Organocatalysts acrolein

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

M. Shi and Y.-L. Shi reported the synthesis and application of new bifunctional axially chiral (thio) urea-phosphine organocatalysts in the asymmetric aza-Morita-Baylis-Hillman (MBH) reaction [176, 177] of N-sulfonated imines with methyl vinyl ketone (MVK), phenyl vinyl ketone (PVK), ethyl vinyl ketone (EVK) or acrolein [316]. The design of the catalyst structure is based on axially chiral BINOL-derived phosphines [317, 318] that have already been successfully utilized as bifunctional catalysts in asymmetric aza-MBH reactions. The formal replacement of the hydrogen-bonding phenol group with a (thio)urea functionality led to catalysts 166-168 (Figure 6.51). 

Serotonin (8) mimics have been used effectively as treatments for a variety of psychiatric illnesses [199-201]. Homotryptamines could be constructed by multistep routes. One-pot synthesis of homotryptamines 277a-k was achieved by the conjugate addition of indoles with acrolein in the presence of the MacMillan organocatalysts (118a, 274) followed by reductive amination (Scheme 60) [201]. 

Chiral secondary amines such as nonracemic imidazolidin-4-ones have been found to be effective asymmetric organocatalysts in the Diels-Alder cyclization of cyclopentadiene and a,p-unsaturated aldehydes [60]. A tyrosine-derived imidazoli-din-4-one was immobilized on PEG to provide a soluble, polymer-supported catalyst 110. In the presence of 110, Diels-Alder cycloaddition of acrolein 112 to 1,3-cyclohexadiene 111 proceeded smoothly to afford the corresponding cycloadduct 113 with high endo selectivity and enantioselectivity up to 92% ee (Scheme 3.31) [61]. 

Table 7.15 Asymmetric Diels-Alder reaction between cyclohexadiene and acrolein using organocatalyst 51 in ionic liquids.

Scheme 6.44 Quadruple domino reaction of N -dimethyl-7H-anisidine, acrolein, and p-nitrostyrene promoted by organocatalyst (S)-104 reported by Enders.

The combination of an imine derived from the reaction of acrolein organocatalyst 1 with simple indoles 84 and nitroalkenes 85 affords the 3-(cyclohexenylmethyl)-indoles 86 (Scheme 7.16) [59]. In this reaction, the indole 84 initiates the Friedel-Crafts-type reaction followed by a Michael reaction with nitroalkenes 85 to the intermediate 87. From this process, a hydrolysis takes place and the resulting compound enters another catalytic cycle involving a Michael/aldol condensation reaction similar to those reported previously. 

Later, Sasai et al. [204] developed another example of domino reaction initiated by the aza-Morita-Bayhs-HiUman reaction followed successively by an aza-Michael reaction, an aldol reaction, and a dehydration. This novel process, induced by a chiral acid-base organocatalyst (20mol%), involved acrolein and various N-tosylarylimines as the substrates, leading to the corresponding highly functionahzed tetrahydropyridines in moderate yields (40-60%) and good enantioselectivities of 80-88% ee. Attempts to extend the scope of the reaction to other activated alkenes such as methylvinylketone failed. 

Meng, X., Huang, Y., Chen, R. (2008). A novel selective aza-Morita-Bayhs-HiUman (aza-MBH) domino reaction and aza-MBH reaction of N-sulfonated imines with acrolein catalyzed by a bifunctional phosphine organocatalyst. Chemistry - A European Journal, 14, 6852-6856. 

It was difficult to activate a-branched aldehydes such as acroleins with secondary amines because of the steric effect of poor generation of the corresponding iminium ions. An enantioselective Diels-Alder reaction with a-substituted acroleins 124 was realized by a primary amine organocatalyst 125 (Scheme 1.45) [68]. Acyclic dienes... 

In the organocatalytic 1,3-dipoIar cycloadditions between A,A -cyclic azomethine imines and acrolein, either exo- or cnrio-cycloadducts could be selectively synthesized with the enantiomerically enriched form by using structurally similar amino acid organocatalysts [17]. Suga et al. have... 

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