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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 stereocenter 2. In 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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Correspondence to Peng Liu or Guangbin Dong.

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 ab initio molecular dynamics (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 (2024). https://doi.org/10.1038/s41586-024-07579-7

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  • DOI: https://doi.org/10.1038/s41586-024-07579-7

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