Iminium activation catalyst design

In order to test the iminium-activation strategy, MacMillan first examined the capacity of various amines to enantioselectively catalyze the Diels-Alder reaction between dienes and a,/ -unsaturated aldehyde dienophiles [6]. Preliminary experimental findings and computational studies proved the importance of four objectives in the design of a broadly useful iminium-activation catalyst (1) the chiral amine should undergo efficient and reversible iminium ion formation (2) high... 

One of the most compelling features of iminium ion catalysis is the proposed mechanistic rationale for the transformations, which leads to highly predictable reaction outcomes. Despite impressive advances and the plethora of reactions reported efforts to provide a detailed mechanistic understanding of the catalytic cycle are limited. The reported work has focussed on the Diels-Alder cycloaddition and has provided useful indicators that could be used in design of more active catalysts. 

Figure 3.1 Factors to be considered when designing a chiral secondary amine catalyst to be used in Michael reactions under iminium activation.

E-ajp-unsaturated ester was employed, while a single diastereoisomer was obtained using the corresponding Z substrate. This reaction design has also been extended to the use of an a,p-unsaturated aldehyde as the initial Michael acceptor, in this case it being necessary to consider the possible dual activation of the Michael donor and acceptor by the catalyst through the formation of the corresponding enamine and iminium intermediates. ... 

In comparison with the widespread application of chiral secondary amines in organocatalytic Diels-Alder reactions, only a few successful examples have been reported with the use of chiral primary amines. In the case of a-substituted acroleins, it is difficult for chiral secondary amines to activate this type of substrates, probably because of poor generation of the corresponding iminium ions. To solve this problem, Ishihara and Nakano designed and synthesized a novel class of primary amine catalysts (55) [24]. Indeed, this type of less bulky ligand proved to be effective for enantioselective Diels-Alder reactions of a-acyloxyacroleins 51 or a-phthalimidoacroleins 53 to produce the desired cycloadducts 52 or 54 with quaternary stereocenters (Scheme 38.16). 

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