Cinchona alkaloids Michael acceptors

With regard to the catalytic asymmetric reaction , only a few successful examples, except those reactions using chiral transition metal complexes, have been reported. For example, the cinchona-alkaloid-catalyzed asymmetric 1,4-addition of thiols or 6-keto esters to Michael acceptors quinidine catalyzed the asymmetric addition of ketene to chloral and the highly enantioselective 1,4-addition of ) -keto esters in the presence of chiral crown ethers to Michael acceptors have been most earnestly studied. 

Anthracenones are another class of C-H acidic compounds suitable to be employed in this reaction (Scheme 4.16) and, in fact, Takemoto s catalyst has been identified as the most efficient catalyst among a series of different thioureas tested, which also included a family of different cinchona alkaloid-derived candidates." The reaction proceeded satisfactorily for a wide variety of aromatic nitroalkenes tested but poorer results were obtained in the case of the p-alkyl substituted Michael acceptors. 

Continuing with the use of cinchona alkaloid-based quaternary ammonium salts as catalysts, phenyl vinyl sulfones have also been employed as Michael acceptors in the reaction with glycine imines using cinchonidinium salt 103a as catalyst both in solution or in a solid-supported version (Scheme 5.33), furnishing similar results to those provided by the corresponding vinyl ketones and acrylates shown in Schemes 5.8 and 5.23. ... 

Subsequent studies demonstrated that the asymmetric Michael addition of trisubstituted carbon nucleophiles promoted by 6 -demethylated Cinchona alkaloids (CPD, CPN, RO-CPD and RO-CPN) could be efficiently achieved using a,p-unsaturated sulfones, enones and enals as Michael acceptors in a highly enantioselective and diastereoselective fashion. 

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 potential of Cinchona alkaloids as nucleophilic catalysts was also demonstrated in Gaunl s cyclopropanation approach by reacting a-halo carbonyl compounds with Michael acceptors in the presence of catalytic amounts of 0-protected Cinchona alkaloids (468—470). This reaction is thought to proceed... 

In 2009, Zhu and Lu reported organocatalytic asymmetric Michael additions of nitroalkanes to another Michael acceptor such as vinyl sulfone mediated by another cinchona alkaloid-derived thiourea catalyst, which afforded the desired Michael products with good enantioselectivities of up to 84% ee (Scheme 1.20). This method in combination with a ready desulfonation represented a new approach to access a-alkylated chiral amines. 

On the other hand, several cinchona alkaloid-derived primary amines have been successfully investigated as organocatalysts for asymmetric Michael additions of ketones to Michael acceptors. As an example, Lu et al. have described the first Michael addition of cyclic ketones to vinyl sulfone catalysed by a catalyst of this type, providing an easy access to chiral a-alkylated carbonyl compounds with high yields and enantioselectivities of up to 96% ee, albeit with moderate diastereoselectivities (<72% de), as shown in Scheme 1.21. This novel methodology was apphed to the synthesis of sodium cyclamate, an important compound in the artificial sweeteners industry. 

Michael donors and acceptors are common components in Brmsted base-mediated catalysis. Such transformations offer an uncomplicated route towards all-carbon quaternary stereocenters. In the most basic form, a,P-unsaturated aldehydes are highly reactive templates towards nucleophilic reactions. Under such conditions, mechanistic studies show no polymerization of the unsaturated aldehydes under cinchona alkaloid catalysis [10]. This absence of polymerization is a key mechanistic indicator that the quinucHdine nitrogen of the catalyst does not act as a nucleophilic promoter. Rather, the quinucHdine nitrogen acts, as predicted, in a Bronsted basic deprotonation-activation of various cyclic and acyclic... 

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