Cinchona alkaloids cascade reactions

In 2010, Zhong and co-workers [32] tried a similar approach using nitrotyrenes and cyclic ketoesters. The reaction occurs through a Michael-Henry cascade reaction catalyzed by bifunctional thiourea catalysts derived from cinchona alkaloids. The reaction furnished the desired bicyclic products 43 in good yields and excellent stereoselectivities (Scheme 10.14). 

The hydrogenolysis/decarboxylation/asymmetric protonation reaction cascade of acyclic benzyl P-oxo-esters such as 47 catalyzed by Pd/C with H2 in the presence of a catalytic amount of cinchonine 43 afforded the (S)-ketone 48 with enantioselec-tivities up to 75% ee, similar to previous results obtained with other P-amino alcohols. The reaction was carried out at room temperature in a short reaction time [28]. The best solvent for both yield and ee was ethyl acetate, compared with acetonitrile and THF. Comparative performances of cinchona alkaloids with other commonly used P-aminoalcohols are displayed on Scheme 7.22. 

The possibilities of enantioselective sulfa-Michael additions using amino derivatives of Cinchona alkaloids are also demonstrated through tandem (cascade, domino) reactions, thus allowing the formation of multiple stereocentres with up to 99% ee. In comparison to Cfnc/zona-thiourea derivatives, natural Cinchona alkaloids or their ethers gave lower... 

In the second case, Melchiorre and co-workers [59] used a Michael—Michael cascade reaction between an unsaturated spirocycle and an enone. This reaction is efficiently catalyzed by a primary amine derived (XIII) in a single step from the cinchona alkaloid hydroquinine. The reaction afforded the final spirooxindoles in... 

An interesting example of aminocatalysis where a chiral primary amine activates a-substituted a,p-unsaturated aldehydes in a cascade sequence for the addition of indoles and azocarboxylate was reported by Melchiorre and coworkers (Scheme 6.16) [43]. Primary amine 128 directly derived from natural cinchona alkaloid was the catalyst of choice, which promoted this cascade reaction providing final adducts 129, as valuable precursors for a-amino acids having two adjacent stereogenic centers, one of which is quaternary, with very high enantioselectivities (83-99%). The yields are moderate to good (31-80%), and different substituents on the indole core (Cl, OMe, Me) are well tolerated. 

Alternatively, Shibata and coworkers first realized the catalytic enantioselective synthesis of trifluoromethyl-substituted 2-isoxazolines 69 in 2010 by developing a cinchona-alkaloid-catalyzed asymmetric conjugate addition/cyclization/dehydration cascade reaction with hydroxylamines 67 and enones 68 (Scheme 2.19). A wide range of substrates could be employed in this reaction to give the desired cyclized products with excellent enantioselectivities [33]. 

Cascade Michael-aldol reaction of mercaptobenzaldehyde with a,P-unsaturated oxazolidinone was realized by a cinchona-alkaloid catalyst (15b) to give benzoth-iopyran in high yields with excellent diastereoselectivity (Scheme 2.57). Contiguous three stereogenic centers were controlled [112]. 

The C9 amino cinchona alkaloid derivatives have been applied in diverse organic reactions, including aldol reactions [105, 106], Knoevenagel condensations [107], and cascade reactions [108]. The first example of an aldol reaction catalyzed by a... 

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