Coarctate reaction for synthesis of fluorescent N-heterocycles, late-stage functionalization, and photo-triggered drug delivery

• Published in: Nature Communications
• Main Authors: Samrat Sahu, Zachary E. Paikin, John M. Talbott, Patrick Czabala, Monika Raj
• Format: Article
• Language: English
• Published: Nature Portfolio 2025-04-01
• Online Access: https://doi.org/10.1038/s41467-025-59057-x

Abstract Coarctate reactions, involving the simultaneous formation and cleavage of two bonds at single or multiple atoms, have remained largely unexplored for biomolecular applications. These reactions are characterized by complex helical orbitals in their transition state and produce unique chemical entities unattainable by other methods. This makes coarctate reactions particularly useful for expanding the chemical diversity and properties of biomolecules. In this study, we apply an azo-ene-yne coarctate reaction to synthesize isoindazole-based N-heterocycles and explore their biomolecular applications. The azo-ene-yne coarctate method demonstrates high chemoselectivity, thus enabling the synthesis of unnatural amino acids and drug conjugates, and late-stage peptide functionalization. These isoindazole-based N-heterocycles exhibit inherent fluorescence, which can be enhanced and red-shifted through electronic tuning. Additionally, we discover a photo-triggered cleavage of the isoindazole moiety from 2-amine-isoindazole, enabling the light-triggered selective delivery of secondary amine and hydroxyl-containing drugs, which represent over 70% of current pharmaceuticals. We also employ a light-triggered method for the selective deprotection of secondary amines and the late-stage functionalization of peptides with isoindazole, enabling access to previously unexplored chemical space.