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Abstract:
Enantiopure carbonyl compounds bearing tetrasubstituted α-stereogenic centers are versatile building blocks for the synthesis of pharmaceuticals, fragrances, and natural products. The direct synthesis of such motifs via asymmetric α-functionalization of the corresponding ketones is a major challenge in both metal- and organocatalysis. In this work we report on development of enol catalysis, a novel strategy allowing the direct enantioselective α-functionalization of carbonyl compounds via Brønsted acid promoted enolization. Within this thesis, we established the generality of this strategy in a variety of enantioselective C–C, C–N and C–O bond forming reactions using simple α-branched and unbranched ketones as substrates. Along the same line of research we developed a highly enantioselective Robinson annulation of 1,3-diketones that afforded derivatives of the synthetically valuable Wieland–Miescher ketone. Furthermore, this strategy was successfully applied to direct α-amination and α-hydroxylation reactions using either diazocarboxylates or nitrosobenzene as reagents. And finally, we discovered that enol catalysis enables serendipitously-discovered α-aryloxylation of ketones using 1,4-benzoquinones. Taken together, this work has established enol catalysis as a generic enantioselective and scalable methodology applicable to a broad scope of challenges of organic synthesis.
