The depsipeptide technique applied to peptide segment condensation: Scope and limitations

I. Coin, P. Schmieder, M. Bienert, M. Beyermann

J. Pept Sci. (2008) 14, 299-306

A promising application of the depsipeptide technique has recently been proposed to provide ideal conditions for segment condensation, in that coupling of peptides bearing a C-terminal depsipeptide unit occurs without giving rise to epimerization at the activated amino acid. This is due to the low tendency of the activated depsipeptide units, in contrast to the corresponding peptide segments, to form optically labile oxazolones. In this work we demonstrate that coupling of depsipeptides via base-assisted activation using HBTU occurs not only without loss of configuration, but even much faster than the coupling of the corresponding all-amide segments. Nevertheless, when the coupling of long depsipeptide segments proceeds slowly, we uncovered the occurrence of beta-elimination at the activated depsipeptide unit, in an extent dependent on the presence of base in the system and on the type of the solvent. Beta-elimination was completely suppressed by using carbodiimide/HOBt activation in a non-polar solvent (DCM), and in more polar media it was limited by substituting TMP for DIEA during HBTU activation, or using particular solvent mixtures (such as DMSO/toluene) for activation via carbodiimide. Finally, we show the application of C-terminal pseudoprolines, in comparison with that of depsipeptide units, to segment coupling.