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Stereoselective cyclohexadienylamine synthesis through rhodium-catalysed [2+2+2] cyclotrimerization

Nature Synthesis volume 1, pages 365–375 (2022)Cite this article

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Abstract

Development of a multicomponent reaction giving a single product is a major goal in synthetic organic chemistry. Catalytic [2+2+2] cyclotrimerization of two distinct alkynes and an alkene with chemo-, regio-, diastereo- and enantiocontrol offers rapid access to highly valued chiral six-membered carbocycles. However, previous [2+2+2]-cyclotrimerization methods have been thwarted by low selectivity and restricted substrate scope. Here we report the rhodium-catalysed [2+2+2] cyclotrimerization of terminal alkynes, alkynoates and cis-enamides to give synthetically valuable chiral cyclohexadienylamines with broad substrate scope and excellent selectivity without the requirement for slow addition or large excesses of reagents. Experimental and theoretical mechanistic studies revealed that the three-component [2+2+2]-cyclotrimerization reaction is highly specific towards use of the cis-enamide.

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Fig. 1: Research background for catalytic three-component [2+2+2] cyclotrimerization.
Fig. 2: Synthetic transformations.
Fig. 3: Experimental mechanistic studies.
Fig. 4: Theoretical mechanistic studies.

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Data availability

The data that support the findings of this study are available in this article and its Supplementary Information (experimental procedures and characterization data). Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under the deposition number CCDC 2068101 ((4R,5S)-(+)-4eaa). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This research was supported partly by Grants-in-Aid for Scientific Research (number JP19H00893 to K.T., number 17H06173 to M.U. and numbers JP20H04661 and JP18H04504 to H.U.) from JSPS (Japan) and CREST (number JPMJCR19R2 to M.U.) from JST (Japan). We thank Takasago International Corporation for the gift of Segphos and H8-BINAP, and Umicore for the support in supplying the rhodium complexes. Allotment of computational resources from and HOKUSAI BigWaterfall (Project G19012, RIKEN) and TSUBAME (Tokyo Institute of Technology) is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Chemical Science and Engineering, Tokyo Institute of Technology, Tokyo, Japan

    Kohei Fujii, Yuki Nagashima, Koji Masutomi & Ken Tanaka

  2. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

    Yuki Nagashima, Takumi Shimokawa, Junichiro Kanazawa & Masanobu Uchiyama

  3. Institute for Molecular Science, Okazaki, Japan

    Haruki Sugiyama

  4. Department of Chemistry, Tokyo Institute of Technology, Tokyo, Japan

    Hidehiro Uekusa

  5. Research Initiative for Supra-Materials (RISM), Shinshu University, Ueda, Japan

    Masanobu Uchiyama

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  1. Kohei Fujii
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Contributions

K.F. designed the project, conducted experimental studies and wrote a draft of the experimental studies. K.M. conducted preliminary experiments. Y.N., T.S., J.K. and M.U. conducted computational studies and wrote a draft of the computational studies. H.S. and H.U. performed the X-ray crystal structure analysis. K.T. designed, advised and directed the project, and wrote the manuscript. All authors edited the manuscript.

Corresponding authors

Correspondence to Masanobu Uchiyama or Ken Tanaka.

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Nature Synthesis thanks Martin Kotora and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Thomas West was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Supplementary information

Supplementary Information

Materials and methods, synthetic experiments, single-crystal X-ray diffraction analysis of (+)-4eaa, computational studies, NMR spectra, HPLC data, references, Figs 1–7 and Tables 1–8.

Supplementary Data 1

Crystal structure of +4eaa; CCDC 2068101.

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Fujii, K., Nagashima, Y., Shimokawa, T. et al. Stereoselective cyclohexadienylamine synthesis through rhodium-catalysed [2+2+2] cyclotrimerization. Nat. Synth 1, 365–375 (2022). https://doi.org/10.1038/s44160-022-00043-2

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