We report a rare example of the transformation of HCF3 into a fluoroalkene functional group through defluoroalkylation. We rationalise product formation through DFT calculations, scale-up the synthes...

Since the re-birth of sulfur-fluoride exchange (SuFEx) chemistry, coined by Sharpless in 2014 as a ‘click’ reaction, the prevalence of sulfur(vi) moieties in medicinal, polymer and materials chemistry...

Sulfonimidamides have emerged as attractive chemical motifs in drug discovery and as sulfonamide bioisosteres that can offer improved pharmacokinetic and physiochemical properties. Here we report a mi...

PhD Project - Development of automated workflows for direct-to-biology drug discovery of kinase inhibitors at Imperial College London, listed on FindAPhD.com

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PhD Project - New dimensions for covalent enantioprobe chemoproteomics at Imperial College London, listed on FindAPhD.com

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Sulfonyl fluorides are now established click reagents that find broad applications in synthesis, chemical biology, and drug discovery. Sulfonyl fluori…

Four-membered heterocycles such as oxetanes and azetidines represent attractive and emergent design options in medicinal chemistry due to their small and polar nature and potential to significantly impact the physiochemical properties of drug molecules. The challenging preparation of these derivatives, especially in a divergent manner, has severely limited their combination with other medicinally and biologically important groups. Consequently, there is a substantial demand for mild and effective synthetic strategies to access new oxetane and azetidine derivatives and molecular scaffolds. Here, we report the development and use of oxetane sulfonyl fluorides (OSFs) and azetidine sulfonyl fluorides (ASFs), which behave as precursors to carbocations in an unusual defluorosulfonylation reaction pathway (deFS). The small-ring sulfonyl fluorides are activated under mild thermal conditions (60 °C), and the generated reactive intermediates couple with a broad range of nucleophiles. Oxetane and azetidine heterocyclic, -sulfoximine, and -phosphonate derivatives are prepared, several of which do not have comparable carbonyl analogs, providing new chemical motifs and design elements for drug discovery. Alternatively, a SuFEx pathway under anionic conditions accesses oxetane-sulfur(VI) derivatives. We demonstrate the synthetic utility of novel OSF and ASF reagents through the synthesis of 11 drug analogs, showcasing their potential for subsequent diversification and facile inclusion into medicinal chemistry programs. Moreover, we propose the application of the OSF and ASF reagents as linker motifs and demonstrate the incorporation of pendant groups suitable for common conjugation reactions. Productive deFS reactions with E3 ligase recruiters such as pomalidomide and related derivatives provide new degrader motifs and potential PROTAC linkers.