Asymmetric Organocatalysis with bis-Silyl Ketene Acetals

Enantiomerically pure α-stereogenic carboxylic acids are encountered in a variety of natural products and pharmaceuticals and are useful substrates for various transformations. The direct synthesis of such motifs via catalytic asymmetric α-functionalization remains challenging in both metal- and organocatalysis. A general approach toward α-functionalization can be envisioned via formation of bis-silyl ketene acetal intermediates followed by functionalization with an electrophilic counterpart. This thesis focuses on the development of enantioselective transformations with bis-silyl ketene acetals, exploring the generality of this strategy within Bronsted and Lewis acid catalysis for a variety of enantioselective C–H and C–C bond forming reactions, using simple and unactivated substrates. This strategy was successfully applied to the deracemization of α-branched aryl carboxylic acids via catalytic asymmetric protonation of bis-silyl ketene acetals with water or methanol as a proton source, delivering valuable products with high enantiomeric purity and high yields, including non-steroidal anti-inflammatory arylpropionic acids, such as Ibuprofen. Furthermore, this strategy showed great potential under Lewis acidic conditions for a direct aminomethylation, allowing the first asymmetric organocatalytic synthesis of β2-amino acids from aliphatic and aromatic unactivated substrates, in very good enantioselectivities and excellent yields. This work opens the field of catalytic asymmetric transformations with bis-silyl ketene acetals for the direct access of enantioenriched α-branched carboxylic acids.