O-Acylation of N-Boc-protected-serine and -threonine with N-Pg-(a-aminoacyl)benzotriazoles afforded the chiral O-acylated isodipeptides at 23 C in yields of 74-91%.The synthesis of peptides and proteins is of great importance to the understanding of biological functions. The solid-phase synthesis of peptides with ''difficult sequences'' remains problematic due to low yields and purity. 1 In addition, intermolecular hydrophobic interactions in ''difficult sequences'' can promote aggregation in solution and hydrogen bond networks in resinbound peptides can form extended structures such as b-sheets. 1b-c,2 Kiso et al. 1d demonstrated that the introduction of an O-acyl in place of an N-acyl residue within a peptide backbone significantly altered the secondary structure of native peptides. Furthermore, these ''O-acyl isopeptides'' or ''click peptides'' ‡ are more hydrophilic, and easier to purify by HPLC. 1d He found that a subsequent O-N intramolecular acyl migration, triggered by change in pH, could rapidly generate a target natural peptide under physiological conditions (pH 7.4) (Fig. 1). 1c,3a This ''O-acyl isopeptide method'' 3 has been used to develop new water-soluble taxoid prodrugs, 4 HIV-1 protease inhibitors, 5 the anti-tumor agent, paclitaxel, 6 difficult sequence-containing peptides including Ac-Val-Val-Ser-Val-Val-NH 2 , 1b,4,7 Alzeheimer's disease-related amyloid b peptide (Ab) 1-42, 4,7-13 and cyclic peptides. 14