Synthesis of Versatile DNA‐Conjugated Aldehydes by Controlled Oxidation of Amines

Aldehyde‐functionalized oligonucleotides have found diverse applications in chemical biology and material science. However, due to the electrophilic nature of aldehydes, incorporating aldehyde functionalities directly into DNA is challenging, particularly for highly reactive alkyl aldehydes. Inspired by natural oxidases, we herein developed a controlled oxidation strategy to generate aldehyde‐functionalized DNAs from synthetically accessible DNA‐conjugated amines in situ. A broad range of DNA‐conjugated alkyl and aryl aldehydes were efficiently produced from the corresponding amines using O2/laccase/TEMPO, with feasible micromole‐scale preparation. Moreover, combining oxidative cleavage of DNA‐conjugated secondary and tertiary amines with reductive amination enabled switchable amine–aldehyde transformation and reversible solid‐phase bioconjugation of DNA probes. Furthermore, the reactivity ‘umpolung’ from nucleophilic amines to electrophilic aldehydes highlights its potential for synthesizing chemically diverse DNA‐encoded libraries (DELs). In summary, the presented controlled oxidation strategy expands the current toolbox to introduce aldehyde functionalities into DNAs within a chemical biological context.