Synthesis and Functionalization of Sulfoximine-Bicyclo[1.1.0]butanes: Functionalizable, Tuneable and Cysteine-Selective Chiral Warheads.

Autor: Zhong Z; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 0BZ, UK., Hocking BJW; Department of Life Sciences, Imperial College London South Kensington Campus, London, SW7 2AZ, UK., Brown CP; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 0BZ, UK., Ma TK; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 0BZ, UK., White AJP; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 0BZ, UK., Mann DJ; Department of Life Sciences, Imperial College London South Kensington Campus, London, SW7 2AZ, UK., Armstrong A; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 0BZ, UK., Bull JA; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 0BZ, UK.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Nov 17, pp. e202420028. Date of Electronic Publication: 2024 Nov 17.
DOI: 10.1002/anie.202420028
Abstrakt: Electrophilic covalent warheads with appropriate reactivity and selectivity are crucial to the investigation of protein function and the discovery of therapeutics. Here we report the synthesis of sulfoximine bicyclo[1.1.0] butanes (BCBs) as novel thiol reactive chiral warheads, achieved in one-pot from methylsulfoximines. Unusually the warhead can then be derivatized, keeping the BCB intact, over 3 vectors: i) sulfoximine N-modification instills a broad range of strain-release reactivity; ii) sp 2 -cross-coupling reactions on aryl-BCB-sulfoximines allows direct diversification, and iii) functionalization of the BCB motif itself is achieved by metalation and trapping with electrophiles. The BCB sulfoximines are shown to react selectively with cysteine including in a protein model (CDK2) under biocompatible conditions. Preliminary data indicate suitability for chemoproteomic applications, and enantioselective cysteine-labelling. The reactivity of sulfoximine BCBs with electron withdrawing groups on nitrogen is comparable to acrylamides with low to moderate reactivity.
(© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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