Synthesis of Hydroxymethyl Side-Chained α-Aminoxy Diamide

Abstract

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 S_N2-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.

Keywords:

• α-Aminoxy acid
• diazotization/bromination
• neighboring carboxyl group participation
• peptide synthesis
• polar side chain

ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China (Project No. 20202001), Fok Ying Tung Education Foundation (Project No. 94023), and Fudan University. D.-W. Z. thanks Fudan University for the Century Star Award.