Organocatalysts phase-transfer

As one type of the most important organocatalysts, phase-transfer catalysts found wide application in asymmetric Michael addition reactions [50]. In 1986, Conn et al. [51] reported the asymmetric Michael addition of indanone derivative to methyl vinyl ketone (MVK) catalyzed by their original catalyst 54 (Scheme 5.25). The... 

Currently, the chiral phase-transfer catalyst category remains dominated by cinchona alkaloid-derived quaternary ammonium salts that provide impressive enantioselec-tivity for a range of asymmetric reactions (see Chapter 1 to 4). In addition, Maruoka s binaphthyl-derived spiro ammonium salt provides the best results for a variety of asymmetric reactions (see Chapters 5 and 6). Recently, some other quaternary ammonium salts, including Shibasaki s two-center catalyst, have demonstrated promising results in asymmetric syntheses (see Chapter 6), while chiral crown ethers and other organocatalysts, including TADDOL or NOBIN, have also found important places within the chiral phase-transfer catalyst list (see Chapter 8). 

The first example of the use of an alkaloid-based chiral phase-transfer catalyst as an efficient organocatalyst for enantioselective alkylation reactions was reported in 1984 [3, 4]. Researchers from Merck used a cinchoninium bromide, 8, as a catalyst... 

Derivatives of commercially available alkaloids, e.g. 8 and 13, have usually been used as the phase-transfer catalyst. Besides these classic standard catalysts, however, efforts have been also made to design novel organocatalysts with new proper-... 

Optimization of the alkaloid phase-transfer catalysts included both the development of improved reaction conditions and the design of more efficient organocatalysts. Addressing this latter issue, O Donnell observed the first remarkable improvement of the enantioselectivity on use of modified alkaloid organocatalysts with an O-substituent, in particular an O-allyl or O-benzyl substituent, for example 23 and 24, respectively. This positive effect of O-alkylated structures was discovered during a detailed mechanistic study [22]. In this study it was found that O-alkylation of the previously used alkaloid catalysts, e.g. 21, and N-alkylated derivatives thereof, e.g. 22, by reaction with an alkyl halide (which is used in 1.2-5... 

Maruoka and co-workers developed an elegant solution by creating phase-transfer-catalysts of type 30 [36], For example, the C2-symmetric N-spiro organocatalyst (S,S)-30, which contains a conformationally flexible biphenyl subunit, efficiently catalyzed the alkylation of glycinate 18 with benzyl bromide, with formation of the product (R)-20b in 95% yield and with 92% ee (Scheme 3.10) [36],... 

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],... 

Use of an organocatalyst in a highly diastereoselective nitroaldol reaction was reported by the Corey group in the synthesis of 123 [128]. This compound is a key building block in the synthesis of the HIV-protease inhibitor amprenavir. The alkaloid-based fluoride salt, 122, was used as an efficient chiral phase-transfer catalyst (this type of catalyst was developed by the same group [129-131]) and led to formation of the (2R,3S) diastereomer (2H,3S)-123 in 86% yield and with a diastereo-meric ratio of d.r. = 17 1 (Scheme 6.53) [128], It is worthy of note that a much... 

A procedure for alkylation of C=0 double bonds in the presence of (metal-free) organocatalysts and non-metallic nucleophiles has been reported by the Iseki group for trifluoromethylation of aldehydes and ketones [185]. On the basis of a previous study of the Olah group [186, 187] which showed the suitability of non-chiral phase-transfer catalysts for trifluoromethylation of carbonyl compounds, Iseki et al. investigated the use of N-benzylcinchonium fluoride, 182, as a chiral catalyst. The reaction has been investigated with several aldehydes and aromatic ketones. Trifluoromethyltrimethylsilane, 181, was used as nucleophile. The reaction was, typically, performed at —78 °C with a catalytic amount (10-20 mol%) of 182, followed by subsequent hydrolysis of the siloxy compound and formation of the desired alcohols of type 183 (Scheme 6.82). 

The first example of a catalytic asymmetric Horner-Wadsworth-Emmons reaction was recently reported by Arai et al. [78]. It is based on the use of a chiral quaternary ammonium salt as a phase-transfer catalyst, 78, derived from cinchonine. Catalytic amounts (20 mol%) of organocatalyst 78 were initially used in the Homer-Wadsworth-Emmons reaction of ketone 75a with a variety of phospho-nates as a model reaction. The condensation products of type 77 were obtained in widely varying yields (from 15 to 89%) and the enantioselectivity of the product was low to moderate (< 43%). Although yields were usually low for methyl and ethyl phosphonates the best enantioselectivity was observed for these substrates (43 and 38% ee, respectively). In contrast higher yields were obtained with phosphonates with sterically more demanding ester groups, e.g. tert-butyl, but ee values were much lower. An overview of this reaction and the effect of the ester functionality is given in Scheme 13.40. 

In the presence of cinchona derivatives as catalysts, peroxides or hypochlorites as Michael donors react with electron-deficient olefins to give epoxides via conjugate addition-intramolecular cyclization sequence reactions. Two complementary methodologies have been developed for the asymmetric epoxidation of electron-poor olefins, in which either cinchona-based phase-transfer catalysts or 9-amino-9(deoxy)-epi-dnchona alkaloids are used as organocatalysts. Mechanistically, in these two... 

For example Shibuguchi, T., Fukuta, Y, Akachi, Y. et al. (2002) Development of new asymmetric two-center catalysts in phase-transfer reactions. Tetrahedron Letters, 45,9539-9543. Ohshima, T., Shibuguchi, T., Fukuta, Y. and Shibasaki, M. (2004) Catalytic asymmetric phase-transfer reactions using tartarate-derived asymmetric two-center organocatalysts. Tetrahedron, 60, 7743-7754. 

These are potent phase transfer organocatalysts for asymmetric a-alkylation of A/-arylideneglycine fert-butyl ester derivatives for the synthesis of chiral a-substituted a-amino acids at extremely low concentrations of catalyst [Ooi et al. Tetrahedron Asymm 17 603 2006],... 

Tokunaga and coworkers reported the enantioselective hydrolysis of enol esters (111) in the presence of catalyst 8b under phase-transfer conditions with aqueous KOH. The proposed mechanism of this reaction has the protonation of the ammonium-enolate ionic complex as the enantioselective step. Their achievement of the first nonbiomimetic asymmetric hydrolysis of esters catalysed by organocatalysts with high catalytic efficiency in buffer-free conditions has considerable potential to replace enzymatic resolutions in industrial processes (Scheme 16.41). ... 

FIGURE 2.46. Representative chiral phase-transfer organocatalysts. 

Some structures of typical chiral phase-transfer organocatalysts can be found in Figure 2.46. 

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