1,3-Dicarbonyl compounds asymmetric Michael addition

The asymmetric Michael addition of 1,3-dicarbonyl compounds to nitrostyrene is promoted by chiral alkaloid catalysts to give the addition products in good chemical yield, but the enantioselectivity is rather low (Eq. 4.47).62... 

Scheme 5.20. Asymmetric Michael addition of 1,3-dicarbonyl compounds.

In recent years, many chiral catalysts for the enantioselective synthesis of optical active 1,5-dicarbonyl compounds have been developed, such as chiral crown ethers with potassium salt bases and chiral palladium complexes, including bimetallic systems. Nakajima and coworkers reported on enantioselective Michael reactions of S-keto esters to a,/3-unsaturated carbonyl compounds in the presence of a chiral biquinoline N,N dioxide-scandium complex, which catalyzed the additions in high yields and with enan-tioselectivities up to 84% ee . Kobayashi and coworkers found that the combination of Sc(OTf)3 with the chiral bipyridine ligand 149 (equation 41) was also effective as a chiral catalyst for asymmetric Michael additions of 1,3-dicarbonyl compounds 147 to a,/3-unsaturated ketones 148. The corresponding Michael adducts 150 were obtained in good to high yields with excellent enantiomeric excesses in most cases (Table 10). 

A more simple thiourea catalyst with amino functionality catalyses the asymmetric Michael addition of 1,3-dicarbonyl compound to nitroolefin [29,30]. In the reaction of malonate to nitrostyrene (Table 9.11) the adduct is satisfactorily obtained when A-[3,5-bis(trifluor-omethyl)phenyl]-A -(2-dimethylaminocyclohexyl)thiourea is used as a catalyst (ran 1), whereas the reaction proceeds slowly when the 2-amino group is lacking (ran2). In addition, chiral amine without a thiourea moiety gives a poor yield and enantioselectivity of the product (run 3). These facts clearly show that both thiourea and amino functionalities are necessary for rate acceleration and asymmetric induction, suggesting that the catalyst simultaneously activates substrate and nucleophile as a bifunctional catalyst. 

Conjugate addition of carbon nucleophiles to electron-poor alkenes is of paramount importance among the enormous community of synthetic processes devoted to carbon-carbon bond formation. In particular, asymmetric Michael additions between a,(S-unsaturated ketone (enone) and 1,3-dicarbonyl compounds allow for access to a variety of optically active adducts affording synthetically useful motifs for the preparation of biologically active natural products and pharmaceutically attractive intermediates (Scheme 9.1). 

SCHEME 9.1. Asymmetric Michael additions between a,(3-unsaturated ketone (enone) and 1,3-dicarbonyl compounds. 

Other Metal Complexes Apart from metal complexes derived from BINOL, other metal complexes, such as the lithium-aluminum amiuo diol complex, " aluminum and nickel salen complex, ruthenium diamine complex, and ruthenium phosphinite diamine complex were also found applicable for the asymmetric Michael addition of 1,3-dicarbonyl compound to cyclic enone. All these metal complexes afforded about 90% of asymmetric induction in the Michael reaction of 2-cyclohexen-l-one and malonate. 

Chen et al. s synthesis In 2007, Chen et al. reported on an organocatlytic asymmetric Michael addition of 1,3-dicarbonyl compounds to enone for the synthesis of warfarin using the cinchona-derived primary amine 9-amino-9-deoxyepiquinine as the organocatalyst (Table 9.14)." In the presence of 9-amino-9-deoxye-piquinine in trifluoroacetic acid, 89-99% of enantio-selectivities and 55-93% of yields were achieved for... 

A chiral quinine-derived squaramide catalysed the highly enantioselective Michael addition of malononitrile to chalcones. The reactions take place at a very low catalyst loading (0.5 mol%) and provide the Michael adducts with high yields and good enan-tioselectivities (up to 96% ee). Chiral bifunctional squaramides have also been used as multiple hydrogen-bond donor-acceptor organocatalysts for the asymmetric Michael addition of nitroolefins to 1,3-dicarbonyl compounds. ... 

Dicarbonyl compounds are versatile stabilized enolate-type nucleophiles in asymmetric Michael addition reactions. In particular, the reaction of 4-hydroxy-2H-chromen-2-one and a,p-enones provided a direct and efficient synthesis of warfarin, a widely prescribed anticoagulant. Recently, Chin reported a simply vicinal... 

The chiral bis(cyclohexyldiamine)-based Ni(ll) complexes were incorporated within the silica framework. The resultant materials were very active and selective as catalysts in the asymmetric Michael addition of 1,3-dicarbonyl compounds to nitroalkenes comparable to those with a homogeneous catalyst. It also could be reused without obviously affecting its enantioselectivity [93]. 

On the other hand, the enantioselective 1,4-addition of carbanions such as enolates to linear enones is an interesting challenge, since relatively few efficient methods exist for these transformations. The Michael reaction of p-dicarbonyl compounds with a,p-unsaturated ketones can be catalysed by a number of transition-metal compounds. The asymmetric version of this reaction has been performed using chiral diol, diamine, and diphosphine ligands. In the past few years, bidentate and polydentate thioethers have begun to be considered as chiral ligands for this reaction. As an example, Christoffers et al. have developed the synthesis of several S/O-bidentate and S/O/S-tridentate thioether... 

The asymmetric allylic C-H activation of cyclic and acyclic silyl enol ethers furnishes 1,5-dicarbonyl compounds and represents a surrogate of the Michael reaction [136]. When sufficient size discrimination is possible the C-H insertion is highly diastereoselective, as in the case of acyclic silyl enol ether 193 (Eq. 22). Reaction of aryldia-zoacetate 192 with 193 catalyzed by Rh2(S-DOSP)4 gives the C-H insertion product 194 (>90% de) in 84% enantiomeric excess. A second example is the reaction of the silyl enol ether 195 with 192 to form 196, a product that could not be formed from the usual Michael addition because the necessary enone would be in its tautomeric naphthol form (Eq. 23). 

In 2013, the Chi group realized an NHC-catalyzed asymmetric p-functional-ization reaction of aldehydes via the transformation of saturated aldehydes to formal Michael acceptors via double oxidation. By using the catalyst derived from the chiral amino indanol triazolium salt in combination with quinone as the oxidant, the p-aryl substituted saturated aldehydes were converted to the o,p-unsaturated acyl azolium intermediates which further reacted with 1,3-dicarbonyl compounds or p-keto esters to generate the corresponding 5-lactones. It was found the use of LiCl and 4 A MS as additives was beneficial to improve the ee s of the products. Notably, the p-alkyl substituted saturated aldehydes were not viable substrates, probably due to the reduced acidity of the p-C—H bonds (Scheme 7.118). 

A highly enantioselective organocatalytic Michael addition of 4-hydroxycouma-rines and related compounds to a,p-unsaturated ketones has been also achieved using imidazolidine catalyst 137 [213]. The reaction, which gives high yields and enantioselectivities for a wide range of cyclic 1,3-dicarbonyl compounds and enones, has been successfully employed for the asymmetric synthesis of the anticoagulant warfarin (Scheme 2.78) and derivatives [213], With respect to the reaction mechanism, very recent studies have demonstrated that the truly active catalyst in the process was the chiral diamine 138, which is formed in catalytic amounts under the reaction conditions by reaction with the hydroxycoumarine (Schane 2.79)... 

S.2.4.3. oL,p-Unsaturated Ketones as Acceptors. The earliest studies on the organocatalytic asymmetric Michael reactions were reported by the group headed by Wynberg [1,83]. The authors found that natural cinchona alkaloids could effectively promote the Michael addition of 1,3-dicarbonyl compounds to a,(3-unsaturated enones. In 2003, Jprgensen and co-workers [84] developed the first highly... 

The second chapter of the book covered the advances in enantioselective nickel(ii)-catalysed conjugate additions. An important breakthrough in the history of the Michael reaction was the achievement of the Michael addition of p-dicarbonyl compounds to a broad variety of electrophiles catalysed by nickel acetylacetonate, described by Nelson in 1979-1980. Since this pioneering contribution, nickel has become one of the preferred metals in catalytic Michael reactions. Later, in 1988, Soai developed the first asymmetric conjugate additions performed under chiral nickel(ii) catalysis. Ever since. 

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