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Dynamic kinetic asymmetric allylation, propargylation and crotylation of ketones using copper catalysis

Nature Synthesis volume 3, pages 1091–1103 (2024)Cite this article

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Abstract

Chiral tertiary alcohols are privileged structures found in numerous bioactive molecules and pharmaceutical agents. However, general and efficient synthetic methods for forming α,β-stereogenic tertiary alcohols bearing two or more contiguous stereocentres are rare. Here we report the development of an enantioconvergent method for the synthesis of α,β-stereogenic tertiary alcohols in a single step by allylation, propargylation or crotylation of racemic α-amino, α-(hetero)aryl and α,α-dialkyl ketones using readily available boronic ester reagents. The identification of the chiral ligand/copper catalytic system enables rapid interconversion and chiral recognition between two enantiomers of racemic ketones, allowing the dynamic kinetic resolution process to occur. The reaction features high levels of diastereoselectivity and enantioselectivity, a wide scope of heterocycle substrates and high functional group compatibility, and provides a general and efficient synthesis of a variety of complex chiral tertiary alcohols otherwise difficult to access, thereby offering a tool for the rapid modification and synthesis of drug molecules.

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Fig. 1: Bioactive α,β-stereogenic tertiary alcohols and their synthesis.
Fig. 2: Scope of enantioconvergent allylation of α-amino ketones.
Fig. 3: Scope of enantioconvergent allylation of α-(hetero)aryl and α,α-dialkyl ketones.
Fig. 4: Scope of enantioconvergent propargylation and crotylation.
Fig. 5: Gramme-scale reactions and diverse transformations.
Fig. 6: Synthetic application.
Fig. 7: Mechanistic experiments and proposed catalytic cycle.

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Data availability

All data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2266504 (4k), 2266505 (10c), 2266506 (11c) and 2266507 (7n). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

Financial support was provided by the National Key R&D Program of China (2022YFA1503702, 2021YFF0701600), the National Natural Science Foundation of China (22325110, 92256303, 21821002, 22171280), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0610000), the Program of Shanghai Academic Research Leader (22XD1424900), the CAS Youth Interdisciplinary Team (JCTD-2021-11), the Ningbo Natural Science Foundation (2022J017) (S.-L.S.), the Natural Science Foundation of Shandong Province (ZR2019BB011) and the Scientific Research Foundation of Qingdao University of Science & Technology (12030430010799) (B.S.).

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Authors and Affiliations

  1. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Bo Sun, Lin-Xin Ruan, Yurong Zhang, Lei Gao & Shi-Liang Shi

  2. State Key Laboratory Base of Eco-chemical Engineering, College of Chemical Engineering, Qingdao University of Science & Technology, Qingdao, China

    Bo Sun, Ruyuan Zhao, Jing Zhang, Ruihan Niu & Quanjian Luo

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Contributions

B.S. developed the catalytic methods, investigated the substrate scope and conducted mechanistic studies. L.-X.R., R.Z., J.Z., R.N., Q.L., Y.Z. and L.G. synthesized substrates and performed partial substrate scope studies. B.S. and S.-L.S. wrote the manuscript. S.-L.S. conceived the project and directed the investigations.

Corresponding authors

Correspondence to Bo Sun or Shi-Liang Shi.

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The authors declare no competing interests.

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Peer review information

Nature Synthesis thanks Jeffrey Johnson 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 Information

Supplementary Tables 1–8, Figs. 1–6, synthetic procedures, scale-up experiments, synthetic transformations and application of the reaction products, control experiments, compound characterization, X-ray crystallography, HPLC analysis and NMR spectra.

Supplementary Data 1

Crystallographic data for compound 4k, CCDC 2266504.

Supplementary Data 2

Crystallographic data for compound 7n, CCDC 2266507.

Supplementary Data 3

Crystallographic data for compound 10c, CCDC 2266505.

Supplementary Data 4

Crystallographic data for compound 11c, CCDC 2266506.

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Sun, B., Ruan, LX., Zhao, R. et al. Dynamic kinetic asymmetric allylation, propargylation and crotylation of ketones using copper catalysis. Nat. Synth 3, 1091–1103 (2024). https://doi.org/10.1038/s44160-024-00567-9

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