Cinchonine derivatives

Dixon et al. screened cinchonine-derived thioureas 117-120 for their performance in the dimethyl malonate Michael addition to tra s-(5-nitrostyrene in dichlo-romethane at room temperature and at -20°C [274]. As shown in Figure 6.38, all candidates revealed comparable activity, but monodentate hydrogen-bond donor 118 exhibited very low asymmetric induction producing the desired Michael... 

Scheme 6.112 Michael addition of thiophenol to an a,p-unsaturated imide catalyzed by cinchonidine-derived thiourea 116 and cinchonine-derived thiourea 117, the first representatives of this class of bifunctional hydrogen-bonding cinchona alkaloid-thioureas.

Figure 6.38 Cinchonine-derived thioureas (10mol% loading) screened in the Michael reaction of dimethyl malonate to trans- 3-nitrostyrene.

Chen and co-workers presented, in 2007, a Michael-type Friedel-Crafts reaction of 2-naphthols and trans-P-nitroalkenes utilizing the bifunctional activating mode of cinchonine-derived catalyst 117 [277]. The nitroalkene was activated and steri-cally orientated by double hydrogen bonding, while the tertiary amino group interacts with the naphthol hydroxy group to activate the naphthol for the nucleophilic P-attack at the Michael acceptor nitroalkene (Scheme 6.117). 

Rozwadowska and coworkers carried out the asymmetric alkylation of isoquino-line Reissert compounds under phase-transfer conditions using cinchonine-derived quaternary ammonium salts as catalysts. The best enantioselectivity was achieved in the benzylation and allylation of 1 -cyano-2-phenoxy carbonyl-1,2-dihydroisoquinoline (17) catalyzed by 2a (Scheme 2.14) [34]. 

The asymmetric aziridination of a, P-unsaturated carboxylic acid derivatives is a direct route to optically active aza-cyclic a-amino acids, and this class of chiral aziridines can also be used as chiral building blocks for the preparation of other amino acids, P-lactams, and alkaloids. Prabhakar and coworkers carried out an asymmetric aziridination reaction of tert-butyl acrylate with O-pivaloyl-N-arylhydroxylamine 25 in the presence of cinchonine-derived chiral ammonium salt 2e under phase-transfer conditions, which furnished the corresponding chiral N-arylaziridine 26 with moderate enantioselectivity (Scheme 2.24) [46],... 

The effect of the nature of the cinchona alkaloid component was then investigated (Scheme 4.4). The cinchonine-derived PTC 9, which are in pseudoenantiomeric relationship to the cinchonidine-derived compound 7, produced the opposite... 

Iseki, Nagai, and Kobayashi prepared cinchonine-derived 4f and 4g from the corresponding bromides by the method B (Scheme 9.5), and realized the asymmetric trifluoromethylation of aldehydes and ketones with trifluoromethyltrimethylsilane (Me3SiCF3) catalyzed by these ammonium fluorides (Schemes 9.9 and 9.10) [19]. Although the enantioselectivities are not sufficiently high, this reaction system should offer a new access to various chiral trifluoromethylated molecules of analytical and medicinal interests through appropriate modifications. 

The opposite enantiomers can be obtained easily simply by changing from the cinchonine-derived catalyst to the cinchonidine analog [21], This contribution by O Donnell et al. served as a starting point for impressive studies from several groups with regard to detailed optimization of the process. 

Dimeric phase-transfer catalysts were also reported by Najera et al., who used cinchonidine- and cinchonine-derived ammonium salts bearing a dimethyl-anthracenyl bridge as a spacer [32]. In the presence of these catalysts high enantioselectivity of up to 90% ee was obtained. 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

Several types of modifiers have been shown to be successful. Common features are a basic nitrogen atom close to one or more stereogenic centers connected to an extended aromatic system. By far the best overall results are obtained with cinchonidine derivatives for an excess of the (R)- and with cinchonine derivatives for the (,S )-alcohols.7... 

In 1992, O Donnell succeeded in obtaining optically active a-methyl-a-amino acid derivatives 49 in a catalytic manner through the phase-transfer alkylation of p-chlorobenzaldehyde imine of alanine tert-butyl ester 48 with cinchonine-derived la as catalyst (see Scheme 4.16) [46]. Although the enantioselectivities are moderate, this study is the first example of preparing optically active a,a-dialkyl-a-amino acids by chiral phase-transfer catalysis. 

Dixon and co-workers independently reported the asymmetric hydrogenbonding catalyzed 1,4-additions of dimethyl malonate to nitroolefins using a cinchonine-derived thiourea catalyst 30 [54]. Catalyst 30 gave good to high yields (81-99%) and good to high enantioselectivities (82-97% ee) for a variety of aromatic, heteroaromatic and aliphatic nitroolefins (Scheme 6.4). Optical purity... 

Similar conditions are also effective for the direct enantioselective epoxidation of a,p-unsaturated carbonyls, as exemplified by the conversion of chalcone (30) to the corresponding ft,/ -epoxide in 97% yield and 84% ee using the 4-iodophenyl cinchonine derivative 32 <02T1623>. Alternatively, the novel polyethylene glycol-supported oligo(L-leucine) catalyst... 

M Reactions were conducted with the cinchonine derived analogue of 27 to afford the opposite enantiomer. Scheme 8.9... 

In 2005, Chen and coworkers found that the epi-cinchonidine/cinchonine-derived thiourea catalysts, 79a,b, can serve as highly active promoters of the Michael addition ofthiophenol to the a,P-unsaturated imide 80 however, the reaction proceeded with low enantioselectivity (up to 17% ee) (Scheme 9.28) [22]. 

As described above, cinchona-based (thio)ureas have proven to be highly efficient H-bond donor catalysts. In 2008, Rawal and coworkers developed a highly promising new family of cinchona-based H-bond donor catalysts such as 157 by replacing the thiourea moiety of cinchona-based thiourea catalysts with the squaramide unit [47]. The squaramide moiety of 157 is able to form two H-bonds to a reactant due to the more accessible reaction site and fixed syn-orientation of the NH-protons. Using only 0.5 mol% of the cinchonine-derived squaramide catalyst 157, various Michael donors 158 and nitroalkenes 130 were smoothly converted to the desired adducts 159 in excellent yield and ee values (up to 99% ee) (Scheme 9.54). 

Scheme 11.2 Development of cinchonine-derived phase-transfer catalysts.

The first example of preparing ophcaHy achve a a-dialkyl-a-anhno acids by chiral PTC was reported by O Donnell in 1992 [36], giving moderate enanhoselec-hvities for the alkylation of p-chlorobenzaldehyde imine of alarhne tert-butyl ester 39a with cinchonine-derived Ic as catalyst (entry 1, Table 11.4). Subsequenhy,... 

The best results are usually obtained with cinchonidine or shghtly altered derivatives such as HCd or 9-methoxy-HCd (MeOHCd) to give the ( h)-alcohol and with cinchonine derivatives to give the (S/-enantiomer, albeit with somewhat lower enantioselectivity. The most effective cinchona modifiers are commercially available or can easily be prepared from these. 

Therefore, under the optimized conditions, 9-ep -dihydroquinine-derived thiourea 71a performed very well in the Michael reaction of diethyl malonate with nitroalkenes, furnishing the final compounds with enantioselectivities around 90% ee (Scheme 4.8). Remarkably, this catalyst also seemed to tolerate the use of (3-alkyl substituted nitroalkenes as substrates, furnishing the expected final compounds with only a small decrease in enantioselectivity, although only a few examples were studied in that case. In an independent work, 9-e i-cinchonine-derived thiourea 72b was also reported to be a very efficient catalyst for this reaction, obtaining the final Michael adducts in... 

On the other hand, 2-naphthols have been used with different success as Michael donors in conjugate Friedel Crafts reactions with nitroalkenes and related substrates (Scheme 4.53). For example, cinchonine-derived thiourea 72b was identified as an excellent promoter for the reaction of a wide variety of 2-naphthols and nitroolefins, providing excellent yields and enantioselectivities. Remarkably, the more challenging p-alkyl substituted nitroalkenes were also found to undergo the reaction in a highly stereoselective way and with comparable yields to those obtained when nitrostyrene derivatives were employed. 

Five years after the successful application of the cinchonine-derived quaternary ammonium catalyst 3 by the Merck research group, O Donnell and... 

Scheme 16.13 Asymmetric Michael addition with cinchonine-derived PTC 3.

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