Suppression of a side reaction associated with N(im)-benzyloxymethyl group during synthesis of peptides containing cysteinyl residue at the N-terminus.

During the synthesis of His-containing peptide, having a Cys residue at the amino terminus, by the HF method, a large quantity of an unexpected product was formed when the His residue was protected by the benzyloxymethyl (BOM) group. This side product was found to be a thioprolyl-peptide which was formed from the Cys-peptide with formaldehyde released from the Bom group by HF. In order to suppress this side reaction, we tried using various scavengers and found that Cys and its derivatives were most effective, although they could not completely suppress the side reaction. Even after the HF reaction, formaldehyde attached to the scavenger or peptide seemed to cause further conversion of the Cys-peptide to thioprolyl-peptide. Thus, proper removal of the formaldehyde from the reaction mixture is essential to reduce the formation of this undesirable product.