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Enantiospecific cross-coupling of cyclic alkyl sulfones

Nature Chemistry volume 16, pages 1445–1452 (2024)Cite this article

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Abstract

Methods to form carbon–carbon bonds efficiently and with control of stereochemistry are critical for the construction of complex molecules. Cross-coupling reactions are among the most efficient and widely used reactions to construct molecules, with reactions enabling the retention or installation of chirality as recent additions to this powerful toolbox. Sulfones are robust, accessible organic electrophiles that have many attractive features as cross-coupling partners; however, since the first example of their use in 1979, there have been no examples of their use in enantioselective, enantiospecific or entantioconvergent cross-couplings. The high acidity of sulfones makes it unclear whether this transformation is even possible outside tertiary systems. Here we report the enantiospecific cross-coupling of cyclic sulfones and Grignard reagents. Up to 99% chirality transfer is observed despite the strong basicity of the Grignard components. In situ monitoring reveals that the cross-coupling is kinetically competitive with competing deprotonation, resulting in a highly enantioselective transformation.

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Fig. 1: Desulfonylative cross-coupling reactions.
Fig. 2: Enantiospecific Ni-catalysed cross-coupling.
Fig. 3: Mechanistic investigations.

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Data availability

Crystal structure data for (S)-1a, [NiBr2(DMPMA)]2 and (R)-17 have been deposited at the Cambridge Crystallographic Data Centre (CCDC 2298851-2298853), and crystallographic data are provided in Supplementary Information. Additionally, the spectroscopic, mass spectrometric, chromatographic and kinetic data that support the findings of this study are also available in Supplementary Information.

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Acknowledgements

This work was supported by a Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) (17K17805 and 21K05068 to M.N.). S.S. thanks the Baden-Württemberg-Stiftung for funding. J.A. and S.S. also thank the support of the Stuttgart-Queen’s Dual MSc Degree Program. C.M.C. and R.N.-S. acknowledge the Natural Science and Engineering Research Council of Canada (NSERC) and the Canada Foundation for Innovation (CFI) for funding. Z.T.A. thanks Queen’s University for funding. JSPS and Nagoya University are acknowledged for funding of this research through The World Premier International Research Initiative (WPI) program. The authors also wish to thank F. Sauriol (NMR), K. McEleney (high resolution mass spectrometry), G. Schatte (XRD), J. Wang (high resolution mass spectrometry) and A. D. Erlich (reaction monitoring assistance).

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Author notes

  1. These authors contributed equally: Roberto Nolla-Saltiel, Zachary T. Ariki.

Authors and Affiliations

  1. Department of Chemistry, Chernoff Hall, Queen’s University, Kingston, Ontario, Canada

    Roberto Nolla-Saltiel, Zachary T. Ariki, Stefanie Schiele, Jana Alpin & Cathleen M. Crudden

  2. Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, Japan

    Roberto Nolla-Saltiel, Yasuyo Tahara, Masakazu Nambo & Cathleen M. Crudden

  3. Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan

    Daisuke Yokogawa

  4. Department of Chemistry, Graduate School of Science, Nagoya University, Nagoya, Japan

    Masakazu Nambo

  5. Carbon to Metal Coating Institute, Queen’s University, Kingston, Ontario, Canada

    Cathleen M. Crudden

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Contributions

M.N. and C.M.C. conceived the concept and supervised the project. R.N.-S., Z.T.A., S.S. and J.A. developed the methodology, optimized cross-coupling conditions and examined the scope of the reaction. Y.T. separated enantiomers of racemic substrates. R.N.-S. developed strategies that enabled the study of the catalytic mechanism (NMR and e.e. monitoring). R.N.-S. and Z.T.A grew samples for XRD. D.Y. and M.N. carried out DFT calculations. R.N.-S., Z.T.A, M.N. and C.M.C. wrote the manuscript with assistance from the co-authors.

Corresponding authors

Correspondence to Masakazu Nambo or Cathleen M. Crudden.

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Nature Chemistry thanks Nicholas Ball and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary methods, Figs. 1–146, Tables 1–6 and references.

Supplementary Data 1

Optimized Cartesian coordinates (CAM-B3LYP) for the calculated structures for (S)-1a, 18, 19-anti, 19-syn, 20, 21, TS_inversion and TS_retention.

Supplementary Data 2

Crystallographic data for compound (S)-1a, CCDC reference 2298851.

Supplementary Data 3

Crystallographic data for compound [NiBr2(DMPMA)]2, CCDC reference 2298852.

Supplementary Data 4

Crystallographic data for compound (R)-17, CCDC reference 2298853.

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Nolla-Saltiel, R., Ariki, Z.T., Schiele, S. et al. Enantiospecific cross-coupling of cyclic alkyl sulfones. Nat. Chem. 16, 1445–1452 (2024). https://doi.org/10.1038/s41557-024-01594-x

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