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Catalytic stereodivergent total synthesis of amathaspiramide D

Nature Synthesis volume 1, pages 393–400 (2022)Cite this article

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Abstract

The configuration of biologically active molecules typically alters their physiological properties, which highlights the importance of preparing and fully characterizing all possible stereoisomers of a lead candidate or a given natural product. However, despite many advances in asymmetric synthesis, it remains challenging to completely control both the absolute and relative configuration in catalyst-mediated asymmetric reactions in which contiguous stereogenic centres are created in a single chemical transformation. Here we report a target-oriented stereodivergent propargylic substitution reaction to access four stereoisomers of amathaspiramide D and its analogues. By combining nickel and copper-catalysed stereodivergent propargylation, the key substituted 2-pyrrolidone intermediate was synthesized with excellent selectivity. The scope of the stereoselective propargylation process was demonstrated across a range of propargylic carbonate and aldimine ester substrates. The synthetic utility of the chiral propargylated α-amino ester products was shown through reductive and cyclization transformations.

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Fig. 1: Overview of Ni/Cu dual catalysis for the stereodivergent total synthesis of amathaspiramide D.
Fig. 2: Stereodivergent propargylation to access four stereoisomers by simply employing the opposite enantiomer of one of the catalysts.
Fig. 3: Completion of the stereodivergent total synthesis of amathaspiramide D.
Fig. 4: Application and extension of the Ni/Cu dual-catalysed stereodivergent propargylic substitution reactions.

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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 at https://zenodo.org/record/6326770#.YiG1suhBwuU, under the Creative Commons Attribution 4.0 international license. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2112078 ((S,R)-6), 2112074 (anti-8), 2112077 (syn-10), 2112076 (syn-11), 2112075 ((S,S)-11) and 1973954 ((S,R)-29). 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, C.G.) and the Fundamental Research Funds for the Central Universities (WK2340000090, C.G.).

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Author notes

  1. These authors contributed equally: Zhuozhuo He, Lingzi Peng.

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

    Zhuozhuo He, Lingzi Peng & Chang Guo

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Contributions

C.G. conceived and designed the study and wrote the paper. Z.H. and L.P. performed the experiments and analysed the data. Z.H. performed the stereodivergent total synthesis of amathaspiramide D. L.P. performed the stereodivergent propargylic substitution reactions. All the authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Chang Guo.

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The authors declare no competing interests.

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Peer review information

Nature Synthesis thanks Dirk Trauner 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 Figs. 1 and 2, text and discussion.

Supplementary Data 1

Crystallographic data for compound (S,R)-6 CCDC 2112078.

Supplementary Data 2

Crystallographic data for compound anti-8 CCDC 2112074.

Supplementary Data 3

Crystallographic data for compound syn-10 CCDC 2112077.

Supplementary Data 4

Crystallographic data for compound syn-11 CCDC 2112076.

Supplementary Data 5

Crystallographic data for compound (S,S)-11 CCDC 2112075.

Supplementary Data 6

Crystallographic data for compound (S,R)-29 CCDC 1973954.

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He, Z., Peng, L. & Guo, C. Catalytic stereodivergent total synthesis of amathaspiramide D. Nat. Synth 1, 393–400 (2022). https://doi.org/10.1038/s44160-022-00063-y

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