2,5 Dihydrooxazole-3-oxides: Design of a protecting group for alpha-ketoacids and application for the synthesis of peptide-derived alpha-ketoacids

Our group has demonstrated the chemoselective decarboxylative condensation of unprotected peptide fragments via an N-terminal hydroxylamine and a C-terminal alpha-ketoacid. Access to the requisite enantiopure peptide-derived alpha-ketoacids has presented a challenge, and the development of synthetic methods for the preparation of alpha-ketoacids are crucial to the success of this project. We disclose a strategy for the chemoselective protection of alpha-ketoacids via direct annulation with oximes to afford 2,5-dihydrooxazole-3-oxides. The resulting cyclic nitrones are configurationally stable, and can be easily elaborated and modified; deprotection is achieved under mild aqueous conditions. We have extended this approach to the synthesis of peptide alpha-ketoacids in solution and solid phase. Successful application of this protocol will facilitate the synthesis of enantiopure peptide-derived alpha-ketoacids without the need for our previously reported late-stage oxidation.