Chemoselective Protection of α-Ketoacids by Direct Annulations with Oximes

Oximes and alpha-ketoacids undergo an unexpectedly facile and chemoselective annulation to afford 2,5-dihydrooxazole 3-oxides. The resulting cyclic nitrones serve as chemically and configurationally stable masked a-ketoacids that can be easily elaborated and manipulated. Deprotection is achieved by mild reduction with zinc metal and hydrolysis. This methodology allows for the protection, elaboration, and deprotection of enantiopure peptide derived, a-ketoacids, which are the key starting materials for the chemoselective ketoacid-hydroxylamine peptide ligation.