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Modified Linear Dextrins (УAcyclodextrinsФ) as New Chiral Selectors for the Gas-Chromatographic Separation of Enantiomers.

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Communications
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: volker.schurig@uni-tuebingen.de
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
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Angew. Chem. Int. Ed. 2005, 44, 4092 –4095
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2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4095
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