Modified Linear Dextrins (УAcyclodextrinsФ) as New Chiral Selectors for the Gas-Chromatographic Separation of Enantiomers.
код для вставкиСкачатьCommunications Enantiomer Separation Modified Linear Dextrins (“Acyclodextrins”) as New Chiral Selectors for the GasChromatographic Separation of Enantiomers** Giuseppe Sicoli, Zhengjin Jiang, Laszlo Jicsinsky, and Volker Schurig* In memory of Jzsef Szejtli Cyclodextrins (CDs) modified by alkylation, acylation, and silylation represent versatile chiral stationary phases (CSPs) for the gas-chromatographic separation of enantiomers.[1] Typically, they are dissolved in semipolar polysiloxanes[2a] or linked chemically to polydimethylsiloxane (Chirasil-Dex).[2b] The mechanism of enantiomer recognition is still not well understood, and the role of the CD cavity is unclear in cases were enantioselectivity is low, as it is in most reported cases (a < 1.1).[1a] We therefore conjectured that the existence of a cavity may not be a prerequisite to chirality recognition in cyclodextrins. This has now been borne out by employing linear dextrins (“acyclodextrins”) as a new generation of carbohydrate-based chiral selectors for the gas-chromatographic separation of enantiomers. Despite the well-known propensity of cyclodextrins to include various organic compounds in their cavities,[3] it seems plausible to consider the ability of modified linear oligosaccharides as selectors for enantioselective chromatography since helical conformations may act as “semicavities” and suitable functionalities may be present. Previously, per-npentylated amylose[4a] and amylose tris(n-butylcarbamate)[4b] were employed for chiral separations by GC, albeit with limited enantioselectivity. Moreover, the ability of native acyclic a-1,4-linked dextrin (i.e. maltoheptaose) to form molecular complexes and its use for chiral separation by capillary zone electrophoresis has been demonstrated,[5a] for example, for racemic 1,12-dimethylbenzo[c]phenanthrene5,8-dicarboxylic acid.[5b] Even with modified cyclodextrins, NMR studies in solution have shown that interactions of the outer surface play an important role in the chiral-recognition process.[6] [*] G. Sicoli, Dr. Z. Jiang, Prof. Dr. V. Schurig Institute of Organic Chemistry University of Tbingen Auf der Morgenstelle 18, 72076 Tbingen (Germany) Fax: (+ 49) 7071-297-6257 E-mail: [email protected] Dr. Z. Jiang King’s College, Department of Pharmacy Micro Separations Group, Frankling-Wilkins Building Stamford Street 150, SE1 9NN London (UK) Dr. L. Jicsinsky CYCLOLAB Ltd. Illatos fflt 7, 1097 Budapest (Hungary) [**] This work was supported by the Graduate College “Chemistry in Interphases” of the German Research Council. 4092 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200500509 Angew. Chem. Int. Ed. 2005, 44, 4092 –4095 Angewandte Chemie Herein, we compare the enantioselectivity of the versatile cyclic chiral selector heptakis(2,3-di-O-acetyl-6-O-tert-butyldimethylsilyl)-b-cyclodextrin (CD7)[7] with that of the acyclic dextrin counterpart heptakis[(1’-O,6-O)-tert-butyldimethylsilyl-(2,3-di-O,4’’-O)-acetyl)]-maltoheptaose (G7, G = glucose), which was for the first time subjected to a two-step derivatization procedure that is well established for cyclic oligosaccharides.[8] Thus, maltoheptaose was first etherified with tert-butyldimethylsilyl chloride (TBDMSCl) at the primary hydroxy sites and then esterified with acetic anhydride at the secondary hydroxy sites. Spectroscopic evidence indicated that the derivatization of the terminal 1’,4’’-hydroxy groups mainly leads to the 1’-O-TBDMS/4’’-O-acetyl derivative. The linear selector G7 was dissolved in the polysiloxane PS 86, and a fused-silica capillary column (20 m 0.25 mm i.d.) was coated according to the static method.[2a] Figure 1. Gas-chromatographic separation of racemic N-trifluoroacetylO-methyl esters of a-amino acids on CD7 (a) and on G7 (b); in each case the dextrin is 20 % (w/w) in PS 86. Columns: 20 m 0.25 mm i.d. fused-silica capillary, film thickness 0.25 mm. For (a): carrier gas: 0.8 bar hydrogen; oven temperature: 90 8C (5 min), temperature program to 120 8C, 0.5 K min 1. For (b): carrier gas: 0.5 bar hydrogen; oven temperature: 80 8C (5 min), temperature program to 120 8C, 0.5 K min 1. Table 1: Retention factor k’ (first eluted enantiomer), enantioseparation factor a, and resolution factor Rs for N-trifluoroacetyl-O-methyl esters of some a-amino acids.[a] The new selector is capable of separating derivatized aamino acid enantiomers. Thus, the racemic N-trifluoroacetylO-methyl esters of a-amino acids could be separated on both CD7 and on the analogous linear dextrin counterpart G7 with optimized temperature programming (Figure 1). Under isothermal conditions (Table 1) cyclic CD7 exhibits a higher enantioseparation factor a than acyclic G7. The retention factors k’ of the enantiomers are quite different for CD7 and G7, and the elution order is reversed for tert-butyl leucine and norvaline (Table 1). In all separations, d enantiomers are eluted after l enantiomers. More intriguing differences are observed for the separation of the racemic N-trifluoroacetylO-ethyl esters of a-amino acids (Table 2). Whereas the enantioselectivity is higher for alanine (Ala) on cyclic CD7 than on acyclic G7, only the two diastereomers of isoleucine (IsoLeu) are separated on cyclic CD7. However, they are further resolved into enantiomers on acyclic G7 (Figure 2 a). Norvaline (Norval, Figure 2 b) and serine (Ser, Figure 2 c) can be separated on acyclic G7 but not on cyclic CD7. Further differences in the retention factor k’ and enantioseparation factor a are evident from Table 2. The role of molecular inclusion cannot be ignored in examples of extreme enantioselectivities that vary with the size of the cavity. For example, the unusually high enantioseparation factor of a = 4.08 was observed for racemic 2-(fluoromethoxy)-3-methoxy-1,1,1,3,3-pentafluoropropane Angew. Chem. Int. Ed. 2005, 44, 4092 –4095 Ala 2-Abu Val Norval tBuLeu k’ CD7 a Rs k’ G7 a Rs 10.2 16.9 28.4 34.1 51.1 1.18 1.23 1.09 1.14 1.25 5.59 4.69 1.75 2.65 12.8 9.9 14.2 15.6 15.9 24.8 1.10 1.04 1.04 1.05 1.02 5.21 2.44 2.02 2.75 1.25 [a] Experimental conditions: 85 8C (isothermal), 0.6 bar H2. Table 2: Retention factor k’ (first eluted enantiomer), enantioseparation factor a, and resolution factor Rs for N-trifluoroacetyl-O-ethyl esters of some a-amino acids. [a] Ala IsoLeu[a] Thr[a] Norval[a] Val[a] Pro[b] Ser[b] Leu[b] Asp[c] Met[d] k’ CD7 a Rs k’ G7 a 26.4 14.3 16.7 52.9 21.7 11.7 20.1 27.3 15.5 37.8 143.8 1.60 1.00 1.00 1.34 1.00 1.08 1.16 1.00 1.01 1.03 1.04 13.6 – – 8.50 – 1.60 6.64 – 0.51 1.15 1.66 10.0 27.0 28.3 24.6 24.9 16.6 39.4 25.3 20.2 1.03 45.7 1.08 1.02 1.02 1.02 1.01 1.03 1.02 1.06 1.00 2.08 1.00 44.2 Rs 4.17 1.25 1.04 0.94 0.84 1.70 1.83 3.03 – – [a] Experimental conditions: 90 8C (isothermal), 0.6 bar H2. [b] 100 8C (isothermal), 0.8 bar H2. [c] 110 8C (isothermal), 0.6 bar H2. [d] 120 8C (isothermal), 0.6 bar H2. www.angewandte.org 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4093 Communications Figure 2. Gas-chromatographic separation of racemic N-trifluoroacetyl-O-ethyl esters of a-amino acids on CD7 (left) and on G7 (right); in each case the dextrin is 20 % (w/w) in PS 86. Columns: 20 m 0.25 mm i.d. fused-silica capillary, film thickness 0.25 mm. For other experimental conditions, see Table 2. (“compound B”, a decomposition product of the narcotic sevoflurane) on CD7 (Figure 3 a). The separation factor drops to a = 2.70 for the g-cyclodextrin analogue CD8 and to a = 1 (no enantiomeric discrimination) for the a-cyclodextrin analogue CD6 (Table 3). Surprisingly, the separation of “compound B” occurs also on G7, although with reduced enantioselectivity (Figure 3 b). Whereas a remarkable difference of enantioselectivity is observed for CD7 and CD8, no such difference is discerned for G7 and G8 (Table 3). More interestingly, enantioselectivity is displayed by acyclic G7 and G8 but not by cyclic CD6 (Table 3). In conclusion, derivatized linear dextrins (“acyclodextrins”) represent a new class of carbohydratebased selectors for gas-chromatographic separation of enantiomers. Comparisons between G7 and CD7 indicate that acyclodextrins are useful for investigations of the role of molecular inclusion. Besides Ntrifluoracetyl amino acid esters, other racemates such as lactones, alcohols, diols, and amides are also amenable to enantiomeric separation by G7. Current trials are concerned with the influence on the number of glucose entities in the linear dextrins for enantiorecognition. Table 3: Enantioseparation factor a of “compound B” on modified cyclic and acyclic dextrins.[a,b] CSP CD6 CD7 CD8 G7 G8 a 1.00 4.08 2.70 1.07 1.06 [a] In each case the dextrin is 20 % (w/w) in PS 86. [b] Columns: 20 m 0.25 mm i.d. fused-silica capillary, film thickness 0.25 mm, carrier gas 0.3 bar hydrogen, oven temperature 30 8C. Experimental Section Figure 3. Gas-chromatographic separation of racemic 2-(fluoromethoxy)-3-methoxy-1,1,1,3,3-pentafluoropropane (“compound B”) on CD7 (a) and on G7 (b); in each case the dextrin is 20 % (w/w) in PS 86. Columns: 20 m 0.25 mm i.d. fused-silica capillary, film thickness 0.25 mm. Carrier gas: 0.3 bar; oven temperature: 30 8C. 4094 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Gas-chromatographic experiments were carried out on an HP 5890 gas chromatograph equipped with a flame ionization detector operated at 250 8C. The carrier gas was hydrogen (99.996 %) (Messer-Griesheim, Frankfurt, Germany), which was used without further purification. The splitting ratio at the injector (held at 220 8C) was set to 1:100. Retention times were determined using a Shimadzu C-R6A data processor (Kyoto, Japan). tert-Butyldimethylsilyl chloride (TBDMSCl) and acetic anhydride were purchased from Aldrich. Heptakis[(1’-O,6-O)-tert-butyldimethylsilyl]-maltoheptaose: Dry maltoheptaose (1 g, 0.87 mmol) was dissolved with vigorous stirring in anhydrous pyridine (15 mL). The solution was cooled in an ice bath, and a solution of TBDMSCl (1.6 g, 10.6 mmol) in anhydrous pyridine (20 mL) was then added dropwise over 4 h. Cooling was continued a further 2 h before the solution was allowed to warm to room temperature. After a further 12 h at RT, the solvent was removed under reduced pressure to give a white solid, which was taken up in CH2Cl2 (30 mL). The CH2Cl2 phase was washed with an aqueous solution of KHSO4 (20 mL, 1m) to remove any residual pyridine and then with saturated aqueous NaCl solution. The CH2Cl2 layer was recovered and concentrated to dryness. Yield: 1.61 g (85 %). The product was used without further purification. A mixture of three silylated linear dextrins was present (with 7 (M1), 8 (M2), and 9 (M3) www.angewandte.org Angew. Chem. Int. Ed. 2005, 44, 4092 –4095 Angewandte Chemie tert-butyldimethylsilyl substituents), as confirmed by mass-spectrometric analysis (ESI-MS): m/z 993 [M1+2 Na]2+, 1056 [M2+2 Na]2+, 1113 [M3+2 Na]2+. From the elemental analysis it is evident that the main species (95 %) is the linear oligosaccharide as its octa-tertbutyldimethylsilyl ether. Elemental analysis (%) calculated for C90H184O36Si8 : C 52.29, H 8.97; found: C 52.20, H 9.35. Heptakis[(1’-O,6-O)-tert-butyldimethylsilyl-(2,3-di-O,4’’-O)-acetyl]maltoheptaose (G7): Crude heptakis[(1’-O, 6-O)-tert-butyldimethylsilyl]-maltoheptaose (1.5 g) were dissolved in anhydrous pyridine (20 mL) and acetic anhydride (18 mL). The solution was stirred for 5 h at 100 8C and then concentrated. The remainder of the solvents were removed by coevaporation with toluene. Column chromatography of the residue eluting with toluene/ethanol (95:5 v/v) afforded amorphous G7. After acetylation of the hydroxy groups at the 2- and 3-positions, the structure of the mixed acetyl/TBDMS selector was elucidated by 1H and 13C NMR spectroscopy. The main species (95 %) of the mixture showed a terminal silyl ether group on the reducing terminus C1 and a terminal acetyl ester group on the nonreducing terminus C4. ESI-MS: m/z: 1365 [M+2 Na]2+ (main species). Elemental analysis (%) calculated for C120H214O51Si8 : C 53.43, H 8.00; found: C 53.35, H 8.17. Received: February 10, 2005 Published online: May 25, 2005 . Keywords: chiral stationary phases · cyclodextrins · enantiomer separation · gas chromatography · linear dextrins [1] a) V. Schurig, H.-P. Nowotny, Angew. Chem. 1990, 102, 969 – 986; Angew. Chem. Int. Ed. Engl. 1990, 29, 939 – 1076; b) W. A. Knig, Enantioselective Gas Chromatography with Modified Cyclodextrins, Hthig, Heidelberg, 1992; c) W. A. 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Mosandl, J. High Resolut. Chromatogr. 1992, 15, 176 – 179. [8] a) K. Takeo, H. Mitoh, K. Uemura, Carbohydr. Res. 1989, 187, 203 – 221; b) A. R. Khan, P. Forgo, K. J. Stine, V. T. DSouza, Chem. Rev. 1998, 98, 1977 – 1996. Angew. Chem. Int. Ed. 2005, 44, 4092 –4095 www.angewandte.org 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4095
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