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Enantioselective propargylic amination and related tandem sequences to α-tertiary ethynylamines and azacycles

Nature Chemistry volume 16, pages 521–532 (2024)Cite this article

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Abstract

Chiral α-tertiary amines and related azacycles are sought-after compounds for drug development. Despite progress in the catalytic asymmetric construction of aza-quaternary stereocentres, enantioselective synthesis of multifunctional α-tertiary amines remains underdeveloped. Enantioenriched α-disubstituted α-ethynylamines are attractive synthons for constructing chiral α-tertiary amines and azacycles, but methods for their catalytic enantioselective synthesis need to be expanded. Here we describe an enantioselective asymmetric Cu(I)-catalysed propargylic amination (ACPA) of simple ketone-derived propargylic carbonates to give both α-dialkylated and α-alkyl–α-aryl α-tertiary ethynylamines. Sterically confined pyridinebisoxazoline (PYBOX) ligands, with a C4 shielding group and relaying groups, play a key role in achieving excellent enantioselectivity. The syntheses of quaternary 2,5-dihydropyrroles, dihydroquinines, dihydrobenzoquinolines and dihydroquinolino[1,2-α]quinolines are reported, and the synthetic value is further demonstrated by the enantioselective catalytic total synthesis of a selective multi-target β-secretase inhibitor. Enantioselective Cu-catalysed propargylic substitutions with O- and C-centred nucleophiles are also realized, further demonstrating the potential of the PYBOX ligand.

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Fig. 1: Chiral α-tertiary propargylamines via ACPA.
Fig. 2: Design and application of chiral sterically confined PYBOX ligands.
Fig. 3: Synthetic application.
Fig. 4: Mechanistic studies and further applications.

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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 the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2212823 (4aa), 2304114 (5e), 2304057 (5l), 2212826 (8h), 2212213 (9a) and 2226279 (22). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We are grateful for financial support from the NSFC (21725203 and 21971067, J.Z.; 21871090, F.Z.), the Shanghai Science and Technology Innovation Action Plan (no. 20JC1416900, J.Z.), the Innovation Program of Shanghai Municipal Education Commission (2023ZKZD37, J.Z.) and the Fundamental Research Funds for the Central Universities. Li-Xin Dai on the occasion of his 100th birthday.

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Authors and Affiliations

  1. State Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China

    Zheng Zhang, Ying Sun, Yi Gong, Da-Liang Tang, Hui Luo, Zhi-Peng Zhao, Feng Zhou & Jian Zhou

  2. College of Chemistry, Sichuan University, Chengdu, China

    Xin Wang

  3. College of Chemistry and Molecular Sciences, Henan University, Kaifeng, China

    Jian Zhou

  4. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai, P. R. China

    Jian Zhou

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  1. Zheng Zhang
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Contributions

J.Z. and F.Z. conceived the idea. Z.Z. performed the experiments. Z.Z., Y.S. and H.L. collected and analysed the data. Z.Z., Y.S., Y.G., D.-L.T., H.L. and Z.-P.Z. prepared the starting materials. X.W. performed the DFT calculation studies. F.Z. and J.Z. directed the project and co-wrote the manuscript.

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Correspondence to Feng Zhou, Xin Wang or Jian Zhou.

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

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Extended data

Extended Data Fig. 1 Less successful examples of challenging substrates.

Despite the broad substrate scope shown in Table 1, there still had some challenging substrates unable to afford the desired amines in satisfactory enantiomeric excess, including carbonates derived from ketones with lesser steric dissimilarities between two substituents, primary amines such as cyclohexyl amine, and acyclic secondary amines such as N-methylaniline. However, the use of our sterically confined PYBOX ligands could still afford obviously better enantioselectivity (for details, see Section 5.3 in SI). Condition A: α-alkyl ester 1 (0.05 mmol), amine 3 (0.06 mmol), CuBr2 (10 mol%), L (12 mol%), N,N-dimethylpiperazine (0.2 mmol) in n-PrOH (0.5 mL) at –20 °C for 2.5 days. Condition B: α-aryl ester 2 (0.05 mmol), amine 3 (0.06 mmol), CuCl2·2H2O (10 mol%), L15 (12 mol%), N-methylpiperidine (0.2 mmol) in MeOH (0.5 mL) at –20 °C for 2.5 days. Yield was determined by 1H NMR with 1,3,5-trimethoxybenzene as internal standard. The e.e. values were determined by chiral HPLC. aAt 0 °C. bRun for 5 days.

Supplementary information

Supplementary Information

Supplementary Tables 1–18, Figs. 1–8, Chiral ligand and starting material preparation, Experimental procedures, Synthetic transformations, Mechanistic studies and Product characterization.

Supplementary Data 1

Crystallographic data for compound 4aa; CCDC reference 2212823.

Supplementary Data 2

Crystallographic data for compound 5e; CCDC reference 2304114.

Supplementary Data 3

Crystallographic data for compound 5l; CCDC reference 2304057.

Supplementary Data 4

Crystallographic data for compound 8h; CCDC reference 2212826.

Supplementary Data 5

Crystallographic data for compound 9a; CCDC reference 2212213.

Supplementary Data 6

Crystallographic data for compound 22; CCDC reference 2226279.

Supplementary Data 7

Computational details and Cartesian coordinates.

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Zhang, Z., Sun, Y., Gong, Y. et al. Enantioselective propargylic amination and related tandem sequences to α-tertiary ethynylamines and azacycles. Nat. Chem. 16, 521–532 (2024). https://doi.org/10.1038/s41557-024-01479-z

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