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Issue 1, 2019
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Vinyl sulfonamide synthesis for irreversible tethering via a novel α-selenoether protection strategy

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Abstract

Vinyl sulfonamides are valuable electrophiles for targeted protein modification and inhibition. We describe a novel approach to the synthesis of terminal vinyl sulfonamides which uses mild oxidative conditions to induce elimination of an α-selenoether masking group. The method complements traditional synthetic approaches and typically yields vinyl sulfonamides in high purity after aqueous work-up without requiring column chromatography of the final electrophilic product. The methodology is applied to the synthesis of covalent fragments for use in irreversible protein tethering and crucially enables the attachment of diverse fragments to the vinyl sulfonamide warhead via a chemical linker. Using thymidylate synthase as a model system, ethylene glycol is identified as an effective linker for irreversible protein tethering.

Graphical abstract: Vinyl sulfonamide synthesis for irreversible tethering via a novel α-selenoether protection strategy

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Publication details

The article was received on 16 Nov 2018, accepted on 11 Dec 2018 and first published on 13 Dec 2018


Article type: Research Article
DOI: 10.1039/C8MD00566D
Med. Chem. Commun., 2019,10, 158-163

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    Vinyl sulfonamide synthesis for irreversible tethering via a novel α-selenoether protection strategy

    G. B. Craven, D. P. Affron, P. N. Raymond, D. J. Mann and A. Armstrong, Med. Chem. Commun., 2019, 10, 158
    DOI: 10.1039/C8MD00566D

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