Iminium-enamine catalysis

Chen and coworkers have reported a new domino Michael-Michael addition reaction between a,a-dicyanoalkene [26] derived from cyclohexanone and benzyli-deneacetone, resulting in a stepwise [4 + 2]-type cycloaddition to afford almost enantiopure bicyclic adduct 15. In contrast to the completely inert function of secondary ammonium salt, a primary amine, 9-amino-9-deoxyepiquinine lo [27], in combination with trifluoroacetic acid, was found to be highly efficient in the activation of the a, 3-unsaturated ketone by tandem iminium-enamine catalysis (Scheme 10.21) [28],... 

Scheme 10.21 Domino Michael-Michael addition by iminium-enamine catalysis.

Sequential Iminium-Enamine Catalysis. Directed Electrostatic Activation. A comparison of the standard catalytic cycles for enamine activation (Scheme 2.1) and for iminium ion activation (Scheme 2.12) show that iminium catalysis proceeds, after the addition of the nucleophile, via an ( )-enamine. In the presence of a suitable electrophile, this enamine gives rise to an iminium ion that after hydrolysis can give rise to an a,p-diftmctionalyzed carbonyl (Scheme 2.13) [85]. Scheme 2.13 also shows that when using a chiral 2-substituted pyrrohdine or an imidazolidinone as the catalyst, the sequential apphcation of the steric model for Michael addition to iminium ions (Figure 2.15) and of the steric model for electrophilic attack to enamines (Figure 2.IB) predicts the absolute stereochemistry of the major isomer obtained in the reaction. 

In fact, this intramolecular version shortly preceded the intermolecular one discussed above, since the first example was disclosed by Kunz and MacMillan in 2005 [89], shortly followed by Jprgensen and co-workers [90]. This approach has proved to be highly versatile, leading to practical enantioselective syntheses of chiral cyclopropanes [89, 91], epoxides [90], and aziridines [92]. Finally, the use of bifunctional synthons in sequential iminium/enamine catalysis provides a very general entry to carbo- and heterocyclic compounds [93]. 

SCHEME 2.14. Intramolecular sequential iminium-enamine catalysis. 

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. 

Conversely, in 2(X)7, Jprgensen disclosed a sequential imiitium-iminium-enamine catalysis as an alternative to... 

SCHEME 2.58 Quadruple iminium-enamine-iminium-enamine catalysis toward spirooxindole derivatives 177. 

SCHEME 6.12 Cascade reaction through iminium-enamine catalysis. 

Scheme 2.7 Asymmetric reductive Michael cyclization and schematic representation of the tandem iminium-enamine catalysis mechanism...

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