O-Acyl isopeptide method for peptide synthesis: Solvent effects in the synthesis of A beta 1-42 isopeptide using O-acyl isodipeptide unit

O-Acyl isopeptide method is an efficient synthetic method for peptides. We designed O-acyl isodipeptide units, Boc-Ser/Thr(Fmoc-Xaa)-OH, as important building blocks to enable routine use of the O-acyl isopeptide method. In the synthesis of an A1-42 isopeptide using O-acyl isodipeptide unit Boc-Ser(Fmoc-Gly)-OH, a side reaction, resulting in the deletion of Ser26 in the O-acyl isopeptide structure, was noticed during coupling of the unit. We observed that the side reaction occurred during the activation step and was solvent-dependent. In DMF or NMP, an intramolecular side reaction, originating from the activated species of the unit, occurred during the activation step. In non-polar solvents such as CHCl3 or CH2Cl2, the side reaction was less likely to occur. Using CH2Cl2 as solvent in coupling the unit, the target A1-42 isopeptide was synthesized with almost no major side reaction.