Iminium-Initiated Cascade Reactions

Other acetalizations or ketalizations in an enamine-initiated cascade process were also reported [59]. 

The cascade reactions induced by iminium catalysis in the first step are defined as iminium-activated cascade reactions, although almost all of the iminium-initiated cascade reactions are followed by an enamine-mediated process in the subsequent step. Considerable effort has been directed to construction of diverse cyclic structures via the iminium-enamine catalytic sequence. 

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Enamine-intramolecular aldol cascades Iminium-initiated cascade reactions... 

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). 

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. 

An impressively short synthesis of (—)-epimyrtine (1098) by Martin and coworkers featured an iminium ion cycUzation cascade initiated by reaction between the monoprotected dialdehyde 1139 and the optically active amine-substituted allylsilane (R)-1140, and terminated by the addition of... 

With a similar strategy of combined diarylprolinol silyl ether and N-heterocyclic carbene catalysts, j0rgensen and coworkers [21] examined the cascade reaction of easily accessible i-keto heteroaryl-sulfones as nucleophiles with a,P-unsaturated aldehydes (Scheme 43.11). In this cascade reaction, following the initial iminium ion-catalyzed Michael reaction of nucleophiles to a,(i-unsaturated aldehydes, the subsequent step was then promoted by carbene catalyst 57 to afford 2,4-disubstituted cyclopentenones 55 via an intramolecular benzoin condensation initiated Smiles rearrangement. The superiority of combinational use of two catalysts in the similar Michael/benzoin cascade reaction was also independently demonstrated by Enders et al. (Scheme 43.12) [22]. 

We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode, although an iminium mode might be involved in the following steps. In this regard, several catalytic cascade sequences, including enamine-enamine, enamine-iminium, and enamine cyclization, are discussed here. 

In an effort to develop new cascade reactions, Zhang et al. envisioned that a linear aldehyde can also be genaated in situ via an extra iminium catalysis from an ot,p-unsaturated aldehyde prior to the triple cascade reaction. Therefore, there would be a possibility of extending the triple cascade reactions to four-component cascade reactions. Based on this design, a four-component quadruple cascade reaction through iminium-enamine-iminium-enamine sequential activation initiated by oxa-Michael addition of alcohol to acrolein in moderate yield (about 50%), excellent diastereoselectivities (>20 1), and excellent enantioselectivities (>99% ee) was accomplished (Scheme 1.33) [47]. 

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 this very active field, Michrowska and List applied the combination of iminium-catalyzed 1,4 hydride addition and subsequent intramolecular 1,4 Michael addition for the one-pot synthesis of ricciocarpin, a molluscicidal natural product isolated from the liverwort Ricciocarpos natans (Scheme 11.29). This cascade reaction could be initiated by the single imidazolidinone (I )-3 that catalyzed both imi-nium hydride addition and Michael addition. Treatment of the Michael adduct with Sm(0/-Pr)3 induced the epimeriza-tion of the aldehyde carbon center to the more thermodynamically stable trans ring junction and subsequent Tishchenko reaction (redox process between the aldehyde... 

Increasing importance has to be attributed to modem tandem (or cascade ) techniques—reaction sequences that can be performed as a one-pot procedure because the first reaction step creates the arrangement of functional groups needed for the second to occur. Schemes 5-7 present some in situ preparations for iminium species, which can then react further with appropriate nucleophiles that are already present (preferably in the same molecule). Most elegantly, in situ generation of iminium ions for tandem processes was performed by a 3,3-sigmatropic (aza-Cope-type) rearrangement (Scheme 5), but also by initial Michael-type addition reactions to vinyl-substituted Atio... 

Conversely, when the reaction was carried out by using Amberlyst A15 (200%) in the presence or absence of liquid BEMP (10%), the only observed reaction product was substituted pyrrole 135, which was isolated in 68% yield product 134 was not present at all in the reaction mixture. However, when the reaction was repeated by using a combination of PS-BEMP (10%) and Amberlyst A15 (200%), the sole reaction product was the desired tetracyclic product 136 -obtained in 83% yield as a 1 1 mixture of diastereoisomers. By using sub-stoichiometric quantities of PS-BEMP (10%) and Amberlyst A15 (50%), an 85% conversion into 136 after 5 days was produced. These results demonstrate that PS-BEMP and Amberlyst A15 can operate as mutually compatible strongly basic and strongly acidic reagents, respectively, in the same vessel to facilitate the Michael-initiated N-acyl iminium ion cyclization cascade. 

Alternatively, a cascade Michael/aldol process has also been devised for the preparation of cyclopentenes also using this iminium/enamine manifold. In this reaction, a malonate reagent containing a functionalized side chain incorporating a formyl group at the appropriate position has been used as the nucleophile initiating the cascade process (Scheme 7.20). The reaction started with the Michael addition of the malonate to the a,(3-unsaturated aldehyde... 

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