Chiral Guanidines-catalyzed Nucleophilic Addition Reactions Using 5H-Oxazol-4-ones: Development of Catalytic Asymmetric Syntheses of Chiral α-Tetrasubstituted Hydroxycarboxylic Acid Derivatives

Chiral alpha-hydroxycarboxylic acids and their derivatives bearing a tetrasubstituted alpha-carbon atom are well-recognized chiral synthons and components of various pharmaceuticals and biologically active natural products. Despite their high demand, preparative methods of these compounds are quite limited due to the difficulty in achieving stereoselective construction of the tetrasubstituted carbon stereogenic center at the alpha-position. To address this issue, we developed asymmetric nucleophilic addition reactions of 5H-oxazol-4-ones to carbon electrophiles using chiral bicyclic guanidine catalysts containing a hydroxyl group at the appropriate position as a preparative method of alpha-tetrasubstituted hydroxycarboxylic acid derivatives. In this article, we introduce the nucleophilic addition reactions with several types of electrophiles, such as aldehydes, alkynyl carbonyl compounds, allenyl carbonyl compounds, vinyl ketones, dienones, and 2-chloroacrylnitrile. Derivatizations of the products of these reactions into corresponding alpha-hydroxycarboxylic acid derivatives and their application to a natural product synthesis are also described.