Solid support-dependent alkylation of tryptophan residues in SPPS using a 2-methoxybenzyl alcohol-based linker

Several side reactions can be encountered in the synthesis of Trp-containing peptides, due to molecular species originating from side chain-protecting groups or from the linker during acidolytic cleavage of the peptide from the resin. The linker can be the source of both alkylation in solution of the indole moiety of the tryptophan side chain and permanent readdition of the cleaved peptide to the resin. We report that both these reactions occur at a high level during the synthesis of Trp-containing peptides on a PEG-PS resin containing a 2-methoxybenzyl alcohol-based linker, in spite of the presence of suitable scavengers in the TFA-based cleavage mixture. Both side reactions are efficiently prevented by the use of a protected analogue of tryptophan, namely Nim-Boc-Trp, previously reported for the synthesis of peptides containing tryptophan and arginine residues.