Iminium-Enamine Activation

Based on these experimental results. Hulling and coworkers investigated the mechanism of the imidazolidinone-catalyzed cascade reaction of a,p-unsaturated butyric aldehydes with 2-methylfuran and chlorinated quinone using density functional theory (DFT) calculations [15]. The results gave a better understanding of the effects of the imidazolidinone catalyst core in the enamine- and iminium-mediated steps and explained the enantioselectivity observed from the experiments depicted above. 

The group of Mac Millan has also exploited the olefin aryl- or alkylamination of a,p-unsaturated aldehydes [16], while the group of Melchiorre investigated independently this transformation by starting from a-substituted a,p-unsaturated 

3 Two C-Heteroatom Bond-Forming Events Different organocascades have been described for diamination, amino oxidation, amino sulfenylation, and amino fluorination of a,p-unsaturated aldehydes. 

In 2010, Jprgensen and coworkers developed a novel organocatalytic strategy for asymmetric formal /ran -aminohydroxylation and frani-dihydroxylation of a,p-unsaturated aldehydes [19]. They proposed a new epoxidation/NaOMe-initiated 

The same group also developed the first organocascade reaction combining dienamine- and iminium-mediated catalysis to produce adducts containing y,p-stereocenters [22]. A y-amino-p-hydroxyalcohol was obtained from 2-heptenal 

---

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). 

The reaction, catalyzed by the 9-amino-9-deoxyepiquinine 2, was proposed to go through an iminium-enamine activation process. 

Scheme 10.1 Mechanism of iminium-enamine activation mode.

SCHEME 231 Proposed cascade iminium-enamine activation. 

In such a way, the formation of five new C—C bonds allowed the synthesis of the desired decahydroacenaph-thylene and decahydrophenalene cores bearing eight novel stereogenic centers with high optical purity (97 to >99% ee). Likewise, employing a linear aldehyde bearing a thioester moiety, the same enamine-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... 

The postulated mechanism starts with the diastereo- and enantioselective domino iminium-enamine activation of enals 95 in the presence of malonate 160 to form the... 

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. 

The use of this catalyst allowed the same authors to elaborate an asymmetric domino Michael-Michael-aldol reaction, involving two aldehydes and a nitroalkene on the basis of an enamine-iminium-enamine activation. The corresponding cyclohexene-carbaldehydes were isolated with virtually complete diastereo- and enantioselectivities, as shown in Scheme 1.63. 

Jprgensen and coworkers exploited an approach in 2005 by designing a three-component reaction involving iminium/enamine activation (Scheme 2.23). They demonstrated that thiols 84 can initiate the sequence by a thia-Michael addition to... 

Figure 35.1 Representative primary and secondary chiral amines (iminium-enamine activation).

The first example of dual organocascade catalysis involving iminium/enamine activation was published in 2005 (Scheme 35.15) [6]. In this report, a, 3-unsaturated... 

Since the early example of a proline-catalyzed asymmetric domino Michael-aldol reaction reported by Bui and Barbas in 2000 [57], a number of these reactions have been successfully developed by several groups. For example, Wang et al. have reported the synthesis of chiral densely functionalized cyclopentenes on the basis of a domino Michael-aldol reaction followed by dehydration between aromatic enals and dimethyl 2-oxoethylmalonate [67]. High yields (63-89%) and enanhose-lectivities (91-97% ee) were obtained by using (S)-diphenylprolinol sUyl ethers as catalysts. On the other hand, the condensation of P-nitroketones 36 onto enals in the presence of 8 was shown by Hong et al. to afford the corresponding domino Michael-aldol products 37 through the iminium-enamine activation mode [68]. 

---