N-Hydroxy amide, as an oxidized amide, finds an unprecedented utility in peptide synthetic chemistry, including the oxidation of the alpha-carbon of the main chain and the development of a new ligation reaction. The O-acylation of the hydroxy amide, followed by Lossen rearrangement, allows the oxidation state of the amide derivative to transfer to a neighboring carbon atom. We found that glycyl hydroxamic acid (GlyHA), which has N-hydroxy amide as a side chain on the Gly alpha carbon, functions as a precursor of alpha-oxidized amino acid derivatives.[1,2] The alpha-oxidized amino acids possessing halogen or heteroatom on the alpha-carbon are useful synthetic intermediates that allow for the derivatization on the main chain of peptides. However, such an oxidized amino acid is easily decomposed upon the regeneration of free amine through the removal of Na-protection of the protected amino acid derivatives. Consequently, the elongation of peptide chains containing alpha-oxidized residues remains to be achieved, and the methodology for regioselective late-stage oxidation of the alpha-carbon has been demanded. In this context, we found that the N-terminal GlyHA residue is converted to the corresponding alpha-isocyanate Gly unit (Gly(NCO)) by selective O-acylation of the N-hydroxy amide followed by Lossen rearrangement for which the free amino group of GlyHA is significantly indispensable. The resulting Gly(NCO) became a glyoxylyl residue by subsequent hydration, decarboxylation, and hydrolysis. Furthermore, an amine-free GlyHA residue in peptide sequence can also be converted to the Gly(NCO) residue by selective O-acylation with an amino acid thioester. Subsequently, the hydrolysis and NaNO2-mediated oxidation allowed for the formation of an acyl iminium intermediate, which accepts a sulfur nucleophile to result in the synthesis of a sactipeptide model.
In contrast, the N-hydroxy amide in the peptide main chain has no hydrogen atom responsible for the Lossen rearrangement. Therefore, the O-acyl-N-hydroxy amide can work as an acylating agent. The N-aminoacyl-N-hydroxy amino acid (NAHA) was proven to be acylated by peptide thioester and the peptidyl unit transferred to the N-terminal amino group through O-N acyl transfer. Consequently, N-terminal residue-independent peptide ligation was achieved using the NAHA residue. In this presentation, we will discuss the potential utility of the N-hydroxy amide in peptide chemistry.