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Stereospecific α-(hetero)arylation of sulfoximines and sulfonimidamides

Nature Synthesis volume 1, pages 170–179 (2022)Cite this article

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Abstract

The occurrence of sulfoximines and sulfonimidoyl groups in biologically active molecules within pharmaceuticals and agrochemicals has notably increased in the past decade. This increase has prompted a wave of discovery of methods to install the S(VI) functionality into complex organic molecules. Traditional synthetic methods to form α-substituted sulfonimidoyl motifs rely on S–C bond disconnections and typically require control of the stereogenic S-centre or late-stage modification at sulfur, and comprise multistep routes. Here, we report the development of a stereospecific, modular SNAr approach for the introduction of sulfonimidoyl functional groups into heterocyclic cores. This strategy has been demonstrated across 85 examples, in good to excellent yield, of complex and diverse heterocycles. Sulfoximines, sulfonimidamides and sulfondiimines are all compatible nucleophiles in the SNAr reaction and, hence, the methodology was applied to the synthesis of four sulfoximine-containing pharmaceuticals. Of these synthetic applications, most notably ceralasertib, an ATR inhibitor currently in clinical trials, was synthesized in an eight-step procedure on a gram scale.

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Fig. 1: Importance, value and accessibility of sulfonimidoyl groups.
Fig. 2: Synthetic routes to access S(VI) nucleophiles.
Fig. 3: Enantiospecific synthesis of BAY 1251152.
Fig. 4: Formal syntheses of pharmaceutical intermediates.
Fig. 5: Target- and diversity-oriented syntheses of ceralasertib.

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Data availability

The experimental data as well as the characterization data for all the compounds prepared during these studies are provided in the Supplementary Information. Crystallographic data are available from the Cambridge Crystallographic Data Centre with the following codes: 52 (CCDC 2087123), 108 (CCDC 2087121), 112 (CCDC 2087124) and 138 (CCDC 2087122).

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Acknowledgements

We gratefully acknowledge the National Institutes of Health (R35-GM142577, J.M.L.) and the Florida Department of Health (Bankhead-Coley #9BC09, J.M.L.) for support of this research. This work has also been supported in part by the Chemical Biology Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292). We thank H. Lawrence and S. Yun for NMR and HRMS support, and C. Shan and Q. Tang for assistance with X-ray crystallographic analysis.

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Authors and Affiliations

  1. Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Zachary P. Shultz, Thomas Scattolin & Justin M. Lopchuk

  2. Department of Chemistry, University of South Florida, Tampa, FL, USA

    Lukasz Wojtas & Justin M. Lopchuk

  3. Department of Oncologic Sciences, College of Medicine, University of South Florida, Tampa, FL, USA

    Justin M. Lopchuk

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  1. Zachary P. Shultz
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Contributions

Z.P.S. and T.S. performed the experiments; Z.P.S. and J.M.L. designed the project and wrote the paper; L.W. performed the X-ray crystallographic analysis.

Corresponding author

Correspondence to Justin M. Lopchuk.

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Competing interests

A provisional patent application naming J.M.L., Z.P.S. and T.S. as inventors has been filed by the H. Lee Moffitt Cancer Center & Research Institute, which covers the synthetic methods for the α-(hetero)arylation of sulfonimidoyl functional groups. The remaining authors declare no competing interests.

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Peer review information

Nature Synthesis thanks Mark Graham, Ulrich Lücking and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Thomas West was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–6, Schemes 1–7, Tables 1–5, procedures and troubleshooting guides.

Supplementary Data 1

Crystallographic data for compound 52.

Supplementary Data 2

Crystallographic data for compound 108.

Supplementary Data 3

Crystallographic data for compound 112.

Supplementary Data 4

Crystallographic data for compound 138.

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Shultz, Z.P., Scattolin, T., Wojtas, L. et al. Stereospecific α-(hetero)arylation of sulfoximines and sulfonimidamides. Nat Synth 1, 170–179 (2022). https://doi.org/10.1038/s44160-021-00011-2

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