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Modular and diverse synthesis of amino acids via asymmetric decarboxylative protonation of aminomalonic acids

Nature Chemistry volume 15, pages 1672–1682 (2023)Cite this article

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Abstract

Stereoselective protonation is a challenge in asymmetric catalysis. The small size and high rate of transfer of protons mean that face-selective delivery to planar intermediates is hard to control, but it can unlock previously obscure asymmetric transformations. Particularly, when coupled with a preceding decarboxylation, enantioselective protonation can convert the abundant acid feedstocks into structurally diverse chiral molecules. Here an anchoring group strategy is demonstrated as a potential alternative and supplement to the conventional structural modification of catalysts by creating additional catalyst–substrate interactions. We show that a tailored benzamide group in aminomalonic acids can help build a coordinated network of non-covalent interactions, including hydrogen bonds, π–π interactions and dispersion forces, with a chiral acid catalyst. This allows enantioselective decarboxylative protonation to give α-amino acids. The malonate-based synthesis introduces side chains via a facile substitution of aminomalonic esters and thus can access structurally and functionally diverse amino acids.

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Fig. 1: Anchoring group strategy for asymmetric decarboxylative protonation.
Fig. 2: Identification and optimization of a benzamide non-covalent interaction anchor.
Fig. 3: Synthesis of amino acids with diverse alkyl chainsa.
Fig. 4: Representative application scenarios of the asymmetric malonic ester synthesis.
Fig. 5: Mechanistic experiments and consideration.
Fig. 6: Origins of enantiocontrol and roles of the anchoring group.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for compound (+)-6 have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition no. CCDC 2206851. These data can be obtained free of charge from the CCDC (http://www.ccdc.cam.ac.uk/data_request/cif). Source data are provided with this paper.

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Acknowledgements

We thank the University of Hong Kong for a start-up fund, the National Natural Science Foundation of China (22201222, X.Q.), the National Key R&D Program of China (2022YFA1505100, X.Q.), the Fundamental Research Funds for the Central Universities (2042022kf1038, X.Q.) and the Research Grants Council of Hong Kong (17304523, Z.H.). 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. J. Yip and B. Yan are acknowledged for mass spectrometry and NMR spectroscopy, respectively. X.Q. acknowledges the supercomputing system in the Supercomputing Center of Wuhan University.

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Authors and Affiliations

  1. State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China

    Wei-Feng Zheng & Zhongxing Huang

  2. College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, China

    Jingdan Chen & Xiaotian Qi

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Contributions

Z.H. conceived and designed the project. W.-F.Z. carried out the experiments. W.-F.Z. and Z.H. analysed the experimental data. J.C. and X.Q. carried out the theoretical studies and analysed the data. All authors wrote the manuscript.

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Correspondence to Xiaotian Qi or Zhongxing Huang.

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Nature Chemistry thanks Tian Lu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Figs. 1–19, experimental procedures, product characterization data, and mechanistic studies.

Supplementary Data 1

Crystallographic data for compound (+)-6; CCDC reference 2206851.

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Statistical source data.

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Zheng, WF., Chen, J., Qi, X. et al. Modular and diverse synthesis of amino acids via asymmetric decarboxylative protonation of aminomalonic acids. Nat. Chem. 15, 1672–1682 (2023). https://doi.org/10.1038/s41557-023-01362-3

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