Organocatalytic Enantioselective Mukaiyama-Mannich Reaction of Isatin-Derived Ketimines for the Synthesis of Oxindolyl-β3,3-Amino Acid Esters.

Abstract

Mukaiyama-Mannich reactions of ester enolate equivalents with aldimines have elegantly been used for the asymmetric synthesis of β-amino acids; nevertheless, the corresponding asymmetric reaction employing ketimines are until unexplored. Herein, we disclose the first organocatalytic enantioselective Mukaiyama-Mannich reaction employing isatin-derived ketimines with unsubstituted silyl ketene acetals towards the scalable synthesis of 2-oxoindolinyl-β3,3-amino acid esters at room temperature with excellent enantioselectivities (ee >99.5%). Ultra-low catalyst loading (as low as 250 ppm) could be used for the quantitative product formation with high enantiopurity. The synthetic utility of this protocol has been showcased in the short step formal synthesis of pharmaceutically demanding (+)-AG-041R, a potent gastrin/CCK-B receptor antagonist.