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β-Carbon activation of saturated carboxylic esters through N-heterocyclic carbene organocatalysis

Nature Chemistry volume 5, pages 835–839 (2013)Cite this article

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Abstract

The activation of the α-carbons of carboxylic esters and related carbonyl compounds to generate enolate equivalents as nucleophiles is one of the most powerful strategies in organic synthesis. We reasoned that the horizons of chemical synthesis could be greatly expanded if the typically inert β-carbons of saturated esters could be used as nucleophiles. However, despite the rather significant fundamental and practical values, direct use of the β-carbons of saturated carbonyl compounds as nucleophiles remains elusive. Here we report the catalytic activation of simple saturated ester β-carbons as nucleophiles (β-carbon activation) using N-heterocyclic carbene organocatalysts. The catalytically generated nucleophilic β-carbons undergo enantioselective reactions with electrophiles such as enones and imines. Given the proven rich chemistry of ester α-carbons, we expect this catalytic activation mode for saturated ester β-carbons to open a valuable new arena for new and useful reactions and synthetic strategies.

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Figure 1: Organocatalytic β-sp3-CH activation of saturated ester.
Figure 2: Synthetic transformation to bioactive molecules.

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Acknowledgements

The authors acknowledge support from the Singapore National Research Foundation (NRF), the Singapore Economic Development Board (EDB), GlaxoSmithKline (GSK) and Nanyang Technological University (NTU). The authors thank R. Ganguly and Y. Li (NTU) for assistance with X-ray structure analysis, and Z. Jin, L. Hao, X. Chen and J. Mo (NTU) for help with catalyst and substrate preparation.

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Authors and Affiliations

  1. Division of Chemistry & Biological Chemistry, Nanyang Technological University, School of Physical & Mathematical Sciences, Singapore, 637371, Singapore

    Zhenqian Fu, Jianfeng Xu, Tingshun Zhu, Wendy Wen Yi Leong & Yonggui Robin Chi

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  1. Zhenqian Fu
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  2. Jianfeng Xu
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  3. Tingshun Zhu
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Contributions

Z.F. conducted most of the experiments. J.X. and W.W.Y.L. conducted some experiments on the hydrazone reactions. T.Z. contributed to the synthetic transformation of catalytic reaction products. Y.R.C. conceptualized and directed the project, and drafted the manuscript with assistance from all co-authors. All authors contributed to discussions.

Corresponding author

Correspondence to Yonggui Robin Chi.

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Crystallographic data for compound 3y (CIF 15 kb)

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Crystallographic data for compound 7j (CIF 14 kb)

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Fu, Z., Xu, J., Zhu, T. et al. β-Carbon activation of saturated carboxylic esters through N-heterocyclic carbene organocatalysis. Nature Chem 5, 835–839 (2013). https://doi.org/10.1038/nchem.1710

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