**Abstract**

Peptides or small-size proteins are important substances for medicines, diagnosis, and molecular biology research. In organic synthesis, the peptide bonds formation is performed in an organic solution (liquid-phase peptide synthesis, LPPS), or on a resin (solid-phase peptides synthesis, SPPS). LPPS can prepare a high volume of peptides, but it is generally required long processes and high cost for peptides preparation and is not appropriate for long-chain peptides. SPPS can prepare longchain peptides until 40 residues in a short time. However, it is difficult to obtain the pure peptides because of no purification of its intermediates. For a solution of these problems, Kent et al. reported native chemical ligation (NCL) method for the preparation of long-chain peptides. Because peptides with a long chain or difficult sequence formed β-sheet structure within a molecule, these peptides have high aggregability and low solubility, and their preparation and purification are generally difficult. Mutter et al. reported 'pseudoproline' method for difficult sequencecontaining peptide preparation. We previously reported a series of prodrugs based on *O*-*N* intramolecular acyl migration. We reported '*O*-isoacylpeptide' method for the preparation of difficult sequence-containing peptides using the prodrug strategy based on *O-N* intramolecular acyl migration.

**Keywords:** difficult sequence-containing peptide, long-chain peptide, *O-N* intramolecular acyl migration, peptide synthesis, isoacylpeptide
