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Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides

Nature Chemistry volume 14, pages 160–169 (2022)Cite this article

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Abstract

Bioisosteres provide valuable design elements that medicinal chemists can use to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides—extremely common pharmacophores—but are rarely examined due to the lack of available synthetic methods. Here we describe a class of reactions for sulfonyl fluorides to form amino-oxetanes by an alternative pathway to the established SuFEx (sulfonyl–fluoride exchange) click reactivity. A defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared. Kinetic and computational studies support the formation of an oxetane carbocation as the rate-determining step, followed by a chemoselective nucleophile coupling step.

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Fig. 1: Defluorosulfonylative coupling of oxetane sulfonyl fluorides with amines.
Fig. 2: Synthesis and reactivity of OSFs.
Fig. 3: Reaction scope on varying the OSF and application towards the synthesis of analogues of benzamide-containing drugs.
Fig. 4: Kinetic and computational analysis of the defluorosulfonylative oxetane amination.

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Data availability

The data supporting the findings of this work are provided in the Supplementary Information. Metrical parameters for the structure of amino-oxetanes 30 and 38, oxetane sulfonate esters 49, 89 and 93, oxetane ether 50 and sulfonyl fluorides 1, 54, 56 and 92 are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/data_request/cif) under reference nos. CCDC 2094791 (1), CCDC 2049639 (30), CCDC 2049640 (38), CCDC 2094792 (49), CCDC 2094793 (50), CCDC 2049754 (54), CCDC 2094794 (56), CCDC 2094795 (89), CCDC 2094871 (92) and CCDC 2094796 (93). Raw and processed characterization data for all novel compounds as well as compiled computational data are available at the Imperial College London Research Data Repository72.

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Acknowledgements

We acknowledge support from The Royal Society (University Research Fellowship UF140161 and URF\R\201019 to J.A.B., URF appointed grant no. RG150444 and URF enhancement grant no. RGF\EA\180031), the EPSRC (CAF to J.A.B. (EP/J001538/1) and a DTP studentship to E.L.B), Imperial College London for a Presidents scholarship (to R.A.C.) and Pfizer and Imperial College London for studentship funding (to J.J.R.). A.J.S. thanks the EPSRC Synthesis for Biology and Medicine CDT and the Oxford-Radcliffe Scholarship for support (EP/L015838/1).

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  1. These authors contributed equally: Juan J. Rojas, Rosemary A. Croft.

Authors and Affiliations

  1. Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London, UK

    Juan J. Rojas, Rosemary A. Croft, Edward L. Briggs, Daniele Antermite, Luka Blagojevic, Peter Haycock, Andrew J. P. White & James A. Bull

  2. Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK

    Alistair J. Sterling & Fernanda Duarte

  3. Pfizer Worldwide Research, Development and Medical, Groton, CT, USA

    Daniel C. Schmitt, Chulho Choi & James J. Mousseau

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Contributions

R.A.C., J.A.B., C.C. and J.J.M. initiated the project. R.A.C., J.J.R., E.L.B., D.A., L.B. and C.C. planned and performed the synthetic experiments and analysed the data. D.C.S. designed, performed and analysed the array screen. J.J.R. and P.H. designed, performed and analysed the kinetic experiments. A.J.P.W. collected, processed and refined single-crystal X-ray diffraction data. A.J.S. and F.D. designed and conducted the computational studies. J.A.B. managed the project. J.J.R., A.J.S., F.D. and J.A.B. wrote the manuscript. All authors discussed the results and contributed to editing the manuscript and preparing the Supplementary Information.

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Correspondence to James A. Bull.

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Supplementary information

Supplementary Information

Extended scope, supplementary discussion, experimental, computational and procedural details, synthesis and characterization data, HPLC and LCMS traces, X-ray crystallographic data, NMR spectra, Supplementary Schemes 1–11, Figs. 1–63 and Tables 1–32.

Supplementary Data 1

Crystallographic data for compound 1; CCDC reference 2094791.

Supplementary Data 2

Crystallographic data for compound 30; CCDC reference 2049639.

Supplementary Data 3

Crystallographic data for compound 38; CCDC reference 2049640.

Supplementary Data 4

Crystallographic data for compound 49; CCDC reference 2094792.

Supplementary Data 5

Crystallographic data for compound 50; CCDC reference 2094793.

Supplementary Data 6

Crystallographic data for compound 54; CCDC reference 2049754.

Supplementary Data 7

Crystallographic data for compound 56; CCDC reference 2094794.

Supplementary Data 8

Crystallographic data for compound 89; CCDC reference 2094795.

Supplementary Data 9

Crystallographic data for compound 92; CCDC reference 2094871.

Supplementary Data 10

Crystallographic data for compound 93; CCDC reference 2094796.

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Rojas, J.J., Croft, R.A., Sterling, A.J. et al. Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides. Nat. Chem. 14, 160–169 (2022). https://doi.org/10.1038/s41557-021-00856-2

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