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Enantioconvergent carbenoid insertion into carbon–boron bonds

Nature Synthesis volume 4, pages 1297–1307 (2025)Cite this article

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Abstract

Developing a unified method that can construct almost all types of chiral centres has been an unrealized aspiration for synthetic chemists. Boron-mediated homologation can generate versatile boron-substituted stereocentres via asymmetric carbenoid insertion, potentially leading to diverse chiral centres. However, limitations of the current methods make it challenging to incorporate a wide range of functionalized carbenoids with high stereochemical control. Here we report an enantioconvergent approach for direct insertion of various carbon-, oxygen-, nitrogen-, sulfur- and silicon-substituted carbenoids into carbon–boron bonds of readily available boronic acid derivatives, which can then be transformed into a wide range of tertiary chiral centres. Excellent stereoselectivity was achieved and enabled by a class of chiral oxazaborolidines derived from inexpensive α-amino esters. Computational studies revealed that the non-C2-symmetric oxazaborolidine features a puckered geometry and the cooperative effects of multiple substituents create an asymmetric environment for effective enantioinduction. This method is scalable, and each chiral centre can be independently controlled by the chiral oxazaborolidine without being influenced by nearby stereocentres. In addition to forming singular chiral centres, iterative operations of this asymmetric homologation simplify syntheses of complex molecules with multiple stereocentres.

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Fig. 1: Strategies for asymmetric boron homologation.
Fig. 2: Design for enantioconvergent boron homologation.
Fig. 3: Computational investigations.
Fig. 4: Scope of the enantioconvergent boron homologation with carbon-substituted carbenoids.
Fig. 5: Asymmetric insertion of heteroatom-substituted carbenoids.
Fig. 6: Synthetic utility.

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Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2311818 (9f) and 2312263 (27). These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

We are grateful for financial support from the University of Chicago and the NIH (R35 GM128779, P.L.). We thank Z. Zhang, X. Liu, S. Anferov and A. Filatov for X-ray crystallography. We thank X. Liu for checking the experimental procedure. DFT calculations were carried out at the University of Pittsburgh Center for Research Computing and the Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) programme, supported by NSF award numbers OAC-2117681, OAC-1928147 and OAC-1928224.

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Authors and Affiliations

  1. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Qiqiang Xie, Jiahao Li & Guangbin Dong

  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    Thomas H. Tugwell, Mithun C. Madhusudhanan & Peng Liu

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  1. Qiqiang Xie
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Contributions

Q.X. and G.D. conceived of the idea and designed the experiments. Q.X. and J.L. conducted the experimental investigation. P.L., T.H.T. and M.C.M. conceived and designed the computational studies. T.H.T. and M.C.M. performed the computational studies. Q.X., T.H.T., P.L. and G.D. wrote the paper. P.L. and G.D. directed the research.

Corresponding authors

Correspondence to Peng Liu or Guangbin Dong.

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The authors declare no competing interests.

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Peer review information

Nature Synthesis thanks Per-Ola Norrby, Tian Qin 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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Extended data

Extended Data Fig. 1 Stereoretentive derivatizations of the homologation product.

Diverse tertiary chiral centres can be formed via versatile stereospecific transformations of the carbon−boron bond. NIS, N-iodosuccinimide; e.s., enantiospecificity.

Extended Data Fig. 2 Summary on how to choose the optimal chiral auxiliary.

The choice of the best auxiliary depends on the substrates and carbenoids employed. X, leaving group.

Supplementary information

Supplementary information

Experimental details, Supplementary sections 1–16, Figs. 1–13 and Tables 1–4.

Supplementary Data 1

Crystallographic data for compound 9f; CCDC reference 2311818.

Supplementary Data 2

Crystallographic data for compound 27; CCDC reference 2312263.

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Xie, Q., Tugwell, T.H., Madhusudhanan, M.C. et al. Enantioconvergent carbenoid insertion into carbon–boron bonds. Nat. Synth 4, 1297–1307 (2025). https://doi.org/10.1038/s44160-025-00836-1

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