Enamine activation cascade reactions

Design of iminium-enamine cascade reactions Iminium-activated Diels-Alder reactions Iminium-activated sequential [4h-2] reactions Iminium-activated [3-h2] reactions Iminium-activated sequential [3-1-2] reactions Iminium-activated [2h-1] reactions... 

Enamine-Iminium-Enamine Cascades The enamine-activated process followed by an mtermolecular iminium-mediated process will undergo a new enamine activation step to afford multisubstituted cyclohexanes via an enantine-intinium-enantine sequence. In this way, multicomponent reaction could be designed to produce complex structures from simple reactants. 

Beyond the organic chemists initial imagination, two unique interconvertible enamine and iminium activation modes have produced a number of unprecedented powerful cascade processes in the formation of diverse complex stractures with high efficiency and excellent stereoselectivities. This not only expands the scope of amino catalysis significantly, but more important, affords new and efficient synthetic methods in organic synthesis. It is expected that new cascade reactions with activation modes will continue to be developed to meet the synthetic danand. 

In 2010, Enders and co-workers developed a quadruple cascade AFC/ Michael/Michael/aldol condensation reaction of indoles, acrolein, and nitroalkenes under the catalysis of diphenylprolinol TMS-ether catalyst (S)-104 following an iminium/enamine/iminium/enamine activation sequence (Scheme 6.42). " The reaction provided a straightforward and efficient entry to 3-(cyclohexenylmethyl)-indoles 105 bearing three stereogenic centers in moderate to excellent yields (23-82%) and excellent stereoselectivity (91 9->95 5 dr and 94->99% ee). 

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. 

The main focus in this chapter will be on combined approaches using enamine catalysis and iminium catalysis especially in one-pot cascade reactions. As discussed in the following examples, the combined use of these two activation modes has led to the development of some of the most impressive and efficient organocatalytic natural product syntheses conducted so far (301-305). 

Double Cascade Reactions Amine-based organocatalysis are often employed for these cascade reactions because they can present a dual-activation mode depending the system involved, via enamine or iminium catalysis. 

Two C-C Bond-Forming Events In 2008, Frechet and coworkers described an impressive asymmetric cascade reaction promoted by soluble star polymers with core-confined catalytic entities [10]. The encapsulation of catalysts into soluble star polymers allowed the use of incompatible catalysts and prevented undesired interactions between these catalytic systems. The organocascade corresponded to a nucleophilic addition of Af-methylindole to a,p-unsaturated aldehydes followed by a Michael addition of the adduct to methylvinylketone (MVK) in the presence of H-bonding additive (Scheme 12.5). Each catalyst - imidazolidinone 8 for the nucleophilic addition and diphenylprolinol methyl ether 9 for the Michael addition - or their combination cannot mediate both reaction steps. In particular, p-toluenesulfonic acid (p-TSA) diminished the ability of the chiral pyrrolidine 9 to effect enamine activation. Therefore, p-TSA and 9 were encapsulated in the core of star polymers, which cannot penetrate each other. Imidazolidone 8 was added to the acid star polymer and diffused to the core to form the salt, which allowed the iminium activation and catalyzed the first step. The second step was catalyzed by the pyrrolidine star polymer in presence of the H-bonding additive 10, which... 

The use of chiral amine catalysts also allows for the combination of alternative activation modes, that is, enamine/ iminium activation in operationally simple one-pot cascade reactions, either with a single catalyst or using multiple catalysts [52]. A broad variety of the organocascade approaches... 

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