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Modular α-tertiary amino ester synthesis through cobalt-catalysed asymmetric aza-Barbier reaction

Nature Chemistry volume 16, pages 398–407 (2024)Cite this article

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Abstract

Unnatural chiral α-tertiary amino acids containing two different carbon-based substituents at the α-carbon centre are widespread in biologically active molecules. This sterically rigid scaffold is becoming a growing research interest in drug discovery. However, a robust protocol for chiral α-tertiary amino acid synthesis remains scarce due to the challenge of stereoselectively constructing sterically encumbered tetrasubstituted stereogenic carbon centres. Herein we report a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides, including alkyl iodides, alkyl bromides and alkyl chlorides, enabling the formation of chiral α-tertiary amino esters with a high level of enantioselectivity and excellent functional group tolerance. Primary, secondary and tertiary organoelectrophiles are all tolerated in this asymmetric reductive addition protocol, which provides a complementary method for the well-exploited enantioselective nucleophilic addition with moisture- and air-sensitive organometallic reagents. Moreover, the three-component transformation of α-ketoester, amine and alkyl halide represents a formal asymmetric deoxygenative alkylamination of the carbonyl group.

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Fig. 1: Introduction for asymmetric alkylative aza-Barbier reaction.
Fig. 2: Synthetic applications.
Fig. 3: Preliminary mechanistic studies.

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Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers CCDC 2215368 (3d), 2260751 (3cc) and 2211548 (21). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All data supporting the findings of this research are available within the Article and its Supplementary Information.

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Acknowledgements

This work was supported by NSFC/China (22171079, 22371071), the Natural Science Foundation of Shanghai (21ZR1480400), the Shanghai Rising-Star Program (20QA1402300), the Shanghai Municipal Science and Technology Major Project (grant no. 2018SHZDZX03), the Program of Introducing Talents of Discipline to Universities (B16017), the China Postdoctoral Science Foundation (2021M701197, 2023T160215), the Shanghai Sailing Program (23YF1408800) and the Fundamental Research Funds for the Central Universities. We thank the Analysis and Testing Center of East China University of Science and Technology for help with NMR and high-resolution mass spectrometry analysis. Y.C. thanks B. Feringa (University of Groningen) and A. Schuppe (Vanderbilt University) for insightful discussions.

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Authors and Affiliations

  1. Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, China

    Xianqing Wu, Hanyu Xia, Chenyang Gao, Baixue Luan, Licheng Wu, Chengxi Zhang, Liting Hou, Ning Liu, Tingting Xia, Haiyan Li, Jingping Qu & Yifeng Chen

  2. State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, China

    Dawei Yang & Jingping Qu

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  1. Xianqing Wu
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Contributions

X.W. and Y.C. conceived the project. X.W., H.X., C.G., B.L., L.W., C.Z., D.Y., L.H., N.L., T.X. and H.L. performed the experiments under the supervision of J.Q. and Y.C.; X.W. and Y.C. wrote the manuscript with the feedback of all other authors.

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Correspondence to Yifeng Chen.

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The authors declare no competing interests.

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Nature Chemistry thanks Marc Presset, Thomas Nugent and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–13 and Tables 1–10.

Supplementary Data 1

Crystallographic data for compound 3cc; CCDC reference 2260751.

Supplementary Data 2

Crystallographic data for compound 3d; CCDC reference 2215368.

Supplementary Data 3

Crystallographic data for compound 21; CCDC reference 2211548.

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Wu, X., Xia, H., Gao, C. et al. Modular α-tertiary amino ester synthesis through cobalt-catalysed asymmetric aza-Barbier reaction. Nat. Chem. 16, 398–407 (2024). https://doi.org/10.1038/s41557-023-01378-9

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