Accessing α-Ketoamides on DNA through a Coupling–Oxidation Strategy

α-Ketoamides are important pharmacophores in drug discovery yet remain underrepresented in DNA-encoded libraries (DELs) owing to the scarcity of robust on-DNA synthetic methods. Here, we describe an on-DNA coupling-oxidation strategy that efficiently yields DNA-conjugated α-hydroxyamides, serving as precursors to α-ketoamides via a subsequent oxidation step. This protocol demonstrates a broad substrate scope with excellent functional group tolerance, particularly with regard to mandelic acid derivatives. Furthermore, it enables the collective transformation of α-hydroxyamide libraries into α-ketoamide libraries, thereby significantly expanding the chemical space accessible to DELs.