Chiral ammonium ketone

Arai and co-workers have used chiral ammonium salts 89 and 90 (Scheme 1.25) derived from cinchona alkaloids as phase-transfer catalysts for asymmetric Dar-zens reactions (Table 1.12). They obtained moderate enantioselectivities for the addition of cyclic 92 (Entries 4—6) [43] and acyclic 91 (Entries 1-3) chloroketones [44] to a range of alkyl and aromatic aldehydes [45] and also obtained moderate selectivities on treatment of chlorosulfone 93 with aromatic aldehydes (Entries 7-9) [46, 47]. Treatment of chlorosulfone 93 with ketones resulted in low enantioselectivities. 

More recently, the same group has used a simpler and more easily prepared chiral ammonium phase-transfer catalyst 99 derived from BINOL in asymmetric Darzens reactions with a-halo amides 97 to generate glycidic tertiary amides 98 (Table 1.13). Unfortunately the selectivities were only moderate to low [48]. As mentioned in Section 1.2.3.1, tertiary amides can be converted to ketones. 

The quaternary ammonium salt 48 derived from (+)-ephedrine was utilized for the enantioselective addition of diethyl zinc to aldehydes.1421 The chiral ammonium fluorides 7 (R=4-CF3 or 2,4-(CF3)2, X=F) were also useful for the enantioselective trifluoro-methylation of aldehydes and ketones with moderate enantioselectivity,1431 shown in Scheme 17... 

M. D. Drew, N. J. Lawrence, W. Watson, S. A. Bowles, The Asymmetric Reduction of Ketones Using Chiral Ammonium Fluoride Salts and Silanes , Tetrahedron Lett. 1997, 38, 5857-5860. 

Attempts to induce stereochemical control in the reduction of prochiral ketones and imines have been reported using chiral ammonium borohydrides [e.g. 16] (see Chapter 12). 

The cycloaddition of aldehydes and ketones with ketene under the influence of quinine or quinidine produce chiral 2-oxetanones [46,47]. Solvolytic cleavage of the oxetanone, derived from chloral, and further solvolysis of the trichloromethyl group leads to (5)- and (R)-malic acids with a 98% ee [46] (the chirality of the product depends on the configuration of the catalyst at C-8 and, unlike other alkaloid-induced reactions, it is apparently independent of the presence of the hydroxyl group). No attempts have been made to catalyse the reaction with chiral ammonium salts. 

In 1978, Wynberg and coworkers reported the first example of a chiral quaternary ammonium fluoride-catalyzed Michael addition of nitromethane to chalcone (Scheme 9.1) [3]. The reaction was performed in toluene at 20 °C with 10mol% of chiral ammonium salt 1 or 3a and excess potassium fluoride (KF, 15 equiv.), yielding the y-nitro ketone with 10-23% enantiomeric excess (ee). The requisite chiral... 

The enantio-determining step of nucleophilic additions to a-bromo-a,y -unsaturated ketones is mechanistically similar to those of nucleophilic epoxidations of enones, and asymmetry has also been induced in these processes using chiral phase-transfer catalysts [20]. The addition of the enolate of benzyl a-cyanoacetate to the enone 31, catalysed by the chiral ammonium salt 32, was highly diastereoselective and gave the cyclopropane 33 in 83% ee (Scheme 12). Good enantiomeric excesses have also been observed in reactions involving the anions of nitromethane and an a-cyanosulfone [20]. 

Enantioselective Darzens Reaction. An enantioselective Darzens reaction between ethyl methyl ketone and chloromethyl p-tolyl sulfone in the presence of a chiral ammonium salt derived from (1) and chloromethylpolystyrene affords an optically active a,p-epoxy sulfone in 23% ee. ... 

Recently, Shibata, Tom, and coworkers demonstrated that a mixture of chiral ammonium bromides, 146 and 147, and tetramethylammonium fluoride (TMAF) [67] or KF [68] can be directly used as a catalyst without the need for the prior isolation of the fluoride salts. By utilizing this catalyst system, the reactions ofvarious aromatic ketones or aldehydes with (TMS)CF3 were completed within a few hours to afford the corresponding products in moderate to high enantioselectivities (Schemes 8.56 and 8.57). 

Optically active a, -epoxy stdfones. - The Darzens reaction of ethyl methyl ketone with chloromethyl / -tolyl sulfone in a two-phase system in the presence of chiral ammonium salts such as N-ethylephedrinium bromide results in a,/3-epoxy sulfones with 0-2.57o optical yields. However, if the supported catalyst (1) is used, optical yields of up to 23% can be obtained as in the example formulated in equation (I). On the other hand, the reaction is slower when the catalyst is supported. The presence of a hydroxy group jS to the nitrogen atom of the catalyst is essential for asymmetric induction. 

Another relevant pioneering report in this context was carried out by Corey, using cinchona-based chiral ammonium salt 103a as catalyst (Scheme 5.5). In this case, the conjugate addition of tert-butyl glycinate benzophenone imine to cyclohexanone and ethyl vinyl ketone was found to proceed with excellent yields and enantioselectivities and, in the cyclohexanone case, also with almost complete diastereoselectivity. Cesium hydroxide was selected for this particular reaction as the most appropriate base to generate the reactive enolate species. 

Further work has been published concerning the use of N-methylephedrinium salts ° and other chiral ammonium salts in the phase-transfer catalysed borohydride reduction of prochiral ketones. 

Drew and Lawrence used the chiral ammonium fluoride salt 14 to activate polymethylhydrosiloxane (PMHS) and triethoxysilane, whereby the latter proved superior and was subsequently used to reduce prochiral ketones in excellent yields but only moderate enantioselectivities (Scheme 32.11). ... 

SCHEME 32.11. Reduction of ketones with chiral ammonium salts. 

Drew M. The asymmetric reduction of ketones using chiral ammonium fluoride salts and silanes. Tetrahedron Lett. 1997 38 5857 5860. 

It was believed that aliphatic bis(ammonium) ketones would not suffer the oxidative instability displayed by the aromatic counterparts (Fig. 1.4). Indeed ketone 7 when using 10 mol% epoxidized a variety of olefins in good yield, but the chiral variants only gave poor ees, for example, ca 10% ee for iran -P-methylstyrene (using catalyst 8). 

The enantioselective addition of a nucleophile to a carbonyl group is one of the most versatile methods for C C bond formation, and this reaction is discussed in Chapter 2. Trifluoromethylation of aldehyde or achiral ketone via addition of fluorinated reagents is another means of access to fluorinated compounds. Trifluoromethyl trimethylsilane [(CF SiCFs] has been used by Pra-kash et al.87 as an efficient reagent for the trifluoromethylation of carbonyl compounds. Reaction of aldehydes or ketones with trifluoromethyltrime-thylsilane can be facilitated by tetrabutyl ammonium fluoride (TBAF). In 1994, Iseki et al.88 found that chiral quaternary ammonium fluoride 117a or 117b facilitated the above reaction in an asymmetric manner (Scheme 8-42). 

Some chiral quaternary ammonium salts are also effective in Michael addition reactions. The Merck catalysts 7 (R=4-CF3, X=Br) and 9 (R=4-CF3, X=Br, 10,11-dihydro) were used tor the Michael additions of 59,61, and 64 to vinyl ketones to give the adducts 60,62, and 65 (isolated as 66), respectively,148,491 with excellent enantioselectivity, as shown in Scheme 19. The Michael addition of the O Donnell imine 23 to the a,(3-unsaturated carbonyl compounds also efficiently proceeded by use of the N-anthracenyl-methyl catalyst 12 (R=allyl, X=Br), giving the Michael adducts 67 (Scheme 20).1251... 

The asymmetric Darzens condensation, which involves both carbon-carbon and carbon-oxygen bond constructions, was realized by use of the chiral azacrown ether 75als2,s ,ss and the quaternary ammonium salts derived from cinchona alka-loids159"621 under phase transfer catalyzed conditions. The a,p-epoxy ketone 80 (R=Ph) was obtained with reasonable enantioselectivity by the reaction of... 

K. Iseki, T. Nagai, Y. Kobayashi, Asymmetric Trifluoro-methylation of Aldehydes and Ketones with Trifluoro-methyltrimethylsilane Catalyzed by Chiral Quaternary Ammonium Fluorides , Tetrahedron Lett. 1994, 35, 3137-3138. 

The ammonium catalyst can also influence the reaction path and higher yields of the desired product may result, as the side reactions are eliminated. In some cases, the structure of the quaternary ammonium cation may control the product ratio with potentially tautomeric systems as, for example, with the alkylation of 2-naph-thol under basic conditions. The use of tetramethylammonium bromide leads to predominant C-alkylation at the 1-position, as a result of the strong ion-pair binding of the hard quaternary ammonium cation with the hard oxy anion, whereas with the more bulky tetra-n-butylammonium bromide O-alkylation occurs, as the binding between the cation and the oxygen centre is weaker [11], Similar effects have been observed in the alkylation of methylene ketones [e.g. 12, 13]. The stereochemistry of the Darzen s reaction and of the base-initiated formation of cyclopropanes under two-phase conditions is influenced by the presence or absence of quaternary ammonium salts [e.g. 14], whereas chiral quaternary ammonium salts are capable of influencing the enantioselectivity of several nucleophilic reactions (Chapter 12). 

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