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Cooperative activation of cyclobutanones and olefins leads to bridged ring systems by a catalytic [4 + 2] coupling

Abstract

Bridged ring systems are widely found in natural products, and successful syntheses of them frequently feature intramolecular Diels–Alder reactions. These reactions are subclassified as either type I or type II depending on how the diene motif is tethered to the rest of the substrate (type I are tethered at the 1-position of the diene and type II at the 2-position). Although the type I reaction has been used with great success, the molecular scaffolds accessible by the type II reactions are limited by the strain inherent in the formation of an sp2 carbon at a bridgehead position. Here, we describe a complementary approach that provides access to these structures through the C–C activation of cyclobutanones and their coupling with olefins. Various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons. The ketone group of the products serves as a convenient handle for downstream functionalization.

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Figure 1: The challenge of bridged ring synthesis.
Figure 2: Proposed catalytic cycle.
Figure 3: Potentials and applications in bridged ring synthesis.

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Acknowledgements

The authors thank Cancer Prevention Research Institute of Texas (R1118) for a start-up fund and the National Institutes of Health (1R01GM109054-01) and the Welch Foundation (F 1781) for research grants. G.D. is a Searle Scholar. The authors thank J. L. Sessler, D. R. Siegel and E. V. Anslyn for loaning chemicals. V. Lynch is acknowledged for assistance with X-ray crystallography. The authors also thank Johnson Matthey for a donation of Rh salts. Chiral Technologies is thanked for a donation of chiral high-performance liquid chromatography columns. S. J. Thompson is thanked for proofreading the manuscript.

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Authors and Affiliations

Authors

Contributions

H.M.K. and G.D. conceived and designed the experiments. H.M.K. performed the experiments. H.M.K and G.D. analysed the data. H.M.K. and G.D. co-wrote the manuscript.

Corresponding author

Correspondence to Guangbin Dong.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary information (PDF 5841 kb)

Supplementary information

Crystallographic data for compound 2a (CIF 17 kb)

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Crystallographic data for compound 2f (CIF 17 kb)

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Crystallographic data for compound 2i (CIF 19 kb)

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Crystallographic data for compound 2n (CIF 15 kb)

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Crystallographic data for compound 2q-i (CIF 1483 kb)

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Crystallographic data for compound 2q-ii (CIF 1348 kb)

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Crystallographic data for compound 8 (CIF 20 kb)

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Crystallographic data for compound 2o-i (CIF 687 kb)

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Crystallographic data for Rh[P(C6H3(CF3)2)3]2COCl (CIF 441 kb)

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Ko, H., Dong, G. Cooperative activation of cyclobutanones and olefins leads to bridged ring systems by a catalytic [4 + 2] coupling. Nature Chem 6, 739–744 (2014). https://doi.org/10.1038/nchem.1989

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