Aminocatalysts

Mechanistically it is proposed that the reaction proceeds via an initial Knoevena-gel condensation of the aldehyde with Meldrum s acid followed by a Diels-Alder reaction of the resulting arylidene Meldrum s acid with an in situ generated chiral dienamine, which is formed in the reaction of the enone with the aminocatalyst. 

As discussed above, all of the cinchona-based quaternary ammonium salts used as catalysts gave only poor to moderate diastereoselectivities and enantioselectivities for direct aldol reactions. Quite recently, a highly enantioselective, catalytic, direct aldol reaction was realized by adopting the enamine catalysis approach [12], in which 9-amino-epi-cinchona alkaloids are employed as aminocatalysts [13, 14]. 

In 2007, Connon and McCooey developed highly efficient, asymmetric syn-selective addition reactions of enolizable carbonyl compounds to nitroolefins by adopting the enamine catalysis approach [48]. The 9-epi-amino cinchona alkaloid derivative (160,9 -epi-DHQDA) as an aminocatalyst promoted the addition ofa variety... 

Noteworthy, in a related transformation, the List group developed the first catalytic enantioselective a-benzylation of branched aldehydes. L-proline gave moderate yields, but promising enantioselectivities. Further screening identified a more sterically encumbered aminocatalyst, which provided benzylated products in optimal yields and enantioselectivities (Scheme 5.25). 

The formal [4 + 2]-Diels-Alder could also be achieved using nonequivalent a,p-unsaturated aldehydes employing L-proline as an aminocatalyst. Chiral dienes were accessible in good yields (61-82%) and modest to good enan-tioselectivities (41-63%) (Scheme 5.37). Reaction temperatures varied from 25 °C to —25 °C to produce optimal enantioselectivities. Hong et al. also described the formal [3 + 3] and [4 + 2] cycloadditions of ot,p-unsaturated aldehydes, providing access to poly-substituted aromatic products in modest to good yields (Scheme 5.38). ... 

Proline derivatives possess a prominent position among the aminocatalysts utilised for carbonyl activation. In combination with the readily tunable properties of the (thio)urea functionality for electrophile activation, the development of bifunctional chiral pyrrolidine-based (thio)ureas was a rational extension. In 2006, Tang and coworkers reported thiourea 55 that can catalyse the conjugate addition reaction between cyclohexanone and nitroalkenes (Scheme 19.63). In the presence of 20 mol% of chiral thiourea 55 and butyric acid as the cocatalyst, the q -products were delivered in high yields (up to 98%) and in excellent diastereo- (up to >99 1 dr) and enan-tioselectivities (up to 98% enantiomeric excess). In addition to aromatic nitroalkenes, aliphatic nitroalkenes were also tolerated, but required a long reaction time (6 days). 

In 2008, Chen and co-workers [56] developed the first organocatalytic asymmetric Michael addition of aromatic ketones to highly active alkylidenemalononi-triles. In the presence of primary aminocatalyst 58, the reaction proceeded well to give the multifunctional adducts with up to 84% ee (Scheme 5.29). 

FIGURE 14.6. Chiral aminocatalysts and co-catalysts used in the sulfa-Michael additions to a,p-unsaturated ketones and hindered a,p-unsaturated aldehydes. 

Notably, Jprgensen demonstrated the possibility of decreasing the catalyst loading to 2.5 mol% for the aminocatalyst 3 and to 1 mol% for 49. He also proved that... 

The aminocatalysts used are the same that are also used when aldehyde-donors are employed. Aldehydes and ketones can be used as acceptors and... 

Aminocatalysts studied for reaction of acetone with p-nitrobenzaldehyde. 

Complementary to the enamine-based reactions, the diarylprolinol silyl ether catalysts can be applied for activation of a,p-unsaturated aldehydes toward conjugate additions through iminium-ion-induced processes. Mechanistically, this conceptually different activation mode draws close parallels to the enamine chemistry (Scheme 2.4) [5]. The secondary aminocatalyst condenses with the enal to form... 

The key feature of iminium-ion activation is the lowering of the LUMO (lowest unoccupied molecular orbital) energy, whereby an increased reactivity of the unsaturated system towards nucleophilic addition is obtained. To better understand the mechanism and kinetics of the iminium-ion formation, several experimental studies and calculations have been performed. Often the reactions are accelerated by the addition of Bronsted acid co-catalysts, which presumably assist the initial condensation. This indicates that the condensation is the rate-determining step in these reactions. In a recent study by Mayr [10], the elec-trophiUcity of different iminium ions obtained from various aminocatalysts and cinnamaldehyde was investigated experimentally (Figure 2.2). 

The carbanion -type reactivity of dienamine activation can be promoted by a silyl-protected diarylprolinol catalyst in the presence of reactive electrophilic species, such as nitroolefins or diarylmethanols (Scheme 2.10) [20]. Although both direct addition (a-addition) and vinylogous addition (y-addition) are viable reaction pathways, the a-reactivity is the more typical one and usually provides better selectivities due to more effective shielding of the a-position by the aminocatalyst. Interestingly, the a-/y-selectivity of dienamine-mediated carbanion -type addition reactions seems to be strongly influenced by the substitution pattern of the enal reactant For example, it was demonstrated that y,y-disubstituted enals favor the a-addition product while y-functionaUzation is the predominant reaction pathway for y-monosubstituted enals. 

An intriguing aspect of trienamine-mediated reactions is the ability of the catalysts to offer sufHcient stereoinduction at the remote C6 center. However, due to the concerted nature of the Diels-Alder reaction, it is suggested that the steric shielding at C3, where a new bond is formed as well, could indirectly extend the chirality relay of the bulky substituent of the aminocatalyst to the distant C6 center, hence providing the experimentally observed excellent enantioselectivities for such reactions (Scheme 2.14). 

One main advantage of aminocatalysts is their ability to promote several activation modes (iminium-enamine) or their high compatibility with other systems allowing for their applications in cascades reactions. 

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