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Catalytic activation of carbon–carbon bonds in cyclopentanones

Abstract

In the chemical industry, molecules of interest are based primarily on carbon skeletons. When synthesizing such molecules, the activation of carbon–carbon single bonds (C–C bonds) in simple substrates is strategically important: it offers a way of disconnecting such inert bonds, forming more active linkages (for example, between carbon and a transition metal) and eventually producing more versatile scaffolds1,2,3,4,5,6,7,8,9,10,11,12,13. The challenge in achieving such activation is the kinetic inertness of C–C bonds and the relative weakness of newly formed carbon–metal bonds6,14. The most common tactic starts with a three- or four-membered carbon-ring system9,10,11,12,13, in which strain release provides a crucial thermodynamic driving force. However, broadly useful methods that are based on catalytic activation of unstrained C–C bonds have proven elusive, because the cleavage process is much less energetically favourable. Here we report a general approach to the catalytic activation of C–C bonds in simple cyclopentanones and some cyclohexanones. The key to our success is the combination of a rhodium pre-catalyst, an N-heterocyclic carbene ligand and an amino-pyridine co-catalyst. When an aryl group is present in the C3 position of cyclopentanone, the less strained C–C bond can be activated; this is followed by activation of a carbon–hydrogen bond in the aryl group, leading to efficient synthesis of functionalized α-tetralones—a common structural motif and versatile building block in organic synthesis. Furthermore, this method can substantially enhance the efficiency of the enantioselective synthesis of some natural products of terpenoids. Density functional theory calculations reveal a mechanism involving an intriguing rhodium-bridged bicyclic intermediate.

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Figure 1: Activation of C–C bonds in ring systems.
Figure 2: Substrate scope.
Figure 3: Gram-scale synthesis and synthetic applications.
Figure 4: DFT-computed pathways for the activation of C–C bonds in cyclopentanones.

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Acknowledgements

This project was supported by the Cancer Prevention Research Institute of Texas (grant R1118), the National Institute of General Medical Science (grant R01GM109054) and the Welch Foundation (grant F1781). G.D. is a Searle Scholar and Sloan fellow. Y.X. acknowledges the International Postdoctoral Exchange Fellowship Program 2015 from the Office of China Postdoctoral Council (OCPC, document 38, 2015). We thank Johnson Matthey for a donation of Rh salts, and Chiral Technologies for donation of chiral high-performance liquid-chromatography columns. We are grateful to Y. Xu for providing 1,4-dioxane, F. Mo for providing some 3-aryl cyclopentanones, and H. Lim for checking the experimental procedures. DFT calculations were performed using supercomputer resources at the Center for Simulation and Modeling at the University of Pittsburgh, and the Extreme Science and Engineering Discovery Environment supported by the National Science Foundation.

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Y.X. and G.D. conceived and designed the experiments. Y.X. performed the experiments. G.L. performed the DFT calculations. Y.X., G.L., P.L. and G.D. co-wrote the manuscript.

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Correspondence to Peng Liu or Guangbin Dong.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks J. Harvey, M. Lautens and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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This file contains Supplementary Text and Data, Supplementary Tables 1-9, Supplementary Figures 1-18 and additional references (see Contents for more details). (PDF 35980 kb)

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Xia, Y., Lu, G., Liu, P. et al. Catalytic activation of carbon–carbon bonds in cyclopentanones. Nature 539, 546–550 (2016). https://doi.org/10.1038/nature19849

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