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A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres

Nature Chemistry volume 15, pages 535–541 (2023)Cite this article

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Abstract

C(sp3)-rich bicyclic hydrocarbon scaffolds, as exemplified by bicyclo[1.1.1]pentanes, play an increasingly high-profile role as saturated bioisosteres of benzenoids in medicinal chemistry and crop science. Substituted bicyclo[2.1.1]hexanes (BCHs) are emerging bicyclic hydrocarbon bioisosteres for ortho- and meta-substituted benzenes, but are difficult to access. Therefore, a general synthetic route to BCHs is needed if their potential as bioisosteres is to be realized. Here we describe a broadly applicable catalytic approach that delivers substituted BCHs by intermolecular coupling between olefins and bicyclo[1.1.0]butyl (BCB) ketones. The SmI2–catalysed process works for a wide range of electron-deficient alkenes and substituted BCB ketones, operates with SmI2 loadings as low as 5 mol% and is underpinned by a radical relay mechanism that is supported by density functional theory calculations. The product BCH ketones have been shown to be versatile synthetic intermediates through selective downstream manipulation and the expedient synthesis of a saturated hydrocarbon analogue of the broad-spectrum antimicrobial, phthalylsulfathiazole.

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Fig. 1: Building emerging, hard-to-access BCH bioisosteres using radical relay catalysis.
Fig. 2: Computational study of the SmI2-catalysed alkene insertion.
Fig. 3: Applications of the SmI2-catalysed alkene insertion.

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Data availability

Materials and methods, experimental procedures, useful information, mechanistic studies, 1H NMR spectra, 13C NMR spectra and mass spectrometry data are available in the Supplementary Information. Crystallographic data for compounds 13s, 13ai, 13aw and 20 have been deposited with the Cambridge Crystallographic Data Centre under accession codes CCDC 2129464, 2129466, 2129467 and 2129468, respectively.

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Acknowledgements

Financial support was provided by the Engineering and Physical Sciences Research Council (Postdoctoral Research Award to S.A. and F.B.; EP/R029938/1), European Union Horizon 2020 programme (Marie Sklodowska-Curie Individual Fellowship to S.A.; EU project 891623—SmART), Engineering and Physical Sciences Research Council Centre for Doctoral Training in Integrated Catalysis (EP/S023755/1) and University of Manchester (lectureship to G.E.M.C.). We thank the University of Manchester for its Computational Shared Facility and associated support services. We are grateful for the assistance provided via the NMR and mass spectrometry services and thank G. Whitehead and I. J. Vitorica-Yrezabal for assistance with the X-ray crystallographic analysis.

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Authors and Affiliations

  1. Department of Chemistry, The University of Manchester, Manchester, UK

    Soumitra Agasti, Frédéric Beltran, Emma Pye, Nikolas Kaltsoyannis, Giacomo E. M. Crisenza & David J. Procter

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  1. Soumitra Agasti
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Contributions

S.A., G.E.M.C. and D.J.P. conceived of the project. S.A. and F.B. designed and performed the experimental work. E.P. performed the computational studies. N.K. supervised the computational studies. S.A., F.B., G.E.M.C. and D.J.P. contributed to the analysis and interpretation of the data. D.J.P. wrote the manuscript with input from all authors.

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Correspondence to David J. Procter.

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Nature Chemistry thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Schemes 1–7, discussion and Tables 1–5.

Supplementary Data 1

Crystallographic data for compound 13ai (CCDC reference 2129466).

Supplementary Data 2

Crystallographic data for compound 13aw (CCDC reference 2129467).

Supplementary Data 3

Crystallographic data for compound 13s (CCDC reference 2129464).

Supplementary Data 4

Crystallographic data for compound 20 (CCDC reference 2129468).

Supplementary Data 5

Coordinates and energies for 21 and 25 and the structures in Supplementary Tables 4 and 5.

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Agasti, S., Beltran, F., Pye, E. et al. A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres. Nat. Chem. 15, 535–541 (2023). https://doi.org/10.1038/s41557-023-01135-y

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