Cinchona Michael reactions

Scheme 19. Asymmetric Michael reaction by use of cinchona alkaloid derivatives.

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

Table 6.7 Cinchona alkaloid-catalyzed Michael reactions of nitroolefins.

Hodge, P., Khoshdel, E. and Waterhouse, J. Michael reactions catalyzed by polymer-supported quaternary ammonium-salts derived from cinchona and ephedra alkaloids, J. Chem. Soc., Perkin Trans. 1, 1983, 2205-2209. 

These cinchona copolymers are efficient catalysts for some asymmetric Michael reactions. Examples are shown in equations (I) and (II). In the second example, use of quinidine-acrylonitrile polymer as catalyst leads to a product with q d + 36.3° when quinidine itself is used, the ao of the product is +3.9°. The figures imply that the copolymer is more stereoselective than the monomer. 

Michael reaction of selenophenols. Selenophenols (and other selenides) undergo enantioselective 1,4-addition to cyclohexenone in the presence of catalytic amounts of cinchona alkaloids. Chemical yields are high optical yields are 10-43%. Usually the optical yield can be enhanced by crystallization. In one case the addition product was converted into an optically active allylic alcohol by hydride reduction followed by selenoxide fragmentation. ... 

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

Aza-Henry reaction is rendered asymmetric by quaternary salts of Cinchona alkaloids. Addition reactions. Changing the 9-hydroxy group of Cinchona alkaloids to a 9-epiamino group not only is synthetically expedient, such products often show excellent catalytic activities in many asymmetric reactions. Those derived from dihydrocinchona alkaloids mediate Michael reactions to good results, including addition of indole to enones, and carbonyl compounds to nitroalkenes. Salt 4 has also been successfully employed in the alkenylation of t-butyl a-aryl-a-cyanoacetate. ... 

Scheme 4.7 Influence of cinchona catalysts structure on the yield and enantioselec-tivity of the Michael reaction of dimethyl malonate with nitrostyrene.

Scheme 4.66 Enantioselective sulfa-Michael reaction of arylthiols with enones catalyzed by natural cinchona alkaloids.

Scheme 4.74 The catalytic enantioselective phospha-Michael reactions using cinchona alkaloid-based catalysts.

In this context, there is a relevant example of a newly designed cinchona-alkaloid derived bis-ammonium salt 105 employed as catalyst in the Michael reaction of cyclic p-ketoesters with methyl vinyl ketone (Scheme 5.12). Excellent yields and moderate enantioselectivities of the corresponding Michael adducts were obtained under the best reaction conditions, which also allowed the use of an organic base (Hiinig base) for the deprotonation of the p-ketoester. However, perhaps the most relevant feature associated to the use of this catalyst is the fact that it can be easily separated from the reaction medium by precipitation in ether, which allowed its recycling for further uses without loss of activity. 

Two examples of hetero-Michael reactions have been reported using these kinds of bis-cinchona alkaloid-based chiral Bronsted bases as catalysts. One of them refers to a sulfa-Michael reaction and the other is a case of an aza-Michael reaction. 

With the development of the enantioselective allylic-allylic alkylation of a,a-dicyanoalkenes and MBH carbonates by dual organocatalysis of commercially available modified cinchona alkaloids and (5)-BINOL, Chen and co-workers have delivered an elegant construction of cyclohexene derivatives. The intramolecular Michael reaction of allylic allylic alkylation product 75a could be cyclized to give the desired cyclohexene 76 in the presence of DBU (Scheme 4.25). In the presence of nucleophile BnNH2, allylic compound 75b furnished an imexpected cyclic product 77 rather than the formal double Michael adduct. Interestingly, the reaction of a,a-dicyanoalkene 79 and MBH carbonate 80 under optimized catalytic conditions directly afforded cyclohexene derivatives 81a-c in... 

Recently an expansion of the electrophile scope of the conjugate addition of sulfur nucleophiles has been reported by different groups. As depicted in Fig. 2.29 for selected examples, Cinchona-denwed catalysts 203 and 205 promote highly enantioselective additions to nitrooleflns [387] and a,p-unsaturated V-acylated oxazolidin-2-ones [388] through non-covalent catalysis. Especially interesting results the Michael reaction to P-substituted nitroacrylates catalyzed by chiral thio-... 

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