Expanding the Reach of Sustainable Solid-Phase Peptide Synthesis: One-Pot, Metal-Free Alloc Removal-Peptide Coupling

While the allyloxycarbonyl (Alloc) protecting group has played a key role in solid-phase peptide synthesis (SPPS), providing access to a wide range of peptides, its removal has suffered from relying on air-sensitive Pd(0) complexes in hazardous solvents. We report metal-free, on-resin Alloc removal using readily available iodine/water in environmentally sensible PolarClean (PC)/ethyl acetate (EtOAc) carried out in a one-pot manner with racemization-free peptide couplings employing both 9-fluorenylmethoxycarbonyl (Fmoc) and Alloc amino acids (AAs). Alloc SPPS has been demonstrated by performing consecutive one-pot Alloc removals-peptide couplings, whereas compatibility with long peptides has been proven by carrying out an Alloc removal-coupling on a 39 AA peptide resin. Upscaling to 10 g was combined with TFA-free peptide resin cleavage, opening up opportunities for employing Alloc-AAs as synthons for sustainable peptide manufacturing.