Saturated carbonyl compounds are, via their enolate analogues, inherently nucleophilic at the α-position; a fundamental reactivity bias which is further enhanced by enamine catalysis for the enantioselective installation of electrophilic reagents. Consequently, organocatalytic α-functionalizations using nucleophilic reagents have remained largely elusive owing to the high requirements of combining polarity inversion and asymmetric induction in a single synthetic transformation. To address this challenge, an organocatalytic umpolung concept has been developed: Treating α-branched aldehydes with a benzoquinone oxidant yields covalent aldehyde/quinone adducts which are labile toward nucleophilic substitution. Early mechanistic investigations reveal that aminocatalytic conditions can promote an unusual S<sub>N</sub>2-driven dynamic-kinetic resolution of such quinone adducts, delivering enantioenriched α-functionalized products from racemic intermediates. This mechanistic manifold is harnessed and applied for the enantioselective α-etherification of aldehydes using readily available oxygen-based nucleophiles. The scope of suitable nucleophilic reagents includes phenols, alcohols, hydroxylamines, oximes, and hydroperoxides, delivering their respective ether products in up to 95% <i>ee</i>. Our studies also demonstrate that high enantioselectivity pivots on a careful match between the nucleophilicity of the coupling partner and the identity of the quinone oxidant. Taken together, these studies provide the basis for an aminocatalytic umpolung protocol that allows for the asymmetric construction of ethers in the α-position of aldehydes.

Oxidative umpolung of organocatalytic enamines: Enantioselective α-etherification of aldehydes using hydroxyl nucleophiles

ACS Spring 2022

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