AJIPHASE®: A Highly Efficient Synthetic Method for One‐Pot Peptide Elongation in the Solution Phase by an Fmoc Strategy

We previously reported an efficient peptide synthesis method, AJIPHASE®, that comprises repeated reactions and isolations by precipitation. This method utilizes an anchor molecule with long‐chain alkyl groups as a protecting group for the C‐terminus. To further improve this method, we developed a one‐pot synthesis of a peptide sequence wherein the synthetic intermediates were isolated by solvent extraction instead of precipitation. A branched‐chain anchor molecule was used in the new process, significantly enhancing the solubility of long peptides and the operational efficiency compared with the previous method, which employed precipitation for isolation and a straight‐chain aliphatic group. Another prerequisite for this solvent‐extraction‐based strategy was the use of thiomalic acid and DBU for Fmoc deprotection, which facilitates the removal of byproducts, such as the fulvene adduct. Extracted, not precipitated: AJIPHASE® is a new method for one‐pot peptide synthesis that makes use of solvent extraction during peptide elongation and does not require any isolation steps. This efficient approach leads to peptides of high purity and benefits from significantly reduced solvent consumption.