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Catalytic reductive desymmetrization of malonic esters

Abstract

Desymmetrization of fully substituted carbons with a pair of enantiotopic functional groups is a practical strategy for the synthesis of quaternary stereocentres, as it divides the tasks of enantioselection and C−C bond formation. The use of disubstituted malonic esters as the substrate of desymmetrization is particularly attractive, given their easy and modular preparation, as well as the high synthetic values of the chiral monoester products. Here, we report that a dinuclear zinc complex with a tetradentate ligand can selectively hydrosilylate one of the carbonyls of malonic esters to give α-quaternary β-hydroxyesters, providing a promising alternative to the desymmetric hydrolysis using carboxylesterases. The asymmetric reduction features excellent enantiocontrol that can differentiate sterically similar substituents and high chemoselectivity towards the diester motif of substrates. Together with the versatile preparation of malonic ester substrates and post-reduction derivatization, the desymmetric reduction has enabled the synthesis of a diverse array of quaternary stereocentres with distinct structural features.

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Fig. 1: Quaternary stereocentres via desymmetrization of malonic esters.
Fig. 2: Zinc-catalysed desymmetric hydrosilylation of malonic esters.
Fig. 3: Application of the reductive desymmetrization.
Fig. 4: Kinetic study and proposed hydride transfer transition states.

Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for 50a reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2025159. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Source data are provided with this paper.

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Acknowledgements

We thank the University of Hong Kong for a start-up fund. We acknowledge funding support from the Laboratory for Synthetic Chemistry and Chemical Biology under the Health@InnoHK Program launched by the Innovation and Technology Commission, the Government of HKSAR. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. C.-M. Che and P. Chiu are acknowledged for their kind support and sharing of chemicals. K.-H. Low, J. Yip and B. Yan are acknowledged for X-ray crystallography, mass spectroscopy and NMR spectroscopy, respectively. We also thank L. Wu for helpful discussion.

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Authors

Contributions

Z.H. conceived and designed the project. P.X. and Z.H. carried out the experiments, analysed the data and wrote the manuscript.

Corresponding author

Correspondence to Zhongxing Huang.

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The authors declare no competing interests.

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Peer review information Nature Chemistry thanks Marcin Kwit and the other, anonymous, reviewers(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1 and 2, experimental procedures, product characterization data and mechanistic studies.

Supplementary Data

Crystallographic data for compound 50a; CCDC reference 2025159.

Source data

Source Data Fig. 2c

Statistical Source Data.

Source Data Fig. 4a

Statistical Source Data.

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Xu, P., Huang, Z. Catalytic reductive desymmetrization of malonic esters. Nat. Chem. (2021). https://doi.org/10.1038/s41557-021-00715-0

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