Cinchonidinium salt

Although several noble-metal nanoparticles have been investigated for the enantiomeric catalysis of prochiral substrates, platinum colloids remain the most widely studied. PVP-stabilized platinum modified with cinchonidine showed ee-values >95%. Several stabilizers have been also investigated such as surfactants, cinchonidinium salts and solvents, and promising ee-values have been observed. Details of a comparison of various catalytic systems are listed in Table 9.16 in one case, the colloid suspension was reused without any loss in enantioselectiv-ity. Clearly, the development of convenient two-phase liquid-liquid systems for the recycling of chiral colloids remains a future challenge. 

Diastereomeric excesses of up 56% have been claimed for the preparation of a-amino-P-hydroxy acids via the aldol condensation of aldehydes with f-butyl N-(diphenylmethylene)glycinate [63]. It might be expected that there would be thermodynamic control of the C-C bond formation influenced by the steric requirements of the substituents, but the use of cinchoninium and cinchonidinium salts lead to essentially the same diastereoselectivity. The failure of both tetra-n-butylammo-nium and benzyltriethylammonium chloride to catalyse the reaction is curious. 

C-alkylated Meldrum s acid derivatives are cleaved asymmetrically by alkoxide anions in the presence of quininium salts to yield chiral half esters (9.2.2) [11]. Thus, benzylquininium and cinchonidinium salts produce fl-hemi-esters and the cincho-nium and quinidinium salts produce the S-hemi-esters from, for example, 2,2,5-trimethyl-5-pheny 1-1,3-dioxane-4,6-dione. 

Phase-transfer catalysed oxidation of ketones with dioxygen under basic conditions in the presence of triethyl phosphite and a cinchonium salt produces a-hydroxy-ketones (Schemes 12.14 and 12.15, Table 12.9) in good overall yield (-95%) and with a high enantiomeric excess [>70% ee using N-(4-trifluoromethyIbenzyl)cincho-nium bromide] [29], Lower asymmetric induction is observed with ephedrinium salts, polymer-supported salts and, surprisingly, by cinchonidinium salts. 

Two different epoxidation reactions have been studied using chiral phase transfer catalysts. The salts 22 and 23 have been used to catalyse the nucleophilic epoxidation of enones (e.g. 24) to give either enantiomer of epoxides such as 25 (Scheme 9) [17]. Once again, the large 9-anthracenylmethyl substituent is thought to have a profound effect on the enantio selectivity of the process. A similar process has been exploited by Taylor in his approach to the Manumycin antibiotics (e.g. Manumycin C, 26) [18]. Nucleophilic epoxidation of the quinone derivative 27 with tert-butyl hydroperoxide anion, mediated by the cinchonidinium salt la, gave the tx,/ -epoxy ketone 28 in >99.5% ee (Scheme 10). 

Corey studied the X-ray crystal structures of cinchonidinium salts and has formulated a model which explains the highly enantioselective alkylation of the enolate of 3 [3]. This model accounts for the sense of asymmetric induction in this process and the importance of the size of the R1 substituent in the salts 1 and 2 the model can be used to rationalise other phase transfer catalysed processes involving similar catalysts. The enolate 37 is thought to be in close contact with the least hindered face of the tetrahedron formed by the four atoms surrounding the quaternary nitrogen atom (the rear face of this tetrahedron is blocked by the bulky 9-anthracenylmethyl group). Alkylation of the less hindered face of 37 leads to the observed enantiomer of the product (see Figure 1). 

The advantages of PTC reactions are moderate reaction conditions, practically no formation of by-products, a simple work-up procedure (the organic product is exclusively found in the organic phase), and the use of inexpensive solvents without a need for anhydrous reaction conditions. PTC reactions have been widely adopted, including in industrial processes, for substitution, displacement, condensation, oxidation and reduction, as well as polymerization reactions. The application of chiral ammonium salts such as A-(9-anthracenylmethyl)cinchonium and -cinchonidinium salts as PT catalysts even allows enantioselective alkylation reactions with ee values up to 80-90% see reference [883] for a review. Crown ethers, cryptands, and polyethylene glycol (PEG) dialkyl ethers have also been used as PT catalysts, particularly for solid-liquid PTC reactions cf. Eqs. (5-127) to (5-130) in Section 5.5.4. 

Continuing with the use of cinchona alkaloid-based quaternary ammonium salts as catalysts, phenyl vinyl sulfones have also been employed as Michael acceptors in the reaction with glycine imines using cinchonidinium salt 103a as catalyst both in solution or in a solid-supported version (Scheme 5.33), furnishing similar results to those provided by the corresponding vinyl ketones and acrylates shown in Schemes 5.8 and 5.23. ... 

Better levels of enantioselectivity have been achieved using different carbamates as nitrogen-atom source to perform this transformation. Hence, using N-chloro-N-sodium benzylcarbamate (6) and cinchoninium salt 7a, as a phase-transfer catalyst, in the aziridination of dimethylpyrazole acrylate 5 afforded the corresponding aziridine [12], which was further treated with N,N-dimethylaminopyridine (DMAP) to give the methyl-ester substituted aziridine 8 (Scheme 27.3). The use of the pseudo-enantiomeric cinchonidinium salt led to the aziridine with the opposite absolute configuration, as expected. 

Better enantioselectivities were obtained with modified cinchoninium salt 6a and its pseudoenantiomer cinchonidinium salt 6b, in which the hydroxy group is deriva-tized as tosyl ester. In this case, both catalysts acted, as was expected, leading to both different aziridine enantiomers with similar enantioselectivity (up to 95% ee), with the enantiomeric excess being highly influenced by the presence of substituents on the aromatic ring of the hydroxamic acid 1 [5]. 

Researchers at Merck documented that the N-benzylated cinchonidinium derivative 112 was an excellent phase-transfer catalyst in the Michael addition of 2-propylindanone 111 to 74 (Scheme 12.14) [108]. The reaction is conducted in a biphasic medium (50% aq. NaOH/toluene) with substoichio-metric quantities of the quaternized cinchonidinium salt 112 [109]. The adduct 113 was isolated in 95 % yield and 80 % ee and served as a key intermediate en route to an asymmetric synthesis of the drug candidate 114 [108]. 

Inspired by the positive effect of dimeric cinchona alkaloid ligands in the Sharpless asymmetric dihydroxylation [55], Jew, Park, and coworkers developed a new family of dimeric cinchona-derived catalysts. The authors first prepared a series of dimeric cinchonidinium salts 24, 25a, and 26 using a phenyl spacer (Figure 12.7)... 

Other research groups also devoted their efforts toward the design and synthesis of new polymeric cinchona-based quaternary ammonium salts. Najera et al. [59] developed the catalyst 29 which incorporates a 9,10-dimethylanthracenyl bridge as a spacer, whereas Siva and Murugan [60] prepared the dimeric cinchonidinium salts 30 using a cyclic tetraamine spacer. Both catalysts exhibited good performance in the asymmetric benzylation of N-(diphenyhnethylene) glycine tert-butyl ester. 

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