Cascade iminium catalysis

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... 

Scheme 7.66 Cascade triple Michael/Michael/aldol reaction combining H-bonding activation and iminium catalysis.

In 2012, the Bencivenni group reported an AFC alkylation/acetalization cascade of 1- and 2-naphthols with a,p-unsaturated cyclic ketones via iminium catalysis. In this reaction, they found that a stoichiometric amount of water was necessary to obtain high ee values and 1-naphthols showed a better stereochemical outcome than 2-naphthols. Unexpectedly, encumbered l//-inden-l-ones could be applied in this system, furnishing the desired products in high yields (Scheme 6.51). 

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... 

When summing up the recent achievements in iminium-activated natural product synthesis, the importance and versatility of this methodology cannot be overemphasized. Besides enamine catalysis, it is due particularly to the considerable achievements made in iminium catalysis that asymmetric organocatalysis has received so much attention over the last few years. As depicted in this chapter, the LUMO-lowering concept originally introduced by MacMillan has found widespread applications in natural product synthesis. In addition, it has been shown, that this activation mode works very well in cascade approaches. This methodology should become more widely utilized in the future (Table 2). 

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. 

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]. 

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. 

More recently, Jang et al. reported a cascade Michael/a-oxyamination reaction of malonates, enals, and a TEMPO-type stable radical by combining iminium catalysis, enamine catalysis, and photoredox catalysis [56], The reaction unified a secondary amine-catalyzed Michael addition of diethyl malonates to enals and a following supported Ru-based photoredox-SOMO catalysis involving a radical trapping event of TEMPO (Scheme 9.61), generating the chiral a, 3-functionalized propanal derivatives with high reactivity and excellent selectivity. 

It is clear that, as understanding of the underlying principles of both iminium ion and enamine catalysis improves, the trae power of these cascade sequences will be fully exploited. It can be expected that introduction of subsequent independent catalytic cycles will add to the complexity and applicabihty of these processes and provide highly regulated cascades that mimic the power of enzymatic pathways. 

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. 

Cascade Catalysis Merging Iminium and Enamine Activations... 

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

On the other hand, a triple Michael/Michael/Aldol cascade sequence has been developed for the synthesis of highly substituted cyclohexanes starting from dimethylmalonate, an a,p-unsaturated aldehyde and a nitroalkene in which H-bonding catalysis and iminium activation were jointly employed for the simultaneous activation of the two Michael acceptors involved in the... 

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). 

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. 

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