Harnessing Oxetane\nand Azetidine Sulfonyl Fluorides\nfor Opportunities in Drug Discovery

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