Investigation on the stability of the Dde protecting group used in peptide synthesis: migration to an unprotected lysine1

An investigation of the stability of the Dde protecting group for amines, used in solid-phase peptide synthesis, shows that an unprotected ε-NH₂ group of lysine can acquire the Dde protection from another ε-NH₂ group or from an α-NH₂ group. An unprotected α-NH₂, however, cannot remove Dde from an ε-NH₂ function. This migration takes place during Fmoc removal from the ε-NH₂ with piperidine and/or during the subsequent washing steps. The Dde migration is also possible in neat dimethylformamide by a direct nucleophilic attack of the free ε-NH₂ group. Addition of piperidine to the reaction medium accelerates the side reaction, probably because of the formation of an unstable piperidine-Dde adduct. Dde migration can he prevented if the 9-fluorenylmethyloxycarbonyl is cleaved with 1,8-diazabicyclo[5,4,0]undec-7-ene for a short reaction time (2%, 3 × 3 min). Finally, this rearrangement is shown to occur both as an intra- and intermolecular reaction between peptides on the same resin bead.