EMTECS · Electrophile-Mediated Three-Component Enantiospecific Cross-Couplings

Electrophile-Mediated Three-Component Enantiospecific Cross-Couplings

The Suzuki-Miyaura cross-coupling of boronic acids and esters with sp2 electrophiles is one of the most powerful C–C bond forming reactions in organic synthesis. It has found widespread application across the areas of pharmaceutical, agrochemical, and materials science. The importance and impact of this transformation was recognised in 2010 with the Nobel Prize in Chemistry (Scheme 1). Despite its broad utility, the scope of the reaction is narrow with respect to sp3 substituted boronic esters. Except for a few specific and isolated examples, secondary and tertiary boronic esters do not react well with sp2 electrophiles, which limits the application of this reaction in asymmetric synthesis. However, due to the potential power of such transformations, there has been increasing interest in finding alternative strategies that enable stereospecific sp3–sp2 cross-couplings. Recently, the host group developed a metal-free, stereospecific cross-coupling reaction of chiral alkyl boronates with electron-rich aromatics, promoted by the use of electrophilic oxidants (Scheme 2). We plan to substantially extend this cross-coupling chemistry through the application of a range of different electrophiles that will not only mediate the cross-coupling process, but also remain in the final product, creating multiple carbon–carbon bonds stereospecifically (Scheme 3). Through the use of this strategy, we expect to prepare doubly functionalised enantiopure aromatic compounds in a very efficient three-component coupling process that utilises readily accessible enantiopure alkyl boronic esters, electron-rich aromatics and various electrophiles.

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