Azide reduction during peptide cleavage from solid support - the choice of thioscavenger?

Peptide azides acquired growing impact because of application in bioconjugation via 'click chemistry' or Staudinger ligation. Furthermore, there are many methods established in organic synthesis addressing the reduction of azides to amines, but no observation of a reductive transformation of peptide azides during SPPS cleavage was yet reported. In the present study, the reduction of peptide azides during SPPS cleavage was investigated depending on the choice of thioscavenger, reacting as reductive species. First observed for short PNA/peptide conjugates the occurring extensive side reaction was also validated for one of the applied azide amino acid building blocks and was further investigated by applying different cleavage cocktails to a series of peptides varying in hydrophobicity and position of the azide moiety in the oligomer sequence. Copyright (C) 2009 European Peptide Society and John Wiley & Sons, Ltd.