Asymmetric cascade reactions

Scheme 17. Asymmetric, organocatalytic three-component multistep reaction cascade...

Only recently, Shibasaki et al. reported on the application of a Sm-Na-(R)-BINOL-complex as catalyst in a reaction cascade consisting of an a.symmetric Michael addition of thiols to a,fS- xn-saturated carbonyl compounds followed by an asymmetric enolate protonation [20]. 

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. 

Novelization of the alkaloids is easy using the methods known in synthetic production, such as catalytic asymmetric reactions and inductions. Organo-catalytic cascade, asymmetric photocycloaddition, cyclization, and asymmetric decarboxylative allylation are used in total synthesis, as well as catalytic asymmetric induction reactions and condensation of alkaloid molecules (two or more). Novelization of alkaloids by total synthesis is generally used by the pharmacological industry around the globe. 

Organocatalytic asymmetric carbon-halogen bond-forming reactions have been combined with other catalytic asymmetric reactions in a single flask to effect cascade reactions. Quintard and Alexakis [78] developed a cascade reaction in which a Cu-catalyzed conjugate addition to an a,p-unsaturated aldehyde was followed by an enamine-catalyzed a-fluorination or chlorination. 

Among all the possible approach to polysubstimted cyclohexane derivatives, Dixon et al. proposed a further and very elegant alternative approach wherein the asymmetric organocatalytic cascade reaction reties on the synergic action of a bifunctional base/Br0nsted acid catalyst 158 and a cyclic secondary amine (5)-76 (Scheme 2.49) [77]. 

P. Galzerano, F. Pesciaioh, A. Mazzanti, G. Bartoli, P. Melchiorre, Angew. Chem. Int. Ed. 2009, 48, 7892-7894. Asymmetric organocatalytic cascade reactions with a-suhstimted a,P-unsaturated aldehydes. 

L. Tian, X.-Q. Hu, Y.-H. Li, P.-F. Xu, Chem. Commun. 2013, 49, 7213-7215. Organocatalytic asymmetric multicomponent cascade reaction via 1,3-proton shift and [3-t2] cycloaddition an efficient strategy for the synthesis of oxindole derivatives. 

In this context. Rueping s group envisioned the asymmetric organocatalytic multiple-reaction cascade version of the abovementioned process in which a six-step sequence was catalyzed by the chiral Brpnsted acid catalyst 21 providing direct access to a broad scope of valuable tetrahydropyridines 26 and azadecalinones 35 with high enantioselectivities (Scheme 11) [99]. 

Galzerano, P., Pesciaioli, F., Mazzanti, A., Bartoh, G., Melchiorre, P. (2009). Asymmetric organocatalytic cascade reactions with a-substituted a,p-unsaturated aldehydes. Angewandte Chemie International Edition, 48, 7892-7894. 

Albrecht, L., Jiang, H., Dickmeiss, G., Gschwend, B., Hansen, S.G., Jprgensen, K. A. (2010). Asymmetric formal fran -dihydroxylation and frafu-aminohydroxylation of a,(3-unsaturated aldehydes via an organocatalytic reaction cascade. Jonmal of the American Chemical Society, 132, 9188-9196. 

In the year 2010, the group of Danishefsky reported the first asymmetric total synthesis of (-)-phalarine by using a Mannich reaction/Wagner-Meerwein rearrange-ment/cyclization cascade sequence (Scheme 13.9) [10], In this reaction cascade, one carbon-nitrogen bond, one carbon-carbon bond, one carbon-oxygen bond, and two new rings were formed. 

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