Abstract
Synthesis of long peptides is generally considered as being a challenge to peptide chemists, in addition to producing significant amounts of toxic waste, such as DMF. Here we show that using solvent-less methods, such as ball milling, enabled the production of the hexapeptide Boc-(Ala-Phe-Gly)2-OBn at the gram scale with high overall yield (77%, 5 linear steps). This is the longest peptide chain synthesized in a ball mill to date, in which the amino acid sequence is precisely controlled. This study complements the current fundamental knowledge required to synthesize longer and more difficult peptide chains (or small proteins) by using peptide fragment couplings in a ball mill.