Direct ring-strain loading for visible-light accelerated bioorthogonal ligation via diarylsydnone-dibenzo[b,f ][1,4,5]thiadiazepine photo-click reactions

Ultra-fast and selective covalent-bond forming reactions with spatiotemporal controllability are foundational for developing a bioorthogonal approach with high manipulability. However, it is challenging to exploit a reporter functional group to achieve these requirements simultaneously. Here, 11 H -Dibenzo[ c , f ][1,2]diazepine and a set of heterocyclic analogues are investigated for both their photo-switching natures and their ability to serve as dipolarophiles in photo-click reactions with diarylsydnone. Sulfur-containing dibenzothiadiazepine (DBTD) is discovered to be an excellent chemical reporter in cycloaddition with visible-light excitation for in-situ ring-strain loading via its ( Z ) → ( E ) photo-isomerization. The bioorthogonal utility of the DBTD tag in spatiotemporally controlled ligation for protein modifications on live cells is also demonstrated. Strained alkenes are valuable reagents for rapid and selective labeling of biomolecules but may undergo side-reactions. Here direct excitation of an azobenzene generates a strained nitrogen-nitrogen double bond in situ which reacts with a photochemically-generated nitrile imine, allowing the labeling of live cells with spatiotemporal control.