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Stereospecific alkenylidene homologation of organoboronates by SNV reaction

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Abstract

Concerted nucleophilic substitution, known as SN2 reaction, is a fundamental organic transformation used in synthesis to introduce new functional groups and construct carbon–carbon and carbon–heteroatom bonds1. SN2 reactions typically involve backside attack of a nucleophile to the σ* orbital of a C(sp3)–X bond (X = halogen or other leaving group), resulting in complete inversion of a stereocentre2. By contrast, the corresponding stereoinvertive nucleophilic substitution on electronically unbiased sp2 vinyl electrophiles, namely concerted SNV(σ) reaction, is much rarer, and so far limited to carefully designed substrates mostly in ring-forming processes3,4. Here we show that concerted SNV reactions can be accelerated by a proposed strain-release mechanism in metallated complexes, leading to the development of a general and stereospecific alkenylidene homologation of diverse organoboronates. This method enables the iterative incorporation of multiple alkenylidene units, giving cross-conjugated polyenes that are challenging to prepare otherwise. Further application to the synthesis of bioactive compounds containing multi-substituted alkenes is also demonstrated. Computational studies suggest an unusual SN2-like concerted pathway promoted by diminishing steric strain in the square planar transition state, which explains the high efficiency and stereoinversive feature of this metallate SNV reaction.

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Fig. 1: Concerted SNV reactions.
Fig. 2: Reaction discovery and mechanistic studies.
Fig. 3: Alkenylidenoid scope for stereospecific alkenylidene homologation.
Fig. 4: Boronate scope for alkenylidene homologation.
Fig. 5: Iterative alkenylidene homologation.

Data availability

All the data generated or analyzed during this study are included in this article and its Supplementary Information. Crystallographic data for the structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 2342622 (Z-3a), CCDC 2341268 (E-Ate-2b–HQ), CCDC 2342623 (Z-3c), CCDC 2342625 (E-3c). These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service (www.ccdc.cam.ac.uk/structures).

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Acknowledgements

University of Chicago, ACS PRF (65249-ND1 to G.D.) and NIGMS (R35GM128779 to P.L.) are acknowledged for research support. We thank Z. Zhang (University of Chicago) and X. Liu (University of Chicago) for X-ray crystallography, J. Kurutz (University of Chicago) for variable temperature NMR experiments, O. Mora (Lane Tech High School) for collecting high-resolution mass spectrometry and infrared spectra of some samples, and Y. Ge (University of Chicago) for checking the experimental procedure. 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 NSF 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, Coco Liu & Guangbin Dong

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

    Christian D. Knox, Mithun C. Madhusudhanan, Thomas H. Tugwell & Peng Liu

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  1. Miao Chen
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Contributions

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

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Correspondence to Peng Liu or Guangbin Dong.

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Nature thanks Qiuling Song and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Applications in modular synthesis of biologically important compounds containing multi-substituted alkenes.

The overall yields for each final product were calculated based on the starting boronates. See Supplementary Information for experimental details.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data Sections 1–12; see contents page for details.

Supplementary Data 1

This file contains the XRD data of E-3c.

Supplementary Data 2

This file contains the XRD data of Z-3c.

Supplementary Data 3

This file contains the XRD data of Z-3a.

Supplementary Data 4

This file contains the XRD data of E-Ate-2b–HQ.

Supplementary Video 1

An AIMD trajectory of the concerted SNV reaction. AIMD trajectory of the 1,2-migration of alkenyl boronate Ate-2l to form 4a-Neop in explicit Et2O solution. The trajectory was created from two separate simulations from pre-equilibrated TS-2l, one going back to reactant Ate-2l, while the other progressing forward to product 4a-Neop.

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Chen, M., Knox, C.D., Madhusudhanan, M.C. et al. Stereospecific alkenylidene homologation of organoboronates by SNV reaction. Nature 631, 328–334 (2024). https://doi.org/10.1038/s41586-024-07579-7

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