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Stereoselective access to [5.5.0] and [4.4.1] bicyclic compounds through Pd-catalysed divergent higher-order cycloadditions

Nature Chemistry volume 12, pages 860–868 (2020)Cite this article

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Abstract

Medium-sized rings, including those embedded in bridged and fused bicyclic scaffolds, are common core structures of myriad bioactive molecules. Among various synthetic strategies towards their synthesis, intermolecular higher-order cycloaddition provides great potential to build complex medium-sized rings from simple building blocks. Unfortunately, such transformations are often plagued with competitive reaction pathways and low levels of site- and stereoselectivity. Herein, we report catalyst-controlled divergent access to three classes of medium-sized bicyclic compounds in high efficiency and stereoselectivity, by palladium-catalysed cycloadditions of tropones with γ-methylidene-δ-valerolactones. Mechanistic studies and density functional theory calculations disclosed that the divergent reactions stem from the different reaction profiles of the diastereomeric intermediates. While one undergoes either O- or C-allylation to provide [5.5.0] or [4.4.1] bicyclic compounds, the unique conformation of the other diastereomer allows an unconventional alkene isomerization to deliver bridgehead alkene-containing bicyclo[4.4.1] compounds. The conversion of these products to diverse complex polycyclic scaffolds has also been demonstrated.

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Fig. 1: Synthesis of bicyclo[5.5.0] and bicyclo[4.4.1] compounds.
Fig. 2: Discovery and mechanistic exploration of divergent bicyclic system synthesis.
Fig. 3: Proposed mechanism and DFT calculations.
Fig. 4: Derivatization of the cycloadducts 3, 4 and 5.

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Data availability

All data generated and analysed during this study are included in this article and its Supplementary Information files. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC) as CCDC 1920222 (3a), 1920223 (4a), 1920224 (5a), 1920225 (5rh), 1920226 (7a), 1920227 (9a), 1920228 (11a) and 1920233 (5q) and can be obtained free of charge from the CCDC via https://www.ccdc.cam.ac.uk/.

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Acknowledgements

We are grateful for financial support from the National University of Singapore (R-143-000-A57-114) and Ministry of Education of Singapore (R-143-000-A94-112). We also thank the Programme of Introducing Talents of Discipline to Universities for support.

Author information

Author notes

  1. These authors contributed equally: Li-Cheng Yang, Ya-Nong Wang.

Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Singapore

    Li-Cheng Yang, Ya-Nong Wang, Ruoyang Liu, Xiao Qian Ng, Binmiao Yang, Zi-Qiang Rong & Yu Zhao

  2. School of Chemistry and Chemical Engineering, Chongqing Key Laboratory of Theoretical and Computational Chemistry, Chongqing University, Chongqing, China

    Yixin Luo & Yu Lan

  3. Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, China

    Binmiao Yang & Zhihui Shao

  4. College of Chemistry and Institute of Green Catalysis, Zhengzhou University, Zhengzhou, China

    Yu Lan

  5. Joint School of the National University of Singapore and Tianjin University, Binhai New City, China

    Yu Zhao

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Contributions

L.-C.Y. and Y.-N.W. designed and performed the experiments. R.L. discovered the key intermediate and implemented the mechanistic studies. Y. Lan and Y. Luo conducted the DFT calculation. X.Q.N., B.Y. and Z.-Q.R. helped with substrate synthesis and data collection. Y.Z. directed the project, analysed the results and wrote the manuscript with Y.-N.W., L.-C.Y., Y. Lan and Z.S.

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Correspondence to Yu Lan, Zhihui Shao or Yu Zhao.

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Extended data

Extended Data Fig. 1 DFT calculations of all the possible cycloadducts and the transition states of C-allylation.

DFT calculations were performed using M06-2X in toluene with dppf as the ligand. The energies are shown in kcal/mol. The values of bond length are given in ångstrom. a, Calculated relative free energies of all possible cycloadducts related to their starting materials 1a and 2a. The observed cycloadducts are marked within boxes. The Gibbs free energy of 3 is higher than 4 and 5. The bridgehead olefin-containing 5a is the most thermodynamic stable cycloadduct. b, Dihedral angle of DC-C2-C1-C11 is the crucial factor to determine divergent synthesis of 4a or 5a. TS-V and TS-VII with flat dihedral angle are more favoured. c, The conformation of 4a’-1 shows that one of H at bridgehead is close to C7 which is proposed to facilitate a rapid 1,5-H shift to deliver 5a.

Extended Data Fig. 2 DFT calculation of TS-II and TS-III for selective formation of 5 vs 4 for 5m-5p.

In contrast to the model substrate, TS-III leading to 5 is favoured over TS-II leading to 4 for bulky substrates. The corresponding dihedral angles (D) in TS-III- 5 m, TS-III-5n and TS-III-5p do not change a lot from the transition state in model reaction (TS-III), while such difference of dihedral angle (DCA-C2-CB-O) from TS-II is more obvious and their energy barriers would increase a lot from TS-II as well. As an overall effect, summarized at the bottom of Fig. 4d, the energy barriers of TS-IIs for 5m-5p are 1.2-2.9 kcal/mol higher than their corresponding TS-III, in contrast to the trend of 4a/5a (–2.0 kcal/mol).

Extended Data Fig. 3 The optimized conditions for 3, 4 and 5.

The detailed experimental conditions for the divergent reactions to deliver 3a, 4a or 5a are summarized. The identities of the ligands for each transformation are included in the bottom of this figure.

Supplementary information

Supplementary Information

General information on substrate synthesis, catalytic method procedures and mechanistic investigation, DFT calculations, complete characterization of reaction products including NMR data and spectra, high-resolution mass spectrometry, single-crystal X-ray data and high-performance liquid chromatography traces to show the enantioenrichment of the compounds, including Supplementary Figs. 1–14 and Tables 1–6.

Supplementary Table 1

B3LYP geometries for all of the cycloadducts, intermediates and transition states.

Supplementary Data 1

Crystallographic data for compound 3a (CCDC reference 1920222).

Supplementary Data 2

Crystallographic data for compound 4a (CCDC reference 1920223).

Supplementary Data 3

Crystallographic data for compound 5a (CCDC reference 1920224).

Supplementary Data 4

Crystallographic data for compound 5rh (CCDC reference 1920225).

Supplementary Data 5

Crystallographic data for compound 7a (CCDC reference 1920226).

Supplementary Data 6

Crystallographic data for compound 9a (CCDC reference 1920227).

Supplementary Data 7

Crystallographic data for compound 11a (CCDC reference 1920228).

Supplementary Data 8

Crystallographic data for compound 5q (CCDC reference 1920233).

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Yang, LC., Wang, YN., Liu, R. et al. Stereoselective access to [5.5.0] and [4.4.1] bicyclic compounds through Pd-catalysed divergent higher-order cycloadditions. Nat. Chem. 12, 860–868 (2020). https://doi.org/10.1038/s41557-020-0503-7

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