Direct Enantioselective α-Alkoxylation of β-Keto Esters Enabled by Umpolung Strategy

Chiral ethers adjacent to a carbonyl group represent a valuable class of motifs; however, their catalytic asymmetric synthesis from readily available carbonyl compounds remains underexplored. Here, we present a catalytic asymmetric umpolung C–O bond-forming reaction of β-keto esters with alkyl hydroperoxides. This protocol employs in situ activation of alkyl hydroperoxides with trichloroacetonitrile, enabling the enantioselective alkoxy transfer to β-keto esters under catalysis by a chiral bifunctional organocatalyst, thereby allowing access to a broad range of highly functionalized, enantioenriched ethers bearing quaternary stereocenters.