Mannich reactions, amino acid enolates

The great importance of nonproteinogenic amino acids including a-substituted derivatives led to numerous investigations of modified amino acid enolates as nucleophiles in both classical alkylation or Mannich reactions and palladium-catalyzed allylic alkylations. 

The asymmetric Mannich reaction of an enolate and an imine furnishing valuable p amino carbonyls is a fundamental C C bond forming process in organic chemistry that has broad utility in organic synthesis particularly for P amino acid synthesis [1]. Extending the enolate component into a dienolate offers the opportunity for a bond forming event with an electrophile both at the a and the y positions of this ambident nucleophile (Scheme 5.1). 

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water (<4 vol%).53 Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31).54 The diastereoselective Mannich-type reaction... 

There are several classes of alkaloids. Among these are purines such as xanthine and caffeine, ter-penes (Chapter 22), polyketides (Chapter 21), and alkaloids derived from amino acids. The basic amino acids ornithine, arginine, histidine, and lysine as well as the aromatic amino acids, anthranilate, and nicoti-nate are some of the starting materials.199 201 Robinson202 203 in 1917 recognized that many alkaloids are derived directly from aromatic amino acids. He proposed that alkaloids arise from Mannich reactions (Eq. 25-12) in which an amine and an aldehyde (probably through a Schiff base) react with a nucleophilic carbon such as that of an enolate anion. Many of the... 

Keywords Catalyst, Alkylation, Allylation, Arylation, Mannich reaction, Carbon-nitrogen double bond, Imine, Nitrone, Aldimine, Organozinc reagents, Silyl ketene acetal, Silyl enol ether, Amine, (3-Amino acid... 

The aldol reaction of an enolate or enolate equivalent with an imine is referred to as the Mannich-type reaction. Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched p-amino acid derivatives, which are versatile chiral building blocks for the synthesis of nitrogen-containing biologically important compounds [23]. Despite the enormous progress made in asymmetric aldol reactions [24], the corresponding asymmet-... 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

M. C. Sharma, A. K. Garcia, J. M. Gonzalez, A. Landa, C. Linden, A. a-Oxymethyl ketone enolates for the asymmetric Mannich reaction. From acetylene and N-alkoxycarbonylimines to /J-amino acids. Angew. Chem. Int. Ed. 2000, 39, 1063-1065. 

We need a formaldehyde equivalent that is less electrophilic than formaldehyde itself and will therefore add only once to enol(ate)s. The solution is the Mannich reaction.7 Formaldehyde is combined with a secondary amine to give an iminium salt that adds 47 to the enol of the aldehyde or ketone in slightly acidic conditions to give the amino ketone (or Mannich base ) 48. If the product of the aldol reaction 50 is wanted, alkylation on nitrogen provides a good leaving group and ElcB elimination does the trick. 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

High anti-diastereoselectivity is observed for several aromatic imines for ortho-substituted aromatic imines the two newly formed stereocenters are created with almost absolute stereocontrol. Aliphatic imines can also be used as substrates and the reaction is readily performed on the gram scale with as little as 0.25 mol% catalyst loading. Furthermore, the Mannich adducts are readily transformed to protected a-hydroxy-/8-amino acids in high yield. The absolute stereochemistry of the Mannich adducts revealed that Et2Zn-linked complex 3 affords Mannich and aldol adducts with the same absolute configuration (2 R). However, the diastereoselectiv-ity of the amino alcohol derivatives is anti, which is opposite to the syn-l,2-diol aldol products. Hence, the electrophiles approach the re face of the zinc enolate in the Mannich reactions and the si face in the aldol reactions. The anti selectivity is... 

In addition, the lithium enolate derived from pseudoephedrine propionamide has been shown to undergo highly diastereoselective Mannich reactions with p-(methoxy)phenyl aldimines to form enantiomerically enriched a,p-disubstituted p-amino acids (Table 10). As observed in alkylation reactions using alkyl halides as electrophiles, lithium chloride is necessary for the reaction of aldimines. With respect to the enolate, the stereochemistry of the alkylation reactions is the same as that observed with... 

This BINAP silver(I) complex was subsequently used by Lectka and coworkers as a catalyst for Mannich-type reactions [35]. Slow addition of silyl enol ether 49 to a solution of tosylated a-imino ester 80 under the influence of 10 mol % (i )-BINAP AgSbFg at -80 °C affords the corresponding amino acid derivative 81 in 95 % yield with 90 % ee (Sch. 20). They reported, however, that (R)-Tol-BINAP-CuC104-(CH3CN)2 was a more effective chiral Lewis acid for the reaction and gave the highest yield and ee at 0 °C. 

Asymmetric alkylation of imines has been employed most frequently for the construction of chiral amino moieties involved in the syntheses of nitrogen heterocycles and amino acids [17]. This approach is also useful for fluorinated amino acid synthesis as shown in Scheme 9.7. Mannich reaction of enolate with imino ester 23 in the presence of L-proline gives a-amino esters 24 and 25 enantio-and diastereoselectively [18]. 

Mannich reaction. When mixed with Sc(OTf)3 an ArNH2, ethyl glyoxylate, and an enol ester assemble to give a 7-keto-Waryl-a-amino acid ester. ... 

Asymmetric Mannich (imine-aldol) reactions give optically active p-amino carbonyl compounds of biological activity. There are two types of Pd-catalyzed asymmetric Mannich-type reactions Lewis acid catalyzed and Pd-enolate reactions. These reactions proceed similarly, but the reaction mechanisms are quite different. 

Sodeoka found that Pd(II) hydroxide complexes of BINAP derivatives 18 are excellent catalysts for asymmetric synthesis. Pd enolates are generated from silyl enol ethers by transmetallation. The asymmetric Mannich-type reaction of silyl enol ether of acetophenone (15) with the imine 16 proceeded smoothly using Pd complex of Tol-BINAP, and the ester of amino acid 17 with 90 % ee was obtained in 95 % yield [3]. 

Mannich-type Reactions. A useful method for the preparation of TV acetylated amino acid derivatives was developed using Cu(OTf)2 as catalyst. Thus, a catalytic amount of Cu(OTf)2 and a chiral diamine ligand (10 mol %) catalyzed the reaction between fV-acylimino esters and silyl enol ethers to afford the corresponding Mannich-type adducts (eq 35) in high yields with high enantioselectivities (80% ee). 

On the other hand, Mannich-type reactions of homoenolates or their synthetic equivalents for the production of y-amino acids have been less studied than those involving enolates. In this context, the same authors applied a closely related preformed dinuclear nickel catalyst derived from Schiff base ligand 8 to induce the asymmetric direct Mannich-type reaction of a-keto anilides with o-Ns-protected imines (Scheme 8.11). The corresponding... 

Based on Mannich-type reactions of N-acryliminoacetates with silyl enol ethers, a new method for the preparation of N-acylated amino acid derivatives via nucleophilic addition to N-acrylimino ester has been developed using a polymer-supported amine and scandium catalysts (Scheme 12.5) [9]. Ethyl N-benzoyl-2-bromoglycine was used as a substrate. It could be readily converted to reactive N-acrylimino ester in situ by treatment with a base. Immobilizations of the amine and the scandium species into polymeric supports prevented loss of activity of the catalyst. The method is simple and provides a convenient method for the preparation of N-acrylated amino acid derivatives. 

While hundreds of Lewis acid catalysts have been developed for organic reactions, Brousted acid catalysts have been paid less attention until recently. Conventional Lewis acids, such as titanium chloride and aluminium chloride, are known to be incompatible with aqueous media. On the other hand, Bronsted acids are stable toward water and oxygen. Thus, they are potential candidates as activators of electrophilic substrates in water. It was found that among various Bronsted acids, HBF4 efficiently catalyzed Mannich -type reactions of silyl enol ethers with aromatic aldehydes derived from activated imines to afford the corresponding p-amino ketones (Scheme 3.1). ... 

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