N-alkylation of amino acid residues by chloromethyl groups. A potential side reaction in the solid phase peptide synthesis

A serious side reaction in the peptide synthesis on the Merrifield resin was observed during attempts to synthesize the TMV fragment, Asn-Pro-Thr-Thr-Ala (101--105). The side reaction is consistent with N-alkylation of the amino groups by the residual chloromethyl groups on the resin, which lowers the total yield and complicates evaluation of monitoring data during the synthesis. It is shown that several amino acids can be N-alkylated in different positions in the peptide chain and in different solvents. The extent of N-alkylation is in some cases 50%.