Cinchona-based primary amine

Asymmetric Cydoaddition Reactions Catalyzed by Cinchona-Based Primary Amines... 

Cinchona-based primary amine catalysis in the asymmetric functionalization of carbonyl compounds 12AG(E)9748. 

Very recently, the same group successfully extended this methodology also to a-branched aldehydes [128], Cinchona based primary amine LX (Scheme 8.27) for activation of aldehydes and (-)-CSA as chiral acid for carbocation formation efficiently catalyzed alkylation reaction, giving best results in solvent system CH3CN/H2O. 

A similar approach was reported by Wang et al. [60] a year later, consisting of a double Michael reaction of simple oxindoles with dienones. The reaction was simply catalyzed by a cinchona-based primary amine catalyst (XIII). The reaction afforded the final spirocyclic oxindoles in good yields and excellent enantioselectivities when diaryldienones were used. The only limitation of the reaction was the need to use carbamate-protected oxindoles thus, the use of unprotected or benzylated oxindoles is ineffective for this transformation. In 2010, the same research group proposed a similar approach [61]. They performed a reaction with an oxindole derivative decorated with a ketone in position 3 of the oxindole and acyclic enones. This reaction was catalyzed by chiral primary amines, affording the final spirooxindoles in good yields and enantioselectivities. 

Cinchona-based primary amines were first applied as chiral catalysts for the iminium ion activation of a,p-unsaturated ketones in 2007. Thus, alkylation product 6 was obtained with moderate optical yield in the reaction between indole 4 and ketone 5 catalyzed by cinchona based amine 3 in the presence of double amount of trifluoroacetic acid (Scheme 3.12). ... 

In 2011 Lan et al. [48] reported an efficient construction of the spiro[cyclohexanone-oxindole] backbone catalyzed by a combination of a chiral cinchona-based primary amine and (R)-BINOL-phosphoric add. It was found that the reaction proceeded much faster with the elevation of temperature from room temperature to 80 C, without affecting either the diastereoselectivities or enantioselectivities (Scheme 21.20). 

Cinchona-based primary amine catalysis in the asymmetric functionalization of carbonyl compounds has been reviewed and their modularly designed thioamide 0 derivatives have been applied successfully to direct cross-aldol reactions between aldehydes and ketones, reactions of activated carbonyl compounds (isatins) with acetylphosphonate as the enol precursor, and C( 1) functionalization of 1,3-dicarbonyl compounds by aldehydes and ketones. Cross-aldol addition to C(3) of isatins by the methyl group of 4-aryl-tra 5 -cf, -unsaturated methyl ketones has also been promoted... 

Deng and co-workers developed the first asymmetric Diels-Alder reactions of a,p-unsaturated ketones and 2-pyrones (Scheme 5.36) [65] with cinchona-based primary amine catalysts 38 or 39. The substrate scopes are substantial and in most cases excellent diastereoselectivity and enantioselectivity were obtained. 

Iminium catalysis has been quite successful for asymmetric epoxidation of a,P-unsaturated carbonyl compounds, particularly, enals. Enones have remained difficult substrates. Recently, List and coworkers reported an enantioselective epoxidation of cyclic enones with either cinchona-based primary amine 38 or a counter-anion catalytic systan 149 combining a chiral vicinal diamine and a chiral phosphoric acid [69], High enantioseleclivities could be achieved in a number of cyclic enones (Scheme 5.40). 

The power of column-like reactors for continuous flow processes lies in the possibility to sequentially link them up in order to carry out multistep syntheses in solution in one run (see also Schemes 1 and 2). Lectka and coworkers utilized conventional fritted and jacketed columns for this purpose. These columns were filled with conventional functionalized polymeric beads [47]. The continuous flow was forced by gravity. En route to / -lactams polymer beads functionalized with the Schwesinger base 17, a cinchona alkaloid derivative 18 as a chiral catalyst, and a primary amine 19 were sequentially employed. They first guaranteed the generation of phenyl ketene from phenyl... 

The conceptually different activation of carbonyl substrates through the formation of a nucleophilic enamine or an electrophilic iminium ion is achieved by use of 9-deo>q -ep/-9-amino Cinchona catalysts. In contrast to typical secondary amine-based catalysts i.e. derived from proline), the primary amine of these modified Cinchona alkaloids can combine also with sterically biased substrates, such as ketones and hindered aldehydes. This class of catalyst has thus allowed the scope of aminocatalysis to be extended beyond unhindered aldehydes/enals, and has proved to be remarkably powerful and general. 

More recently, it has been reported that primary amines derived from cinchona alkaloids [75] as well as proline derivatives [76], combined with achiral Brpnsted or Lewis acids, may also efficiently catalyze the enantioselective Biginelli reaction. Alternatively, a carbohydrate-based bifnnctional primary amine-thiourea catalyst was developed for this transformation, with similar enantiocontrol [77]. 

In the second reaction, a Michael-Michael cascade between an unsaturated oxin-doles 17 and enones 22 was shown to be catalyzed by a primary amine-derived catalyst (II) (Scheme 10.3). The reaction afforded the spirooxindoles 23 in excellent yields and diastereo and enantioselectivities. Wang used a similar approach in the reaction of isatylidene malononitriles and enones [12]. The reaction was catalyzed by the dual combination of cinchona-based chiral primary amine and BINOL phosphoric acids to afford the spirocycles in excellent yields (88-99%), diastereo (up to 99 1 dr), and enantioselectivities (95-99% ee). 

While asymmetric counteranion-directed catalysis (ACDC) has been estab-hshed as a powerful strategy in iminium catalysis, enamine-based asymmetric counteranion-directed catalysis has not yet been developed. Recently, Lu et al. [32] demonstrated that the combination of a cinchona alkaloid-derived primary amine and chiral camphorsuhnnic acid (CSA) results in an effective ion-pair catalyst for the directed asymmetric amination of a-branched aldehydes through enamine activation (Scheme 43.21). 

Very recently, the combination of a cinchona-based chiral primary amine and a chiral phosphoric acid has been demonstrated by Wang and coworkers [36] as a powerful and synergistic catalyst system for the double Michael addition of isatylidene malononitriles with a,P-unsaturated ketones (Scheme 43.23). Various novel chiral spiro[cyclohexane-l,3 -indoline]-2, 3-diones were obtained in high... 

Despite the excellent results of epoxidation of simple a,p-unsaturated aldehydes, a general method for the epoxidation of a-branched ot,P-unsaturated aldehydes was challenging. After several years, the process was realized by the combination of a chiral primary Cinchona-based amine and a chiral phosphoric acid as cocatalysts, making it possible to achieve high efficiency (Schane 1.65) [107]. It is believed that chiral phosphoric acid provides additional enantiodisaimination in both steps as a chiral counterion in 160a and as a Brpnsted acid in 160b. This is supported by the match or mismatch observed when the phosphoric adds (7 )-TRIP and (S)-TRIP were used in parallel studies. 

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