Diazo DOC: A Diazomethane Sulfonyl Fluoride Surrogate for Diversity-Oriented Clicking and SuFEx-Driven Protein Labeling

Abstract Diversity-oriented clicking (DOC) is a unified click approach for the modular synthesis of lead-like structures through the application of the wider family of click transformations. Here, we present a diazomethane sulfonyl fluoride surrogate, tert-butyl(((diazomethyl)sulfonyl)methoxy)dimethylsilane (tBu-DMSM, a diazo DOC hub), as the latest connective hub in DOC, marking a significant advancement in the field. Through a series of processes that adhere to many of the click chemistry principles, followed by silyl deprotection and electrophilic fluorination, we highlight the potential of this DOC hub in the synthesis of a library of unprecedented clickable heterocycles (tetrazoles, 3,3′-cyclopropyl spirooxindoles, and benzo[d]oxepines). The diversification of these novel cores through sulfur fluoride exchange (SuFEx) click chemistry yields the corresponding sulfonate esters, showcasing the versatility of the DOC strategy. Additionally, simple removal of the silyloxymethane group increases the scope further for the selective synthesis of heterocycles, with tBu-DMSM acting as a diazomethane alternative or a one carbon synthon. Furthermore, the utility of this method is showcased in the synthesis of a novel aggregation-induced emission (AIE) fluorescent tetrazole probe for covalent protein labeling via SuFEx, revealing selective and structure-dependent protein modification.