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Ligand-enabled palladium-catalysed enantioselective synthesis of α-quaternary amino and glycolic acids derivatives

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Abstract

α-Quaternary amino and glycolic acids have found application in many biologically relevant compounds and pharmaceuticals. For example, α-quaternary amino acids can act as modifiers of peptide conformation, compared with natural amino acids. Although there are numerous enantioselective methods for the synthesis of α-quaternary amino and glycolic acids through α-alkylation, α-arylation routes are challenging. Here we report two protocols for the enantioselective synthesis of chiral α-aryl quaternary amino acids and glycolic acids derivatives, respectively, using palladium catalysis with two unique sulfinamide phosphine (Sadphos) ligands. The methods employ two common heterocycles, azlactones and 5H-oxazol-4-ones, as amino acid and glycolic acid precursors and show a broad substrate scope, with high yields and excellent enantioselectivity. Density functional theory calculations of the transition-state structures, studying non-covalent interactions and using natural bond orbital analysis, reveal that C–H···O interactions between the ligand and the substrate play a critical role in the efficient stereocontrol.

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Fig. 1: Background and project synopsis.
Fig. 2: Competitive experiments and kinetic study.
Fig. 3: Gram-scale reaction and transformation of products.
Fig. 4: DFT study of transition-state structures for reductive elimination.

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Data availability

The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2233239 (5ab). These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service, www.ccdc.cam.ac.uk/structures.

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Acknowledgements

We gratefully acknowledge funding support from the National Key R&D Program of China (2021YFF0701600, J.Y. and J.Z.), NSFC (21901043, J.Y.; 21921003, J.Z.; 22031004, J.Z.), STCSM (21ZR1445900, J.Y.) and Shanghai Municipal Education Commission (20212308, J.Z.).

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Authors and Affiliations

  1. Department of Chemistry, Fudan University, Shanghai, China

    Shutao Qi, Wenshao Ye, Yunkai Hua, Liangkai Pan, Junfeng Yang & Junliang Zhang

  2. Fudan Zhangjiang Institute, Shanghai, China

    Junfeng Yang

  3. School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, China

    Junliang Zhang

  4. School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, China

    Junliang Zhang

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  1. Shutao Qi
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  2. Wenshao Ye
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  3. Yunkai Hua
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Contributions

J.Y. conceived the project and analysed the data. J.Y. and J.Z wrote the manuscript. S.Q. performed most of the experiments. W.Y., Y.H. and L.P. contributed to the synthesis of ligands and substrate. J.Y. did the DFT calculations. All authors discussed the results and commented on the manuscript.

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Correspondence to Junfeng Yang or Junliang Zhang.

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Nature Synthesis thanks Giovanni Amarante and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary handling editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary Information

Supplementary Figs. 1–6, Discussion and Tables 1–9.

Supplementary Data 1

Crystallographic Data for 5ab, CCDC 2233239.

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Qi, S., Ye, W., Hua, Y. et al. Ligand-enabled palladium-catalysed enantioselective synthesis of α-quaternary amino and glycolic acids derivatives. Nat. Synth 3, 357–367 (2024). https://doi.org/10.1038/s44160-023-00448-7

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