Stereospecific alkenylidene homologation of organoboronates by SNV reaction

Miao Chen, Christian D. Knox, Mithun C. Madhusudhanan, Thomas H. Tugwell, Coco Liu, Peng Liu () and Guangbin Dong ()
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Miao Chen: University of Chicago
Christian D. Knox: University of Pittsburgh
Mithun C. Madhusudhanan: University of Pittsburgh
Thomas H. Tugwell: University of Pittsburgh
Coco Liu: University of Chicago
Peng Liu: University of Pittsburgh
Guangbin Dong: University of Chicago

Nature, 2024, vol. 631, issue 8020, 328-334

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07579-7

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