach was successfully applied to the synthesis of amyloid β-peptide (Aβ) (1-40) and also its reversed Aβ (40-1) as an inactive control peptide.