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

• Published in: Angewandte Chemie 2024-11
• Main Authors: Zhong, Zhenhao, Hocking, Brad J. W., Brown, Charles P., Ma, Tsz-Kan, White, Andrew J. P., Mann, David J., Armstrong, Alan, Bull, James Adam
• Format: Article
• Language: English
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202420028

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) sp2‐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.