Catalytic reductive desymmetrization of malonic esters

Desymmetrization of fully substituted carbons with a pair of enantiotopic functional groups is a practical strategy for the synthesis of quaternary stereocentres, as it divides the tasks of enantioselection and C−C bond formation. The use of disubstituted malonic esters as the substrate of desymmetrization is particularly attractive, given their easy and modular preparation, as well as the high synthetic values of the chiral monoester products. Here, we report that a dinuclear zinc complex with a tetradentate ligand can selectively hydrosilylate one of the carbonyls of malonic esters to give α-quaternary β-hydroxyesters, providing a promising alternative to the desymmetric hydrolysis using carboxylesterases. The asymmetric reduction features excellent enantiocontrol that can differentiate sterically similar substituents and high chemoselectivity towards the diester motif of substrates. Together with the versatile preparation of malonic ester substrates and post-reduction derivatization, the desymmetric reduction has enabled the synthesis of a diverse array of quaternary stereocentres with distinct structural features. The desymmetrization of easily accessible malonic esters represents an attractive approach towards the formation of chiral quaternary stereocentres, but is largely limited to enzymatic hydrolysis. Now, a zinc-catalysed asymmetric hydrosilylation reaction—that works with a broad scope of substrates—has been shown to reduce one of the esters to a primary alcohol with excellent enantiocontrol.