Synthesis of cyclam-capped β-cyclodextrin-bonded silica particles for use as chiral stationary phases in capillary electrochromatography

Article abstract of DOI:10.1016/S0040-4039(02)00286-1

β-Cyclodextrin (β-CD) was anchored onto silica particles at its C(2) position, derivatized primarily at the C(6) position by treatment with bromoacetyl bromide, and finally reacted with two types of cyclams to form cyclam-capped β-CD-bonded silica particles. When used as chiral stationary phases in capillary electrochromatography, these novel bonded silica particles exhibited excellent enantioselectivities for chiral separations.

Full text of DOI:10.1016/S0040-4039(02)00286-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2463–2466
Synthesis of cyclam-capped b-cyclodextrin-bonded silica particles
for use as chiral stationary phases in capillary
electrochromatography
a
b
b
b
b
Yinhan Gong, Guoping Xue, Yanqiao Xiang, Jerald S. Bradshaw, Milton L. Lee and
a,
Hian Kee Lee *
a
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
b
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602-5700, USA
Received 3 January 2002; revised 30 January 2002; accepted 6 February 2002
Abstract—b-Cyclodextrin (b-CD) was anchored onto silica particles at its C(2) position, derivatized primarily at the C(6) position
by treatment with bromoacetyl bromide, and finally reacted with two types of cyclams to form cyclam-capped b-CD-bonded silica
particles. When used as chiral stationary phases in capillary electrochromatography, these novel bonded silica particles exhibited
excellent enantioselectivities for chiral separations. © 2002 Elsevier Science Ltd. All rights reserved.
Development of new chiral stationary phases (CSP)
with high selectivities to separate chiral molecules is one
of the most active areas of liquid chromatography
These CSPs have shown excellent enantioselectivities.
Since cyclams have similar structures and properties to
crown ethers, it was of interest to us to prepare cyclam-
capped b-CD particles for comparison with our previ-
ously synthesized crown ether-capped b-CD particles.
In this paper, we describe a synthetic method to pre-
pare two types of cyclam-capped b-CD-bonded silica
particles. Better enantioselectivities were obtained using
the cyclam-capped b-CD-bonded phases compared to
the crown ether-capped b-CD bonded phases in capil-
lary electrochromatography.
(
LC); chiral LC is an important technique in the phar-
maceutical industry. Many chiral separations have been
accomplished using b-cyclodextrin-type bonded silica
1
particles as CSPs in LC. However, one drawback in
utilizing cyclodextrins has been the low binding con-
2
stants for most guest molecules. It was reported that
2–4
the crown ether-capped b-CDs exhibited high bind-
ing constants for several guest molecules. Recently, it
was shown that the combination of a crown ether and
b-CD as a buffer additive in capillary electrophoresis
The synthetic strategies for the synthesis of the required
cyclam ligands 4 and 8 are outlined in Scheme 1.
Tris-t-butyl carbamate-substituted cyclam 1 was syn-
(
CE) sometimes produced better enantioseparations
than did either selector alone due to cooperative func-
5–7
tioning of the b-CD and the crown ether. However,
many crown ethers, cyclams and derivatized CDs can-
not be used as CE additives due to their high UV–vis
absorption or poor solubility in water. Alternatively,
they can be bonded onto silica to use as CSPs in LC.
9
thesized as described. Compound 3 was synthesized by
reductive amination of 8-benzenesulfonamido-2-quino-
10
linecarboxaldehyde 2 with 1 using NaBH(OAc) as
3
the reducing agent in 85% yield. Removal of the Boc
protecting groups was easily accomplished in an excel-
1
1
lent yield (95%) using CF CO H to give ligand 4. Key
We have previously reported a method involving suc-
cessive multiple-step liquid–solid phase reactions on the
silica surface to prepare crown ether-capped b-CD8-
bonded silica particles for use as new CSPs in LC.
3
2
intermediate 5 for ligand 8 has already been prepared
using formaldehyde and cyclam as the starting
12
reagents. Treatment of 5 with 2-(bromomethyl)-6-
1
3
(
hydroxymethyl)-pyridine 6 in CH CN gave disubsti-
14
3
tuted macrotricycle 7 in 90% yield. Ligand 8 was
obtained in quantitative yield after basic hydrolysis of 7
in NaOH (3 M) at room temperature. The synthetic
details for the preparation of ligands 4 and 8 will be
published in due course.
Keywords: chiral stationary phase; enantiomeric separation; cyclam;
crown ether; b-cyclodextrin; capillary electrochromatography.
*
Corresponding author. Tel.: (65)-6874-2995; fax: (65)-6779-1691;
e-mail: chmleehk@nus.edu.sg
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00286-1

2
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Y. Gong et al. / Tetrahedron Letters 43 (2002) 2463–2466
H
Boc
Boc
Boc
Boc
H
N
N
N
N
N
N
N
N
N
O
HN SO2
N
1) CF3CO2H
2
NH
Boc
SO2
2) NaOH/CH Cl
Boc
2
2
NaBH(OAc)3/DCE
(Boc)2O
CH2Cl2
1 (Yield 19%)
3 (Yield 85%)
H
N
N
N
N
H
H
H
N
N
N
N
NH
N
H
H
SO2
H
N
4
(Yield 95%)
HCHO
OH
Br
N
N
N
N
6
N
N
N
Cyclam
2 Br
OH
CH3CN
N
N
N
OH
5
(Yield 96%)
7 (Yield 90%)
NaOH
H
N
N
N
N
N
OH
H
N
OH
8
(Quantitative yield)
Scheme 1. Synthesis of cyclam derivatives 4 and 8.
The b-CD was anchored onto the silica gel particles
are positively charged. The positively charged cyclam-
capped b-CD can supply extra electrostatic interac-
tions with ionizable solutes and enhance the dipolar
interactions with polar neutral solutes. This can
enhance the host–guest interaction with the solute
and improve chiral recognition and selectivity. Since
at the C(2) secondary hydroxyl position to form com-
1
5
8
pound 9 as reported. The more reactive C(6) pri-
1
6,17
mary hydroxyl groups
are then available for
further reactions. Compound 9 was first treated with8
seven equivalents of bromoacetyl bromide to form 10
2
+
(
see Scheme 2). Due to the fact that the seven C(6)
the side arms in the cyclams can also include Ni
+
hydroxyl groups of the attached CD are more reac-
tive and less sterically hindered than those at C(2) or
C(3),
ions that have higher positive charges than Na or
+
K
ions, and the positively charged cyclam center is
1
6,17
and they are also less sterically hindered
nearer to the b-CD compared to 4%-aminobenzo-18-
than the secondary hydroxyl group in the spacer arm,
we believe that the majority of the bromoacetate
units are attached at the C(6) positions. Thus, com-
pound 10 has a b-CD containing some 6-O-bromoac-
etate groups and is attached to silica through its 2-O
position, as shown in Scheme 2. Compound 10 was
then treated with the two cyclams to form the
cyclam-capped b-CD-appended silica materials 11 and
crown-6 and 4%-aminobenzo-15-crown-5-capped b-CD-
8
bonded particles, particles 11 and 12 have stronger
electrostatic and dipolar interactions with solutes and,
accordingly, show better enantioselectivities than the
crown ether-capped b-CD-bonded phases. It was
found that, for labetalol and 2-amino-1,2-
diphenylethanol which have two chiral centers, only
partial separation of the four stereoisomers can be
achieved on the 4%-aminobenzo-18-crown-6 and 4%-
aminobenzo-15-crown-5 capped b-CD-bonded phases,
however, baseline separation of the four stereoisomers
is easily achieved on bonded phases 11 and 12
(shown in Fig. 1). The cooperative functionings of
b-CD, cyclam and its side arms are important for
chiral recognition.
1
8
1
2. Since the amine groups in the cyclam ring are
more reactive than the other functional groups in
cyclams 4 and 8, the two cyclams must be appended
to the b-CD via the nitrogen atom(s) in the ring, as
shown in Scheme 2. Because of steric constraints, it is
unlikely that the cyclam is attached to the b-CD via
two linkages, although there are two or three amine
groups in the cyclam rings.
In summary, cyclam-capped b-CD-bonded silica parti-
cles were synthesized using a convenient successive
multiple-step liquid–solid phase reaction on the silica
gel surface. These bonded silica materials have excel-
lent enantioselectivities due to the cooperative func-
tioning of the cyclam and b-CD when used as CSPs
in CEC.
Since 11 and 12 have a chiral selector with three
recognition sites, i.e. b-CD, cyclam and its side arm,
they exhibit excellent enantioselectivities when used as
19
CSPs in capillary electrochromatography (CEC).
2+
After inclusion of the metal ion (Ni ) from the run-
ning buffer into the cyclam unit, particles 11 and 12

Y. Gong et al. / Tetrahedron Letters 43 (2002) 2463–2466
2465
Scheme 2. Synthesis of the two cyclam-capped b-CD-bonded silica particles.
Figure 1. (A) CEC separation of the four stereoisomers of labetalol using compound 11 as stationary phase. Conditions: 75 mm
i.d.×30 cm effective length fused silica column (38.5 cm total length) packed with 11 (1.5 mm, 100 A on Alltech Exsil porous silica
particles, Deerfield, IL, USA); 10 mM Tris buffer (pH 8.6) containing 2 mM Ni(ClO ) /acetonitrile (30:70 v/v), 15 kV, 254 nm
,
4
2
UV detection. (B) CEC separation of the four stereoisomers of 2-amino-1,2-diphenylethanol using compound 12 as stationary
phase. Conditions: 75 mm i.d.×30 cm effective length fused silica column (38.5 cm total length) packed with 12 (1.5 mm, 100 A
on Alltech Exsil porous silica particles, Deerfield, IL, USA); 10 mM Tris buffer (pH 8.6) containing 2 mM Ni(ClO ) /acetonitrile
,
4
2
(
40:60 v/v), 20 kV, 210 nm UV detection.

2
466
Y. Gong et al. / Tetrahedron Letters 43 (2002) 2463–2466
calcd for C H N O S: C, 62.87; H, 7.31. Found: C, 62.63;
Acknowledgements
26
36
6
2
H, 7.17%.
1
2. Royal, G.; Dahoui-Gindrey, V.; Dahoui, S.; Tabard, A.;
Guilard, R.; Pullumbi, P.; Lecomte, C. Eur. J. Org. Chem.
1998, 1971–1975.
Yinhan Gong gratefully acknowledges an Ang Kok
Peng Memorial Fund Scholarship award from the
National University of Singapore that allowed a study
leave at Brigham Young University where the described
synthetic work was carried out.
13. Newcomb, M.; Timko, J. M.; Walba, M.; Cram, D. J. J.
Am. Chem. Soc. 1977, 99, 6392–6398.
1
14. Compound 8: H NMR (200 MHz) l 7.40–7.10 (m, 6H);
4.76 (br., 2H); 4.65 (s, 4H), 3.82 (s, 4H), 2.80 (br., 2H),
2
.72–2.70 (m, 12H), 2.59 (t, J=4.4 Hz, 4H), 1.81 (m, 4H);
+
References
HRMS (FAB) m/z, calcd for C H N O (M+1) :
24
39
6
2
4
43.3137, found: 443.3142. Anal. calcd for C H N O : C,
24 38 6 2
1
2
3
4
5
6
7
8
9
. Ahuja, S. Chiral Separations by Chromatography; Oxford
University Press: New York, 2000; p. 99.
. Park, J. W.; Lee, S. Y.; Park, K. K. Chem. Lett. 2000, 6,
65.13; H, 8.65. Found: C, 64.95; H, 8.87.
15. Compound 9 was prepared using 1.5 mm porous silica. An
elemental analysis of C, 7.75; H, 1.87 shows a concentra-
−
1
5
94–595.
. Willner, I.; Goren, Z. J. Chem. Soc., Chem. Commun. 1983,
469–1470.
tion of anchored b-CD of 160 mmol g .
16. Easton, C. J.; Lincoln, S. F. Modified Cyclodextrins:
Scaffolds and Templates for Superamolecular Chemistry;
Imperial College Press: London, 1999, Chapter 2.
17. Pikramenou, Z.; Nocera, D. G. Inorg. Chem. 1992, 31,
532–536.
1
. Suzuki, I.; Obata, K.; Anzai, J.; Ikeda, H.; Ueno, A. J.
Chem. Soc., Perkin Trans. 2 2000, 1705–1710.
. Armstrong, D. W.; Chang, L. W.; Chang, S. S. C. J.
Chromatogr. A 1998, 793, 115–134.
. Huang, W. X.; Xu, H.; Fazio, S. D.; Vivilecchia, R. V. J.
Chromatogr. B 1997, 695, 157–162.
. Kuhn, R.; Wagner, J.; Walbroehl, Y.; Bereuter, T. Elec-
trophoresis 1994, 15, 828–834.
. Gong, Y.; Xue, G.; Bradshaw, J. S.; Lee, M. L.; Lee, H.
K. J. Heterocycl. Chem. 2001, 38, 1317–1321.
. Boitrel, B.; Andrioletti, B.; Lachkar, M.; Guilard, R.
Tetrahedron Lett. 1995, 36, 4995–4998.
18. Cyclam-capped b-CD-bonded silica particles 11 and 12
were prepared as shown in Scheme 2. They were each
washed successively with MeCN, water, acetone and
MeOH and then extracted with acetone in a Soxhlet
extractor overnight and dried in vacuum at 50°C for 6 h.
An elemental analysis for 11 of C, 13.11; H, 1.89; N, 1.43
−
1
shows a concentration of the cyclam in 11 of 166 mmol g
−
1
(for C) and 170 mmol g (for N) or about 1.05 cyclams
per b-CD molecule. The elemental analysis for 12 of C,
13.57; H, 1.84; N, 1.32 shows a concentration of the cyclam
1
1
0. Xue, G.-P.; Bradshaw, J. S.; Dalley, N. K.; Savage, P. B.;
−
1
−1
Izatt, R. M.; Prodi, L.; Montalti, M.; Zaccheroni, N.
in 12 of 158 mmol g (for C) and 157 mmol g (for N) or
Tetrahedron Lett., submitted.
about 0.98 cyclams per b-CD molecule.
1
3D
1. Compound 4: H NMR (200 MHz, CDCl ) l 7.95–7.90 (m,
19. CEC was performed using an HP
CE instrument
3
3
H), 7.50 (t, J=3.2, 1H), 7.32–7.16 (m, 5H), 7.10 (t, J=3.2
Hz, 1H), 3.92 (s, 2H), 3.05–2.96 (m, 8H), 2.81–2.68 (m,
H), 1.99–1.87 (m, 4H); HRMS (FAB): m/z, calcd for
(Hewlett–Packard, Waldbronn, Germany) equipped with
a UV diode-array detector. Supporting evidence for chiral
separation was accomplished by comparing UV spectra for
the stereoisomers from 200 to 254 nm wavelengths.
8
+
C H N O S (M+1) : 497.2702, found: 497.2698. Anal.
26
37
6
2