INVESTIGATION ON THE STABILITY OF THE DDE PROTECTING GROUP USED IN PEPTIDE-SYNTHESIS - MIGRATION TO AN UNPROTECTED LYSINE

An investigation of the stability of the Dde protecting group for amin es, used in solid-phase peptide synthesis, shows that an unprotected e psilon-NH2 group of lysine can acquire the Dde protection from another epsilon-NH2 group or from an alpha-NH2 group. An unprotected alpha-NH 2, however, cannot remove Dde from an epsilon-NH2 function. This migra tion takes place during Fmoc removal from the epsilon-NH2 with piperid ine and/or during the subsequent washing steps. The Dde migration is a lso possible in neat dimethylformamide by a direct nucleophilic attack of the free epsilon-NH2 group. Addition of piperidine to the reaction medium accelerates the side reaction, probably because of the formati on of an unstable piperidine-Dde adduct. Dde migration can be prevente d if the 9-fluorenylmethyloxycarbonyl is cleaved with 1,8-diazabicyclo [5.4.0]undec-7-ene for a short reaction time (2%, 3 x 3 min). Finally, this rearrangement is shown to occur both as an intra-and intermolecu lar reaction between peptides on the same resin bead. (C) Munksgaard 1 998.