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‐NH 2 group of lysine can acquire the Dde protection from another ε‐NH 2 group or from an α‐NH 2 group. An unprotected α‐NH 2 , however, cannot remove Dde from an ε‐NH 2 function. This migration takes place during Fmoc removal from the ε‐NH 2 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‐NH 2 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.