Visible Light Mediated Click Reactions of Diazoenals: Direct Access to Bicyclo[4.1.0]heptane-Fused Polycycles with Potential Application as Insulin Aggregation Inhibitors

Visible light-induced photoclick chemistry is a powerful synthetic tool, combining the precision of photochemistry with the modularity of click reactions. Herein, we report a novel class of bench-stable acceptor-acceptor diazo compounds diazoenals, that enable visible light-mediated photoclick reactions with vinyl arenes, generating cyclopropane-fused tetralin, decalin, and tetrahydrophenanthrene motifs having up to five stereocenters with excellent yield and diastereoselectivity, under aqueous conditions. These diazoenals exhibit enhanced photophysical properties, absorbing in the visible region, and upon irradiation, generate free enalcarbene intermediates that facilitate a selective mode of reactivity. Notably, these new class of photoclick products were found to be effective inhibitors of insulin aggregation, and the enal-tethered cyclopropylcarbazole completely rescued HEK293T cells from insulin fibril-mediated toxicity, highlighting the bioactive and biocompatible nature of this molecule. This work underscores the versatility of diazoenals in visible light-driven transformations, particularly in photoclick reactions, offering a sustainable and biocompatible synthetic platform for complex molecular architectures with potential bio-applications.