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 amines, used in solid-phase peptide synthesis, shows that an unprotected epsilon-NH2 group of lysine can acquire the Dde protection from another epsilon-NH2 group or from an alpha-NH2 group. An unprotected alpha-NH2, however, cannot remove Dde from an epsilon-NH2 function. This migration takes place during Fmoc removal from the epsilon-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 epsilon-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 be prevented 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 intermolecular reaction between peptides on the same resin bead.
Augustyns
K
K
Institute of Organic Chemistry, University of Tübingen, Germany. augustyn@uia.ua.ac.be
Kraas
W
W
Jung
G
G
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004126:Dimethylformamide; D004355:Drug Stability; D005449:Fluorenes / Q000737:chemistry; D008239:Lysine / Q000737:chemistry*; D013058:Mass Spectrometry; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry
D000596:Amino Acids; D005449:Fluorenes; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D010455:Peptides; D010880:Piperidines; C032727:piperidine; D004126:Dimethylformamide; D008239:Lysine