Phase quinine-derived

For a similar series of chalcone derivatives the use of aqueous sodium hypochlorite in a two phase system (with toluene as the organic solvent) and the quinine derivative (32) as a chiral phase-transfer catalyst, produces epoxides with very good enantiomeric excesses and yields1981. 

New brush-type phases (donor-acceptor interactions) are appearing all the time. " Examples are stationary phases comprising quinine derivatives and trichloro-dicyanophenyl-L-a-amino acids as chiral selectors. Quinine carbamates, which are suitable for the separation of acidic molecules through an ionic interaction with the basic quinine group, are also commonly used but in general they are classified with the anion-exchange type of chiral selectors (see further) because of their interaction mechanism, even though r-donor, r-acceptor properties occur. (Some separations on Pirkle-type CSPs are shown in Table 2.)... 

Michael additions of C-nudeophiles such as the indanone 1 have been the subject of numerous further studies For example, the reaction between the indanone 1 and methyl vinyl ketone was effected by a solid-phase-bound quinine derivative in 85% yield and with remarkable 87% ee by d Angelo, Cave et al. [5], Co-polymers of cinchona alkaloids with acrylonitrile effected the same transformation Kobaya-shi and Iwai [6a] achieved 92% yield and 42% ee and Oda et al. [6b] achieved almost quantitative yield and up to 65% ee. Similarly, partially resolved 2-(hydroxy-methyl)quinudidine was found to catalyze the reaction between 1 and acrolein and a-isopropyl acrolein with induction of asymmetry, but no enantiomeric excesses were determined [7]. As shown in Scheme 4.4, the indanone 7 could be added to MVK with up to 80% ee under phase-transfer conditions, by use of the Cinchona-derived PT-catalysts 9a and 9b, affording the Michael-product 8 or enf-8, respectively [8]. The adducts 8 or ent-8 were intermediates in the stereoselective Robinson anellation of a cydohexenone ring to the indanone 7 [8],... 

Lammerhofer and Lindner [62] reported on the enantiomer separation of deriva-tized amino acids on an ODS-packed capillary with a chiral quinine-derived selector as buffer additive in two different modes (i) in an electrophoretically dominated mode at high electrolyte concentration and (ii) in an electroosmotically dominated mode at a low electrolyte concentration. Enantiomer separation in the electrophoretically dominated mode (i) leads to high efficieny (about two to three times higher than in LC) but to a moderate enantioselectivity (about the same as in LC). In the electroosmotically dominated mode (ii) a higher enantioselectivity but a lower efficiency (even inferior to LC) occurs. The separations can also been performed in a non-aque-ous buffered mobile phase. Pressurization (8-10 bar) of the flow system on both ends of the separation capillary was applied. 

A somewhat more successful approach to asymmetric Darzens reactions has been observed in the reaction of a-halosulfones with aldehydes under phase-transfer conditions <07T8099>. The reaction of an a-chlorosulfone with benzaldehyde in the presence of quinine derived phase-transfer catalyst 11, provides the epoxide in excellent yield with very good enantioselectivity. The use of RbOH as the base was crucial to both yield and enantioselectivity. 

Until recently, little success had been achieved in developing a highly enantioselective version of the Darzens reaction. Several investigations of chiral phase-transfer catalysts for this condensation, in which low or modest asymmetric induction is obtained, have been reported. These include the use of N-alky -N-methylephedrinium halides, the quinine-derived salt (120), and polyamino acids. A related study has examined the use of achiral phase-transfer catalysts in the condensations of carbonyl compounds and the asymmetric chloromethylsulfonate ester (121). The same group of researchers subsequently reported similar studies employing the sulfonamides (122)-(124). ... 

In sharp contrast to the oxidation reactions of electron-rich olefins just described, attempts to carry out nucleophilic epoxidation reactions of a,p-unsaturated carbonyl compounds have enjoyed only limited success (Scheme 8.7) [19]. The most successful attempts have been with chalcones, using standard basic peroxidation conditions with additives such as a quinine-derived phase-transfer catalyst first... 

In the case above, the photocatalyst operates via a redox step. Alternatively it could chemically react, as is the case for the hydroxylatitMi of p-keto esters 46 that occurs with a significant enantioselectivity and has been obtained in the presence of a quinine-derived phase-transfer catalyst at —13 °C via singlet oxygen (TPP as the sensitizer). This is an example of B in Scheme 8.14, for the synthesis of 47 [34]. 

Fig. 11 Elution profiles corresponding to the separation of increasing amounts of DNB ( )-Leu using a quinine derivative as CS. (a) Classical elution mode CS/racemate molar ratios 2.6, 1.3, and 0.8, respectively. Solvent system MIBK-acetone-ammonium acetate buffer 0.1 M pH 8.0 (2 1 2), 10 mM CS. (b) pH-Zone-refining. Stationary phase, MIBK containing TEA (10 mM) and the CS (10 mM) mobile phase, water containing ammonia (20 mM). CS/racemate molar ratios 0.85, 0.61, and 0.45, respectively. In all cases the first eluting isomer corresponds to the R enantiomer. Vertical left axis, arbitrary absorbance units. Vertical right axis, pH Horizontal axis, time. Adapted from [64]...

The asymmetric epoxidation of the chalcone type of substrate has also been accomplished using other types of chiral catalysts [15]. Wynberg was the first to use chiral ammonium salts, and obtained chalcone oxide with 55% ee using alkaline hydrogen peroxide as the stoichiometric oxidant and a quinine-derived quaternary ammonium salt as the chiral phase transfer catalyst [16]. More recently, Lygo... 

Figure 12.5 Quinine-derived quaternary ammonium salt phase-transfer catalysts.

C. Hofstetter, P. S. Wilkinson, T. C. Pochapsky, NMR Structure Determination of Ion Pairs Derived from Quinine A Model for Templating in Asymmetric Phase-Transfer Reductions by BH4" with Implications for Rational Design of Phase-Transfer Catalysts , J. Org. Chem 1999, 64, 8794-8800. 

A limited study has been made of the role of the structure of the catalyst in the phase-transfer epoxidation reaction (77). The catalysts tried were mainly salts of quinine (3a-g), cinchonidine (4), ephedrine (5), and a camphor derivative (6) (Figure 14). The conclusions were as follows ... 

The first silica-supported CSP with a cinchona alkaloid-derived chromatographic ligand was described by Rosini et al. [20]. The native cinchona alkaloids quinine and quinidine were immobilized via a spacer at the vinyl group of the quinuclidine ring. A number of distinct cinchona alkaloid-based CSPs were subsequently developed by various groups, including derivatives with free C9-hydroxyl group [17,21-27] or esterified C9-hydroxyl [28,29]. All of these CSPs suffered from low enantiose-lectivities, narrow application spectra, and partly limited stability (e.g., acetylated phases). 

FIGURE 1.30 Micro-HPLC separation of all 4 stereoisomers of the dipeptide alanyl-alanine as FMOC derivatives (a) and DNP-derivatives (b), respectively, on a 0-9-(tert-butylcarbamoyl)quinine-based CSP. Experimental conditions Column dimension, 150 X 0.5 mm ID mobile phase (a) acetonitrile-methanol (80 20 v/v) containing 400 mM acetic acid and 4 mM triethylamine, and (b) methanol-0.5 M ammonium acetate buffer (80 20 v/v) (pHa 6.0) flow rate, 10 ixLmin temperature, 25 C injection volume, 250 nL detection, UV at 250 nm. (Reproduced fromC. Czerwenka et al., J. Pharm. Biomed. Anal., 30 1789 (2003). With permission.)... 

The effect of mobile phase composition, including pH and organic modifiers, was carried out on the chiral resolution of leucine derivatives on the fert-butyl carbamoylated quinine-based CSP [2], The results of these findings are given in Table 2. This table shows that the best resolution was obtained at pH 5, 2mM concentration of buffer, 60% methanol, and 80% acetonitrile concentrations, separately. In another study, the same authors [4] studied the influence of the mobile phase, pH, and temperature on the chiral resolution of leucine derivatives. The effect of temperature on the chiral resolution of leucine derivatives is shown in Figure 2. It is clear from this figure that the chiral... 

All catalytic enantioselective versions of the Darzens condensation are based on the use of chiral phase-transfer agents, e.g. the cations 184a,b derived from ephed-rine, quinine/quinidine-based ammonium ions such as 185a,b, or the crown ether 186. 

Phase-transfer catalysis has been widely been used for asymmetric epoxidation of enones [100]. This catalytic reaction was pioneered by Wynberg et al., who used mainly the chiral and pseudo-enantiomeric quaternary ammonium salts 66 and 67, derived from the cinchona alkaloids quinine and quinidine, respectively [101-105],... 

Three chiral stationary phases that were prepared by derivatizing y-mercaptopropylsilanized silica gel with quinine (CSP II), quinidine (CSP III), and cinchonidine (CSP IV), have been used for the successful resolution of N-acyl derivatives of fl-hydroxyphenethylamines [25]. UV and CD detectors set at 270 nm were used in series. The effectiveness of the separation and the detection are illustrated in Figure 6 for the resolution of the N-(3,5-dinitrobenzoyl) derivative of phenylethanolamine on CSP III. 

Another type of CSP able to undergo charge transfer interaction is the one developed by Lindner s group [101], In order to determine the interactions between the quinine CSP and the enantiomeric analytes, a detailed computational study was undertaken of the interaction of this stationary phase with 3,5-dinitrobenzoyl derivatives of leucine (Figure 22-27) [102],... 

Another approach is electrochromatography with capillary columns packed with an achiral stationary phase, preferentially a reversed-phase type material. The chiral SO is added to the background electrolyte, and may be adsorbed onto the stationary phase by a secondary equilibration process. Enantioseparations in this additive mode have been reported with cyclodextrin type SOs )504-507) and with a chiral ion-pair agent derived from quinine 1508) as mobile phase additives. 

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