Incorporation of Acid-Labile Masking Groups for the Traceless Synthesis of C-Terminal Peptide α-Ketoacids

An optimized protocol for the masking of aketoacids with acid-labile cyclic acetal protecting groups is reported. Unlike prior approaches, these new conditions allow the synthesis of protected alpha-ketoacids bearing aromatic, hindered alkyl, and protected polar side chains. Attachment to a Wang-type linker and solid support provides a resin that delivers fully unprotected C-terminal peptide a-ketoacids upon resin cleavage. These peptides are the key starting materials for chemical protein synthesis using the a-ketoacid hydroxylamine ligation.