Synthesis and functionalization of sulfoximine-bicyclo[1.1.0]butanes: functionalizable, tuneable and cysteine-selective chiral warheads
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2025-01-01
Date Acceptance
2024-11-16
Citation
Angewandte Chemie International Edition, 2025, 64 (5)
ISSN
1433-7851
Publisher
Wiley
Journal / Book Title
Angewandte Chemie International Edition
Volume
64
Issue
5
Copyright Statement
© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://onlinelibrary.wiley.com/doi/10.1002/anie.202420028?msockid=09f6d6da35156ce526b9c2fa344f6dbd
Publication Status
Published
Article Number
e202420028
Date Publish Online
2024-11-17