Solvent‐Enabled Selective Electrochemical Decarboxylative Acetoxylation of Fmoc‐Protected Peptides

Electrochemical decarboxylative acetoxylation of Fmoc-protected peptides via anodic oxidation of the carboxylic acid is challenging under conventional conditions, due to the lability of the Fmoc protecting group. Using selected cosolvents which can be oxidized at higher potentials than the target carboxylic acid but lower than the protecting group, the electrochemical acetoxylation is enabled under constant current conditions.

The synthesis of peptide-based linkers for antibody-drug conjugates involves an oxidative decarboxylation step. Traditional Hofer–Moest electrolysis conditions are not suitable to achieve this transformation due to the presence of an oxidatively labile Fmoc-protecting group. Herein, a solvent-enabled electrochemical procedure has been established, whereby the solvent electrochemical window prevents degradation of the protecting group. The method has been demonstrated for several relevant peptides in good to very good yields (64–92%).

Zum Volltext