Facile Synthesis of Internal and C-Terminal Peptide α-Ketoamides with Fmoc-Solid Phase Peptide Synthesis

We report a general and operationally simple method for the solid phase synthesis of -ketoamide peptides using standard Fmoc solid phase peptide synthesis. The method delivers deprotected peptide -ketoamides directly upon resin cleavage without any additional steps, and tolerates all side chain functional groups. A small collection of C-terminal and internal -ketoamide peptides - including two reported protease inhibitors (HCV and SUB1) - were prepared in good yields. In addition, we demonstrate that our method serves as versatile platform for the convenient preparation of cyclic -ketoamide peptides, photocagged peptide -ketoamides, and fluorescently labeled peptides.