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Enantioselective synthesis of P-stereogenic allenylphosphines through Ni-catalysed propargylic substitution

Nature Synthesis volume 1, pages 738–747 (2022)Cite this article

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Abstract

Typical methods for the synthesis of P-stereogenic allenylphosphine derivatives depend on chirality transfer from P-stereogenic substrates and require multiple synthetic steps. Now we report a Ni-catalysed enantioselective propargylic substitution reaction for the synthesis of P-stereogenic allenylphosphine derivatives from propargylic carbonates and secondary phosphines. Using in situ generated secondary phosphines, after a reduction of the corresponding phosphine oxides, a wide range of allenylphosphine derivatives with a P-stereogenic centre were synthesized with a high enantiocontrol (up to 97% e.e.). The method was also applied to the enantioconvergent synthesis of the P,axial-stereogenic 1,3-disubstituted allenylphosphines, using secondary propargylic carbonates as substrates with excellent enantio- and diastereocontrol (up to 97% e.e. and 14:1 d.r.) without the need for racemization or symmetrization of the secondary propargylic carbonates. The chiral phosphine products were readily incorporated into transition metal complexes with retention of stereopurity. Experimental and computational mechanistic studies suggest that the process proceeds through an enantioconvergent reaction mechanism, which gives enantioenriched phosphine products from a racemic mixture of secondary propargylic carbonates.

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Fig. 1: Functionalized P-stereogenic phosphines and Ni-catalysed propargylic substitution reactions.
Fig. 2: Derivatization of allenylphosphine and allenylphosphine oxide.
Fig. 3: Experimental mechanistic studies of Ni-catalysed propargylic substitution reactions with secondary phosphines.
Fig. 4: Computation calculations for the Ni-catalysed propargylic substitution reaction with secondary phosphines.
Fig. 5: Proposed mechanism for the Ni-catalysed propargylic substitution with secondary phosphines.

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Data availability

All data are available in the manuscript or the Supplementary materials. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2079669 (3av), 2079668 (3a-Ir) and 2071745 (Ni-PH). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We are grateful for financial support from the National Key R&D Program of China (2018YFA0702001), NSFC (22071224, 21901235), USTC (KY2060000143) and USTC Research Funds of the Double First-Class Initiative (YD2060002010). The numerical calculations in this paper weere done on the supercomputing system in the Supercomputing Center of University of Science and Technology of China. Y. Shao of Lanzhou University is acknowledged for refinement of the XRD data of compounds 3a-Ir and Ni-PH.

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  1. These authors contributed equally: Wei-Han Wang, Yue Wu.

Authors and Affiliations

  1. Department of Chemistry, University of Science and Technology of China, Hefei, China

    Wei-Han Wang, Yue Wu, Hai-Tao Wang, Peng-Jia Qi, Wen-Ning Lan & Qing-Wei Zhang

  2. Ganjiang Innovation Academy, Chinese Academy of Sciences, Ganzhou, China

    Hai-Tao Wang & Wen-Ning Lan

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Contributions

W.-H.W. carried out the experimental and data-analysis work. Y.W. carried out the computational studies. H.-T.W., P.-J.Q. and W.-N.L. performed the synthesis of the substrates. Q.-W.Z. designed the reaction, directed the project and wrote the paper with feedback from all the authors.

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Correspondence to Qing-Wei Zhang.

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Supplementary information

Supplementary Information

Supplementary Table 1, Figs, 1–8, detailed experimental data and copies of NMR spectrum and HPLC chromatography.

Supplementary Data 1

X-ray crystallographic data for compound 3a-Ir. CCDC 2079668.

Supplementary Data 2

X-ray crystallographic data for compound 3av. CCDC 2079669.

Supplementary Data 3

X-ray crystallographic data for compound Ni-PH. CCDC 2071745.

Supplementary Data 4

.xyz file of computed structures.

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Wang, WH., Wu, Y., Wang, HT. et al. Enantioselective synthesis of P-stereogenic allenylphosphines through Ni-catalysed propargylic substitution. Nat. Synth 1, 738–747 (2022). https://doi.org/10.1038/s44160-022-00123-3

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