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Modular synthesis of 1,2-azaborines via ring-opening BN-isostere benzannulation

Nature Chemistry volume 16, pages 269–276 (2024)Cite this article

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Abstract

1,2-Azaborines represent a unique class of benzene isosteres that have attracted interest for developing pharmaceuticals with better potency and bioavailability. However, it remains a long-standing challenge to prepare monocyclic 1,2-azaborines, particularly multi-substituted ones, in an efficient and modular manner. Here we report a straightforward method to directly access diverse multi-substituted 1,2-azaborines from readily available cyclopropyl imines/ketones and dibromoboranes under relatively mild conditions. The reaction is scalable, shows a broad substrate scope, and tolerates a range of functional groups. The utility of this method is demonstrated in the concise syntheses of BN isosteres of a PD-1/PD-L1 inhibitor and pyrethroid insecticide, bifenthrin. Combined experimental and computational mechanistic studies suggest that the reaction pathway involves boron-mediated cyclopropane ring-opening and base-mediated elimination, followed by an unusual low-barrier 6π-electrocyclization accelerated by the BN/CC isomerism. This method is anticipated to find applications for the synthesis of BN-isostere analogues in medicinal chemistry, and the mechanistic insights gained here may guide developing other boron-mediated electrocyclizations.

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Fig. 1: Synthetic methods to access 1,2-azaborines.
Fig. 2: Proposed strategy and reaction discovery.
Fig. 3: Derivatization and synthetic applications.
Fig. 4: Preliminary mechanistic studies.

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Data availability

The data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for the structure of 3ay have been deposited at the Cambridge Crystallographic Data Centre, under deposition no. 2150659. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This project was supported by the University of Chicago, NIGMS (1R21GM144048-01, G.D. and R35GM128779, P.L.) and the National Science Foundation (CHE-1764328, K.N.H.). H.L. acknowledges a Suzuki Postdoctoral Fellowship from the University of Chicago. V. Rawal is thanked for thoughtful discussions. X. Liu is acknowledged for X-ray crystallography. DFT calculations were performed at the Center for Research Computing at the University of Pittsburgh and with supercomputer resources at NSF XSEDE. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

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

    Hairong Lyu, Zhijie Chen, Yifei Wu & Guangbin Dong

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

    Thomas H. Tugwell & Peng Liu

  3. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Garrett A. Kukier, Aneta Turlik & K. N. Houk

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Contributions

H.L. and G.D. conceived and designed the experiments. H.L., Z.C. and Y.W. performed experiments. T.H.T., G.A.K., A.T., K.N.H. and P.L. designed and conducted the DFT calculations. H.L., T.H.T., K.N.H., P.L. and G.D. wrote the manuscript. P.L. and G.D. directed the research.

Corresponding authors

Correspondence to K. N. Houk, Peng Liu or Guangbin Dong.

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Competing interests

A patent application has been filed (applicant: University of Chicago; name of inventor(s): Guangbin Dong, Hairong Lyu, Zhijie Chen, Yifei Wu; application no., 63/376,889; status of application, pending; specific aspect of manuscript covered in patent application, ‘New azaborine structures’). The remaining authors declare no competing interests.

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Nature Chemistry thanks Michael Lo 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. 1–10, Table 1, experimental details, computational details, data and spectra.

Supplementary Data 1

Crystallographic data for compound 3ay; CCDC reference 2150659.

Supplementary Data 2

DFT xyz coordinates.

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Lyu, H., Tugwell, T.H., Chen, Z. et al. Modular synthesis of 1,2-azaborines via ring-opening BN-isostere benzannulation. Nat. Chem. 16, 269–276 (2024). https://doi.org/10.1038/s41557-023-01343-6

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