STEFs ‐ Activated Vinylogous Protein‐Reactive Electrophiles

We report the synthesis of a class of semi‐oxamide vinylogous thioesters that we have designated STEFs and the use of these agents as new electrophilic warheads. This includes preparation of both simple probes that contain this reactive motif as well as its installation on a more complex kinase inhibitor scaffold. A key aspect of STEFs is their reactivity towards both thiol‐ and amine groups and we substantiate that amine‐conjugations in peptidic and proteinogenic samples can be facilitated by initial, fast conjugation to proximal thiol residues. We provide evidence that both the selectivity and the reactivity can be tuned by the structure of STEFs and given the unique ability of this functionality to conjugate via an addition‐elimination mechanism, STEFs are electrophilic warheads that could find broad use in chemical biology.

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