Michael iminium-enamine activation mode

Scheme 10.3 Domino Michael/Michael reaction through iminium-enamine activation mode.

Since the early example of a proline-catalyzed asymmetric domino Michael-aldol reaction reported by Bui and Barbas in 2000 [57], a number of these reactions have been successfully developed by several groups. For example, Wang et al. have reported the synthesis of chiral densely functionalized cyclopentenes on the basis of a domino Michael-aldol reaction followed by dehydration between aromatic enals and dimethyl 2-oxoethylmalonate [67]. High yields (63-89%) and enanhose-lectivities (91-97% ee) were obtained by using (S)-diphenylprolinol sUyl ethers as catalysts. On the other hand, the condensation of P-nitroketones 36 onto enals in the presence of 8 was shown by Hong et al. to afford the corresponding domino Michael-aldol products 37 through the iminium-enamine activation mode [68]. 

As mentioned, the applications of chiral secondary amines in domino processes have been numerous, mainly because of the dual mechanism of activation allowing easy incorporation of other reactions [7, 8]. The first of these processes involves an iminium-enarnine (Scheme 7.1a), and the second an enamine-iminium activation (Scheme 7.1b), both of which can be in operation in domino reactions involving Michael reactions. These modes of action rely on the lower energy lowest unoccupied molecular orbital (LUMO) for the iminium ion and a rise in the highest occupied molecular orbital (HOMO) energy for enamine activation, which are discussed in further detail in Chapter 10 of this book [9, 10]. In the... 

Enders et al. [75] developed a synthesis of polyfunctionalized 3-(cyclohex-enylmethyl)-indoles 125 via a quadruple domino Friedel-Crafts-type Michael-Michael-aldol condensation reaction, in 2010. This cascade sequence is initiated by a Friedel-Crafts reaction of indole (126) by an iminium activation mode to the enal, followed sequentially by an enamine- and an iminium-mediated Michael addition. After an intramolecular aldol-condensation, four C-C bonds are formed and the domino product is constructed bearing three contiguous stereogenic centers (Scheme 10.34). 

Chiral imidazolidin-4-ones-chiral secondary amines-had already been successfully used in asymmetric synthesis before they started their own career as organo-catalysts [1]. They were deployed as chiral auxiliaries for alkylation processes [2], Michael additions [3], and aldol reactions [4], For syntheses of this class of catalyst see Reference [5]. The ability to activate both carbonyl compounds by enamine formation as well a, 3-unsaturated carbonyl compounds by intermediate formation of iminium ions makes imidazolidin-4-ones a valuable class of organocatalysts in both series. Thus, they can roughly be divided by their mode of activation into enamine [6] or iminium [7] catalysis (Scheme 4.1). These catalysts were successfully deployed in a wide range of several important enantioselective C-C bond formation and functionalization processes. Figure 4.1 shows the chiral imidazo-lidinones covered in this chapter. 

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