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Asymmetric O-propargylation of secondary aliphatic alcohols

Nature Catalysis volume 3, pages 672–680 (2020)Cite this article

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A Publisher Correction to this article was published on 08 June 2020

Abstract

The asymmetric O-alkylation of secondary aliphatic alcohols remains a substantial challenge in chemistry. Such a challenge largely stems from the steric demand of each reactant, in addition to the relatively low nucleophilicity of alcohols. Here, we report the development of a base-free, Cu-catalysed propargylic substitution reaction that enables the efficient, asymmetric O-propargylation of secondary aliphatic alcohols. Mechanistic studies implied key factors to slow down the undesired decomposition process of electrophiles in this reaction, which opened up the possibility of using secondary aliphatic alcohols as nucleophilic substrates. This asymmetric O-alkylation reaction proceeds under almost neutral conditions, tolerates a broad scope of functional groups and shows remarkable chemoselectivities. This method is amenable to the modification of natural products and commercial drugs. The products obtained could be readily elaborated to various classes of enantioenriched α,α′-disubstituted ethers that are difficult to access by other methods.

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Fig. 1: Synthetic challenges to asymmetric alkylation of secondary aliphatic alcohols, and our approach.
Fig. 2: Mechanistic insights into the Cu-catalysed APS reaction provided by kinetic studies.
Fig. 3: Substrate scope of the Cu-catalysed asymmetric O-propargylation of secondary aliphatic alcohols.
Fig. 4: Product derivatization.
Fig. 5: Mechanistic studies.
Fig. 6: Role of Ph2SiF2 in this reaction.

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Data availability

The data supporting the findings of this study are available within the manuscript and its Supplementary Information file. Experimental details and full spectroscopic characterization data for all new compounds, as well as copies of NMR spectra, are provided in the Supplementary Information. Crystallographic data relating to this study have been deposited in the Cambridge Crystallographic Data Centre (CCDC) database under deposition numbers 1951205 and 1952086. These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

This work is supported by funding from the National Key Research and Development Program (2018YFA0903300) and National Natural Science Foundation of China (21922106 and 21772125), and start-up funding from Sichuan University and The Open Project of the State Key Laboratory of Natural Medicines (3144060211). We acknowledge J. J. Chruma (Sichuan University) for helpful discussions and manuscript revision. We thank D. Luo from the Analytical and Testing Center of Sichuan University for help with X-ray analysis.

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Authors and Affiliations

  1. Department of Emergency, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

    Ren-Zhe Li, Da-Qi Liu & Dawen Niu

  2. School of Chemical Engineering, Sichuan University, Chengdu, China

    Ren-Zhe Li, Da-Qi Liu & Dawen Niu

  3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China

    Dawen Niu

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D.N. conceived of the idea, guided the project and wrote the manuscript, with feedback from the other authors. R.-Z.L. and D.-Q.L. conducted the experiments and analysed the results.

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Correspondence to Dawen Niu.

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Supplementary information

Supplementary Information

Supplementary methods, Figs. 1–6, references and spectra.

Supplementary Data 1

Crystallographic Data of 26ah in Fig. 3

Supplementary Data 2

Crystallographic data of the copper complex in Fig. 5c.

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Li, RZ., Liu, DQ. & Niu, D. Asymmetric O-propargylation of secondary aliphatic alcohols. Nat Catal 3, 672–680 (2020). https://doi.org/10.1038/s41929-020-0462-9

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