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Intermolecular asymmetric functionalization of unstrained C(sp3)–C(sp3) bonds in allylic substitution reactions

Nature Synthesis volume 3, pages 1011–1020 (2024)Cite this article

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Abstract

Catalytic asymmetric functionalization of unstrained C(sp3)–C(sp3) bonds is a promising strategy to edit the structure of a molecule stereoselectively, but such reactions are rare. Existing methods for the catalytic functionalization of C–C bonds typically involve C–C bonds in strained structures. Here we report a strategy to achieve unexplored enantioselective functionalizations of allylic C(sp3)–C(sp3) bonds. Protocols for both kinetic resolution and dynamic kinetic asymmetric transformation are established to construct new C–C bonds at the position of a C(sp3)–C(sp3) bond in the reactant. This study shows that enantioselective functionalizations can be achieved even at unstrained C–C bonds, and an alkyl C–C bond can also work as a leaving group instead of a stable product in enantioselective allylic substitution reactions. Mechanistic experiments and density functional theory calculations reveal that deracemization by the formation of dienes enables the process to occur as a dynamic kinetic asymmetric transformation.

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Fig. 1: Background and our design.
Fig. 2: Scope of asymmetric allylic C(sp3)–C(sp3) bond alkylation via KRa.
Fig. 3: Scope of asymmetric allylic C(sp3)–C(sp3) bond alkylation via DYKAT and applicationsa.
Fig. 4: Experimental mechanistic studies for DYKAT process.
Fig. 5: DFT calculations of the reaction between 1b and 2i under conditions for DYKAT.

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Data availability

All relevant data are available within the paper and in the Supplementary Information files.

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Acknowledgements

Z.-T.H. acknowledges the Science and Technology Commission of Shanghai Municipality (grant no. 22ZR1475200), National Natural Science Foundation of China (grant nos. 22071262 and 22371292), Strategic Priority Research Program of the Chinese Academy of Sciences (grant no. XDB0610000), Ningbo Natural Science Foundation (grant no. 2023J036), State Key Laboratory of Organometallic Chemistry and Shanghai Institute of Organic Chemistry for financial support. J.F.H. acknowledges financial support from National Institutes of Health (grant no. 1R35GM130387).

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Author notes

  1. These authors contributed equally: Ye-Wei Chen, Yehao Qiu.

Authors and Affiliations

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

    Ye-Wei Chen, Yang Liu & Zhi-Tao He

  2. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, China

    Ye-Wei Chen & Guo-Qiang Lin

  3. Department of Chemistry, University of California, Berkeley, CA, USA

    Yehao Qiu & John F. Hartwig

  4. School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

    Zhi-Tao He

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Contributions

Z.-T.H. conceived the project. Y.-W.C. and Y.L. performed the experiments. Y.Q. conducted the DFT calculations. Z.-T.H., J.F.H. and G.-Q.L. supervised the project. Z.-T.H. wrote the manuscript with the feedback from all authors. Z.-T.H. and J.F.H. coreviewed and edited the manuscript.

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Correspondence to John F. Hartwig or Zhi-Tao He.

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Nature Synthesis thanks Xi-Sheng Wang, Ronglin Zhong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Chen, YW., Qiu, Y., Liu, Y. et al. Intermolecular asymmetric functionalization of unstrained C(sp3)–C(sp3) bonds in allylic substitution reactions. Nat. Synth 3, 1011–1020 (2024). https://doi.org/10.1038/s44160-024-00555-z

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