Chiral Phosphoric Acid Catalyzed Direct Aldol Reactions of Glyoxylates

Significance

A Brønsted acid catalyzed direct asymmetric aldol reaction of ketones with glyoxylates is reported. Chiral phosphoric acid 1 was found to be a suitable catalyst for the reaction of ethylglyoxylate with various ketones. The corresponding aldol products were obtained in moderate to good enantioselectivities and good yields. Also the recyclability of the catalyst was demonstrated. The syn-diastereoselectivity of this method complements analogous sec-amine-catalyzed reactions.

Comment

Over the last years enamine catalysis has become the most powerful tool for conducting direct catalytic asymmetric aldol reactions. Despite the tremendous progress and the huge numbers of different catalysts and procedures available, the reaction still suffers from some ­limitations regarding the substrate scope. For instance, acetophenones, enones and fused cyclic ketones are still challenging aldol nucleophiles in enamine catalysis. The herein reported approach, the Brønsted acid catalyzed direct asymmetric ­aldol reaction, is complementary in this respect and gives access to such aldol products in optically active form. Although the electrophilic component is limited to highly reactive glyoxylates, this work nicely shows the versatility and prospects of chiral Brønsted acid catalysis. After Akiyama’s initial report of chiral Brønsted acid catalyzed intramolecular aldol condensations (Angew. Chem. Int. Ed. 2009, 48, 4226; Synfacts 2009,796), this report discloses a new chapter of chiral phosphoric acid catalyzed aldol reactions.