Harnessing Oxetane and Azetidine Sulfonyl Fluorides for Opportunities in Drug Discovery

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 physiochemical properties of drug molecules. The challenging preparation of these derivatives, especially in a divergent manner, has severely limited the combination of oxetanes 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. Herein, we report the development and use of oxetane sulfonyl fluorides (OSF) and azetidine sulfonyl fluorides (ASF), 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 ºC), and the generated reactive intermediates couple with a broad range of nucleophiles. This reactivity enables the generation of new chemical motifs that make attractive design elements for drug discovery. Notably, oxetane and azetidine-heterocyclic, -sulfoximine and -phosphonate derivatives are prepared, several of which do not have comparable carbonyl analogues. 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 analogues, 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.