Cascade reaction asymmetric organocatalytic

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

Most AFC alkylation reactions are focused on relatively reactive furans, pyrroles, and indoles, whereas benzene derivatives are much less explored. The Wang group reported the organocatalytic asymmetric synthesis of chromane and dihydrobenzopyrane derivatives 121 from readily available 1-naphthols and a,p-unsaturated aldehydes by the AFC alkylation/cyclization cascade reaction (Scheme 6.49). The process appeared to have a broad substrate... 

The synthesis of carbocycles via a two-component cascade reaction in an asymmetric fashion has attracted much attention from the chemical community. Due to his importance in natural products, the synthesis of cyclopropanes, cyclopentanes, and cyclohexanes has been one of the common goals for organocatalytic methodologies. The high stereoselectivity achieved, green procedures, and soft conditions make this organocatalytic approximation one of the most attractive ones to build complex cyclic scaffolds. 

Enders et al. [54] developed an asymmetric organocatalytic domino reaction of y-nitroketones 83 and enals. The reaction, catalyzed by compound VII, renders the final cyclohexene 84 via a Michael-Aldol cascade reaction followed by dehydration, with moderate yields and diastereoselectivities and good enantioselectivities (Scheme 10.23). Two years later, the same research group reported a related reaction starting from 2-(nitromethyl)benzaldehyde [55]. The reaction proceeds via a domino nitroalkane-Michael-aldol condensation reaction that leads to the final 3,4-dihydronaphthalenes in excellent yields and enantioselectivities. 

One of the first highly enantioselective examples of multicomponent cascade reactions in orgnocatalysis was developed by Enders et al. [62] in 2006. In this report they describe an asymmetric organocatalytic triple cascade reaction for the construction of tetrasubstituted cyclohexenecarbaldehydes (93) starting from from enals (15), nitroalkenes (28), and enolizable aldehydes (94) (Scheme 10.27). In this work, they did the sequential creation of three bonds by a high enantioselective combination of enamine-iminium-enamine catalysis for a triple cascade reaction. 

SCHEME 10.27. Asymmetric organocatalytic triple cascade reaction. 

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. 

SCHEME 2.30 Organocatalytic asymmetric FC alkylation/cyclization cascade reaction of 2-naphthols with P,y-unsaturated a-ketoesters. 

SCHEME 2.40 Asymmetric organocatalytic three-component cascade reaction. 

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]. 

Xie, X., Peng, C., He, G., Leng, H.-J., Wang, B., Huang, W., Han, B. (2012). Asymmetric synthesis of a structurally and stereochemicaUy complex spirooxindole pyran scaffold through an organocatalytic multicomponent cascade reaction. Chemical Communications, 48, 10487-10489. 

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. 

Phosphoric acid 25a was successfully employed for mediating enantioselective synthesis of 1,3-disubstituted isoindolines from electrophilic bifunctional substrates (containing an imine and a Michael acceptor site) and indoles [33]. Catalyst 7a was used effectively in an organocatalytic asymmetric F-C alkylation/cyclization cascade reaction between 1-naphthols and a,(i-unsaturated aldehydes to give chro-manes in good yields and select vities (Scheme 3 5.18) [ 10]. Furthermore, 2-naphthols and p,y-unsaturated a-keto ester also reacted in a F-C alkylation/dehydration sequence, in the presence of a thiourea catalyst and a catalytic amount of concentrated sulfuric acid, affording optically active naphthopyran derivatives [54]. 

Scheme 42.16 Asymmetric organocatalytic triple cascade by way of an enamine-iminium ion-enamine activation of aldehydes. Protocol point the minor diastereomer was determined as the 5-epimerof 59 all substrates added at the outset of the reaction.

Enders D, Hilttl MRM (2006) Control of four stereocentres in a triple cascade organocatalytic reaction. Nature 441 861-863 Enders D, Kallfass U (2002) An efficient nucleophilic carbene catalyst for the asymmetric benzoin condensation. Angew Chem Int Ed Engl 41 1743-1745... 

Other developments related to organocatalytic asymmetric Michael reaction such as cascade, C—X bond formation reactions, and application in the synthesis of complex natural products are discussed in a later section of this book. 

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