Synthesis of a new enantiopure chiral aza crown ether and its application in enantiomeric separation

Article abstract of DOI:10.1002/jhet.5570420602

A new enantiopure chiral aza crown ether (S,S)-1,7-bis(4-phenyl-5-hydroxy- 2-oxo-3-zapentyl)-1,7-diaza-12-crown-4 ligand (1) has been synthesized and used as a chiral selector in the enantiomeric separation of D/L-carnitine by capillary electrophoresis.

Full text of DOI:10.1002/jhet.5570420602

Sep-Oct 2005
Synthesis of a New Enantiopure Chiral Aza Crown Ether and Its
Application in Enantiomeric Separation
1043
Cheng-Yun Wang1,2,* , Da-Hui Wang , Tao-Hua Leng , Qing-Sen Yu
2
1
1
1
Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. China
2
Institute of Environmental Engineering, Zhejiang University, Hangzhou, 310027, P. R. China
Received December 17, 2004
A new enantiopure chiral aza crown ether (S,S)-1,7-bis(4-phenyl-5-hydroxy-2-oxo-3- zapentyl)-1,7-
diaza-12-crown-4 ligand (1) has been synthesized and used as a chiral selector in the enantiomeric separa-
tion of D/L-carnitine by capillary electrophoresis.
J. Heterocyclic Chem., 42, 1043 (2005).
Introduction.
L-Carnitine plays an important role in the transport of fatty
acids across the mitochondrial membrane by the trans-
ferase and translocase enzyme system [4]. Recently, L-car-
nitine and its derivatives have been proved to possess
interesting pharmacological and nutritional properties [5],
however D-carnitine has been shown to have a consider-
able toxic effect on biochemical processes [6].
Since Pedersen first synthesized macrocyclic polyether
compounds (crown ethers), a wide variety of crown ethers
have been prepared and utilized in alkali and alkaline earth
metal cation determination and separation due to their
superior binding ability for these metal ions. Recently, a
considerable number of studies on complexation of chiral
alkylammonium salts [1] and chiral amino acids [2] by
chiral crown ethers have been reported. Macrocyclic com-
pounds containing nitrogen atoms, known as aza crown
ethers, are of particular interest because one or more side
arms can be attached to them, and these compounds have
the ability to form strong and selective interactions with
guest molecules, such as primary and quarternary alkylam-
monium salts. So, a number of aza crown ether analogues
were used in chiral recognition [3]. In the present paper we
report the synthesis and application of a new enantiopure
chiral aza crown ether (S,S)-1,7-bis(4-phenyl-5- hydroxy-
Results and Discussion.
The synthesis is shown in Scheme 1. Compound 1 was
prepared by alkylation of the diaza crown ether 2 with
enantiopure chiral chloro compound 5 in the presence of
anhydrous potassiun carbonate. 1,7-Diaza-12-crown-4 lig-
and (2) was obtained after acidic hydrolysis of the ditosyl
derivative 3 followed by neutralization [7]. Ditosyl deriva-
tive 3 was obtained by cyclization of the disodium salt of
bissulfonamide 4 [8] with diethylene glycol ditosylate in
strong basic conditions. (2S)-N-(1-Phenyl-2-hydroxy-
ethyl)- chloroacetamide (5) was prepared by the reaction
of the amino alcohol 6 [9] with chloroacetyl chloride [10].
The structure of compound 1 was confirmed by elemental
2
-oxo-3-azapentyl)-1,7-diaza-12-crown-4 ligand (1)
which was used successfully in the enantiomeric separa-
tion of D/L-carnitine by capillary zone electrophoresis.
1
13
analysis, IR, MS, H NMR and C NMR spectra.
The use of enantiopure chiral aza crown ethers in the
separation of enantiomers have scarcely been reported in
the past. We have used the enantiopure chiral aza crown
ether 1 as a chiral selector for the separation of enan-
tiomers in capillary zone electrophoresis. The enan-
tiomeric separation was performed using (S,S)-1,7-bis(4-
phenyl-5-hydroxy-2-oxo-3-azapentyl)-1,7-diaza-12-
crown-4 ligand (1) in the presence of sulfonated
D/L-carnitine
Scheme 1

1
044
C.-Y. Wang , D.-H. Wang, T.-H. Leng, Q.-S. Yu
Vol. 42
β-cyclodextrin with a degree of substitution 3~4 (Sigma-
Aldrich, USA). Under optimal conditions D- and L-carni-
tine derivatized with 4’-bromophenacyl bromide (accord-
ing to the literature procedure [11], see Scheme 2) were
separated completely (see Figure 1), whereas using only
sulfonated β-cyclodextrin, enantiomeric separation was
obtained with poor efficiency.
ric acid at 95~100 °C for 48 hours, followed by work-up with 6 N
hydrochloric acid. The acidic solution was made basic with satu-
rated aqueous potassium hydroxide then extracted with chloro-
form to give 1,7-diaza-12-crown-4 ether (2) as a colorless solid
1
(
68.5%), mp: 84-85 °C (literature [12] mp: 83-84 °C); H nmr
(
CDCl ): δ 2.83 (8H, t, J=5.9, N-CH ), 3.64 (8H, t, J=5.9, CH -
3
2
2
+
O); ms m/z (%): 175 (M +1, 10.4), 113 (4), 106 (59), 100 (11), 88
(66), 57 (100),44 (46); ir νmax: 3260, 2937, 1138, 1029, 916 cm .
-1
EXPERIMENTAL
Enantiopure chiral amino alcohol 6 and enantiopure chiral
chloro compound 5 were prepared following the literature proce-
dures [9,10]. (2S)-N-(1-phenyl-2-hydroxyethyl)-chloroacetamide
Infrared spectra were recorded on a Nicolet spetrophotometer;
H NMR and C NMR spectra were recorded on an Avance
1
5
1
13
(5) is a colorless solid (82.4%), mp: 106-108 °C; [α] +44.78
(c
D
1
DMX 500 spectrometer and chemical shifts were reported relative
to the solvent peak. MS spectra were obtained on a HP5989B
instrument. Electrophorograms were recorded on P/ACE 2000
instrument with a 32 Karat software for data collection. A positive
power supply of 25 kV was used with a constant current mode of
operation. Capillaries of effective length of 60cmx75µm i.d. were
used and the temperature was 25 °C. The buffer solution used for
separation consisted of 50 mmol/L phosphoric acid, 1.25% (w/v)
of sulfonated β-cyclodextrin, 0.94% (w/v) of compound 1 (in ace-
tonitrile). The detection was carried out at 260 nm.
2.01, CH CN); H nmr (CDCl ): β 2.04 (1H, br, OH), 3.91-3.94
3
3
(2H, m, CH -O), 4.09-4.12 (2H, m, CH -Cl), 5.10-5.12 (1H, m,
2
2
+
CH-N), 7.26-7.40 (6H, m, Ar and NH); ms m/z (%): 214 (M ,
0.84), 182 (49), 106 (100), 91 (11), 77 (24), 51(15); ir νmax: 3314,
-
1
1667, 1540, 1454, 1044, 756 cm .
(
S,S)-1,7-Bis(4-phenyl-5-hydroxy-2-oxo-3-azapentyl)-1,7-diaza-
1
2-crown-4 Ligand (1).
A stirred mixture of 1,7-diaza-12-crown-4 ether (2) (0.35
g, 2.0 mmoles), anhydrous potassium carbonate (1.12 g, 8.1
mmoles) and (2S)-N-(1-phenyl-2-hydroxyethyl)- chloroac-
etamide (5) (0.88 g, 4.1 mmoles) in 30 ml of acetonitrile was
Compounds 3 and 4 were prepared according to the literature
procedures [7,8]. Hydrolysis of 3 was performed with 97 % sulfu-

Sep-Oct 2005
Synthesis of a New Enantiopure Chiral Aza Crown Ether
1045
heated under reflux for 12 hours. The reaction mixture was
cooled and evaporated to dryness under reduced pressure.
The residue separated into two layers after water was added.
The organic layer was separated and the aqueous one was
extracted by chloroform. The organic layers were combined
and dried over anhydrous potassium carbonate. The solvent
was evaporated under reduced pressure and the residual yel-
low oil was purified by chromatography on silica gel using a
mixture of methylene chloride-methanol- 28% aq. ammonia
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Ramachandran, J. Org. Chem., 64, 721 (1999); [d] M. Nazhaoui, J. P.
Joly, S. Kitane, M. Berrada. J. Chem. Soc., Perkin Trans. I, 3845
(
1998); [e] H. Nishi, K. Nakamura, H. Nakai, T. J. Sato, J.
Chromatogr. A, 757, 225 (1997); [f] Y. Walbroehl, J. Wagner, J.
Chromatogr. A, 680, 253 (1994).
[
2a] K. Verleysen, T. Bosch, P. Sandra, Electrophoresis, 20, 2650
(
[
1999); [b] M. G. Schmid, G. J. Gubitz, J. Chromatogr. A, 709, 81 (1995);
c] R. Kuhn, C. Sreinmetz, T. Bereuter, P. Hass, F. Erni, J. Chromatogr. A,
(
10:10:1) as eluent, to give the aza crown ether 1 as a pale
666, 367 (1994); [d] R. Kuhn, F. Stoeklin, F. Erni, Chromatographia, 33,
32 (1992).
[3a] J. S. Bradshaw, P. Huszthy, J. T. Redd, X. X. Zhang, T. M.
Wang, J. K. Hathaway, J. Young, R. M. Izatt. Pure Appl. Chem., 67, 691
1
5
1
yellow oil (0.81g, 76.7%). [α] +30.3 (c 0.846, CH Cl ); H
D
2
2
nmr (CDCl ): δ 1.88 (2H, br, -OH), 2.53 (8H, t, J=6.1, CH -
3
2
N), 3.19 (4H, s, N-CH -CON), 3.45-3.49 (2H, m, CH -O),
2
2a
(
1995); [b] P. Huszthy, M. Oue, J. S. Bradshaw, C. Y. Zhu, T. Wang, N. K.
3
4
(
.61-3.63 (8H, t, J=6.1, CH -O), 3.76-3.81 (2H, m, CH2b-O),
2
Dalley, J. C. Curtis, R. M. Izatt, J. Org. Chem., 57, 5383 (1992); [c] J. S.
Bradshaw, P. Huszthy, C. W. McDaniel, C. Y. Zhu, N. K. Dalley, R. M.
Izatt, S. Lifson J. Org. Chem., 55, 3129 (1990).
.98-5.01 (2H, m, CH-N), 7.27-7.37 (10H, m, Ar), 8.39-8.41
2H, m, NH); 1 C nmr (CDCl ): δ 172.0(C=O), 139.2(Ar,
3
3
C ), 129.2(Ar, C ), 128.2(Ar, C ), 127.0 (Ar, C ), 66.8, 66.3,
6
1
(
7
1
3
2
4
[
4a] S. V. Pande, R. Parvin, J. Biol. Chem., 251, 6683 (1976); [b] J.
Bremer, J. Biol. Chem., 237, 3628 (1962).
5] C. Vogt, S. Kressig, J. Chromatogr. A, 745, 53 (1996).
[6] C. Vogt, A. Georgi, G. Wener, Chromatographia, 40, 287 (1995).
+
2.5, 56.1, 54.3, 51.2; ms m/z (%): 529 (M+1 , 2), 364 (14),
32 (25), 118 (37), 106 (75), 100 (78), 91 (43), 77 (48), 56
[
71), 42 (100); ir νmax: 3257, 2940, 1665, 1594, 1453, 1096,
-
1
01 cm .
[7]
(1974).
J. E. Richman, T. J. Atkins, J. Am. Chem. Soc., 96, 2268
Anal. Calcd. for C H N O : C, 63.64; H, 7.58; N, 10.61.
2
8 40 4 6
[
8] E. Weber, F. Vogtle, Chem. Ber., 109, 1803 (1976).
Found: C, 63.55; H, 7.60; N, 10.57.
[
9] M. .J. McKennon, A. I. Meyers, K. Drautz, M. Schwarm, J.
Org. Chem., 58, 3568 (1993).
REFERENCES AND NOTES
[
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*
Corresponding author: wangcy295@sohu.com, fax: +86-
571-87951239.
1a] O. P. Kryatova, I. V. Korendovych, E. V. Rybak-Akimova,
[11] P. E. Minkler, C. L. Hoppel, Clin. Chim. Acta, 212, 55 (1992).
0
[12]
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[
Tetrahedron, 29, 1629 (1973).