Investigation of Nitrile Oxide-Alkyne 1,3-Dipolar Cycloadditions and Their Potential Viability for Synthesis of Stapled Peptides

Abstract

The nitrile oxide-alkyne 1,3-dipolar cycloaddition reaction is a concerted reaction between a nitrile oxide, which is usually generated in situ, and an alkyne to afford an isoxazole. This reaction has been previously used in post-synthetic modification of nucleic acids. This work examines the potential utility of the nitrile oxide-alkyne 1,3- dipolar cycloaddition reaction in the synthesis of stapled peptides. Stapled peptides, or hydrocarbon cross-linked peptides, show potential as drugs to target protein-protein interactions in the body. The nitrile oxide-alkyne cycloaddition, if efficient, could solve some of the issues currently present in stapled peptide synthesis, including the use of toxic copper catalysts in the more common azide-alkyne 1,3-dipolar cycloaddition. Multiple nitrile oxide-alkyne cyclization attempts proved successful with simple starting materials. Subsequently, two amino acids, one containing an aldehyde and another containing an alkyne, were synthesized. The amino acids were not able to successfully participate in the nitrile oxide-alkyne cycloaddition. More research is required to optimize the procedure for this reaction before it can be used in a stapled peptide.