N-Hydroxy amide, as an oxidized amide, finds utility in peptide chemistry, including the oxidation of the main chain alpha-carbon and the development of a new ligation reaction. The O-acylation of the hydroxy amide is followed by Lossen rearrangement; therefore, the oxidation state of the amide derivative is transferred to a neighboring carbon atom. We found that glycyl hydroxamic acid (GlyHA), a Gly derivative possessing N-hydroxy amide as a side chain, functions as a precursor of alpha-oxidized amino acid derivatives.[1,2] Such oxidized derivatives are useful synthetic intermediates that allow for the derivatization of peptides but are easily decomposed upon the regeneration of free amine. Consequently, the methodology for regioselective late-stage oxidation of the alpha-carbon has been demanded. Recently, we found that the N-terminal GlyHA residue is converted to the corresponding alpha-isocyanate Gly unit (Gly(NCO)) by O-acylation of the GlyHA followed by Lossen rearrangement. The resulting Gly(NCO) finally became a glyoxylyl residue. Furthermore, a GlyHA residue in the peptide sequence can also be converted to the Gly(NCO) residue. Subsequently, the hydrolysis and NaNO2-mediated oxidation allowed for forming an acyl iminium intermediate, which can be converted to a sactionine linkage.
In contrast, the N-hydroxy amide in the peptide main chain 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. In this presentation, we will discuss the potential utility of the N-hydroxy amide in peptide chemistry.