Formation of Fmoc–β‐alanine during Fmoc‐protections with Fmoc–OSu

Abstract

During the Fmoc-protection of H–α-Me–Val–OH, an unknown side product was found and isolated. The characterization using various analytical methods led unambiguously to the result that Fmoc–β-Ala–OH was formed during the reaction. The reagent Fmoc–OSu was proven to be the source of Fmoc–β-Ala–OH, following a mechanism that involved many deprotonation and elimination steps and a Lossen-type rearrangement as key sequence. The impurity Fmoc–β-Ala-OH was found in a variety of reactions in which Fmoc–OSu was applied, either in the reaction mixture or as a contamination of the crude product. Purification of the Fmoc–amino acid derivatives from this impurity incurred high costs and significant reductions in yield. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.