Michael enantioselective phase-transfer catalyst

A chiral phase transfer catalyst was dissolved in ionic liquid media for the enantioselective Michael reaction of dimethyl malonate with l,3-diphenylprop-2-en-l-one with K2CO3 203). The phase-transfer catalyst was a chiral quininium bromide (Scheme 20). The reaction proceeded rapidly with good yield and good enantioselectivity at room temperature in all three ionic liquids investigated, [BMIM]PF6, [BMIM]BF4 and [BPy]BF4. In the asymmetric Michael addition, the enantioselectivity or the reaction in [BPy]Bp4 was the same as in conventional organic solvents. 

As mentioned above, the enantioselective Michael addition of P-keto esters to a,P-unsaturated carbonyl compounds represents a useful method for the construction of densely functionalized chiral quaternary carbon centers. One characteristic feature of designer chiral phase-transfer catalyst lh in this type of transformation is that it enables the use of a,p-unsaturated aldehydes as an acceptor, leading to the... 

Arai et al. also reported another BINOL-derived two-center phase-transfer catalyst 31 for an asymmetric Michael reaction (Scheme 6.11) [8b]. Based on the fact that BINOL and its derivatives are versatile chiral catalysts, and that bis-ammonium salts are expected to accelerate the reaction due to the two reaction sites - thus preventing an undesired reaction pathway - catalyst 31 was designed and synthesized from the di-MOM ether of (S)-BINOL in six steps. After optimization of the reaction conditions, the use of 1 mol% of catalyst 31a promoted the asymmetric Michael reaction of glycine Schiff base 8 to various Michael acceptors, with up to 75% ee. When catalyst 31b or 31c was used as a catalyst, a lower chemical yield and selectivity were obtained, indicating the importance of the interaction between tt-electrons of the aromatic rings in the catalyst and substrate. In addition, the amine moiety in catalyst 31 had an important role in enantioselectivity (34d and 34e lower yield and selectivity), while catalyst 31a gave the best results. 

Recently, chiral phase-transfer-catalyzed asymmetric Michael addition has received much attention, and excellent enantioselectivity (up to 99% ee) has been reported using cinchona alkaloid-derived chiral phase-transfer catalysts [40]. Among noncinchona alkaloid-derived chiral phase-transfer catalysts Shibasaki s tartrate derived C2-symmetrical two-center catalyst provided a Michael adduct with up to 82% ee [41]. 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

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],... 

The glycinate Schiff base of benzophenone 17 was also shown to be a suitable Michael donor for the asymmetric 1,6-addition to the activated dienes 44 having ketones, esters, and sulfones as substituents. Using Corey s phase-transfer catalyst, 16, the corresponding allylated products 47 were obtained as a single E-isomer with high enantioselectivity (from 92 to 98% ee). The synthetic utility of this reaction... 

Recently, we addressed the importance of a dual-functioning chiral phase-transfer catalyst such as 73 for obtaining a high level of enantioselectivity in the Michael addition of malonates to chalcone derivatives [58]. For instance, the reaction of diethyl malonate with chalcone in toluene under the influence of K2CO3 and 73 (3 mol%) proceeded smoothly at -20 °C with excellent enantioselectivity, while the selectivity was markedly decreased when 74 possessing no hydroxy functionality was used as catalyst (Scheme 11.16). 

Wynberg and co-workers reported the first example of a chiral quaternary ammonium fluoride-catalyzed Michael addition of nitromethane to chalcone [48], Although the enantioselectivity in the initial report was modest, a range of chiral phase-transfer catalysts, in particular based on cinchona alkaloids, were reported. 

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... 

Very high enantioselectivities in the PTC Michael addition of 1,3-dicarbonyl compounds to enones have been achieved by Maruoka et al. [189,233] As shown in Scheme 2.86, just a 2 mol% of the binaphthyl-derived phase-transfer catalyst 124b [Scheme 2.70, 124, Ar=3,5-((CFj)jC H3)] in the presence of 10 mol% of solid KjC03, is able to achieved a highly efQdent and enantioselective addition of 2-(9-fluorenoxycarbonyl)cyclopentanone to methyl vinyl ketone [189]. 

The enantioselective phase-transfer catalyzed Michael addition of A-(diphenyl-methylene)glycine fert-butyl ester to several Michael acceptors such as methyl acrylate, cyclohex-2-enone and ethyl vinyl ketone was initially studied by Corey et al. employing 0(9)-aUyl-Af-9-anlhraceny]melhylcinchonidimum bromide (173) (Fig. 2.24) as catalyst and cesium hydroxide as base [272]. Different studies followed this pioneering woik, presenting diverse modifications over the standard procedure such as the employment of non-ionic bases [273], variations of the nucleophile functionality [274], and using new chiral phase-transfer catalysts, the most attention paid to this latter feature. For instance, catalyst 173 was successfully employed in the enantioselective synthesis of any of the isotopomers of different natural and unnatural amino acids... 

Complementary to the above-presented enantioselective sequences Michael addition/a-alkylation of bromomalonates, a related powerful gem-dialkylative process was also proposed recently [38]. a-Dialkylation of imines 25 with 1,4-dihalo-but-2-ene 26 using a cinchonidine derivative J as phase-transfer catalyst proceeded smoothly in the presence of aqueous NaOH to give the (l/ ,25)-l-amino-2-vinylcyclopropanecarboxylic acid derivatives 27 with generally good diastereose-lectivity but with enantiomeric excesses not exceeding 80% (Scheme 5.10). 

Mirza-Aghayan et al. [51] reported a heterogeneous Michael addition of N-acetylaminomalonate to chalcone, in the presence of a chiral phase-transfer catalyst (N-benzyl-N-methylephedrinium bromide) and potassium hydroxide. The reaction was realized in toluene as well as in the absence of the solvent The authors observed that sonication enhances the rate of the reaction by 4—5 times with no loss of enantioselectivity compared to conventional stirring. For the reaction carried out without solvent at 60 °C for 5 min the product was isolated in 82% yield and 40% ee. This phenomenon is connected to homogenization of the reaction mixture and mass transfer enhancement. 

To overcome the low diastereoselectivities reported in the Michael addition of prochiral nitroalkanes to enones, Maruoka and coworkers reported the use N-spiro quaternary ammonium salt (108) as phase-transfer catalysts [98a]. As shown in Scheme 33.30, the results in terms of yields and diastereo- and enantioselectivities were excellent. A year later, the same research group expanded the scope of the reaction with the use of silylnitronates instead of nitroalkanes [98b]. 

Since heterocycles containing a trifluoromethyl group are representatives of a major structure type in agricultural and medicinal chemistry, Shibata ct al. have developed a novel enantioselective synthesis of trifluoromethyl-substituted 2-isoxazolines 46 on the basis of a domino oxa-Michael-intramolecular hemi-aminahzation-dehydration reaction of hydroxylamine with a range of ( )-trifluoromethylated enone derivatives 47 [81]. This process, which employed N-3,5-bis(trifluoromethyl)benzyl-quinidinium bromide 48 as a chiral phase-transfer catalyst combined with CsOH as a base provided a series of trifluoromethyl-substituted 2-isoxazolines 46 in high yields and enantioselectivities of up to 94% ee (Scheme 37.8). 

Instead of using chloramine-T (pKa 13.5), the employment of more nucleophilic chloramine salt, A-chloro-A-sodiobenzyloxycarbamate (pKa 15.3), allows for an efficient aziridination of electron-deficient olefins (Michael acceptors) in the presence of a solid-liquid phase-transfer catalyst (Scheme 2.38) [57]. The reaction would involve an ionic pathway where the Michael-addition of chloramine salt to alkenes and the following back-attack of the resulting enolate at the electrophilic N-center to cyclize. This reaction was successfully extended to the asymmetric aziridination of the enones that have an auxiliary, to produce chiral aziridines with good enantioselectivities up to 87% ee. Another option to aziridinate electron-deficient alkenes is the utilization of... 

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