Michael reactions, asymmetric

Substantial efforts have been made by several groups to develop enantioselectiveMichael reaction in mechanochanical conditions. Michael addition of propanal (R =Me) 81 to /ran5-p-nitrostyrene (R2=Ph) 82 was used as a model reaction for enantioseleclive 

Enantioselective Michael reaction of propanal to frans-p-nitrostyrene. 

Reproduced with permission Horn Veverkov E, PoUckovi V. Liptakov L. K menov E MeSarov M. Toma 5, Sebesta R. Orgarocataiyst efficiency in the Michael additions of aldehydes to nitroaikenes in water and in a bal-mii. ChemCatChem 2012 4 101 -8. Copyright (2012), Wiley. 

CHAPTER 2 Carbon-Carbon Bond-Forming Reactions 

Entry Product R2 Catalyst/ Method Yield %) dr (syn anti) ee syn antif 

In a continuation of the work described above, the Merck group also found (2) to be an efficient catalyst for the asymmetric Michael addition of indanone (4) to methyl vinyl ketone (5).t l The product (6) was formed in 95% yield and 80% e.e. Interestingly the diastereomer 

An earlier and closely related asymmetric Michael reaction was reported by Wynberg and Hermann.151 The ketoester (7) in this case is acidic enough to be deprotonated by quinine (8), whose structure is similar to cinchonine but enantiomeric at the two key stereogenic 

Octahedral complexes of transition metal ions with bidentate ligands can display chirality  

The method described above results in asymmetric induction at the nucleophile. Asymmetry can also be induced at the Michael acceptor. An example of this involving C-S bond formation is shown below. (For the sake of consistency, this reaction is considered with the C-C bond forming reactions.) 

The chiral catalyst (15) is derived from natural 5,5-hydroxyproline, and serves to deprotonate the thiophenol. A tight ion pair is formed with (14), rather reminiscent of that in asymmetric phase-transfer catalysis. In a non-polar solvent such as toluene, solvation is at a premium, so one would expect the hydroxy of the catalyst to hydrogen bond to the carbonyl of the enone (17). 

The heterobimetallic catalyst prepared from (R,R)-3-aza-benzyl-l,5-dihydroxy-l,5-diphenylpentane was used for the asymmetric Michael addition reaction of malo-nates and thiophenols to enones [49]. The polymer-supported version of the chiral 

Asymmetric Michael reactions are known to be well-catalyzed by the AlLi-bis(binaphthoxide) complex (ALB) [51]. In order to immobilize such a highly organized multicomponent asymmetric catalyst, Sasai developed a new strategy based on the use of a catalyst analogue [52]. Si-tethered binaphthol 86 as a stable catalyst analogue was copolymerized with methyl methacrylate and ethylene glycol 

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Thus the product in such cases can exist as two pairs of enantiomers. In a di-astereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture. Many such examples have been reported. In many of these cases, both the enolate and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, (E) enolates gave the syn pair of enantiomers (p. 146), while (Z) enolates gave the anti pair. Addition of chiral additives to the reaction, such as proline derivatives, or (—)-sparteine lead to product formation with good-to-excellent asynunetric induction. Ultrasound has also been used to promote asymmetric Michael reactions. Intramolecular versions of Michael addition are well known. ... 

On the other hand, chiral sulfur-containing but noncoordinating ligands such as sulfonamides have been widely used in the asymmetric Michael reaction. In 1997, Sewald et al. reported the use of a series of chiral sulfonamides depicted in Scheme 2.25 in the Cu-catalysed conjugate addition of ZnEt2 to 2-cyclohexenone. Even the use of a stoichiometric amount of catalyst did not allow the enantioselectivity to be higher than 31% ee. 

Azoniaspirocycles have been derived from L-tartrate for use as phase-transfer catalysts <2002TL9535>. Catalyst 158 was synthesized in a straightforward manner (Equation 36), then used for catalytic asymmetric Michael reactions an example is shown (Equation 37). 

Table 6. Catalytic asymmetric Michael reactions promoted by the AlMbis(R)-binaphthoxide) complex (AMB).

The mechanistic considerations of a catalytic asymmetric Michael reaction suggest that the reaction of a alkali metal enolate derived from a malon-ate derivative with an enone should lead to an intermediary aluminum enolate. Is it possible that such an A1 enolate could then be trapped by an... 

Scheme 18. Asymmetric Michael reaction by use of crown ethers.

Scheme 20. Asymmetric Michael reaction of the O Donnell imine 23.

A. Loupy, A. Zaparucha, Asymmetric Michael Reaction under PTC Conditions without Solvent. Importance of re Interactions for the Enantioselectivity , Tetrahedron Lett. 1993, 34, 473-476. 

For an example of asymmetric Michael reaction using guanidine-based catalysts, see Ma, D. Cheng, K. Tetrahedron Asym. 1999, 10, 713-719. 

Ishikawa and co-workers also reported a class of structurally modified guanidines for promotion of the asymmetric Michael reaction of ierf-butyl-diphenylimino-acetate to ethyl acrylate [124,125]. In addition to a polymer support design (Scheme 69), an optical resolution was developed to achieve chiral 1,2-substituted ethylene-l,2-di-amines, a new chiral framework for guanidine catalysis. The authors discovered that incorporating steric bulk and aryl substituents in the catalyst did improve stereoselec-tivitity, although the reactivity did suffer (Scheme 70, Table 4). 

Scheme 6.68 Typical adducts obtained from the 12-catalyzed asymmetric Michael reaction between malononitrile and a.P-unsaturated N-acyl pyrrolidinones (cyclic imides) the values in parentheses refer to reactions at lower concentration (0.1 M).

Figure 6.26 Multiple hydrogen-bonding tertiary amine-functionalized thioureas screened in the asymmetric Michael reaction between trans-P-nitrostyrene and acetylacetone at 10mol% loading.

The utility of C9-epi-DHQ thiourea 122 for the catalysis of asymmetric Michael reactions [149-152] was further demonstrated by the Wang group [282] in 2006. 

Almost simultaneously, the Wang group pubUshed an additional application of binaphthyl thiourea catalyst 148 [314]. Asymmetric Michael reactions [149-152] of... 

Chiral metal alkoxides and naphthoxides have been used as catalysts for asymmetric Michael reaction. An early successful example was reported by Cram et al., who used 4 mol % of KO Bu-chiral crown ether 8 complex as the catalyst to afford the Michael adduct with up to 99% ee (Scheme 8D.7) [16], In this case KO Bu complexed with chiral crown ether 8 plays two... 

TABLE 8D.l. Catalytic Asymmetric Michael Reaction with LnSB (10 mol %)... 

Figure 8D.5. Proposed Catalytic Cycle of the Asymmetric Michael Reaction Promoted by LSB.

TABLE 8D.2. Catalytic Asymmetric Michael Reactions Promoted by LSB in CH2C12... 

Another highly useful heterobimetallic catalyst is the aluminum-lithium-BINOL complex (ALB) prepared from LiAlH4 and 2 equiv. of (/ )-BINOL. The ALB catalyst (10 mol %) is also effective in the Michael reaction of enones with various malonates, giving Michael products generally with excellent enantioselectivity (91-99% ee) and in excellent yields [23]. These results ate summarized in Table 8D.3. Although LLB and LSB complement each other in their ability to catalyze asymmetric nitroaldol and Michael reactions, respectively, the Al-M-(/ )-BINOL complexes (M = Li, Na, K, and Ba) are commonly useful for the catalytic asymmetric Michael reaction. 

Third heterobimetallic asymmetric catalyst reported by Shibasaki et al., gallium-sodium-BINOL complex (GaSB) 26 and indium-potassium-BINOL complex (InPB), are also rather effective catalysts for asymmetric Michael reactions, and GaSB was better than InPB in terms of enantioselectivity. The GaSB catalyst was prepared from GaCl3, NaO Bu (4 mol equiv. to... 

A chiral quartemary ammonium salt works as a chiral-phase transfer catalyst, and this chemistry has been applied to asymmetric Michael reaction by Corey et al. (Scheme 8D.16) [33]. It has been shown that the cinchonidine salt 28, which has been designed by rigidifying... 

Recent advances in the catalytic asymmetric Michael reactions have made it possible to achieve enantioselectivity higher than 90% ee in these processes rather routinely. These reactions have just begu n to be used as key steps in the syntheses of natural products or other useful compounds. In many cases, however, more than 10 mol % of catalysts are necessary to achieve high chemical yield and enantioselectivity at present. In consideration of the limited natural resources on... 

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