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

Abstract

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 tri uoromethyl 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.

High pressure initiated solvent and catalyst-free instant Paal–Knorr reactions

“…6 With the development of reliable, often benchtop instruments the applications of HHP in synthetic chemistry have expanded. The more recent examples include hydrogenation, 7 the addition of enamines to Michael acceptors, 8 enantioselective Mannich reactions, 9 lipase-catalyzed esterification, 10 diastereoselective asymmetric nitro-aldol reaction, 11 Michael, 12 and aza-Michael reactions, 13,14 Diels–Alder reactions, 15 and Friedel–Crafts alkylation of indoles. 16 Despite the promising developments, high pressure synthesis is still in its infancy.…”

Organocatalyzed Asymmetric Mannich Reaction: An Update

“…In continuation of our interest in asymmetric synthesis of name reactions, [16–26] in this review, we wish to highlight the recent developments achieved and reported in asymmetric Mannich reaction. It is worthy to mention that the application of asymmetric organocatalyzed‐Mannich reaction in the total synthesis of naturally occurring compounds and heterocycles as power tool, has been extensively reviewed [4,27–43] …”

Evidence for an enolate mechanism in the asymmetric Michael reaction of α,β-unsaturated aldehydes and ketones via a hybrid system of two secondary amine catalysts

“…6 However, in recent asymmetric reactions, catalytically generated enamines are essentially the key intermediates. In this context, chiral secondary and primary amines act as catalysts for the a-functionalization of ketones in bond forming reactions such as the aldol reaction, 3,7 Mannich reaction, 3,8 Michael reaction, 3 a-aminoxylation 3 and a-aminations. 3 In the Mannich reaction of acetone catalysed by a primary amine-thiourea organocatalyst, an enol mechanism was proposed, 9 while an enamine mechanism is proved by calculation and 13 C kinetic isotope effects in the Michael reaction of acetone catalysed by a similar catalyst.…”