Photocatalytic Aldehyde Allylation for Site‐Specific <scp>DNA</scp> Functionalization

Comprehensive Summary Enhancing the DNA toolbox with innovative photochemical reactions is pivotal for advancing nucleic acid‐based technologies. Aldehyde groups, versatile bioorthogonal handles for imine formation under acidic conditions, are particularly valuable due to their roles in nucleic acid epigenetics. Here, we present the first photocatalytic on‐DNA aldehyde allylation, enabling precise DNA functionalization under mild, neutral aqueous conditions. Our approach utilizes a photocatalytic polarity‐reversal reaction between DNA‐conjugated benzaldehydes and allyl sulfones. This reaction demonstrates exceptional chemoselectivity while preserving DNA integrity. By varying allyl sulfones, we achieve site‐specific labeling of non‐native DNA with the aldehyde group and cross‐linking with DNA‐bearing allyl sulfones. Furthermore, our method facilitates selective labeling and pull‐down enrichment of 5‐formylpyrimidine nucleotides among complex cellular DNA. This photocatalytic on‐DNA aldehyde transformation expands the limited bioorthogonal photochemical toolboxes, providing novel avenues for functionalizing both non‐native and native aldehyde modifications on DNA.