Reactions iminium/enamine-catalyzed

The dual nature of enamine-iminium pairs allows unique possibilities for domino processes. Reactions of enamines with electrophiles afford electrophilic iminium ions that are ready to react with another (internal or external) nucleophile. Conversely, reactions of unsaturated imininm ions with nucleophiles afford enamines. Examples of intramolecular enamtne-catalyzed domino processes are depicted in Scheme 35. In all of these reactions, both enamine and iminium mediated steps can be distinguished. 

The reaction, catalyzed by the 9-amino-9-deoxyepiquinine 2, was proposed to go through an iminium-enamine activation process. 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

MacMillan and co-workers [79] pioneered the development of entirely organo-catalyzed cascade reactions. In his seminal report, iminium-catalyzed Friedel-Crafts reactions were followed by enamine-catalyzed a-chlorinations (Scheme 13.40). In this same report, an iminium-catalyzed conjugate reduction was followed by an enamine-catalyzed a-chlorination (not shown). In both of these cascade reactions, a single catalyst was used for both the iminium- and enamine-mediated reactions. Alternatively, MacMillan demonstrated that it was possible to use one catalyst for an iminium-catalyzed conjugate reduction and a different catalyst for an enamine-catalyzed a-fluorination (Scheme 13.40) [79]. Such cycle-specific cascade reactions allow access to both the anti (shown) and syn diastereomers of the product simply by using the opposite enantiomer of the catalyst for one of the two reactions in the cascade. 

In 2010, Brenner-Moyer and co-workers [80] reported an organocatalytic enantioselective olefin aminofluorination reaction, in which an iminium-catalyzed aza-Michael addition preceded an enamine-catalyzed a-fluorination reaction (Scheme 13.41) [80]. This reaction was a rare example of a catalytic enantioselective olefin aminohalogenation reaction, and it furnished precursors to enan-tioenriched a-fluoro-(3-amino acids. 

The examples depicted so far have made use primarily of single organocatalytic transformations conducted typically quite early in the multi-step sequences applied towards the syntheses of complex natural products. In contrast, more and more reports describing organocatalytic cascade reactions or combined approaches using different organocatalytic key transformations to achieve a complex synthesis have been reported over the last several years (30, 32, 176-178). In this chapter, the application of combined enamine-catalyzed approaches for the syntheses of natural products will be described. Examples using different activation modes (e.g. enamine and iminium activation) will be discussed later. 

For a merged metal catalyzed (cross-metathesis) and organocatalyzed (iminium/ enamine) cascade reaction see Reference [111]. 

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]. 

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