Exploiting oxetane sulfonyl fluorides to access new chemical space for medicinal chemistry
Ollie Symes, James Bull Imperial College London, UK
Introduction: 3,3-Disubstituted oxetanes provide attractive motifs for medicinal chemistry due to their low molecular weight, high polarity and defined three-dimensional shape. [1] As a potentially valuable replacement for carbonyl and gem -dimethyl groups, as well as providing a new design element, 3,3‑disubstituted oxetanes have experienced an increased interest from the medicinal chemistry community. [1,2,3] We are interested in developing new synthetic methods to improve access to diverse 3,3‑disubstituted oxetanes. Our group recently developed a novel reaction whereby oxetane sulfonyl fluorides undergo defluorosulfonylation (deFS) to generate a tertiary oxetane carbocation, which is then trapped by amines to provide amino-oxetanes as potential amide isosteres. [4] Herein, we describe the use of oxetane sulfonyl fluorides to access new, polar and previously inaccessible 3,3-disubstituted oxetanes.
Results and discussion: Divergent reactivity of oxetane sulfonyl fluorides has been established. By tuning solvent polarity and temperature we have unlocked the SuFEx reactions of oxetane sulfonyl fluorides, alongside expanding the deFS reactivity to a wide range of polar nucleophiles. All 3,3-disubstituted oxetane motifs prepared access new chemical space and are inaccessible through other current methodologies. SuFEx: By using harder nucleophiles and lower temperatures in apolar solvents, the SuFEx pathway becomes favoured over deFS, providing access to new sulfur (VI)-oxetane motifs. Amines, N ‑heteroaromatics, phenols and alcohols, once deprotonated with a strong base, react through SuFEx to provide oxetano‑sulfonamides and oxetano-sulfonate esters, respectively. deFS: N -Heteroaromatics including imidazoles, pyrazoles, triazoles and tetrazoles all react smoothly, providing oxetane substituted heterocycles in high yields. Tri-alkyl phosphite reagents react via a Michaelis-Arbuzov mechanism, with the released fluoride ions able to de-alkylate the phosphonium ion intermediate to afford the oxetane phosphonate products. Analogous reactivity has also been observed with alkyl phosphonites and phosphinites. NH-sulfoximines can trap the oxetane carbocation to provide the N ‑protected sulfoximine. Trimethylsilylazide, activated by the released fluoride ions of the deFS, generates the oxetane azide which undergoes CuAAC click chemistry for further functionalisation. Conclusions and future work: Oxetane sulfonyl fluorides have been demonstrated as tuneable reactive intermediates that can act as a platform for facile and rapid access to new 3,3-disubstituted oxetane motifs. Future work will continue to explore the range of nucleophiles amenable to the deFS and SuFEx reactivity, enabling further access to new 3,3-disubstituted oxetane motifs of significant medicinal interest. References 1. J. A. Bull, R. A. Croft, O. A. Davis, R. Doran, K. F. Morgan, Chem. Rev. 2016 , 116 , 12150–12233. 2. J. A. Burkhard, G. Wuitschik, M. Rogers-Evans, K. Müller, E. M. Carreira, Angew. Chem. Int. Ed. 2010 , 49 , 9052–9067. 3. J. J. Rojas, J. A. Bull, J. Med. Chem. 2023 , DOI: 10.1021/ACS.JMEDCHEM.3C01101. 4. J. J. Rojas, R. A. Croft, A. J. Sterling, E. L. Briggs, D. Antermite, D. C. Schmitt, L. Blagojevic, P. Haycock, A. J. P. White, F. Duarte, C. Choi, J. J. Mousseau, J. A. Bull, Nat. Chem. 2022 , 14 , 160–169.
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© The Author(s), 2023
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