Synthesis of Hydroxymethyl Side-Chained α-Aminoxy Diamide

Unnatural polar α-aminoxy acid residue with proteingenous hydroxymethyl side chain, a building block of the peptidomimetic foldamer of α-aminoxy peptide, was synthesized starting from natural amino acid L-serine. The starting material, L-serine, undergoes a reaction sequence to produce compound 1 in three steps: (1) the neighboring carboxyl group participates in diazotization/bromination to transform the amino group to a bromo group, (2) the C-terminal carboxyl group is protected, and (3) bromide is SN2-displaced by N-hydroxyl phthalimide to introduce a N‒O bond. After several conventional deprotection/coupling reactions, compound 1 is easily transformed to an α-aminoxy diamide, which can be widely used in peptidomimetics design.