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Synthesis of cycloheptanoids through catalytic enantioselective (4 + 3)-cycloadditions of 2-aminoallyl cations with dienol silyl ethers

Nature Synthesis volume 1, pages 883–891 (2022)Cite this article

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Abstract

Development of enantioselective cycloaddition reactions involving three-carbon units (n + 3) is challenging because of the instability of the required zwitterionic three-carbon units. The reactivity of these zwitterionic species is particularly intriguing due to the prevalence of odd-numbered carbocyclic ring motifs in natural products. Although cycloadditions with 2-oxyallyl cations are generally well developed, cycloadditions are rare with 2-aminoallyl cations, with catalytic examples limited to intramolecular reactions involving furan derivatives. Here we report a method for copper-catalysed formation of 2-aminoallyl cations from ethynyl methylene cyclic carbamates and subsequent enantioselective (4 + 3)-cycloaddition reactions between 2-aminoallyl cations and dienol silyl ethers. The seven-membered ring carbocyclic products are formed in good yields and with high enantiocontrol. The synthetic utility of the reaction products has been demonstrated through a series of reductive, cross-coupling and cyclization transformations. Mechanistic studies reveal that the reaction involves a dinuclear copper catalyst and occurs stepwise, with formation of the second C–C bond as the turnover-limiting step.

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Fig. 1: Enantioselective cycloadditions of 2-oxyallyl and 2-aminoallyl cations.
Fig. 2: Synthetic application of the reaction products.
Fig. 3: Mechanistic studies on catalytic enantioselective (4 + 3)-cycloaddition of 2-aminoallyl cations with dienol silyl ethers.

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Data availability

The experimental data and the characterization data for all the compounds prepared during these studies are provided in the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers 2141995 (3ka), 2141996 (4aa), 2175552 (6a), 2175546 (7) and 2141998 ((L2-Cu)2(BF4)2). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (numbers 21871150, 22071118 and 22188101 for W. Z.) and the Fundamental Research Funds for Central University. We thank the Haihe Laboratory of Sustainable Chemical Transformations for financial support.

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Authors and Affiliations

  1. State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, China

    Lulu Shen, Zitong Lin, Bin Guo & Weiwei Zi

  2. Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, China

    Weiwei Zi

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Contributions

W.Z. conceived and supervised this work. L.S. conducted studies and prepared the Supplementary Information. Z.L. and B.G. synthesized some substrates and catalysts. All the authors co-wrote the manuscript.

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Correspondence to Weiwei Zi.

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Nature Synthesis thanks Pauline Chiu, Mike Shipman 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 sections 1–10.

Supplementary Data 1

Crystallographic data for 3ka CCDC 2141995.

Supplementary Data 2

Crystallographic data for 4aa CCDC 2141996.

Supplementary Data 3

Structure factors file for compound 4aa CCDC 2141996.

Supplementary Data 4

Crystallographic data for 6a CCDC 2175552.

Supplementary Data 5

Crystallographic data for 7 CCDC 2175546.

Supplementary Data 6

Crystallographic data for (L2-Cu)2(BF4)2 CCDC 2141998.

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Shen, L., Lin, Z., Guo, B. et al. Synthesis of cycloheptanoids through catalytic enantioselective (4 + 3)-cycloadditions of 2-aminoallyl cations with dienol silyl ethers. Nat. Synth 1, 883–891 (2022). https://doi.org/10.1038/s44160-022-00150-0

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