Cinchonidinium derivative

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]. 

The N-anthracenylmethyl cinchonidinium catalyst 12 (R=PhCH2, X=HF2) was applied to the aldol reaction of the silyl ether 43 derived from the... 

The stereospecific C-alkylation of a range of benzylic ketones, such as tetralones, 2-phenylcyclohexanones and cycloheptanones, and 2-phenyl-y-lactones, has also been described [8]. For example, Af-(4-trifiuoromethylbenzyl)cinchonidinium bromide catalyses the reaction of 1,5-dibromopentane with 7-methoxy-l-methyl-2-tetralone to yield the (R)-l-(5-bromopentyl) derivative (75% yield with 60% ee). 

The aldehyde (3.38 mmol) and the cinchonidinium catalyst (40 mg, 16.9 imol) in CH2C12 (0.8 ml) are added to the O-silyl ketene acetal (0.676 mmol), derived from... 

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. 

This asymmetric phase-transfer method has been applied to enantio-selective Robinson annelation as shown in Scheme 14 (41). First, alkylation of a 1-indanone derivative with the Wichtetie reagent as a methyl vinyl ketone equivalent in the presence of p-CF3BCNB gives the S-alkylation product in 92% ee and 99% yield. With 1 -(p-trifluoro-methylbenzyl)cinchonidinium bromide, a pseudo-enantiomeric diaste-reomer of p-CF3BCNB, as catalyst, the -alkylation product is obtained in 78% ee and 99% yield. These products are readily convertible to the... 

The enolate derived from the Schiff base 3 has been added to a,/ -unsaturated esters and ketones with a high level of enantioselectivity. For example, in the presence of 10 mol% lb, the enolate of the glycine derivative 3 was added to cyclohexenone with excellent diastereo-selectivity to give the ketoester 20 with >99% ee (Scheme 7) [15]. Promising results have also been obtained in the Michael additions of malonates to chalcone deriviatives [16], The novel cinchonidinium bromide lg was found to be the most effective catalyst for this transformation, yielding the Michael adduct 21 with 70% ee (Scheme 8). 

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). 

Keto esters represent interesting substrates that permit ready and various opportunities for further stmctural manipulation, but until 2002 only limited asymmetric a-alkylation procedures were developed [85]. In 2002, Dehmlow et al. [86] demonstrated the use of cinchonidinium bromide Ic in asymmetric a-alkylation of p-ketoester 24 when the corresponding benzylated product 29 (Scheme 8.11, entry 1) was obtained in excellent yield (97%), satisfying 46% ee. Better results in terms of enantioselectivity (up to 97% ee) were reported by Kim and co-workers [87], who showed the effectiveness of bulky cinchonine-derived catalysts IL in asymmetric a-alkylation of P-ketoesters(Scheme 8.11, entry 2). An asymmetric a-alkylation procedure with broad generahty in terms of the stmcture of P-ketoesters 25 and alkyl hahdes under PTC with C2-symmetric PTC L was developed by Maruoka and co-workers [88] (Scheme 8.11, entry 3). Further optimization led to the development of a reliable route for the asymmetric synthesis of not only a,a-dialkyl-P-hydroxy and p-amino esters, but also functionalized aza-cyclic a-amino esters [89], a-alkylated ketolactones [90], and functionalized a-benzoyloxy-P-ketoesters [91]. Shghtly changed catalyst XXV (Scheme 8.12) was also successfully used for the constmction of enantiomerically enriched various a-alkyl-a-fluoro-P-keto esters... 

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)... 

---