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Combining nickel and squaramide catalysis for the stereodivergent α-propargylation of oxindoles

Nature Synthesis volume 1, pages 322–331 (2022)Cite this article

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Abstract

Stereoisomers of drugs can have different therapeutic outcomes or side effects, and regulatory agencies require the bioactivity of all stereoisomers of pharmaceutical candidates to be evaluated during the drug discovery and development process. However, relatively few methods can lead to all possible stereoisomers of molecules containing contiguous stereocentres. Here we report a combination of nickel and squaramide catalysis as a versatile strategy for stereodivergent α-propargylation of oxindoles. Effective with both primary and secondary propargylic ammonium salt substrates, the reported process gives a range of α-propargylated oxindole products with excellent regio- and stereocontrol. The stereochemical outcome of the reaction can be programmed through choice of the appropriate enantiomers of the nickel and squaramide catalysts. The synthetic utility of this stereodivergent methodology is demonstrated through its application to the synthesis of a number of natural products, (−)-physovenine, (−)-esermethole and (−)-physostigmine.

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Fig. 1: Design plan for dual nickel/squaramide catalysis for stereodivergent propargylation to access all stereoisomers.
Fig. 2: Synthetic utilities.
Fig. 3: Stereodivergent transformations.
Fig. 4: Mechanistic studies.
Fig. 5: Proposed catalytic cycle.

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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. NMR data in a mnova file format and HPLC traces are available from Zenodo at https://zenodo.org/record/6043896#.YgcR_upBwuU, under the Creative Commons Attribution 4.0 International licence. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2080170 (3a) (https://www.ccdc.cam.ac.uk/mystructures/structuredetails/c36ae01e-99a6-eb11-9699-00505695281c) and 2080169 (7h) (https://www.ccdc.cam.ac.uk/mystructures/structuredetails/6774b318-99a6-eb11-9699-00505695281c). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We acknowledge financial support from the National Natural Science Foundation of China (grant no. 21971227, to C.G.), the Anhui Provincial Natural Science Foundation (grant no. 1808085MB30, to C.G.) and the Fundamental Research Funds for the Central Universities (grant no. WK2340000090, to C.G.).

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Authors and Affiliations

  1. Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, China

    Qingdong Hu, Zhuozhuo He, Lingzi Peng & Chang Guo

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  1. Qingdong Hu
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  2. Zhuozhuo He
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  3. Lingzi Peng
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  4. Chang Guo
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Contributions

C.G. conceived the study. Q.H. performed the experiments and analysed the data. Z.H. and L.P. synthesized some of the substrates and ligands. All authors discussed the results and prepared the manuscript.

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Correspondence to Chang Guo.

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Nature Synthesis thanks Xinfang Xu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary information

Supplementary Fig. 1, text and discussion and Tables 1–7.

Supplementary Data 1

Crystallographic data for compound 3a CCDC 2080170.

Supplementary Data 2

Crystallographic data for compound 7h CCDC 2080169.

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Hu, Q., He, Z., Peng, L. et al. Combining nickel and squaramide catalysis for the stereodivergent α-propargylation of oxindoles. Nat. Synth 1, 322–331 (2022). https://doi.org/10.1038/s44160-022-00050-3

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