Further studies on the side reactions associated with use of N(pi)-benzyloxymethylhistidine

The use of N(alpha)-tert.-butyloxycarbonyl-N(pi)-benzyloxymethylhistidine [Boc-His(Bom)] in peptide synthesis results in a serious level of side products arising from the generation of formaldehyde during the HF cleavage reaction. In particular, when treating a His(Bom)-containing peptide having Cys at the N-terminus by HF, this leads to almost complete conversion of the Cys-peptide to thiazolidyl (Thz)-peptide unless precautions are taken. Also, the reaction of formaldehyde with the N-terminal Trp and the N-methylanthranyl (Nma) group was found to produce tetrahydro-beta-carboline and dihydroquinazolin derivatives, respectively, upon isolation from HF mixtures. The addition of cysteine as a scavenger in HF proved to be effective for suppressing modification arising from the generation of formaldehyde.