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Selective dynamic kinetic asymmetric aldehyde–alkyne reductive coupling

Nature Synthesis volume 4, pages 1630–1639 (2025)Cite this article

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Abstract

Developing general protocols that control multiple types of selectivity in a single transformation is challenging yet highly desirable for the synthesis of complex molecules. Here we describe a N-heterocyclic carbene–nickel catalyst that enables simultaneous control over chemo-, regio-, E/Z-, diastereo- and enantioselectivity in a dynamic kinetic resolution (DKR) asymmetric aldehyde–alkyne reductive coupling reaction. This method provides a straightforward synthesis of enantioenriched allylic alcohols from easily available substrates, and has broad scope and excellent functional group compatibility. We applied this protocol to the modification of profen-type drugs and the formal synthesis of sphingosine. Control experiments reveal that the stereocontrol is influenced by the rate of racemization. We expect the reported process to further stimulate the development of dynamic kinetic resolution chemistry and simplify the synthesis of valuable complex molecules.

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Fig. 1: Multiple selectivities in reactions and the DKR aldehyde–alkyne reductive coupling.
Fig. 2: Scope of nickel-catalysed enantioconvergent reductive coupling of α-aryl aldehydes and alkynes.
Fig. 3: Scope of nickel-catalysed enantioconvergent reductive coupling of α-amino/α-alkoxy aldehydes and alkynes.
Fig. 4: Scope of nickel-catalysed enantioconvergent reductive coupling of α,α-dialkyl aldehydes and alkynes.
Fig. 5: Synthetic applications and drug modification.
Fig. 6: Control experiments.

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Data availability

All data supporting the findings of this study 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 (CCDC), under deposition numbers 2416723 (6fa) and 2416724 (4ta). 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 work is supported by the National Key R&D Program of China (2022YFA1503700), the National Natural Science Foundation of China (22325110, 92256303, 22171280, 22501291), the Strategic Priority Research Program of the CAS (XDB0610000, XDA0540000), the Program of Shanghai Academic Research Leader (22XD1424900), the CAS Youth Interdisciplinary Team (JCTD-2021-11) and the Ningbo Natural Science Foundation (2022J017) (S.-L.S.).

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Author notes

  1. These authors contributed equally: Guang Chen, Jia-Ming Liu.

Authors and Affiliations

  1. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Guang Chen, Jia-Ming Liu, Lin-Xin Ruan & Shi-Liang Shi

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  1. Guang Chen
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  2. Jia-Ming Liu
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Contributions

G.C., J.-M.L. and L.-X.R. developed the catalytic method and conducted the mechanistic studies. S.-L.S. conceived of the projects and directed the investigations. S.-L.S. and G.C. wrote the paper.

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Correspondence to Shi-Liang Shi.

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Nature Synthesis thanks the anonymous reviewers 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 (download PDF )

Experimental details, Supplementary Sections 1–14, Tables 1–9 and Figs. 1–3.

Supplementary Data 1

X-ray crystallographic data for 6fa, CCDC 2416723.

Supplementary Data 2

X-ray crystallographic data for 4ta, CCDC 2416724.

Source data

Source Data Fig. 6 (download XLSX )

Source data for Fig. 6b.

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Chen, G., Liu, JM., Ruan, LX. et al. Selective dynamic kinetic asymmetric aldehyde–alkyne reductive coupling. Nat. Synth 4, 1630–1639 (2025). https://doi.org/10.1038/s44160-025-00887-4

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