Preparation of C-terminal peptide alpha-ketoacids for decarboxylative ligation and application to synthesis of cyclopeptides

During the studies of chemoselective amide-bond forming decarboxylative condensation between alpha-ketoacids and hydroxylamines, the availability of the ligation partners is a key factor for practical utilization of this ligation method. The preparation of alpha-ketoacids has been achieved through a mild oxidation of the corresponding cyanosulfur ylides. Facile preparation of the peptide sulfur ylides with standard peptide coupling protocols combining with a robust, chemoselective oxidation process allowed generation of C-terminal peptide alpha-ketoacids with minimal epimerization, which were directly used in chemoselective peptide ligation reactions with N-alkyl hydroxylamines.;To develop a general strategy for the easy access to larger peptide derived sulfur ylides, the elongation of a peptide sequence was accomplished on a conventional tetrahydrothiophene-based sulfonium solid support. This strategy enables the preparation of C-terminal peptide sulfur ylides with flexible choices and combinations of peptide residues. These solid-phase synthesized sulfur ylides serve as precursors to provide C-terminal alpha-ketoacids via a chemoselective oxidation. In addition to great tolerance to standard Fmoc-based standard coupling conditions, the practical method offers promising compatibility with most of side chains-unprotected amino acids. This convenient preparation and utilization of cyanosulfur ylide has made possible the generation of enantioenriched alpha-ketoacids with desired lengths and peptide residues. Furthermore, with incorporation of N-terminal nitrone-derived amino acid as the last residue during solid-phase peptide synthesis, the strategy was applied to intramolecular ligations for non-Cys containing cyclic conjugations.