Sequential 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... 

Finally, the sequential iminium-enamine asymmetric catalysis was notably exploited by Roy and Chen in the kinetic resolution of nitroallyhc acetates 203 (Scheme 2.68) [92],... 

Roy, S., Chen, K. (2012). Three-component organocascade kinetic resolution of racemic nitroallylic acetates via sequential iminium/enamine asymmetric catalysis. Organic Letters, 14, 2496-2499. 

In an effort to develop new cascade reactions, Zhang et al. envisioned that a linear aldehyde can also be genaated in situ via an extra iminium catalysis from an ot,p-unsaturated aldehyde prior to the triple cascade reaction. Therefore, there would be a possibility of extending the triple cascade reactions to four-component cascade reactions. Based on this design, a four-component quadruple cascade reaction through iminium-enamine-iminium-enamine sequential activation initiated by oxa-Michael addition of alcohol to acrolein in moderate yield (about 50%), excellent diastereoselectivities (>20 1), and excellent enantioselectivities (>99% ee) was accomplished (Scheme 1.33) [47]. 

The ability of the diarylprolinol catalysts to participate in both enamine- and iminium-ion achvations makes them ideal for the sequential addition of nucleophiles and electrophiles through cascade catalysis (Scheme 2.8). Conjugate addition of a nucleophile to the iminium ion forms a transient enamine intermediate 3, which can effectively react with an electrophile in the a-position, forming an a,P-disubstituted adduct. This process commonly proceeds to afford the products in good yields and with high enantio- and diastereoselectivities. If the nucleophile and electrophile are part of the same molecule, cyclic products are obtained. The cascade concept has been widely explored and some illustrative examples are given below [13, 17]. 

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