Iminium cascade reactions

The same system was used by Frechet s group of to achieve a multicomponent one-pot cascade reaction with mutually interfering acid and proline-derived pyrrolidine catalysts [31]. The concept is illustrated in Figure 5.1. The protonation of imidazo-lidone (3) by the immobilized PSTA (5) gives the desired iminium catalyst (6), while... 

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... 

In a collection of insightful pieces of work Enders has incorporated an iminium ion conjugate addition of nitroalkanes to a,P-unsaturated aldehydes into a triple cascade reaction generating up to four contiguous stereocentres in one pot, again indicative of the complexity attainable from superficially simple catalysts and techniques [175-177] (Scheme 46). 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

Enders et al. elegantly applied diphenylprolinol silyl ether 6a as a catalyst for triple cascade reactions (Scheme 10.18), wherein 6a played the roles ofboth enamine catalyst and iminium catalyst. It should be noted that the four stereocenters were completely controlled[36].Theproposedcatalyticcycleofthe triplecascade isshownin Scheme 10.2. 

Scheme 7.39 Combining iminium and A -heterocydic cabene catalysis in a cascade reaction.

According to the proposed mechanism (Scheme 6.20), the first step of this cascade reaction is protonation of the substituted pyridine by CPA to generate the pyridinium salt 51. Then, the reduction of 51 by 1,4-hydride transfer from the Hantzsch ester gives the enamine intermediate 52, which isomeri-zes to iminium 53 in the presence of CPA. The subsequent AFC reaction will afford the desired product and release the chiral phosphoric acid. 

Furthermore, the asymmetric PS reaction has been applied as a key step in the cascade reaction to build up chiral polycyclic compounds. In 2009, Dixon and coworkers [71] developed a chiral phosphoric acid 8f-catalyzed cyclization cascade between tryptamines and enol lactones, leading to the products in good yields and with good to excellent enantioselectivities. This was further extended to the reaction of tryptamines and ketoacids, which were more readily available than enol lactones [72]. By using diarylprolinol silyl ether as catalyst, the other cascade transformations involving Michael addition, iminium formation and PS cyclization were also efficiently realized [73]. 

One of the first highly enantioselective examples of multicomponent cascade reactions in orgnocatalysis was developed by Enders et al. [62] in 2006. In this report they describe an asymmetric organocatalytic triple cascade reaction for the construction of tetrasubstituted cyclohexenecarbaldehydes (93) starting from from enals (15), nitroalkenes (28), and enolizable aldehydes (94) (Scheme 10.27). In this work, they did the sequential creation of three bonds by a high enantioselective combination of enamine-iminium-enamine catalysis for a triple cascade reaction. 

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. 

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