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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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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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.
The authors declare no competing interests.
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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).
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.
B3LYP geometries for all of the cycloadducts, intermediates and transition states.
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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
Nature Communications (2021)