Michael/aldol cascade iminium activation

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 the process, activation of a,P-unsaturated aldehydes by a chiral organocatalyst produces iminiums which trigger a Michael-aldol cascade process to afford intermediates which undergo spontaneous dehydration to give oc,p-unsaturated aldehydes 129. 

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). 

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

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). 

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). 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

This catalytic cascade was first realized using propanal, nitrostyrene and cinnamaldehyde in the presence of catalytic amounts of (9TMS-protected diphenylprolinol ((.S )-71,20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst (S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi et al. 2005). The following hydrolysis liberates the catalyst, which is now able to form the iminium ion of the a, 3-unsaturated aldehyde C to accomplish in the second step the conjugate addition of the nitroalkane (Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8) (Enders and Hiittl 2006). 

Another impressive example of dienamine-iminium cascade catalysis was developed during the total synthesis of a-tocopherol 59 by Liu et al. [31]. This natural product is a member of the vitamin E family and possesses remarkable biological activity. The key step in the total synthesis of this natural product involved an organocatalytic aldol/oxa-Michael cascade reaction for construction of the core... 

Structure (Scheme 3.9). A mechanism that has been proposed is shown in Scheme 3.10. Intermediate 60 was formed upon activation of phytal 56 by dien-amine catalysis. Subsequently, an intermolecular aldol reaction between phytal 56 and aldehyde 55 occurred in the presence of catalyst 57. Finally, the tricyclic core structure 58 was built after the adjacent phenol group captured the newly formed iminium ion 61 via an oxa-Michael reaction. The cascade product desired was obtained in 58% yield with 97% diastereomeric excess. The total synthesis of natural product a-tocopherol was achieved through a four-step chemical synthesis. 

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