Gram‐Scale Synthesis of a Hexapeptide by Fragment Coupling in a Ball Mill

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