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Synthesis of alkenyl boronates through stereoselective vinylene homologation of organoboronates

Nature Synthesis volume 3, pages 337–346 (2024)Cite this article

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Abstract

Matteson homologation of organoboronates is an attractive approach for constructing aliphatic carbon chains via iterative insertion of carbenoids. However, the corresponding homologation that can introduce alkene moieties to molecular backbones remains elusive. Here we report the development of a stereoselective vinylene homologation reaction of various alkyl and aryl boronates. The reaction proceeds through diastereoselective consecutive insertion of a silyl- and an alkoxy-substituted carbenoid, followed by a Peterson-type elimination. A diverse range of alkenyl boronates can be formed in good yield and with good to excellent trans selectivity. Density functional theory calculations reveal the origin of diastereoselectivity in carbenoid insertion and how Lewis acids with different sulfide binding affinities affect the competing SN2- and SN1-type 1,2-boronate migration pathways with distinct levels of stereospecificity. This protocol has been applied to the programmable synthesis of piperamide-family natural products through iterative vinylene and methylene homologations. Guided by mechanistic understanding, the use of oxyphilic Lewis acids has enabled the development of a cis-selective vinylene homologation.

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Fig. 1: Vinylene homologation and strategy design.
Fig. 2: Mechanistic studies.
Fig. 3: Synthetic applications.
Fig. 4: Z-Vinylene homologation of aryl boronates.

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Data availability

All the data generated or analysed during this study are included in this 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 number 2260049 (8). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

The University of Chicago Women’s Board (G.D.), ACS Petroleum Research Fund (65249-ND1 to G.D.) and National Institute of General Medical Sciences (R35GM128779 to P.L.) are acknowledged for research support. We thank Q. Xie (University of Chicago) for checking the experimental procedure and S. Ochi (University of Chicago) for X-ray analysis. Computational studies were performed at the Center for Research Computing at the University of Pittsburgh and the Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) programme, supported by National Science Foundation award numbers OAC-2117681 and OAC-2138259.

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Authors and Affiliations

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

    Miao Chen & Guangbin Dong

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

    Thomas H. Tugwell & Peng Liu

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  2. Thomas H. Tugwell
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Contributions

G.D. and M.C. conceived and designed the experiments. M.C. performed the experiments and analysed the data. P.L. and T.H.T. conceived and designed the computational studies. T.H.T. performed the computational studies. M.C., T.H.T., P.L. and G.D. prepared the paper together.

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Correspondence to Peng Liu or Guangbin Dong.

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Nature Synthesis thanks Elena Fernández, Vittorio Pace, Aurélien de la Torre and the other, anonymous, reviewer 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 Figs. 1–6, Tables 1–7, experimental procedures and NMR spectra.

Supplementary Data 1

Crystallographic data for compound 8; CCDC reference 2260049.

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Chen, M., Tugwell, T.H., Liu, P. et al. Synthesis of alkenyl boronates through stereoselective vinylene homologation of organoboronates. Nat. Synth 3, 337–346 (2024). https://doi.org/10.1038/s44160-023-00461-w

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