Chiral stationary phase CHIRALCEL

The potential for use of chiral natural materials such as cellulose for separation of enantiomers has long been recognized, but development of efficient materials occurred relatively recently. Several acylated derivatives of cellulose are effective chiral stationary phases. Benzoate esters and aryl carbamates are particularly useful. These materials are commercially available on a silica support and imder the trademark Chiralcel. Figure 2.4 shows the resolution of y-phenyl-y-butyrolactone with the use of acetylated cellulose as the adsorbent material. 

The enantiomeric purity is determined by chiral stationary phase, supercritical fluid chromatographic (CSP-SFC) analysis (Berger Instruments, Daicel Co. CHIRALCEL OD column 4% methanol, 180 psi, 3.0 mUmin flow rate detection at 220 nm). Racemic 1-phenylpropanol exhibited base-line separation of peaks of equal intensity arising from the R-isomer (tp, 2.74 min) and the S-isomer (tp, 3.10 min) whereas the synthetic alcohol showed these peaks in the ratio 97.7 / 2.3. This chromatographic method allowed for identification of the trace contaminants propiophenone (tp, 1.63 min) and benzyl alcohol (tp 3.40 min). 

The ratio of the enantiomeric benzyl amide products was determined by analyzing a diluted aliquot of the quenched reaction mixture by HPLC using a chiral stationary phase column (Chiralcel OD, Daicel Chemical Co.). Since racemization is a pseudo-first-order kinetic process, these data (along with the time zero value) are sufficient for determination of the intrinsic rate of racemization kR. The half-life for racemization lRU2 can be directly calculated from the l/d ratio (or % enantiomeric excess, %ee) where t was the time of benzylamine addition (the delay time) ... 

The crude mixture was monitored by chiral stationary phase (CSP) HPLC (eluent hexane/isopropanol 95/5, 0.5mLmin, Chiralcel OD-H). After 2 h, (i/f,25)-l-phenyl-3,4-dihydronaphthalene oxide (80% ee) was obtained as the major enantiomer (fR=13.9 min) with 100% conversion (calculated using the internal standard) the minor 1S,2R) enantiomer eluting first (rR=10.1 min). 

The mixture was extracted with diethyl ether (three times). The combined organic layers were washed with brine and dried over sodium sulfate. After concentration in vacuo, the residue was purified by silica gel flash column chromatography (hexane/ethyl acetate = 20/1-3/1) to give (5)-l (426.3 mg, 74%, 98% ee) as a colourless solid. The enantiomeric excess of (5)-l was determined by chiral stationary-phase HPLC analysis DAICEL CHIRALCEL OD-H, j-PrOH/hexane 1/4, flow rate l.OmLmin tR 14.0 min [(R)-isomer)] and 21.3 min [(5)-isomer), detection at 254 nm]. ... 

Gaffney [89] reported the reverse order of elution of 2-phenoxypropanoic acid on Chiralcel OB CSP when different alcohols were used. In 2001 Aboul-Enein and Ali [63] observed the reverse order of elution of nebivolol enantiomers on a Chiralpak AD chiral stationary phase when ethanol and 2-propanol were used separately as the mobile phases. However, the best resolution was obtained when ethanol served as the mobile phase. The inversion of the elution may be due to the different conformation of the polysaccharide CSPs [63]. The pattern of conversion of order of elution using different ratios of ethanol and 2-propanol is shown in Figure 15. 

The optical resolution was achieved in most cases on an analytical scale by chromatography [52] (see the example in Figure 5.14) using chiral stationary phases of the Chiralcel OD or Chiralpak AD-H type. The separation factors vary between close to 1 and 2.36. 

Modified-C02 mobile phases excel at stereochemical separations, more often than not outperforming traditional HPLC mobile phases. For the separation of diastereomers, silica, diol-bonded silica, graphitic carbon, and chiral stationary phases have all been successfully employed. For enantiomer separations, the derivatized polysaccharide, silica-based Chiralcel and Chiralpak chiral stationary phases (CSPs) have been most used, with many applications, particularly in pharmaceutical analysis, readily found in the recent literature (reviewed in Refs. 1 and 2). To a lesser extent, applications employing Pirkle brush-type, cyclodextrin and antibiotic CSPs have also been described. In addi-... 

For situations in which the impurity is an enantiomer, the choice of stationary phase will be limited to chiral stationary phases. For a typical screen, the four common Daicel phases (Chiralcel OD, OJ, and Chiralpak AD, AS) are tried first. The initial screen for these columns is done with... 

The tracer pulse method was also used by Bliimel et al. [112] to determine the binary isotherms of the enantiomers of l-phenoxy-2-propanol on Chiralcel OD, by Lindholm et al. [113] to determine the binary isotherms of methyl-mandelate on Chiral AGP, and by Mihlbachler et al. [1] to determine those of the enantiomers of Troger s base on Chiralpak AD. In this last case, an imusual isotherm was obtained, illustrated in Figure 4.28. The adsorption of the more retained (+) enantiomer is not competitive the amoimt adsorbed by the chiral stationary phase at equilibrium with a constant concentration of the (+) enantiomer is independent of the concentration of the (-) enantiomer. On the other hand, the adsorption of the less retained enantiomer is cooperative the amoimt of this (-) enantiomer adsorbed by the CSP at equilibrium with a constant concentration of this enantiomer increases with increasing concentration of the (+) enantiomer. The isotherm data are best accounted for by an isotherm model derived assuming multilayer adsorption. 

Under a nitrogen atmosphere, a hexane solution of butyllithium (650 pL, 1.00 nunol) was added to bromobenzene (157 mg, 1.00 mmol) in Et20 (0.5 itiL) at 0 X. The mixture was stirred at room temperature for 1 h and then cooled to -78 °C. Trimethoxyborane (104 mg, 1.00 mmol) was added to the reaction mixture. The mixture was stirred at -78 C for 30 min and then at room temperature for 1 h. To the mixture were added H2O (18 mg, 1.00 mmol), isopropyl tra s-2-hexenoate (262) (62 mg, 0.40 mmol), and a solution of Rh(acacXC2H4)2 (3.1 mg, 12 pmol) and (S)-BINAP (9.0 mg, 14 pmol) in dioxane (2.0 mL). The whole mixture was heated at 100 C for 3 h. Addition of saturated aqueous sodium bicarbonate followed by ethyl acetate extraction and chromatography on silica gel (hexane ethyl acetate = 10 1) gave 90 mg (96% yield) of isopropyl 3-phenylhexanoate 264 as a colorless oil. HPLC analysis was performed on a Shimadzu LC-9A (Shimadzu Corp. Nakagyo-ku, Kyoto, Japan) and a JASCO PU- 980, with a JASCO UV-970 UV detector (Jasco Inc., Easton, MD, U.S.A), liquid chromatographic system with chiral stationary phase columns Chiralcel OD-H, OJ and OG, (95% ee). ... 

Preparative Methods The enantiopure sulfonamide la is prepared via sulfonylation of (7J. -l,2-diaminocyclohexane 2 in the presence of an excess of triethylamine (eq 1). Use of excess amine base is essential for obtaining a high yield of the bis-sulfonamide. Synthesis of related bis-sulfonamides is easily accomplished by substituting the desired sulfonyl chloride in the former procedure. Recrystallization of the bis-sulfonamide la from hexane/ethyl acetate and drying over P2O5 allows for isolation of the analytically pure reagent. Methanesulfonyl chloride and (/ ,/5-l,2-diaminocyclohexane 2 are commercially available from a number of sources. However it should be noted that racemic 1,2-diaminocyclohexane 2 can be resolved via formation of the tartrate salt. Typically, the diamine can be obtained in >99 1 enantiomeric ratio (er) after two crystallizations from water. Determination of the enantiopurity of the diamine is accomplished via formation of the bis-3-toluyl amide and analysis via chiral stationary phase HPLC (Chiralcel AD hexane/r-PrOH 95 5, 1.0 mLmin ). 

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