Cascade enamine activations

Enamine-enamine in three-component cascades Enamine-activated double a-functionalization Robinson annulations Enamine-iminium cascades... 

Cascade Catalysis Merging Iminium and Enamine Activations... 

Cascade Processes Initiated by Conjugate Addition via Enamine Activation... 

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). 

Simultaneously, the same group developed a complementary sy -selective Mannich/a-amination cascades starting with simple aromatic imines, acetaldehyde, and di- er7-butyl azodicarboxylate via enamine activation with a diaryprolinol silyl ether catalyst (Scheme 16.2) [3]. The corresponding 2,3-diaminoalcohols are obtained in low to moderate yields after in situ reduction and with high diastereo-and enantioselectivities. 

SCHEME 231 Proposed cascade iminium-enamine activation. 

On the wave of such impressive results, other notable research groups addressed their efforts to the development of alternative and complementary triple cascade procedures. For instance, amazing contributes have been published, over the years, by Melchiorre et al. that successfully suggested a practical synthesis of several spirocyclic oxindoles and then-analogues [72]. Exploiting the enamine-iminium-enamine activation mode of aminocatalysis, the organocatalytic triple cascade process disclosed by the Spanish group provided the stereoselective construction of all-carbon quaternary... 

Chiral secondary amine could be employed to catalyze this cascade process. Kim et al. utilized Jprgensen catalyst 53 successfully to catalyze the cascade [1,5]-HT/ ring closure sequences of o-A -pyrrolidinyl-substituted cinnamaldehydes 51 via sequential iminium and enamine activation, affording chiral tetrahydroquinolines 52 in high enantioselectivities (Scheme 19, a) [98]. Products incorporated with 7- to... 

Tu et al. reported a Macmillan s catalyst 172-catalyzed asymmetric a-alkylation of tetrahydrofuran 170 containing an a,p-unsaturated aldehyde, via which chiral spiroether 171 could be prepared (Scheme 64) [129]. The sequential [l,5]-hydride transfer/cyclization was facilitated via cascade iminium/enamine activation. The presence of strong acid was indispensable to ensure sufficient electrophilicity of the iminium intermediate. Theoretically, substrate 170 reacts with 172 to give iminium intermediate I. Owing to the steric interaction of the bulky ferf-butyl group, the E enamine II is formed preferentially upon [1,5]-HT, which exists in two possible conformers III and IV. Because of dipole repulsion between the cyclic-oxocarbe-nium and enamine moieties in conformer III, IV is the more favored conformer, which undergoes intramolecular C-C bond formation to afford the final product 171. 

Two C-C Bond-Forming Events In 2008, Frechet and coworkers described an impressive asymmetric cascade reaction promoted by soluble star polymers with core-confined catalytic entities [10]. The encapsulation of catalysts into soluble star polymers allowed the use of incompatible catalysts and prevented undesired interactions between these catalytic systems. The organocascade corresponded to a nucleophilic addition of Af-methylindole to a,p-unsaturated aldehydes followed by a Michael addition of the adduct to methylvinylketone (MVK) in the presence of H-bonding additive (Scheme 12.5). Each catalyst - imidazolidinone 8 for the nucleophilic addition and diphenylprolinol methyl ether 9 for the Michael addition - or their combination cannot mediate both reaction steps. In particular, p-toluenesulfonic acid (p-TSA) diminished the ability of the chiral pyrrolidine 9 to effect enamine activation. Therefore, p-TSA and 9 were encapsulated in the core of star polymers, which cannot penetrate each other. Imidazolidone 8 was added to the acid star polymer and diffused to the core to form the salt, which allowed the iminium activation and catalyzed the first step. The second step was catalyzed by the pyrrolidine star polymer in presence of the H-bonding additive 10, which... 

The synthesis is initiated by the organocatalyzed cascade that activates a,p-unsaturated aldehyde 8 with the formation of an iminium ion (Scheme 14.2). In this way, the imidazolidinone catalyst allows hydride transfer from the Hantzsch dihydropyridine 9 onto the highly activated conjugated alkene 11, which creates the nucleophilic enamine intermediate 12. Because of the chirality of the organocatalyst, stereoselective Michael addition (97% ee) to the adjacent enone occurs, with minor preference for the cis diastereomer (2 1 dr). Fortunately, this undesired diastereomer slowly epimerizes to the required trans isomer, which produces (-l-)-ricciocarpin A when treated with samarium triisopropoxide. Besides the Cannizzaro-like redox disproportionation, which allows the lactone producing Evans-Tihchenko reaction to occur, samarium(III) also enhances the epimerization to the trans isomer and therefore produces the desired isomer in high selectivity. 

Another strategy is to use an organocatalytic cascade merging iminium and enamine activation. First, there is a condensation... 

To demonstrate the power of this concept the sesquiterpene (-)-aromadendran-ediol was synthesized by the same authors using this cascade enamine-iminium activation concept. 

Scheme 42.16 Asymmetric organocatalytic triple cascade by way of an enamine-iminium ion-enamine activation of aldehydes. Protocol point the minor diastereomer was determined as the 5-epimerof 59 all substrates added at the outset of the reaction.

Design of enamine-iminium cascades Examples of [4-1-2] reactions with enamine-activated dienes Inverse-electron-demand [4-1-2] reactions with enamine-activated dienophiles Enamine-iminium-enamine cascades... 

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. 

---