Mannich addition

The focus in this section is the electrophilic a-functionalization of 2,2-dimethyl-l,3-dioxan-5-one. Various reactions have been carried out, such as alkylations, aldol additions, Mannich reactions, and transition metal-catalyzed reactions. Conditions were described for diastereoselective transformations, or auxiliary controlled diastereoselective transformations, providing enantiomerically pure products, and enantioselectively catalyzed reactions using organo-catalysts. 

The best catalyst for this transformation was AgSbFg (10 mol%), and (3-ketoesters, malonates, and silyl enol ethers have been used for the nucleophilic addition on the pyridinium intermediate DD. The dihydroisoquinolines 48 have been further used in several reactions in order to assemble the framework of various alkaloids. One example is given in the formation of dihydroisoquinoline 49, bearing a pendent a, 3-unsaturated ketone. Compound 49 can rearrange to the tetracycle 50 (related to the core structure of karachine, Scheme 5.23), using TMSOTf, via a tandem Michael addition-Mannich reaction process (intermediates EE and FF). 

In accordance with the generally accepted mechanism ofthe MBH reaction, the aza MBH reaction involves, formally, a sequence of Michael addition, Mannich type reaction, and (3 elimination. A commonly accepted mechanism is depicted in Scheme 13.2. A reversible conjugate addition of the nucleophilic catalyst to the Michael acceptor generates an enolate, which can intercept the acylimine to afford the second zvdtterionic intermediate. A proton shift from the a carbon atom to the P amide followed by P elimination then affords the aza M BH adduct with concurrent regeneration of the catalyst [5]. 

Scheme 11.13 Conjugate addition/Mannich reaction using the chiral sulfinyl imine 56 [24].

Scheme 11.16 Conjugate addition/Mannich reaction using TADDOL-based ligand 67 [26].

Scheme 11.17 Conjugate addition/Mannich reaction for the synthesis of isoindoline 71...

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

Guo, S., Xie, Y, Hu, X., Xia, C., Huang, H. (2010). Diastereo- and enantioselective catalytic tandem Michael addition/Mannich reaction Access to chiral isoindohnones and azetidines with multiple stereocenters. Angewandte Chemie International Edition, 49, 2728-2731. 

In 2011, the Fukuyama group reported the first total synthesis of (-)-conophylline, whose structure consists of two pentacyclic aspidosperma skeletons (Scheme 13.5) [6]. The two aspidosperma skeletons were both constructed through a similar intramolecular Michael addition/Mannich reaction cascade stfategy, which could produce three new rings and three new stereogenic centers with complete stereoselectivity in just one step. 

Scheme 13,5 Total synthesis of (—)-conophylline (37) employing an intramolecular Michael addition/Mannich cascade reaction.

However, diastereoselective transformations like this are not to be discussed within this monograph, as they do not fulfill the criteria of asymmetric synthesis, according to Marckwald s definition (in today s language) this would mean [...] those reactions, or sequences of reactions, which produce chiral nonracemic substances from achiral compounds with the intermediate use of chiral nonracemic materials, but excluding a separation operation [35]. Thus, diastereoselective conversions not included for that reason in this book are, for example, aldol additions, Mannich reactions, and Michael additions of enolates to ketones, imines, and cx,P-unsaturated carbonyl compounds, respectively, with any chiral skeleton. For such stereoselective enolate reactions that are not asymmetric syntheses, the reader is referred to the literature, which treated this topic in a comprehensive manner [36]. 

After subsequent Claisen condensation with a second equivalent acetyl-CoA, 4-(l-methyl-pyrrolidin-2-yl)-3-oxobu-tanoyl-CoA 25a/b is formed, the link between pyrrolidine and tropane alkaloid biosynthesis. From this intermediate, characteristic pyrrolidine alkaloids, such as hygrine (26) and cuscohygrine (27), two alkaloids commonly found in coca leaves [9], are formed either directly by hydrolysis and subsequent decarboxylation (for 26) or via an additional Mannich reaction with the aforementioned IV-methyl-A -pyrrolinium cation (23) followed by hydrolysis and decarboxylation (27). 

In terms of enamine and iminium ion catalysis, an intramolecular cascade conjugate addition/Mannich reaction was shown to be effectively catalyzed by 36 [108]. The reaction involves the construction of a tetracycUc structure from the indoyl methyl enone shown in Scheme 6.53. The highest enantioselectivities were obtained with addition of nitrobenzoic acid and with ethyl acetate as the solvent... 

In addition, Mannich adducts can be further transformed into various bioactive molecules such as P-lactams, amino sugars, imino sugars, and amino alcohols... 

C-l,4-addition/Mannich-type cyclization through respective intermediates 303 and 304. This finding invoked historical perspectives from Prelog s work in 1949 [139] and the enamine work of Stork et al. in the 1950s [140]. With the latter case, a distinct contrast could be generalized whereby cycloadditions of a,(3-unsaturated carbonyl systems with enamines mostiy led to carbo-[3+3] cycloaddition [138], and those with enaminones, or vinylogous amides, almost exclusively proceeded down the pathway of an aza-[3+3] cycloaddition. 

With y,5-unsaturated /3-ketocarboxylic acid esters as nucleophiles, l-alkyl-3-alkoxy-carbonyl-4-[2- " C]piperidones can be formed via a tandem Michael addition/Mannich... 

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