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Synthesis of chiral sulfinate esters by asymmetric condensation

Nature volume 604, pages 298–303 (2022)Cite this article

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Abstract

Achiral sulfur functional groups, such as sulfonamide, sulfone, thiol and thioether, are common in drugs and natural products. By contrast, chiral sulfur functional groups are often neglected as pharmacophores1,2,3, although sulfoximine, with its unique physicochemical and pharmacokinetic properties4,5, has been recently incorporated into several clinical candidates. Thus, other sulfur stereogenic centres, such as sulfinate ester, sulfinamide, sulfonimidate ester and sulfonimidamide, have started to attract attention. The diversity and complexity of these sulfur stereogenic centres have the potential to expand the chemical space for drug discovery6,7,8,9,10. However, the installation of these structures enantioselectively into drug molecules is highly challenging. Here we report straightforward access to enantioenriched sulfinate esters via asymmetric condensation of prochiral sulfinates and alcohols using pentanidium as an organocatalyst. We successfully coupled a wide range of sulfinates and bioactive alcohols stereoselectively. The initial sulfinates can be prepared from existing sulfone and sulfonamide drugs, and the resulting sulfinate esters are versatile for transformations to diverse chiral sulfur pharmacophores. Through late-stage diversification11,12 of celecoxib and other drug derivatives, we demonstrate the viability of this unified approach towards sulfur stereogenic centres.

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Fig. 1: Diverse chiral sulfur pharmacophores for drug discovery and their synthesis.
Fig. 2: Optimization of reaction conditions.
Fig. 3: Reaction scope.
Fig. 4: Functionalization and diversification of drugs.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information.

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Acknowledgements

We acknowledge support from Nanyang Technological University for Tier 1 grant (RG2/20). This research was supported by the Ministry of Education, Singapore, under its Academic Research Fund Tier 2 (MOE2019-T2-1-091). This work was supported by the A*STAR Computational Resource Centre through the use of its high-performance computing facilities. The computational work for this article was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg).

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Authors and Affiliations

  1. Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore

    Xin Zhang, Esther Cai Xia Ang, Ziqi Yang, Choon Wee Kee & Choon-Hong Tan

  2. Process and Catalysis Research, Institute of Chemical and Engineering Sciences, Singapore, Singapore

    Choon Wee Kee

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  1. Xin Zhang
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  2. Esther Cai Xia Ang
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  3. Ziqi Yang
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Contributions

C.-H.T. and X.Z. conceived the research; X.Z. is responsible for experimental design and data analysis; X.Z., E.C.X.A., and Z.Y. performed the experiments and compounds testing; C.W.K. contributed to mechanistic discussion; C.-H.T. and X.Z. prepared the manuscript with input from all authors.

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Correspondence to Xin Zhang or Choon-Hong Tan.

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Zhang, X., Ang, E.C.X., Yang, Z. et al. Synthesis of chiral sulfinate esters by asymmetric condensation. Nature 604, 298–303 (2022). https://doi.org/10.1038/s41586-022-04524-4

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