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Asymmetric synthesis of sulfoximines, sulfonimidoyl fluorides and sulfonimidamides enabled by an enantiopure bifunctional S(VI) reagent

Nature Chemistry volume 16, pages 183–192 (2024)Cite this article

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Abstract

An increased interest to expand three-dimensional chemical space for the design of new materials and medicines has created a demand for isosteric replacement groups of commonly used molecular functionality. The structural and chemical properties of chiral S(VI) functional groups provide unique spatial and electronic features compared with their achiral sulfur- and carbon-based counterparts. Manipulation of the S(VI) centre to introduce structural variation with stereochemical control has remained a synthetic challenge. The stability of sulfonimidoyl fluorides and the efficiency of sulfur fluorine exchange chemistry has enabled the development of the enantiopure bifunctional S(VI) transfer reagent t-BuSF to overcome current synthetic limitations. Here, we disclose a reagent platform that serves as a chiral sulfur fluorine exchange template for the rapid asymmetric synthesis of over 70 sulfoximines, sulfonimidoyl fluorides and sulfonimidamides with excellent enantiomeric excess and good overall yields. Furthermore, the practical utility of the bifunctional S(VI) transfer reagent was demonstrated in the syntheses of enantiopure pharmaceutical intermediates and analogues.

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Fig. 1: Chiral S(VI) functional groups and their preparation.
Fig. 2: Asymmetric synthesis of pharmaceutically relevant compounds and intermediates from t-BuSF.

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Data availability

All data, including experimental procedures, compound characterization data and stability analysis data, are available within the article and its Supplementary Information. X-ray crystallographic data for the structures within this article and the Supplementary Information have been deposited with the Cambridge Crystallographic Data Centre. The data can be obtained free of charge from www.ccdc.cam.ac.uk/structures/. Compounds with X-ray structures: (S)-t-BuSF (CCDC 2243804), 2a (CCDC 2243801), 3f (CCDC 2243803), 4a (CCDC 2243800), 7a (CCDC 2243808), 7d (CCDC 2243809) 7e (CCDC 2243805), 7f (CCDC 2243806), 7i (CCDC 2243802), 7k (CCDC 2243799), 7l (CCDC 2243807), 9a (CCDC 2243810) and S6a (CCDC 2243798).

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Acknowledgements

We thank H. Lawrence (H. Lee Moffitt Cancer Center and Research Institute) and L. Calcul (University of South Florida) for NMR and high-resolution mass spectrometry support, and Q. Tang (USF) for assistance with X-ray crystallographic analysis. We gratefully acknowledge the National Institutes of Health (National Institute of General Medical Sciences; R35-GM142577, 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 and Research Institute, a National Cancer Institute designated Comprehensive Cancer Center (P30-CA076292) and the University of South Florida’s Chemical Purification Analysis and Screening Core Facility.

Author information

Authors and Affiliations

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

    Shun Teng, Chuan Shan, Lukasz Wojtas & Justin M. Lopchuk

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

    Zachary P. Shultz & 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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Contributions

S.T., Z.P.S. and J.M.L. designed the study. S.T., Z.P.S. and C.S. performed the experiments and interpreted the results. C.S. and L.W. performed the X-ray crystallographic analysis. Z.P.S. and J.M.L. prepared the manuscript for publication.

Corresponding author

Correspondence to Justin M. Lopchuk.

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Competing interests

A patent application naming J.M.L., Z.P.S. and S.T. as inventors has been filed by H. Lee Moffitt Cancer Center and Research Institute, which covers the synthetic methods and development regarding a chiral bifunctional S(VI) reagent for the asymmetric synthesis of sulfur-containing functional groups. The remaining authors declare no competing interest.

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Peer review information

Nature Chemistry thanks Yantao Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary discussions, Figs. 1–27, Tables 1–18, NMR spectra and HPLC chromatograms.

Supplementary Data 1

Crystallographic data for compound t-BuSF; CCDC reference 2243804.

Supplementary Data 2

Crystallographic data for compound 2a; CCDC reference 2243801.

Supplementary Data 3

Crystallographic data for compound 3f; CCDC reference 2243803.

Supplementary Data 4

Crystallographic data for compound 4a; CCDC reference 2243800.

Supplementary Data 5

Crystallographic data for compound S6a; CCDC reference 2243798.

Supplementary Data 6

Crystallographic data for compound 7k; CCDC reference 2243799.

Supplementary Data 7

Crystallographic data for compound 7a; CCDC reference 2243808.

Supplementary Data 8

Crystallographic data for compound 7i; CCDC reference 2243802.

Supplementary Data 9

Crystallographic data for compound 7f; CCDC reference 2243806.

Supplementary Data 10

Crystallographic data for compound 7l; CCDC reference 2243807.

Supplementary Data 11

Crystallographic data for compound 7e; CCDC reference 2243805.

Supplementary Data 12

Crystallographic data for compound 7d; CCDC reference 2243809.

Supplementary Data 13

Crystallographic data for compound 9a; CCDC reference 2243810.

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Teng, S., Shultz, Z.P., Shan, C. et al. Asymmetric synthesis of sulfoximines, sulfonimidoyl fluorides and sulfonimidamides enabled by an enantiopure bifunctional S(VI) reagent. Nat. Chem. 16, 183–192 (2024). https://doi.org/10.1038/s41557-023-01419-3

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