The Asymmetric Catalytic Mannich Reaction Catalyzed by Organocatalyst ^|^mdash; A Personal Account ^|^mdash;

Abstract

The Mannich reaction is a synthetically useful method for the construction of nitrogen-containing molecules. Organocatalysts have been successfully applied to the Mannich reaction. Our group has been engaged in research on the organocatalyst-mediated Mannich reaction since the early days of its development in 2002. We have developed a proline-mediated three-component Mannich reaction of aldehyde, ketone and p-anisidine under the high pressure induced by water-freezing. Proline was found to effectively promote the cross Mannich reaction of two different aldehydes to afford the Mannich product with syn-selectivity and excellent enantioselectivity, conditions successfully employed as a key reaction for the stereoselective synthesis of the N-terminal amino acid moiety of Nikkomycin B and Bx. A trifluoromethyl-substituted diarylprolinol silyl ether is an effective organocatalyst of the Mannich reaction with acetaldehyde as nucleophile. It is also effective in the desulfonylative Mannich reaction of aliphatic aldehyde, α-chloroacetaldehyde and α-keto aldehyde which are employed as a precursor of the imine, affording the desired Mannich products with anti-selectivity and excellent enantioselectivity. As the obtained Mannich products are useful chiral building blocks which can be prepared by this simple procedure, the present methods are important for the synthesis of nitrogen-containing molecules.