Mechanism asymmetric Michael reaction

Figure 4. Proposed mechanism for the La-BINOL (La-17)-catalyzed asymmetric Michael reaction.

Figure 31. Proposed mechanism for the catalytic asymmetric Michael reaction promoted by LSB.

Figure 6.21 The proposed mechanism of Michael reaction of enones with malonates catalyzed by (R, i )-Ln-M-linked BINOL complex, a bifunctional asymmetric catalyst developed by Shibasaki.

Very recently N-terminal prolyl peptides have been suggested as another attractive class of aldol catalyst. Tang et al. [132] mention in a footnote that the dipeptide Pro-Thr-OMe catalyzes the reaction of acetone with p-nitrobenzaldehyde to give the corresponding aldol in 69% ee. Reymond et al. have studied a peptide library and also found that several N-terminal prolyl peptides catalyze the same asymmetric aldolization [124]. Independently, Martin and List showed that N-terminal prolyl peptides catalyze the direct asymmetric aldol reaction of acetone with p-nitrobenzaldehyde and the asymmetric Michael reaction between acetone and j5-nitrostyrene (Scheme 4.37) [135]. Mechanisms have so not yet been proposed for these reactions. 

Of interest from the mechanistic point of view is the formation of only one diastereoisomer in the methylation step VII/119 — VII/124. Two possible explanations are discussed in the literature [3]. First, a stereoselective methylation of the aldehyde group takes place under the influence of the nitro group leading to the correct stereochemistry in VII/124. The second possibility involves the titanium reagent. An equilibrium can exist between the diastereoisomeric mixture VII/121 and the pure VII/123 via the isomer VII/122. By quenching the equilibrium mixture, only the thermodynamically most stable isomer would be obtained [3]. A differentiation of the two mechanisms seems possible using chiral reaction conditions. Treatment of the chiral (-)-VII/119 (50 % ee), prepared by an asymmetric Michael addition of acrylaldehyde and 2-nitrocyclohexa-none in the presence of cinchonine [84], with achiral dimethyltitaniumdiisopro-poxide yields only achiral methylation products. This experiment shows that no stereoselective methylation takes place. The second consideration, then seems to be more likely (Scheme VII/24)7). 

In this chapter, we present the contributions of computational chemistry toward understanding the mechanism and chemistry for three reactions involving nucleophilic attack. The 8 2 reaction, with emphasis on the gas versus solution phase, is presented first Next we describe the critical contribution that computational chemists made in developing the theory of asymmetric induction at carbonyl and vinyl compounds. The chapter concludes with a discussion on the collaborative efforts of synthetic and computational chemists in developing organic catalysts, especially proline and proline-related molecules, for the aldol, Mannich and Michael reaction, and other related reactions. 

The first prominent catalytic asymmetric Michael-type addition reaction of an organolithium reagent was shown by the reaction of 1-naphthy[lithium with 1-fluoro-2-naphthylaldehyde imine in the presence of 6 to afford the binaphthyls in high ee. Only catalytic amounts of 6 (0.05 mol%) effects the reaction to give 82% ee, in which an enantioselective Michael-type addition-elimination mechanism is operative (Eq. (12.12)) [31],... 

Scheme 5.3. Proposed mechanism for the asymmetric Henry and Michael reactions catalyzed by NAP-MgO. (Reproduced with permission from Ref. 64, American Chemical Society,...

An organocatalytic asymmetric formal [3 + 2] cycloaddition reaction of isocya-noesters 218 to nitroolefins 210 leading to highly optically active dihydropyrroles 220 was reported by Gong, et al., Scheme 3.70 [87], The proposed mechanism is depicted in Scheme 3.70 the cinchona alkaloid chiral base 219 promote an asymmetric Michael addition of isocyanoesters to electron-deficient olefins (nitroolefins), and subsequent intramolecular cyclization of the intermediate to afford the dihydropyrroles 220. 

Stereospecific Michael addition reactions also may be catalyzed by hydrolytic enzymes (Scheme 2.205). When ot-trifluoromethyl propenoic acid was subjected to the action of various proteases, lipases and esterases in the presence of a nucleophile (NuH), such as water, amines, and thiols, chiral propanoic acids were obtained in moderate optical purity [1513]. The reaction mechanism probably involves the formation of an acyl enzyme intermediate (Sect. 2.1.1, Scheme 2.1). Being an activated derivative, the latter is more electrophilic than the free carboxylate and undergoes an asymmetric Michael addition by the nucleophile, directed by the chiral environment of the enzyme. In contrast to these observations made with crude hydrolase preparations, the rational design of a Michaelase from a lipase-scaffold gave disappointingly low stereoselectivities [1514-1517]. 

The mechanism of this asymmetric cycloaddition reaction is rationalized by Michael addition of a carbanion in the 7r-allylpalladium complex 17 (generated from (5s)-15) to acrylonitrile followed by the nncleophilic substitution from the back side of the palladium catalyst in 18 (Scheme 7). 

Intramolecular Michael Reaction of Aldehydes. Imidazolidinone catalyst 1 mediates the asymmetric intramolecular Michael addition of simple aldehydes to enones at rt (eq 15). The reaction is thought to proceed via an enamine mechanism but a dual-activation mechanism involving both enamine and iminium catalysis can also be considered. When a catalytic amount of 1 was used, products were obtained in excellent yield although in low enantioselectivity (eq 15). Better selectivity was observed, however, when catalyst 2 was used (eq 15). 

The reaction mechanism was proposed to have iminium intermediate (Scheme 9.3). The iminium moiety is formed between L-prolinate and enone (intermediates A and B). Then, the malonate attacks the 3-carbon of the enone to afford the asymmetric Michael adduct. For iminium intermediate A, malonate with metal counter cation is located at a suitable position to approach the (3-carbon of the enone from the same side of the armed metal salt Considering about intermediate B, the distance between malonate and P-carbon of the enone is relatively too far for reaction to take place. 

Figure 8D.7. Proposed Mechanism for the Catalytic Asymmetric Tandem Michael-Aldol Reaction Promoted by ALB.

Whilst the elementary steps of the reaction were postulated in the earliest publications [3], and remain (globally) even today as the core of the mechanistic discussion, the fine details of the reaction - and in particular those controlling the asymmetric induction - have been highlighted only recently. The first critical mechanism [15a, 45, 46], which is based on pressure-dependence data, established a reversible Michael addition of the nucleophilic base to the activated al-kene (Scheme 5.3). In the following step, the formed zwitterionic enolate 11 adds to the electrophile and forms a second zwitterionic adduct 13. This step was considered to be the rate-determining step (RDS) of the reaction. Subsequent proton transfer and release of the catalyst provides finally the desired product 14. 

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