Iminium 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... 

Organocatalysis have emerged recently as one of the cornerstones for the enanti-oselective synthesis of C-C or C-heteroatom bonds. Owing to the easy prediction of the stereochemical outcome of the reactions, iminium activation and specific Michael reactions is one of the most studied reaction types in organocatalysis. In the literature, we can find multiple approaches to the organocatalytic Michael reaction using different catalysts or nucleophiles, most of them with exceptional levels of stereoselectivity. Moreover, these simple additions to enals or enones have inspired multiple organocatalytic tandem and cascade reactions and, in our view, open up a new pathway for the enantioselective construction of complex scaffolds in one-pot procedures. 

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. 

Cascade Addition-Cyclization Reactions Given the importance of cascade reactions in modem chemical synthesis, the MacMillan group has proposed expansion of the realm of iminium catalysis to include the activation of tandem bond-forming processes, with a view toward the rapid constraction of natural products. In this context, the addition-cyclization of tryptamines with a,p-unsaturated aldehydes in the presence of imidazolidinone catalysts 11 or 15 has been accomplished to provide pyrroloindoline adducts in high yields and with excellent enantioselectivities (Scheme 11.3a). This transformation is successful... 

This dual enamine/iminium activation profile in cascade Michael/aldol reactions can also be found even in some early reports, mostly focused on the self-dimerization of enals catalyzed by proline or analogues derived thereof, which generally proceeded with low enantioselect vities. There is not a clear and definitive mechanistic pathway confirmed for these reactions, although the most widely accepted proposal for the dimerization of enals (Scheme 7.4) ° involved sequential activation of one molecule of the substrate as a dienamine (Michael donor) and another molecule as iminium ion (Michael acceptor). 

Tricarbonyl compounds have also been employed as potential 1,3-dinucleophiles able to undergo a first Michael addition step with a,p-unsatu-rated aldehydes and which can afterwards react with the remaining formyl group for the formation of a cyclohexane ring (Scheme 7.23). This has led to the development of a couple of cascade processes consisting of a Michael reaction proceeding in an asymmetric fashion by iminium activation of the enal. 

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). 

Recently, Alexakis and Quintard [93] reported an interesting example in the acyclic series exploiting the reactivity of vinyl sulfones in an enamine/iminium activated three-component oxa-Michael/Michael cascade in the presence of enals and oximes, leading to highly optically enriched products (Scheme 16.44). The reaction can also be initiated by an aza-Michael or a thia-Michael addition. 

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. 

Employing the high potential of iminium ion activation, MacMillan and coworkers were able to directly access the key intermediate 320 in a single operation cascade reaction between the tryptamine-derived indole derivate 321 and propynal (226) in the presence of their trademark catalyst 227. As illustrated in Scheme 74, the reaction is assumed to proceed via two iminium catalysis cycles (Diels-Alder cyclization first, followed by conjugate addition). It is worth noting that the authors considered either the possibility of intermediate 322 to directly enter the second... 

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). 

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