Conjugate additions chiral phase-transfer catalysts

Chiral ion pairs (B, Fig. 2.2) can be formed by deprotonation of the pronucleophile with a chiral Brpnsted base or employing an achiral base and a chiral phase-transfer catalyst. Chiral phase-transfer catalysis (PTC) [8] illustrates how ion pairing interactions can be used to carry out the enantioface discrimination in conjugate addition reactions. In both cases, the chiral cation is responsible for... 

Chiral quaternary ammonium salts are competent phase-transfer catalysts for the conjugate addition of nitroalkanes to a,p-unsaturated ketones. Pioneering work by Wynberg and Colonna groups about the enantioselective Michael addition of nitroalkanes to chalcones employing chiral phase-transfer catalysts derived from Cinchona... 

Chiral phase-transfer catalysts have been often used as promoters in the conjugate addition of activated malonates to a,p-unsaturated ketones. Phase-transfer catalysts are stronger bases compared to the amine catalysts so their use was initially focused on the conjugate addition of less-acidic nucleophiles where chiral amines had not been successful. Thus, different chiral phase-transfer systems such as iV-alkylated cinchonium derivative 143 (Scheme 2.85) [206, 228] and ephedrinium... 

Fig. 2.24 Chiral phase-transfer catalysts for the conjugate addition of glycine derivatives...

Tartrate-derived chiral phase-transfer catalysts 175 and 176 (Fig. 2.24) have been synthesized and successfully employed in the conjugate addition of amino acid derivatives to different Michael acceptors such as acrylates and vinyl ketones [280]. 

A short synthesis of (-f)-monomorine (1562) by Maruoka and coworkers used the chiral phase-transfer catalyst (R)-1672 to mediate an enantioselective conjugate addition between enone 1673 and the imine-protected glycine ester 1674 (Scheme 213). In a remarkable one-pot reaction, the intermediate adduct 1675 was then treated with Hantzsch ester (diethyl 2,6-dimethyl-l,4-dihydropyridine-3,5-dicarboxylate) in mildly acidic medium, which brought about deprotection of the acetal and imine as well as a double reductive amination in which the dihydropyridine acted as the hydrogen transfer agent. The resulting indolizidine ester (—)-1676 was... 

The structural motifs of some excellent chiral crown ethers have been derived from easily accessible natural products. For example, a (+)-camphor-based chiral aza-crown ether 7 was developed and successfully apphed in asymmetric conjugate addition by Brunet [11]. The use of D-glucose-based crown ethers 8 and 9 as chiral phase-transfer catalysts has been intensively studied by Bako and colleagues in the asymmetric Michael addition [12], Darzens condensation [13], and epoxidation [14]. Another carbohydrate-derived chiral crown ether 10 was prepared from chiro-inositol by Aldyama and coworkers, which successfully enabled the enantioselective conjugate addition of N-(diphenylmethylene) glycine tert-butyl ester to several electrophiles [15]. 

Murphy and coworkers prepared similar guanidinium salts 54 from commercially available ethyl (J )-3-hydroxybutyrate and (S)-(—)-mahc acid [86]. The application of the catalysts 54 in the phase-transfer-catalyzed epoxidation of the chalcones delivered high enantioselectivities. Recently, Tan and coworkers developed a series of chiral pentanidium salts 55, which could be successfully applied to the asymmetric phase-transfer-catalyzed conjugate addition [87] as well as a-hydroxylation reactions [88]. 

Although quaternary onium bromides and chlorides as phase-transfer catalysts are generally beUeved to require base additives for phase-transfer reactions of active methylene and methine compounds, which were discussed above, we have recently discovered an hitherto unknown base-free neutral phase-transfer reaction system in asymmetric conjugate additions (Scheme 14.5) [23]. The reactions were efficiently promoted by chiral bifunctional ammonium bromide (S)-7 under neutral conditions with water-rich biphasic solvent. The role of hydroxy groups in the bifunctional catalyst was clearly shown in the transition-state model of the reaction based on the single-crystal X-ray structure of ammonium amide [23b] and nitro-nate [23c]. 

Cram s pioneering work had a significant impact in the design of new chiral crown ethers as phase-transfer catalysts. Koga synthesized a series of C2-symmetric chiral crown ethers 2-4 from optically active diols, and systematically investigated their performance in the asymmetric conjugate addition of methyl phenylacetate to methyl acrylate [8]. Recently, a novel BINOL-based aza-crown ether 5 was developed by Jaszay et al. [9], which was proved to be effective for the asymmetric conjugate addition reaction. Takizawa and coworkers applied a chiral spiro crown ether 6 to the asymmetric benzylation... 

Conformational rigidity and flexibility are two key features for the development of an efficient chiral catalyst. Ma and coworkers developed a new generation of chiral dinuclear phase-transfer catalysts 47 by connecting two structurally rigid BINOL-derived chiral N-spiro quaternary ammonium salts with a flexible linker [80]. These catalysts were proven to act via dual activation of both nucleophiles and electrophiles and to be very efficient catalysts for the conjugate addition of hindered nitroalkanes to enones. Notably, a completely reversed enantioselectivity could be easily switched with catalysts (S,S)-47a and (S,S)-47b, which differ in the length of the methylene chain of the linker but not in the chiral element of backbone. 

The enantioselective conjugate cyanations of electron-deficient alkenic acceptors were also reported by Ricci et al. [42], Deng et al. [51], and Shibata et al. [30] with cinchona-derived phase-transfer catalysts. Moreover, Deng and Shibata applied these conjugate additions of acetone cyanohydrin to develop the enantioselective catalytic routes to chiral dihydropyridazinones, pyrollines, and pyrrohdines, which are the core units of many bioactive compounds (Scheme 12.26). 

Use of the preformed Z-silyl enol ether 18 results in quite substantial anti/syn selectivity (19 20 up to 20 1), with enantiomeric purity of the anti adducts reaching 99%. The chiral PT-catalyst 12 (Schemes 4.6 and 4.7) proved just as efficient in the conjugate addition of the N-benzhydrylidene glycine tert-butyl ester (22, Scheme 4.8) to acrylonitrile, affording the Michael adduct 23 in 85% yield and 91% ee [10]. This primary product was converted in three steps to L-ornithine [10]. The O-allylated cinchonidine derivative 21 was used in the conjugate addition of 22 to methyl acrylate, ethyl vinyl ketone, and cydohexenone (Scheme 4.8) [12]. The Michael-adducts 24-26 were obtained with high enantiomeric excess and, for cydohexenone as acceptor, with a remarkable (25 1) ratio of diastereomers (26, Scheme 4.8). In the last examples solid (base)-liquid (reactants) phase-transfer was applied. 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

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