Novel crown ethers on glucose based glycolipids

Article abstract of DOI:10.1016/j.carres.2011.03.002

A series of crown ethers involving lauryl glucoside were synthesized and their assembly behavior in water was studied. The synthesis applied a simple protection scheme based on benzylidenation for the glycolipid, and cation templating for the macrocycle. A sequential build-up of the crown ether by bis-hydroxylethylation of the glucoside followed by reaction with di-, tri-, or tetraethylene glycol ditosylate provided better yields of the macrocycle compared to a single step cyclization with tetraethylene glycole ditosylate. The macrocycles containing up to six oxygens showed significantly higher affinity for sodium than for potassium, while more effective potassium complexation was found for the 21-crown-7 compound. The ion binding affinity leads to a slight but significant increase of the CMC of the crown ether containing surfactant in water upon the addition of sodium electrolyte.

Full text of DOI:10.1016/j.carres.2011.03.002

Carbohydrate Research 346 (2011) 891–896
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Novel crown ethers on glucose based glycolipids
Karem Sabah a,b, Thorsten Heidelberg a, , Rauzah Hashim a
⇑
a Chemistry Department, Faculty of Science, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia
b Chemistry Department, University of Kufa, 38001 Najaf, Iraq
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of crown ethers involving lauryl glucoside were synthesized and their assembly behavior in
water was studied. The synthesis applied a simple protection scheme based on benzylidenation for the
glycolipid, and cation templating for the macrocycle. A sequential build-up of the crown ether by bis-
hydroxylethylation of the glucoside followed by reaction with di-, tri-, or tetraethylene glycol ditosylate
provided better yields of the macrocycle compared to a single step cyclization with tetraethylene glycole
ditosylate. The macrocycles containing up to six oxygens showed significantly higher affinity for sodium
than for potassium, while more effective potassium complexation was found for the 21-crown-7 com-
pound. The ion binding affinity leads to a slight but significant increase of the CMC of the crown ether
containing surfactant in water upon the addition of sodium electrolyte.
Received 1 December 2010
Received in revised form 21 February 2011
Accepted 3 March 2011
Available online 8 March 2011
Keywords:
Glycolipid
Macrocycle
Cation templating
Surfactant
Ó 2011 Elsevier Ltd. All rights reserved.
Alkali earth complexation
1. Introduction
group and the hydrophobic chain, as displayed in Figure 1, reduces
the ability of the surfactant to form a lamellar phase, which forms
Macrocyclic ligands, like crown ethers,1 have wide application
potential, due to their ability to increase the solubility of selected
ions. Most of them are based entirely on fossil resources. However,
compounds involving carbohydrates2–4 have been studied in the
attempt to modify the cation selectivity.5–7 While crown ether
based surfactants have been described,8–10 no glycolipid
containing a crown ether has been reported so far. Glycolipids,
especially alkyl glycosides, have gained interest as non-ionic
surfactants with high biodegradability.11 Although their
application potential is wide, material costs favor high-end
products, especially in life science, for example, drug delivery. The
incorporation of a macrocyclic ligand in a surfactant based drug
carrier, for example, a vesicle, provides an opportunity to influence
the local ion concentrations around the surfactant assembly, and
thus opens an opportunity for new bio-related applications. Besides
reported effects of macrocyclic ligands on proteins,12 crown ethers
may affect the local concentration ratio of sodium and potassium
ions with possible implications on the electric signal transition in
the biological nerve system if a reasonable preference of the ligand
for either sodium or potassium cations can be achieved.
the basis for vesicles. In addition, repulsive interactions of cations
residing in the macrocyclic head groups destabilize surfactant
assemblies. While stable lamellar systems may be achieved by
mixing crown ether based surfactants with suitable co-surfactants,
differing interactions of structurally diverse head groups
complicate the formation of homogeneous assemblies. Better
chances are expected for mixtures of structurally similar surfac-
tants. In view of the life-science application potential of glycolipids,
we, therefore, aimed to synthesize and study the properties of
macrocyclic substitution on glycolipids.
2. Results and discussion
2.1. Synthesis
The initial synthetic approach was based on benzylidenation of
lauryl glucoside, leading to the glycol 4, which is a suitable
The spherical structure of a crown ether upon metal complexa-
tion implies a large surface area for the polar head group of a
crown ether-based surfactant. According to packing theory,13
a
huge difference between the surface areas of the macrocyclic head
⇑
Corresponding author. Tel.: +60 3 7967 7170, fax: +60 3 7967 4193.
E-mail addresses: karemchemist@gmail.com (K. Sabah), heidelberg@um.edu.my
Figure 1. Model of an 18-crown-6 surfactant based on a core structure reported by
Tavano et al.,28 the surface area of the polar head group (black in front view) is
much bigger than that of the hydrophobic chain (light color).
(T. Heidelberg).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.03.002

892
K. Sabah et al. / Carbohydrate Research 346 (2011) 891–896
OAc
O
AcO
AcO
OAc
OAc
1
BF3 OEt2
C12H25OH
RO
RO
Ph
Ph
O
O
O
O
HO
OR
OC12H25
HO
OC12H25
4a
PhCH(OMe)2
[TsOH]
O
RO
RO
O
O
O
OC12H25
RO
EG4Ts2
O
O
2
3
R = Ac
R = H
OC12H25
NaH, THF
RO
15-crown-5
OR
14%
O
O
4b R = H
R = CH2CO2tBu
O
5
EG2Ts2
7
8
R2 = CHPh
R = H
NaH, THF
LiAlH4
50%
RO
RO
RO
RO
Ph
O
O
EG4Ts2
KOtBu
EG3Ts2
O
O
O
OC12H25
OC12H25
O
NaH, THF
tBuOH/diox
OC12H25
O
40%
42%
O
O
OH
HO
O
O
6
O
O
21-crown-7
18-crown-6
O
O
O
O
O
O
O
11 R2 = CHPh
12 R = H
9
R2 = CHPh
10 R = H
Figure 2. Synthesis of macrocyclic ethers on lauryl glucoside at positions O-2 and O-3.
precursor for the build-up of the macrocycle. Figure 2 provides an
overview of the synthesis. Due to the high costs of dodecyl b-gluco-
pyranoside, glycolipid 3 was synthesized by boron trifluoride-
catalyzed glycosylation of lauryl alcohol with b-glucose
pentaacetate 1.14 The selectivity of the glycosylation is rather
before.20 Recently a surprisingly high yield (>90%) for a macrocycle
on
benzylidenated phenyl glucoside has been reported.21
a
However, a closer look into the experimental section involving
comparison of the reaction conditions with various other authors
suggests an overestimation of this reaction yield, probably due to
remaining solvent contents. In order to improve the yield, we
aimed to increase the reactivity of the glycolipid building block.
Therefore, we converted the secondary sugar hydroxyl groups to
primary alcohols by hydroxyethylation.20 The process applied
carboxymethylation followed by reduction,22,23 leading to an overall
yield of 74% without the need for chromatographic purification.
While intermediate 5 contained leftover reagent, namely tert-butyl
bromoacetate, the corresponding bromoethanol could be removed
by evaporation and extraction. In addition to providing higher
reactivity, the new macrocycle precursor 6 enables an easy synthesis
of 18-crown-6 and higher macrocyles, without the requirement of
highly expensive reagents, for example, pentaethylene glycol.
Applying a combination of sodium templating and high dilution
methods on intermediate 6 furnished the macrocyclic ethers 7 and
low, leading to considerable a-impurities in 2. Although anomeric
purification of acetylated glycolipids by chromatography is possi-
ble,15 we decided to continue the synthesis without. A simple
extraction approach16 was applied to remove excess alcohol, and
after deacetylation sugar impurities based on remaining peracetate
during the glycosylation. Benzylidenation of lauryl glucoside 3 pro-
vided an anomeric mixture of 4a and 4b,17 out of which the latter
could be crystallized as an anomerically pure compound.17 Glyco-
lipid 4b was obtained in 53% yield based on the peracetate 1 with-
out any chromatography step. This yield can be improved by
chromatography of the remaining mixture, leading to an additional
11% for each 4a and 4b.
For the build-up of the macrocyclic ether, a cation templating
approach18 was applied rather than the alternate high dilution
technique.19 Reaction of 4b with tetraethyleneglycol ditosylate18
using sodium hydride as a base and templating reagent led to
the targeted 15-crown-5 macrocycle 7 in 14%. Similar low macro-
cyle yields for analogous methyl glycosides have been reported
More details provided in Supplementary data.

K. Sabah et al. / Carbohydrate Research 346 (2011) 891–896
893
HO
OC12H25
OH
O
OR2
O
OR
O
O
LiAlH4
EG3Ts2
R2O
R1O
O
BnO
O
OC12H25
OC12H25
NaH, THF
O
O
OR1
OBn
OR
O
4b R1 = H, R22 = CHPh
13 R1 = Bn, R22 = CHPh
14 R1 = Bn, R2 = H
16
19-crown-6
O
EG2Ts2 NaH, THF
O
15 R1 = Bn, R2 = CH2CO2tBu
OC12H25
OR
17 R = Bn
18 R = H
O
O
O
OR
O
16-crown-5
O
O
19 R = Bn
20 R = H
Figure 3. Synthesis of macrocyclic ethers on lauryl glucoside at positions O-4 and O-6.
9
in 50% and 40% after chromatography, respectively, thus
phase.à The phenomenon can be explained based on packing
theory.13 Increasing surface area of the surfactant’s polar domain
due to the bulky macrocycle favors a columnar or spherical assembly
depending on the level of bulkiness. In case of the 4,6-linkage the
increase in volume of the polar domain is distributed over all three
space directions, which still enables the formation of a columnar
assembly. The 2,3-attachment, on the other hand, practically only
increases the surface area without adding to the head-group length,
thus only allowing spherical aggregates.à This observation indirectly
confirms our initial concerns about the packing constraints of
macrocyclic-based surfactants.
Increased hydrophilicity upon introduction of the macrocycle
should enhance the molecular solubility of the glycolipid, thus
increasing its CMC. In fact, a moderate increase of the CMC was
detected.à Moreover, the cation complexing ability leads to higher
CMCs in the presence of alkali salts, as demonstrated in Table 1.
This translates to a reduction of the assembly stability upon the
presence of suitable sized cations, which may lead to advantages
for future drug delivery systems based on an electrolyte induced
release of vesicle contents.
It is well known that crown ethers exhibit a size specific
selectivity for cations.25,18 Commonly 15-crown-5 ligands are
reported to favor sodium, while the homolog 18-crown-6
compounds prefer potassium.26 In order to evaluate the ion-bind-
ing selectivity, mass spectrometry (using electrospray ionization)
was applied on the macrocyclic glycolipids in the presence of
excess electrolyte comprising of an equimolar ratio of potassium
and sodium ions. Table 2 lists the results and compares them with
both, the base glycolipid as well as with unsubstituted 15-crown-5
and 18-crown-6. All macrocyclic glycolipids with up to six donor
atoms exhibited higher affinity for sodium than for potassium. In
general, the attachment of the sugar seems to increase the selectiv-
ity for the smaller sodium ion, probably due to conformational
restrictions for the crown ether. Particularly the crown-5
compounds 8 and 20 show interesting ion selectivities, exceeding
considerably increasing the overall yield of 7 in consistence with
previous reports on similar reactions.20 The lower yield for the
18-crown-6 derivative, 9, suggested possible improvements by
applying potassium hydride instead of the sodium analog, based
on usually higher binding affinities of 18-crown-6 for K. However,
the corresponding reaction did not lead to significant changes.
Attempts to access 12-crown-4 by using ethylene glycol ditosylate
failed, probably due to an elimination process on the tosylate24 and
inefficient templating since no lithium salt was applied. On the
other hand, the 21-crown-7 compound 11 could be accessed by
using tetraethylene glycol ditosylate with potassium templating.
Final deprotection by hydrogenolysis furnished the macrocyclic
glycolipids 8, 10, and 12 in more than 90% yield.
The easy protection of the hydroxyl groups at C-4 and C-6
enables not only the synthesis of macrocycles involving the 2
and 3 position of the glucoside, but also provides access to macro-
cyclic compound linked through the hydroxyl groups at C-4 and
C-6 as displayed in Figure 3. The reaction sequence involved ben-
zylation of the hydroxyl groups in 4b followed by acid catalyzed
cleavage of the benzylidene acetal in 13 to provide 14,17 which
could be crystallized. Application of the strategy described above
led to the macrocycles 17 and 19 in, which upon hydrogenolysis
gave the glycolipids 18 and 20, respectively. The reaction yields
for the macrocycles on 2,3 and 4,6 did not vary significantly,
indicating an efficient templating and, hence, ability of the geomet-
rically less favorable 1,5-di-oxa-ligand to form complexes. Like for
the preparation of the 2,3-based macrocycles, the preparation of 18
and 20 only requires a single chromatographic purification on
stage of the protected crown ethers 17 and 19.
2.2. Physical properties
Unlike the corresponding base glycoside 3, the macrocyclic
glycolipids containing a macrocyclic ether on positions 2,3 of the
glucose, that is, 8, 10, and 12, do not exhibit liquid crystalline
phases in contact with water, while the glycolipids with macro-
cycle attachment on 4,6, that is, 18 and 20, show only the columnar
à
Additional information available in Supplementary data.

894
K. Sabah et al. / Carbohydrate Research 346 (2011) 891–896
Table 1
the logarithmic concentration determines the CMC. Surface tension
measurements were measured at rt in 5 replicates with a standard
Critical micelle concentrations of selected crown ether glycolipids29
deviation below 0.1 mN mÀ1
.
Compound
Crown ether
CMC (mmol/L)
3b
8
—
0.1929
0.29
0.40
0.21
0.31
4.1.1. Hydroxyethylation of sugar glycols
15-Crown-5
8 + Na+
10
A1 (Alkylation): A solution of the glycol (8 mmol) in toluene
(30 mL) was treated with aqueous NaOH (25 mL, 50%) and
Bu4NÁHSO4 (1.4 g, 4 mmol) and stirred vigorously at 10 °C for
18-Crown-6
19-Crown-6
18
t
30 min. BrCH2CO2 Bu (6.25 g, 32 mmol) was rapidly dropped in
and stirring was continued for another 30 min, after which TLC
(hexane–EtOAc 4:1) indicated complete conversion. Water
(50 mL) and hexane (100 mL) were added and the mixture was
stirred for 10 min before the organic layer was passed through a
short layer of silica gel. A2 (reduction): A solution of the diester
(8 mmol) in THF (30 mL) was cooled to 0 °C. LiAlH4 (2 equiv) was
added and the reaction was stirred for 2 h. Excess reagent was
destroyed by the addition of water (1 mL), followed by aqueous
NaOH (1 mL, 15%) and more water (3 mL). After 15 min stirring
at rt Al(OH)3 was filtered off and the solvent was evaporated. The
residue was dissolved in CH2Cl2 and extracted with water, dried
over MgSO4, and evaporated.
Table 2
Cation selectivity of crown ether glycolipids according to mass spectroscopy27
Compound
Crown ether
Cation selectivity
K+
Na+
(%)
30
3b
8
20
10
18
12
Reference
Reference
—
1
>10
>10
ꢀ1
ꢀ1
1
1
1
1
1
1
15-Crown-5
16-Crown-5
18-Crown -6
19-Crown -6
21-Crown -7
15-Crown-5
18-Crown-6
30
30
20
10
10
10
50
ꢀ1
4
1
1
5
4.1.2. Synthesis of crown ethers
A solution of 6 or 16 in THF (ꢀ170 mL/mmol) was treated with
NaH (10 equiv, 55% in paraffin oil) and heated at reflux for 1 h. A
solution of the respective ethylene glycol ditosylate (1 equiv) in
THF (ꢀ170 mL/mmol) was added dropwise over a period of 3 h.
The mixture was refluxed for another 72 h, before the solvent
was evaporated. The residue was taken up in CH2Cl2, washed
successively with water and dried over MgSO4. The solvent was
evaporated and the crude product purified by chromatography
(hexane–EtOAc 3:1).
with 11:1 (the data in Table 2 are adjusted to significant figures)
the one of basic 15-crown-5 considerably. Addition of acetic acid
(5 equiv with respect to total alkali ions) did not lead to significant
changes in the intensities, nor were additional ions, especially
M+H, detected. This suggests that the measured data correspond
with the ion affinity.
3. Conclusion
4.1.3. Hydrogenolysis of protecting groups
Glycolipid based crown ethers of variable sizes, ranging from
15-crown-5 to 21-crown-7, involving different positions on the
sugar can be prepared in good yields by cation templating based
on hydroxyethylated alkyl glucosides and oligoethylene glycol
ditosylates. The introduction of ethylene glycol units on the sugar
prior to the formation of the macrocycle enhances the efficiency of
the synthesis significantly. The crown ethers enhance the solubility
of the surfactants in water slightly, thus increasing the CMC. Due to
their affinity for cation complexation, crown ether attached
glycolipids exhibit higher solubility in the presence of suitable
sized cations. The cation selectivity for glycolipid based crown
ethers depends on the ring size of the macrocycle. Crown ethers
involving six or less oxygen atoms favor sodium over potassium.
Both, cation selectivity and the effect of suitable electrolytes on
the solubility, give rise to potential medical applications, that is,
for drug delivery.
The benzylidated or benzylated crown ether was dissolved in
MeOH (ꢀ100 mL), treated with HOAc (5 drops) and Pd/C (25 mg,
10%) and the reaction was stirred under H2 atmosphere (4 bar)
overnight. The catalyst was removed by membrane filtration and
the solvent was evaporated to furnish clean final products.
4.2. n-Dodecyl 4,6-O-benzylidene-2,3-bis-(2-hydroxyethyl)-b-D-
glucopyranoside (6)
Compound 4b17,§ (3.5 g, 8.0 mmol) was reacted according to
general procedure A1 to furnish 5 (4.8 g, 90 %) as a colorless oil.
The intermediate 5– (2.65 g, 4 mmol) was subjected to general
reaction procedure A2 to give 6 as a colorless syrup (1.78 g, 85 %,
77 % based on 4b). [
a
]
D = À42.5 (c 0.2, CHCl3). 1H NMR (400 MHz,
CDCl3) d = 7.51–7.28 (m, 5H, Ph), 5.54 (s, PhCH), 4.40 (d, H-1), 4.35
(dd, H-6eq), 4.00–3.48, 3.35–3.18 (2 m, 14 H), 3.38 (ddd, H-5),
1.67–1.60 (m, 2 H, b-CH2), 1.32–1.23 (m, 18 H, bulk-CH2), 0.88 (t,
4. Experimental
3
H, CH3), 3J1,2 = 8.0, 3J4,5 = 10.0, 3J5,6ax = 10.0, 3J5,6eq = 5.0,
2J6eq,6ax = 10.5 Hz. 13C NMR (100 MHz, CDCl3) d = 129.24, 128.42,
4.1. General methods
126.05 (Ph), 103.84 (C-1), 101.61 (PhCH), 82.11 (C-2), 81.50, 81.43
(C-3, C-4), 74.68 (2CH2OR), 70.69 (
62.25 (2 CH2OH), 31.99 (b), 29.75, 29.71, 29.68, 29.43 (bulk-CH2),
26.02 ), 22.77 -1), 14.20
). HRMS: [M+Na]+ calcd for
29H48O8Na: 547.3247, 548.3280 (32%), found: 547.3240 (100%),
a), 68.80 (C-6), 66.13 (C-5),
Melting points were determined on an optical polarizing
microscope with hot stage as well as by DSC and are uncorrected.
Optical rotations were measured at 589 nm in 10 cm cells at room
temperature. NMR spectra were recorded on Jeol Lambda and ECA
DELTA spectrometers at 400 MHz for 1H and 100 MHz for 13C,
respectively. Assignment of 1H signals and coupling constants
partially applied COSY and homolog J-resolved spectra, while 13C
signals are based on HMQC spectra. Critical micelle concentrations
were determined by surface tension measurements. The
intersection of the concentration dependent and the high concen-
tration independent regions in the plot of the surface tension vs.
(
c
(
x
(x
C
548.3535 (33%).
§
Synthetic procedure for 4b in Supplementary data.
Spectral data for 5 in Supplementary data.
–

K. Sabah et al. / Carbohydrate Research 346 (2011) 891–896
895
4.3. n-Dodecyl 4,6-O-benzylidene-2,3-O-[15-crown-5]-b-
D
-
CD3OD) d = 4.28 (d, H-1), 4.04–3.15 (m, 27 H), 3.17 (ddꢀt, H-3),
1.63–1.52 (m, 2 H, b-CH2), 1.40–1.15 (m, 18 H), 0.88 (t, 3 H, CH3),
glucopyranoside (7)||
3
3
3
3J1,2 = 8.0, J2,3 = 9.0, J3,4 = 9.0, J4,5 = 9.0 Hz. 13C NMR (100 MHz,
CD3OD) d = 105.12 (C-1), 86.56 (C-3), 83.61 (C-2), 77.84 (C-5),
73.98, 73.25, 72.19, 72.14, 71.93 (CH2O), 71.83 (C-4), 71.62,
71.40, 70.87 (CH2O), 62.77 (C-6), 33.05 (b), 30.75, 30.71, 30.67,
Compound
6 (315 mg, 0.6 mmol) was reacted with NaH
(260 mg, 6 mmol) and diethylene glycol ditosylate (249 mg,
0.6 mmol) in THF (total 200 mL) according to general procedure
B to give waxy yellow solid 7 (180 mg, 50%). [
a
]
D = +30.5 (c 0.2,
30.43 (bulk-CH2), 27.19 (c), 23.65 (x-1), 14.31 (x). HRMS:
CHCl3). 1H NMR (400 MHz, CDCl3) d = 7.51–7.28 (m, 5 H, Ph),
5.51 (s, PhCH), 4.40 (d, H-1), 4.31 (dd, H-6eq), 4.05–3.46 (m, 21
H), 3.34 (ddd, H-5), 3.19 (dd, H-2), 1.67–1.55 (m, 2 H, b-CH2),
[M+Na]+ calcd for C28H54O10Na: 573.3615, 574.3648 (31%, 113C),
found: 573.3617 (100%), 574.3654 (33%).
3
1.32–1.23 (m,18 H, bulk-CH2), 0.88 (t, 3 H, CH3), J1,2 = 8.0,
4.7. n-Dodecyl 2,3-O-[21-crown-7]-b-D-glucopyranoside (12)
3
3
3
3J2,3 = 9.0, J4,5 = 9.0, J5,6ax = 10.0, J5,6eq = 5.0 Hz, 2J6 = 10.5 Hz.
13C NMR (100 MHz, CDCl3) d = 137.63 (Ph-C), 129.18, 128.49,
126.22 (Ph-CH), 104.26 (C-1), 101.13 (PhCH), 82.53 (C-2), 81.58,
81.54 (C-3, C-4), 72.61, 72.52, 71.17 (2), 70.64, 70.55 (2), 70.20
Compound 6 (315 mg, 0.6 mmol) was dissolved in tBuOH
(100 mL) containing KOtBu (150 mg, 1.5 mmol). The mixture was
heated with stirring for 1 h, before a solution of tetraethylene
glycol ditosylate (301 mg, 0.6 mmol) in dioxane (100 mL) was
added dropwise in a period of 3 h. The mixture was heated at reflux
overnight. After evaporation of the solvent, the residue was taken
up in CH2Cl2 and washed successively with water and dried over
MgSO4. The solvent was evaporated and the crude product purified
by chromatography (hexane–EtOAc 3:1) to furnish 11 as a yellow
syrup (178 mg, 42%). The product 11 (140 mg, 0.20 mmol) was
reacted according to general procedure C to give 12 (112 mg, 92%).
(2) (8 CH2O,
a), 68.73 (C-6), 65.73 (C-5), 31.66 (b), 29.39 (3),
29.09 (bulk-CH2), 25.68
(c), 22.39 (x-1), 13.79 (x). HRMS:
[M+Na]+ calcd for C33H54O9Na: 617.3666, 618.3699 (37%), found:
617.3640 (100%), 618.3727 (44%, 1 13C). Elemental Anal. Calcd for
C33H54O9: C, 66.64; H, 9.15. Found: C, 66.16; H, 8.69.
4.4. n-Dodecyl 2,3-O-[15-crown-5]-b- -glucopyranoside (8)
D
Compound 7 (100 mg, 0.16 mmol) was reacted according to
general procedure C to give colorless waxy 8 (81 mg, 95%). Phases:
Phases: only isotropic,
[
a]
D = À16.5 (c 0.2, CHCl3). 1H NMR
(400 MHz, CD3OD) d = 4.29 (d, H-1), 4.18–3.43 (m, 28 H), 3.33 (ddꢀt,
H-4), 3.21 (mc, H-5), 3.20 (ddꢀt, H-3), 3.05 (dd, H-2), 1.64–1.48 (m, 2
H, b-CH2), 1.40–1.15 (m, 18 H), 0.88 (t, 3 H, CH3), 3J1,2 = 8.0, 3J2,3 = 9.0,
3J3,4 = 9.0, 3J4,5 = 9.0 Hz. 13C NMR (100 MHz, CD3OD) d = 104.91 (C-1),
86.45 (C-3), 84.03 (C-2), 77.73 (C-5), 73.72, 73.00, 72.40, 72.19,
72.15, 71.94, 71.85 (CH2O), 71.84 (C-4), 71.83, 71.68, 71.35, 71.30,
70.93 (CH2O), 62.77 (C-6), 33.04 (b), 30.76, 30.72, 30.70, 30.46,
Lb 62 °C (
D
H 30 kJ/mol) Iso, [
a
]
D = À20.5 (c 0.2, CHCl3). 1H NMR
(400 MHz, CD3OD) d = 4.28 (d, H-1), 4.04–3.55 (m, 19 H, 8 CH2O,
a
-CH2a, H-6a, H-6b), 3.48 (dt,
a
-CH2b), 3.33 (ddꢀt, H-4), 3.19
(ddd, H-5), 3.17 (ddꢀt, H-3), 3.01 (dd, H-2), 1.61–1.52 (m, 2 H,
3
b-CH2), 1.40–1.21 (m, 18 H), 0.88 (t,
3 H, CH3), J1,2 = 8.0,
3J2,3 = 9.0, J3,4 = 9.0, J4,5 = 9.5, J5,6a = 5.0, J5,6b = 2.5 Hz. 13C NMR
(100 MHz, CD3OD) d = 105.10 (C-1), 86.56 (C-3), 83.61 (C-2),
77.82 (C-5), 73.99, 73.24, 72.19, 72.13, 71.92 (CH2O), 71.82 (C-4),
71.61, 71.40, 70.87 (CH2O), 62.76 (C-6), 33.05 (b), 30.75, 30.72,
3
3
3
3
30.43 (bulk-CH2), 27.19
(c), 23.65 (x-1), 14.32 (x). HRMS:
[M+Na]+ calcd for C28H54O10Na: 617.3877, 618.3910 (33%, 113C),
found: 617.3822 (100%), 618.3256 (37%).
30.67, 30.43 (bulk-CH2), 27.19 (c), 23.65 (x-1), 14.32 (x). HRMS:
[M+Na]+ calcd for C26H50O9Na: 529.3353, 530.3386 (29%, 113C),
found: 529.3357 (100%), 530.3441 (34%).
4.8. n-Dodecyl 2,3-di-O-dibenzyl-4,6-bis-O-[2-hydroxyethyl]-b-
D-glucopyranoside (16)
4.5. n-Dodecyl 4,6-O-benzylidene-2,3-O-[18-crown-6]-b-
D-
Compound 14 (2.0 g, 4.6 mmol) was reacted according to
glucopyranoside (9)
general procedure A1 to provide 15 as a colorless syrup (2.87 g,
90%). The intermediate 15 (2.5 g, 3.6 mmol) was directly converted
according to general procedure A2 to provide 16 as a colorless
Compound 6 (315 mg, 0.6 mmol) was reacted with 260 mg
(6 mmol) NaH and triethylene glycol ditosylate (249 mg,
0.6 mmol) in THF (total 200 mL) according to general procedure
syrup (1.73 g. 85%/75% based on 14). [a]
D = +5 (c 0.2, CHCl3). 1H
NMR (400 MHz, CDCl3) d = 7.38–7.25 (m, 10 H, Ph), 4.94 (2 d,
2 H, Bn), 4.74 (d, Bn), 4.68 (d, Bn), 4.37 (d, H-1), 3.92–3.31
(m, 15H), 3.40 (dd, H-2), 1.68–1.57 (m, 2H, b-CH2), 1.40–1.18
B
to give pure 9 as a white semisolid (169 mg, 44 %).
[
a
]
D = À32.5 (c 0.2, CHCl3). 1H NMR (400 MHz, CDCl3) d = 7.49–
3
3
2
7.45 and 7.39–7.33 (2 m, 2+3 H, Ph), 5.51 (s, PhCH), 4.40 (d, H-1),
4.31 (dd, H-6eq), 4.06–3.47 (m, 25 H), 3.33 (ddd, H-5), 3.19 (dd,
H-2), 1.67–1.60 (m, 2 H, b-CH2), 1.32–1.23 (m, 18 H), 0.88 (t, 3 H,
(m, 18 H), 0.86 (t, 3 H, CH3), J1,2 = 8.0, J2,3 = 9.0, JBn = 11.0 Hz.
13C NMR (100 MHz, CDCl3) d = 128.67, 128.65, 128.39, 128.24,
128.05, 127.98 (Ph), 103.86 (C-1), 84.14 (C-3), 82.30 (C-2), 78.50
(C-4), 75.64, 74.75 (CH2OR), 74.33 (C-5), 74.04, 73.30 (Bn), 70.27,
CH3), J1,2 = 8.0, J2,3 = 9.0, J4,5 = 10.0 Hz, J5,6eq = 5.0, 2J6 = 10.5 Hz.
13C NMR (100 MHz, CDCl3) d = 138.82 (Ph-C), 129.18, 128.50,
126.23 (Ph-CH), 104.27 (C-1), 101.13 (PhCH), 82.53 (C-2), 81.59,
81.55 (C-3, C-4), 72.61, 72.52, 71.17 (2), 70.64, 70.55, 70.53,
3
3
3
3
70.18 (C-6,
29.36, 29.31, 29.17, 29.07 (bulk-CH2), 25.86 (
14.19
). HRMS: [M+Na]+ calcd for C36H56O8Na: 639.3873,
640.3906 (40%), found: 639.3932 (100%), 640.3952 (46%).
a
), 62.48, 61.66 (CH2OH), 31.65 (b), 29.48, 29.39,
c
), 22.67 ( -1),
x
(x
70.20, 70.18 (CH2O,
a), 68.73 (C-6), 65.80 (C-5), 31.66 (b), 29.39,
29.35, 29.32, 29.09 (bulk-CH2), 25.68 (c), 22.39 (x-1), 13.78 (x).
HRMS: [M+Na]+ calcd for C35H58O10Na: 661.3928, 662.3961 (39%,
113C), found: 661.3919 (100%), 662.4533 (44%).
4.9. n-Dodecyl 2,3-O-dibenzyl-4,6-O-[19-crown-6]-b-D-
glucopyranoside (17)
4.6. n-Dodecyl 2,3-O-[18-crown-6]-b-
D
-glucopyranoside (10)
Compound 16 (325 mg, 0.5 mmol) was reacted with NaH
(220 mg, 5.0 mmol) and triethylene glycol ditosylate (230 mg,
0.5 mmol) in THF (total 200 mL) according to general procedure
Compound 9 (100 mg, 0.15 mmol) was reacted according to
general procedure C to give 10 (82 mg, 95%). Phases: Lb 51 °C
B to give 17 as a colorless syrup (147 mg, 40%). [a]D = +9 (c 0.2,
(D
H 19 kJ/mol) Iso, [
a
]
D = À17 (c 0.2, CHCl3). 1H NMR (400 MHz,
CHCl3). 1H NMR (400 MHz, CDCl3) d = 7.40–7.25 (m, 10 H, Ph),
||
Alternative synthesis procedure for 7 in Supplementary data.
Spectral data for 11 in Supplementary data.

896
K. Sabah et al. / Carbohydrate Research 346 (2011) 891–896
4.92 (d, Bn), 4.89 (d, Bn), 4.73 (d, Bn), 4.68 (d, Bn), 4.35 (d, H-1),
4.03 (dd, H-6a), 4.00–3.45 (m, 20 H, 8 CH2O, 2 -CH2, H-3, H-6b),
27.01 (
26H50O9Na: 529.3353, 530.3386 (29%), found: 529.3432 (100%),
530.4245 (34%).
c), 23.67 (x-1), 14.32 (x
). HRMS: [M+Na]+ calcd for
a
C
3.42 (ddd, H-5), 3.37 (dd, H-2), 3.28 (ddꢀt, H-4), 1.70–1.52 (m, 2
H, b-CH2), 1.40–1.20 (m, 18 H, bulk-CH2), 0.85 (t, 3 H, CH3),
3
3
3
3
3
3J1,2 = 8.0, J2,3 = 9.5, J3,4 = 9.0, J4,5 = 9.0, J5,6a = 2.0, J5,6b = 6.0,
4.13. Mass spectrometry
2
2J6 = 10.5, JBn = 11.0 Hz. 13C NMR (100 MHz, CDCl3) d = 128.57,
128.40, 128.20, 128.08, 127.85, 127.78 (Ph), 103.66 (C-1), 84.70
(C-3), 82.24 (C-2), 78.85 (C-4), 75.47, 74.73 (Bn-CH2), 74.50 (C-5),
72.29, 71.24, 71.18, 70.77, 70.61, 70.53, 70.48, 70.41, 70.36,
High-resolution mass spectra were recorded on an Agilent
Technologies 6530 Accurate Q-TOF LC–MS system, applying
MeOH–water eluents. A gas flow of 250 °C hot nitrogen at 5 mL,
min and electrospray ionization at 125 V were applied. For ion
selectivity measurements an electrolyte comprising of 1 mM of
each KBr and NaBr replaced the water in the eluent. Measurements
70.18, 70.15 (10 CH2O, C-6,
a), 31.63 (b), 29.47, 29.38, 29.35,
29.19, 29.06 (bulk-CH2), 25.85 (c), 22.36 (x-1), 13.76 (x). HRMS:
[M + Na]+ calcd for C42H66O10Na: 753.4554, 754.4587 (47%, 113C),
found: 753.4543 (100%), 754.4639 (53%).
were performed in duplicates. In
a controlling experiment
10 mmol acetic acid per liter was added to the electrolyte.
4.10. n-Dodecyl 4,6-O-[19-crown-6]-b-D-glucopyranoside (18)
4.14. Computer simulation
Compound 17 (120 mg, 0.16 mmol) was reacted according to
general procedure C to give 18 (69 mg, 95%). Phases: Lb 66 °C
The structure in Figure 1 was obtained by MOPAC minimization
in Chem3D using the AM1 theory. A sodium templating cation was
applied to obtain a conformation of the macrocycle suitable for
complexation. This cation was finally removed from the structure.
(D
H
24 kJ/mol) Iso,
[a
]
D = À11.5 (c 0.2, CHCl3). 1H NMR
(400 MHz, CDCl3) d = 4.16 (d, H-1), 4.00–3.29 (m, 25 H, OCH2,
a
-CH2, H-3, H-6), 3.48 (mc, H-5), 3.40 (ddꢀt, H-4), 3.13 (dd, H-2),
1.61–1.51 (m, 2H, b-CH2), 1.39–1.20 (m, 18H, bulk-CH2), 0.85 (t,
3H, CH3), J1,2 = 8.0, J2,3 = 9.0, J3,4 = 9.0, J4,5 = 9.0 Hz. 13C NMR
(100 MHz, CDCl3) d = 104.80 (C-1), 80.03 (C-4), 78.23 (C-5), 76.27
(C-3), 75.36 (C-2), 73.19 (C-6), 72.21, 72.11, 72.04, 71.96, 71.89
3
3
3
3
Acknowledgment
This work was supported by the University of Malaya under
research Grants FP349/2008A, PS236/2009A and RG026/09AFR.
(2), 71.78 (2), 71.56, 71.26, 71.11 (10 CH2O,
a
), 33.04 (b), 30.75,
30.70, 30.53, 30.43 (bulk-CH2), 27.01 (
c
), 23.54 ( -1), 14.31 ( ).
x
x
HRMS: [M+Na]+ calcd for C28H54O10Na: 573.3615, 574.3648 (31%,
113C), found: 573.3670 (100%), 574.4332 (33%).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2011.03.002.
4.11. n-Dodecyl 2,3-O-dibenzyl-4,6-O-[16-crown-5]-b-D-
glucopyranoside (19)
References
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0.5 mmol) in THF (total 200 mL) according to general procedure
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(c 0.2, CHCl3). 1H NMR (400 MHz, CDCl3) d = 7.38–7.25 (m, 10 H,
Ph), 4.92 (d, Bn), 4.89 (d, Bn), 4.73 (d, Bn), 4.67 (d, Bn), 4.36 (d,
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8CH2O,
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a-CH2a), 3.93–3.47 (m, 18H,
a
3
3
(m, 18H, bulk-CH2), 0.86 (t,
3 H, CH3), J1,2 = 8.0, J2,3 = 9.5,
3J3,4 = 9.0, J4,5 = 9.0, J5,6a = 2.0, J5,6b = 6.0, 2J6 = 10.5, JBn = 11.0,
3
3
3
2
3J ,b = 6.0, 2J = 9.5 Hz. 13C NMR (100 MHz, CDCl3) d = 128.59,
a
a
128.42, 128.35, 128.10, 127.88, 127.80 (Ph), 103.67 (C-1), 84.71
(C-3), 82.25 (C-2), 78.84 (C-4), 75.49, 74.74 (Bn-CH2), 74.50(C-5),
72.30, 71.20, 70.69, 70.53, 70.47, 70.42, 70.42, 70.19 (2) (8 CH2O,
C-6,
a), 31.65 (b), 29.48, 29.48, 29.40, 29.36, 29.32, 29.21, 29.08
(bulk-CH2), 25.85 (
c
), 22.31 (x-1), 13.77 (x
). HRMS: [M+Na]+ calcd
for C40H62O9Na: 709.4292, 710.4325 (44%, 1 13C), found: 709.4302
(100%), 710.4433 (54%).
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4.12. n-Dodecyl 4,6-O-[16-crown-5]-b-D-glucopyranoside (20)
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general procedure C to give 20 (77 mg, 95%). Phases: Lb 57 °C
(
D
H 22 kJ/mol) Iso, [
a
]
D = À12 (c 0.2, CHCl3). 1H NMR (400 MHz,
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H-6b), 3.95 (dd, H-6a), 3.38 (ddꢀt, H-3), 3.31 (mc, H-5) 3.13 (ddꢀt,
H-4), 3.10 (dd, H-2), 1.60–1.50 (m, 2H, b-CH2), 1.36–1.20 (m,18 H,
3
3
3
bulk-CH2), 0.84 (t, 3H, CH3), J1,2 = 8.0, J2,3 = 9.0, J3,4 = 9.0,
3J4,5 = 9.0, J5,6a = 2.0, 2J6 = 11.0 Hz. 13C NMR (100 MHz, CD3OD)
3
d = 104.68 (C-1), 80.49 (C-4), 78.72 (C-5), 75.97 (C-3), 75.44 (C-2),
73.42 (C-6), 72.14, 72.08, 71.93, 71.78, 71.74 (2), 71.67, 71.40,
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a), 33.06 (b), 30.77, 30.73, 30.55, 30.45 (bulk-CH2),
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