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Organocatalytic asymmetric deoxygenation of sulfones to access chiral sulfinyl compounds

Nature Chemistry volume 15, pages 185–193 (2023)Cite this article

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Abstract

Over the past decades, many efficient methodologies have been developed that allow for the enantioselective synthesis of chiral sulfinyl compounds. However, the enantioselective deoxygenation of hexavalent sulfones for the formation of chiral sulfinyl compounds still remains one of the major challenges in the fields of asymmetric synthesis and organosulfur chemistry. Here we have demonstrated that a synergistic combination of organocatalysis and the incorporation of a cyano group into the sulfone generates a chiral sulfinic species as an active intermediate. A wide range of chiral sulfinates with high enantioselectivities could then be acquired using alcohols as nucleophiles, and the subsequent transformations allowed the collective preparation of a variety of chiral sulfinyl compounds. Density functional theory calculations revealed that the catalytic cycle involves a quinuclidine-assisted stepwise 1,2-cyano group transfer, base-assisted intermolecular substitution with alcohol and regeneration of the active catalyst. The enantioselectivity was determined by the cyano migration step.

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Fig. 1: Enantioselective deoxygenation of sulfones and our design blueprint.
Fig. 2: Reaction design and plausible mechanism.
Fig. 3: Investigation of the reaction mechanism.
Fig. 4: Synthetic transformations.

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Data availability

All relevant data supporting the findings of this study, including experimental procedures and compound characterization, NMR and HPLC are available within the Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 1941245 (P3e), 2141490 ((R)-5) and 2141488 ((S)-11). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Source data are provided with this paper.

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Acknowledgements

This study was supported by the Fundamental Research Funds for the Central Universities (grants: 2021CDJQY-035 to W.Q. and 2022CDJXY-025 to S.H.), the National Natural Science Foundation of China (grants: 21901026 to W.Q. and 21922101 to H.Y.) and the Natural Science Foundation of Chongqing (grant: cstc2021jcyj-jqX0019 to H.Y.).

Author information

Author notes

  1. These authors contributed equally: Shengli Huang, Zhen Zeng.

Authors and Affiliations

  1. Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chemical Biology Research Center, School of Pharmaceutical Sciences, Chongqing University, Chongqing, People’s Republic of China

    Shengli Huang, Nan Zhang, Wenling Qin & Hailong Yan

  2. School of Chemistry and Chemical Engineering, Chongqing Key Laboratory of Theoretical and Computational Chemistry, Chongqing University, Chongqing, People’s Republic of China

    Zhen Zeng & Yu Lan

  3. Green Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou, People’s Republic of China

    Yu Lan

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Contributions

H.Y. and W.Q. conceived and directed the project. S.H. designed and performed the experiments. S.H. and Z.Z. prepared the Supplementary Information. S.H., Z.Z. and N.Z. analysed and interpreted the experimental data. W.Q., H.Y., Y.L. and Z.Z. wrote the paper. Z.Z. and Y.L. performed the DFT calculations. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Wenling Qin, Yu Lan or Hailong Yan.

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Nature Chemistry thanks Choon-Hong Tan 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 Tables 1–5, Figs. 1–26, experimental data, synthesis and characterization data, NMR spectra, X-ray crystallographic data and DFT calculation data.

Supplementary Data 1

Crystallographic data for compound P3e; CCDC reference 1941245.

Supplementary Data 2

Crystallographic data for compound (R)-5; CCDC reference 2141490.

Supplementary Data 3

Crystallographic data for compound (S)-11; CCDC reference 2141488.

Supplementary Data 4

Cartesian coordinates for all optimized structures.

Source data

Source Data Fig. 2

Numerical data for panel c.

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Huang, S., Zeng, Z., Zhang, N. et al. Organocatalytic asymmetric deoxygenation of sulfones to access chiral sulfinyl compounds. Nat. Chem. 15, 185–193 (2023). https://doi.org/10.1038/s41557-022-01120-x

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