New modified single chained glycolipids. Part 1: Synthesis of deoxy and partially O-methylated glycolipids with or without a sulfur containing spacer

Article abstract of DOI:10.1016/S0009-3084(01)00196-7

A way to synthesize neoglycolipids with high yields and anomeric purity is described. Starting point of the synthesis strategy is the glycosylation of allyl alcohol with definite steric orientation. Introduction of the hydrophobic moiety was achieved by photoaddition of n-hexadecanethiol and 3-mercaptopropionic acid followed by amidation with n-hexadecylamine, respectively. In order to investigate the influence of different carbohydrate headgroups in the physicochemical behavior of the general glycolipid, especially the orientation of the alkyl chain, a range of neoglycolipids was synthesized. Beside the differences in the configuration between unfunctionalized glycopyranoses like D-glucose, D-galactose and D-mannose, a number of deoxy and partially O-methylated sugar derivatives was prepared. The divergences concerning the different carbohydrate headgroups and the hydrophobic moiety, respectively, can be compared to relatively simple structured glycolipids with hexadecyl residue and without spacer function.

Full text of DOI:10.1016/S0009-3084(01)00196-7

Chemistry and Physics of Lipids
14 (2002) 139–147
1
www.elsevier.com/locate/chemphyslip
New modified single chained glycolipids. Part 1: synthesis of
deoxy and partially O-methylated glycolipids with or
without a sulfur containing spacer
M. Schmidt, S.K. Chatterjee, B. Dobner, P. Nuhn *
Institute of Pharmaceutical Chemistry, Martin-Luther-Uni6ersity, Wolfgang-Langenbeck-Strasse 4, D-06120 Halle/Saale, Germany
Received 23 April 2001; received in revised form 8 October 2001; accepted 10 October 2001
Abstract
A way to synthesize neoglycolipids with high yields and anomeric purity is described. Starting point of the synthesis
strategy is the glycosylation of allyl alcohol with definite steric orientation. Introduction of the hydrophobic moiety
was achieved by photoaddition of n-hexadecanethiol and 3-mercaptopropionic acid followed by amidation with
n-hexadecylamine, respectively. In order to investigate the influence of different carbohydrate headgroups in the
physicochemical behavior of the general glycolipid, especially the orientation of the alkyl chain, a range of
neoglycolipids was synthesized. Beside the differences in the configuration between unfunctionalized glycopyranoses
like
D-glucose, D-galactose and D-mannose, a number of deoxy and partially O-methylated sugar derivatives was
prepared. The divergences concerning the different carbohydrate headgroups and the hydrophobic moiety, respec-
tively, can be compared to relatively simple structured glycolipids with hexadecyl residue and without spacer function.
©
2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Synthesis; Neoglycolipid; Carbohydrate; Spacer
1
. Introduction
processes, e.g. inflammatory response or immune
response (Lee and Lee, 1995). The specificity of
this ligand–receptor binding is dependent on the
configurational features of the hydrophilic sugar
moiety. So a complete knowledge and descrip-
tion of the orientation, conformation and surface
density are of decisive importance for further
investigations. The utilization of natural glyco-
Neoglycoconjugates are of growing interest in
the understanding of biological phenomena as
well as the physicochemical behavior of model
systems. It is well known that interactions be-
tween natural carbohydrates on the surface of
cells are responsible for a range of recognition
X
conjugates, e.g. Sialyl Lewis (T o¨ pfer et al.,
1
994) is very difficult because of the problematic
isolation and the difficulties of total synthesis
based on the complexity of these compounds. So
*
Corresponding author.
E-mail address: nuhn@pharmazie.uni-halle.de (P. Nuhn).
0
009-3084/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S0009-3084(01)00196-7

1
40
M. Schmidt et al. / Chemistry and Physics of Lipids 114 (2002) 139–147
the interest in simple structured neoglycolipids
with the possibility to vary the structure concern-
ing the carbohydrate domain and the hydropho-
bic anchor is rising up. It was shown that the
character of the terminal sugar headgroup deter-
minates the efficiency of the ligand coupling to the
receptor (Ladisch et al., 1992). Furthermore such
an interaction can only occur when the carbohy-
drate domain is separated from the hydrophobic
moiety ergo the size of the spacer in the molecule
has to be optimized according to the specific
receptor (Berthelot et al., 1998). Finally the struc-
ture of the hydrophobic lipid anchor has an influ-
ence on the properties of the general glycolipid
with regard to the length of the alkyl chain and its
orientation.
Main problem of conventional neoglycolipid
synthesis is the relatively low overall yield of the
glycosylation step between glycosyl donor and
acceptor including the stereoselectivity especially
in the case of long chain alcohols. A range of
improvements concerning the glycosylation meth-
ods was accomplished but the low reactivity of
long chain alcohols is the crucial point of the
synthesis. In continuation of our efforts devoted
to the synthesis of glycolipids as membrane-
bound stabilizing carbohydrates (Wilhelm et al.,
2. Material and methods
NMR spectra were recorded in a Bruker AC
500 spectrometer at a frequency of 400 MHz with
TMS as an internal standard. Mass spectra were
obtained by using a Finnigan MAT 710 spectrom-
eter. The ionization was effected at 4.5 kV both in
negative and positive mode. Elemental analyses
were performed with a CHNS-932 apparatus
(
LECO Corporation). Column chromatography
was carried out with silica gel 60 (0.04–0.2 mm,
Merck) and preparative, centrifugally accelerated,
radial, thin layer chromatography with a Chro-
matotron (Harrison Research). All reactions were
performed under argon atmosphere. Solvents
were dried before use. All chemicals were pur-
chased directly from Aldrich and Fluka.
2.1. Synthesis
2.1.1. General method for 1,2-trans-glycosylation
using TMS-triflate
TMS-triflate (0.01 mol) was added to a solution
of peracetylated monosaccharide 1 (0.01 mol) in
dry CH Cl (20 ml) and freshly activated molecu-
2
2
lar sieves and stirred for 30 min at 20 °C. Hex-
adecanol (0.01 mol) was added and the mixture
stirred overnight at room temperature.
1
995) we developed a strategy which makes use of
Next day it was filtered under dry condition,
the reactive allyloxy group as a glycosyl acceptor
into the carbohydrate molecule. Photoaddition of
the double bond with a long chain thiol or with
filtrate was made basic with NaHCO
tracted with CH Cl . The organic extract was
3
and ex-
2
2
washed with water and dried. The residue ob-
tained after evaporation of the solvent was dis-
solved in MeOH and deacetylation was achieved
3-mercaptopropionic acid followed by amidation
affords a range of new compounds which are
characterized by different structured carbohydrate
headgroups. The varying terminal sugar residues
containing partially deoxygenated or O-methy-
lated domains were synthesized to investigate bio-
chemically the influence of the hydrogen bonding
strength contingent on the stereoscopic arrange-
ment of the hydroxy groups in the ligand receptor
binding. This neoglycolipids and a number of
conventionally prepared glycosides with the hex-
adecyloxy aglycon are destined for first physico-
chemical investigations to the conformational
orientation of the alkyl chain by differential scan-
ning calorimetry, X-ray diffraction and Raman
spectroscopy.
with NH –MeOH followed by purification
through chromatography over silica gel led to the
desired products 2a–d.
3
2
.1.1.1. Hexadecyl i-
D
-glucopyranoside (2a). MS
+
(
(
ES, positive ions): m/z 427.58 (M+23) ; R
CHCl /MeOH 8:2) 0.58; yield 32%; Anal. Calc.
f
3
for C H O : C, 65.31; H, 10.96. Found: C,
22
44
6
6
5.04; H, 10.89%.
2.1.1.2. Hexadecyl 6-O-methyl-i-
D
-glucopyra-
noside (2b). MS (ES, positive ions): m/z 441.61
+
(M+23) ; R (CHCl /MeOH 8:2) 0.66; yield
f
3
17%; Anal. Calc. for C H O : C, 65.99; H,
23
46
6
11.08. Found: C, 65.88; H, 11.15%.

M. Schmidt et al. / Chemistry and Physics of Lipids 114 (2002) 139–147
141
2
.1.1.3. Hexadecyl 3-O-methyl-i-
D
-glucopyra-
J=9.4 and 9.7 Hz, 1H, 4-H), 5.25 (dd, J=9.4
and 9.5 Hz, 1H, 3-H), 5.79–5.81 (m, 1H,
CH ꢀCHꢁCH ): MS (ES, positive ions): m/z
noside (2c). MS (ES, positive ions): m/z 441.61
+
(
M+23) ; R (CHCl /MeOH 8:2) 0.65; yield
f 3
2
2
+
1
1
3%; Anal. Calc. for C H O : C, 65.99; H,
411.36 (M+23) ; R (petroleum ether/EtOAc
23
46
6
f
1.08. Found: C, 65.95; H, 11.17%.
6:4) 0.42; yield 62%; Anal. Calc. for C H O : C,
17
24 10
5
2.58; H, 6.23. Found: C, 52.52; H, 6.28%.
2
.1.1.4. Hexadecyl 6-deoxy-i- -glucopyranoside
D
(
2
2d). MS (ES, positive ions): m/z 411.58 (M+
2
.1.2.3. Allyl 2,3,4,6-tetra-O-acetyl-i- -galac-
D
+
3) ; R (CHCl /MeOH 8:2) 0.58; yield 15%;
1
f
3
topyranoside (4c). H NMR (CDCl ): l=1.96,
2
3
Anal. Calc. for C H O : C, 68.00; H, 11.41.
Found: C, 67.92; H, 11.26%.
22
44
5
.03, 2.04, 2.14 (4s, 12H, 4 COCH ), 4.08–4.19
3
(
m, 4H, 5-H, ꢀOCH , 6-H), 4.31 (dd, J=1.6 and
2
5
4
5
.9 Hz, 1H, 6%-H), 4.49 (d, J=8.3 Hz, 1H, 1-Hb),
2
.1.2. General method for the synthesis of the
.98 (dd, J=7.8 and 10.4 Hz, 1H, 2-H), 5.17–
peracetylated allyl glycopyranosides 4
.28 (m, 3H, ꢀCHꢁCH , 4-H), 5.36 (dd, J=3.5
2
A solution of peracetylated monosaccharide
and 10.4 Hz, 1H, 3-H), 5.79–5.88 (m, 1H,
CH ꢀCHꢁCH ); MS (ES, positive ions): m/z
(
0.01 mol) in dry CH Cl (15 ml) was stirred with
2 2
2
2
BF ·Et O (0.011 mol) at room temperature for 1
+
3
2
4
6
5
11.36 (M+23) ; R (petroleum ether/EtOAc
f
h. Allyl alcohol (0.015 mol) was then added to it
and stirred at room temperature for 4 h. This was
then cooled to 0 °C and the mixture stirred with
:4) 0.41; yield 73%; Anal. Calc. for C H O : C,
17
24 10
2.58; H, 6.23. Found: C, 52.54; H, 6.27%.
saturated NaHCO to basify and to destroy the
3
2
.1.2.4. Allyl 6-O-methyl-2,3,4-tri-O-acetyl-i-
D
-
Lewis acid it was stirred for another 30 min. The
resulting mixture was then extracted with ether
and washed with water. Chromatographic
purification led to the allyl glycosides 4 in good
yield.
1
glucopyranoside (4d). H NMR (CDCl ): l=1.93,
3
1
ꢀ
2
.95, 1.98 (3s, 9H, 3 COCH ), 3.35 (s, 3H,
3
OCH ), 3.61–3.65 (m, 1H, 5-H), 4.00–4.09 (m,
3
H, 6-H, 6%-H), 4.18–4.30 (m, 2H, ꢀOCH ), 4.49
2
(
d, J=7.8 Hz, 1H, 1-Hb), 4.93 (dd, J=7.6 and
9
.6 Hz, 1H, 2-H), 4.97 (dd, J=9.5 and 9.8 Hz,
1H, 4-H), 5.17 (dd, J=9.4 and 9.6 Hz, 1H, 3-H),
.11–5.22 (m, 2H, ꢀCHꢁCH ), 5.73–5.82 (m, 1H,
2
.1.2.1. Allyl 2,3,4,6-tetra-O-acetyl-h-
D
-mannopy-
1
ranoside (4a). H NMR (CDCl ): l=1.96, 2.01,
3
5
2
2
ꢀ
6
.08, 2.13 (4s, 12H, 4 COCH ), 3.96–4.03 (m, 2H,
3
CH ꢀCHꢁCH ); MS (ES, positive ions): m/z
2
2
OCH ), 4.06–4.10 (dd, J=2.3 and 12.1 Hz, 1H,
2
+
3
6
5
83.35 (M+23) ; R (petroleum ether/EtOAc
f
-H), 4.14–4.19 (m, 1H, 5-H), 4.24–4.28 (dd,
:4) 0.45; yield 66%; Anal. Calc. for C H O : C,
16
24
9
J=5.2 and 12.2 Hz, 1H, 6%-H), 4.84 (d, J=1.8
3.33; H, 6.71. Found: C, 53.17; H, 6.82%.
Hz, 1H, 1-Ha), 5.20–5.37 (m, 5H, ꢀCHꢁCH ,
2
2-H,
4-H,
3-H),
5.82–5.92
(m,
1H,
CH ꢀCHꢁCH ); MS (ES, positive ions): m/z
2.1.2.5. Allyl 3-O-methyl-2,4,6-tri-O-acetyl-i-D-
2
2
+
1
4
6
5
11.36 (M+23) ; Rf (petroleum ether/EtOAc
glucopyranoside (4e). H NMR (CDCl ): l=2.04,
3
:4) 0.44; yield 93%; Anal. Calc. for C H O : C,
2.58; H, 6.23. Found: C, 52.53; H, 6.26%.
2.05, 2.06 (3s, 9H, 3 COCH ), 3.36 (s, 3H,
17
24 10
3
ꢀOCH ), 3.52–3.57 (m, 1H, 5-H), 4.01–4.23 (m,
3
4
H, 6-H, 6%-H, ꢀOCH ), 4.41 (d, J=8.0 Hz, 1H,
2
2
.1.2.2. Allyl 2,3,4,6-tetra-O-acetyl-i- -glucopy-
D
1-Hb), 4.94–5.14 (m, 2H, ꢀCHꢁCH ), 4.95 (dd,
2
1
ranoside (4b). H NMR (CDCl ): l=2.00, 2.02,
J=7.7 and 9.6 Hz, 1H, 2-H), 5.13 (dd, J=9.5
and 9.6 Hz, 1H, 4-H), 5.20 (dd, J=9.4 and 9.5
Hz, 1H, 3-H), 5.76–5.85 (m, 1H, CH ꢀCHꢁCH );
3
2
.04, 2.08 (4s, 12H, 4 COCH ), 3.67–3.71 (m, 1H,
3
5
-H), 4.07–4.14 (m, 2H, ꢀOCH ), 4.17–4.22 (dd,
2
2
2
+
J=2.53 and 12.24 Hz, 1H, 6-H), 4.24–4.31 (dd,
J=4.66–12.24 Hz, 1H, 6%-H), 4.55 (d, J=7.8 Hz,
MS (ES, positive ions): m/z 383.356 (M+23) ;
R (petroleum ether/EtOAc 6:4) 0.36; yield 54%;
f
1
H, 1-Hb), 5.00–5.12 (m, 2H, ꢀCHꢁCH ), 5.18
Anal. Calc. for C H O : C, 53.33; H, 6.71.
Found: C, 53.19; H, 6.81%.
2
16 24
9
(
dd, J=7.9 and 9.5 Hz, 1H, 2-H), 5.21 (dd,

1
42
M. Schmidt et al. / Chemistry and Physics of Lipids 114 (2002) 139–147
2
.1.2.6. Allyl 2-deoxy-3,4,6-tri-O-acetyl-i-
D
-ara-
2.01, 2.02, 2.04 (4s, 12H, COCH ), 2.42 (t, 2H,
3
1
binohexopyranoside (4f). H NMR (CDCl ): l=
1
3
ꢀSCH (CH ) −), 2.51 (t, 2H, ꢀSCH (CH ) Oꢀ),
3
2
2 14
2
2 2
.78–1.85 (m, 1H, 2-H), 1.98, 2.01, 2.07 (3s, 9H,
3.73–3.88 (m, 2H, ꢀOCH ꢀ), 4.02–4.07 (dd, J=
2
COCH ), 2.21–2.26 (m, 1H, 2%-H), 3.92–4.14
2.3 and 12.3 Hz, 1H, 6-H), 4.12–4.17 (m, 1H,
5-H), 4.25–4.29 (dd, J=5.2 and 12.2 Hz, 1H,
6%-H), 4.87 (d, J=1.7 Hz, 1H, 1-Ha), 5.17–5.42
(m, 3H, 2-H, 4-H); MS (ES, positive ions): m/z
3
(m, 5H, 6-H, 6%-H, ꢀOCH , 5-H), 4.26 (dd, J=
2
1
ꢀ
5
2.3 and 4.6 Hz, 1H, 1-Hb), 4.94–5.17 (m, 2H,
CHꢁCH ), 4.98 (t, J=9.9 Hz, 1H, 4-H), 5.29–
2
+
.34 (m, 1H, 3-H), 5.83–5.93 (m, 1H,
685.88 (M+39) ; R (CHCl /Et O 8:2) 0.54; yield
f
3
2
CH ꢀCHꢁCH ); MS (ES, positive ions): m/z
95%; Anal. Calc. for C H O S: C, 61.27; H,
9.04; S, 4.96. Found: C, 61.23; H, 9.11; S, 5.00%.
2
2
33 58 10
+
3
6
5
53.32 (M+23) ; Rf (petroleum ether/EtOAc
:4) 0.47; yield 53%; Anal. Calc. for C H O : C,
4.54; H, 6.71. Found: C, 54.47; H, 6.75%.
15
22
8
2.1.3.2. (4-Thiaicosyl) 2%,3%,4%,6%-tetra-O-acetyl-i-
1
D
-glucopyranoside (5b). H NMR (CDCl ): l=
3
2
.1.2.7. Allyl 6-deoxy-2,3,4-tri-O-acetyl-i-
D
-glu-
0.84–0.87 (t, 3H, ꢀCH ), 1.22–1.28 (s, 26H,
3
1
copyranoside (4g). H NMR (CDCl ): l=1.55 (d,
ꢀCH ꢀ), 1.50–1.56 (m, 4H, ꢀSCH CH ꢀ), 1.98,
3
2
2
2
3
3
ꢀ
H, ꢀCH ), 1.97, 2.01, 2.02 (3s, 9H, 3 COCH ),
2.00, 2.02, 2.06 (4s, 12H, COCH ), 2.44 (t, 2H,
3
3
3
.51–3.55 (m, 1H, 5-H), 4.03–4.33 (m, 2H,
ꢀSCH (CH ) ꢀ), 2.50 (t, 2H, ꢀSCH (CH ) Oꢀ),
2
2 14
2
2 2
OCH ), 4.49 (d, J=8.01 Hz, 1H, 1-Hb), 4.80
3.61–3.69 (m, 2H, ꢀOCH ꢀ), 3.89–3.95 (m, 1H,
2
2
(
dd, J=7.5 and 9.5 Hz, 1H, 2-H), 4.95 (dd,
5-H), 4.18–4.26 (m, 2H, 6-H, 6%-H), 4.47 (d,
J=7.8 Hz, 1H, 1-Hb), 4.94 (dd, J=7.8 and 9.5
Hz, 1H, 2-H), 5.03 (dd, J=9.4 and 9.6 Hz, 1H,
J=9.5 and 9.5, 1H, 4-H), 5.11–5.18 (m, 2H,
ꢀ
3
CHꢁCH ), 5.22 (dd, J=9.6 and 9.7 Hz, 1H,
2
-H), 5.78–5.87 (m, 1H, CH ꢀCHꢁCH ); MS (ES,
4-H), 5.16 (dd, J=9.5 and 9.8, 1H, 3-H); MS
2
2
+
+
positive ions): m/z 453.32 (M+23) ; Rf
(ES, positive ions): m/z 685.88 (M+39) ; R
f
(
petroleum ether/EtOAc 6:4) 0.5; yield 54%; Anal.
(CHCl /Et O 8:2) 0.53; yield 95%; Anal. Calc. for
3
2
Calc. for C H O : C, 54.54; H, 6.71. Found: C,
C H O S: C, 61.27; H, 9.04; S, 4.96. Found: C,
33 58 10
1
5
22
8
54.45; H, 6.74%.
61.21; H, 9.13; S, 5.01%.
2
.1.3. General method for the photoaddition
2.1.3.3. (4-Thiaicosyl) 2%,3%,4%,6%-tetra-O-acetyl-i-
1
reaction of hexadecyl thiol to the peracetylated
allyl glycopyranosides 4
To a solution of 4 (0.01 mol) in 5 ml CHCl3
hexadecyl thiol (0.05 mol) was added. The mix-
ture was stirred in a quartz flask under argon
atmosphere at room temperature and irradiated at
D
-galactopyranoside (5c). H NMR (CDCl ): l=
3
0.83–0.88 (t, 3H, ꢀCH ), 1.23–1.27 (s, 26H,
3
ꢀCH ꢀ), 1.49–1.53 (m, 4H, ꢀSCH CH ꢀ), 1.97,
2
2
2
2.04, 2.05, 2.17 (4s, 12H, 4 COCH ), 2.46 (t, 2H,
3
ꢀSCH (CH ) ꢀ), 2.51 (t, 2H, ꢀSCH (CH ) Oꢀ),
2
2 14
2
2 2
3.63–3.69 (m, 2H, ꢀOCH ꢀ), 4.09–4.22 (m, 4H,
2
254 nm for 2 h.
5-H, ꢀOCH , 6-H), 4.34 (dd, J=1.8 and 5.8 Hz,
2
Detection of the quantitative reaction of double
1H, 6%-H), 4.53 (d, J=8.5 Hz, 1H, 1-Hb), 4.99
(dd, J=7.8 and 10.5 Hz, 1H, 2-H), 5.16–5.23 (m,
1H, 4-H), 5.42 (dd, J=3.3 and 10.4 Hz, 1H,
3-H); MS (ES, positive ions): m/z 669.87 (M+
bond was achieved by a solution of bromine in
MeOH. The mixture was diluted with water and
CHCl , the organic phase was separated and dried
3
+
over Na SO . The residue obtained after filtration
23) ; R (CHCl /Et O 8:2) 0.48; yield 95%; Anal.
2
4
f
3
2
and evaporation of the solvent was purified by
flash chromatography (petroleum ether/EtOAc
Calc. for C H O S: C, 61.27; H, 9.04; S, 4.96.
Found: C, 61.18; H, 9.12; S, 4.99%.
33 58 10
8:2 v/v) to give 5 in good yield.
2
.1.3.4. (4-Thiaicosyl) 6%-O-methyl-2%,3%,4%-tri-O-
1
2
D
.1.3.1. (4-Thiaicosyl) 2%,3%,4%,6%-tetra-O-acetyl-h-
acetyl-i-
D
-glucopyranoside (5d).
H
NMR
1
-mannopyranoside (5a). H NMR (CDCl ): l=
(CDCl ): l=0.84–0.91 (t, 3H, ꢀCH ), 1.18–1.39
3
3
3
0
.82–0.86 (t, 3H, ꢀCH ), 1.23–1.28 (s, 26H,
(s,
26H,
ꢀCH ꢀ),
1.50–1.55
(m,
4H,
3
2
ꢀCH ꢀ), 1.51–1.57 (m, 4H, ꢀSCH CH ꢀ), 1.99,
ꢀSCH CH ꢀ),1.98, 2.00, 2.02 (3s, 9H, 3 COCH ),
2
2
2
2
2
3

M. Schmidt et al. / Chemistry and Physics of Lipids 114 (2002) 139–147
143
2
.44 (t, 2H, ꢀSCH (CH ) ꢀ), 2.50 (t, 2H,
1.98, 2.0, 2.04 (3s, 9H, 3 COCH ), 2.49 (t, 2H,
2
2 14
3
ꢀ
SCH (CH ) Oꢀ), 3.39 (s, 3H, ꢀOCH ), 3.89–3.95
ꢀSCH (CH ) ꢀ), 2.53 (t, 2H, ꢀSCH (CH ) Oꢀ),
2
2 2
3
2
2 14
2
2 2
(
m, 1H, 5-H), 4.07–4.09 (m, 2H, 6-H, 6%-H),
3.55–3.58 (m, 1H, 5-H), 4.08–4.39 (m, 2H,
4
1
2
.13–4.21 (m, 2H, ꢀOCH ), 4,47 (d, J=8.0 Hz,
ꢀOCH ), 4.53 (d, J=8.2 Hz, 1H, 1-Hb), 4.86 (dd,
2
2
H, 1-Hb), 4.94 (dd, J=7.6 and 9.7 Hz, 1H,
J=7.7 and 9.6 Hz, 1H, 2-H), 4.99 (dd, J=9.5
and 9.7 Hz, 1H, 4-H), 5.27 (dd, J=9.6 and 9.8
Hz, 1H, 3-H); MS (ES, positive ions): m/z 611.84
-H), 5.06 (dd, J=9.3 and 9.7 Hz, 1H, 4-H), 5.13
(
dd, J=9.5 and 9.7 Hz, 1H, 3-H); MS (ES,
+
+
positive ions): m/z 657.86 (M+39) ; R (CHCl /
(M+23) ; R (petroleum ether /EtOAc 6:4) 0.32;
f
3
f
3
Et O 8:2) 0.59; yield 95%; Anal. Calc. for
2
yield 95%; Anal. Calc. for C H O S: C, 62.23;
31 56 8
C H O S: C, 62.11; H, 9.45; S, 5.18. Found: C,
H, 9.59; S, 5.44. Found: C, 62.17; H, 9.65; S,
5.42%.
3
2
58
9
62.05; H, 9.54; S, 5.13%.
After deacetylation of 5 with NH –MeOH
3
2
.1.3.5. (4-Thiaicosyl) 3%-O-methyl-2%,4%,6%-tri-O-
finally the glycolipids 6 were obtained in good
yield.
1
acetyl-i-
D
-glucopyranoside (5e).
H
NMR
(
CDCl ): l=0.84–0.89 (t, 3 H, ꢀCH ), 1.18–1.42
3
3
(
s, 26H, ꢀCH ꢀ), 1.50–1.57 (m, 4H, ꢀSCH CH ꢀ),
2
2
2
2
.1.3.8. (4-Thiaicosyl) h-
D
-mannopyranoside (6a).
2
ꢀ
3
4
.04, 2.05, 2.06 (3s, 9H, 3 COCH ), 2.44 (t, 2H,
+
3
MS (ES, positive ions): m/z 501.73 (M+23) ; R
f
SCH (CH ) ꢀ), 2.51 (t, 2H, ꢀSCH (CH ) Oꢀ),
2
2 14
2
2 2
(
CHCl /MeOH 8:2) 0.56; yield 73%; Anal. Calc.
3
.37 (s, 3H, ꢀOCH ), 3.43–3.48 (m, 1H, 5-H),
3
for C H O S: C, 62.72; H, 10.53; S, 6.70. Found:
25
50
6
.07–4.21 (m, 4H, 6-H, 6%-H, ꢀOCH ), 4.37 (d,
2
C, 62.67; H, 10.57; S, 6.74%.
J=8.0 Hz, 1H, 1-Hb), 4.95 (dd, J=7.8 and 9.5
Hz, 1H, 2-H), 5.00 (dd, J=9.4 and 9.6 Hz, 1H,
2
.1.3.9. (4-Thiaicosyl) i-
MS (ES, positive ions): m/z 501.73 (M+23) ; R
f
D
-glucopyranoside (6b).
4
-H), 5.05 (dd, J=9.5 and 9.7 Hz, 1H, 3-H); MS
+
+
(
(
ES, positive ions): m/z 657.86 (M+39) ; R
CHCl /Et O 8:2) 0.41; yield 95%; Anal. Calc. for
f
(CHCl /MeOH 8:2) 0.54; yield 82%; Anal. Calc.
3
3
2
for C H O S: C, 62.72; H, 10.53; S, 6.70. Found:
C, 62.65; H, 10.58; S, 6.72%.
C H O S: C, 62.11; H, 9.45; S, 5.18. Found: C,
25 50
6
3
2
58
9
62.03; H, 9.52; S, 5.23%.
2
.1.3.6. (4-Thiaicosyl) 2%-deoxy-3%,4%,6%-tri-O-ace-
2
.1.3.10. (4-Thiaicosyl) i-
D-galactopyranoside
1
tyl-i-
D
-arabinohexopyranoside (5f).
H NMR
(
6c). MS (ES, positive ions): m/z 501.73 (M+
(
(
CDCl ): l=0.86–0.89 (t, 3H, ꢀCH ), 1.24–1.27
+
3
3
23) ; R (CHCl /MeOH 8:2) 0.66; yield 78%;
Anal. Calc. for C H O S: C, 62.72; H, 10.53; S,
25 50 6
6
f 3
s, 26H, ꢀCH ꢀ), 1.54–1.59 (m, 4H, ꢀSCH CH ꢀ),
2
2
2
1
3
ꢀ
3
4
ꢀ
.78–1.88 (m, 1H, 2-H), 2.01, 2.03, 2.09 (3s, 9H,
.70. Found: C, 62.67; H, 10.61; S, 6.74%.
COCH ), 2.21–2.26 (m, 1H, 2%-H), 2.48 (t, 2H,
3
SCH (CH ) ꢀ), 2.58 (t, 2H, ꢀSCH (CH ) Oꢀ),
2
2 14
2
2 2
2.1.3.11. (4-Thiaicosyl) 6%-O-methyl-i- -glucopy-
D
.44–3.50 (m, 1H, 6-H), 3.72–3.78 (m, 1H, 6%-H),
.03–4.07 (m, 1H, 5-H), 4.08–4.14 (m, 2H,
ranoside (6d). MS (ES, positive ions): m/z 531.75
+
(
M+39) ; R (CHCl /MeOH 8:2) 0.78; yield
f 3
OCH ), 4.28 (dd, J=12.3 and 4.7 Hz, 1H, 1-
2
7
1
3%; Anal. Calc. for C H O S: C, 63.38; H,
26 52 6
0.64; S, 6.51. Found: C, 63.33; H, 10.71; S,
Hb), 4.94 (t, J=9.8 Hz, 4-H), 5.27–5.33 (m, 1H,
3
2
-H); MS (ES, positive ions): m/z 611.84 (M+
3) ; R (CHCl /Et O 8:2) 0.55; yield 95%; Anal.
+
6.57%.
f
3
2
Calc. for C H O S: C, 62.23; H, 9.59; S, 5.44.
3
1
56
8
Found: C, 62.18; H, 9.62; S, 5.41%.
2.1.3.12. (4-Thiaicosyl) 3%-O-methyl-i-D-glucopy-
ranoside (6e). MS (ES, positive ions): m/z 531.75
+
2
.1.3.7. (4-Thiaicosyl) 6%-deoxy-2%,3%,4%-tri-O-ace-
(M+39) ; R (CHCl /MeOH 8:2) 0.76; yield
f
3
1
tyl-i-
D
-glucopyranoside (5g). H NMR (CDCl ):
85%; Anal. Calc. for C H O S: C, 63.38; H,
3
26 52 6
l=0.83–0.92 (t, 3H, ꢀCH ), 1.21–1.37 (s, 26H,
10.64; S, 6.51. Found: C, 63.32; H, 10.72; S,
6.54%.
3
ꢀ
CH ꢀ), 1.53–1.57 (m, 7H, ꢀSCH CH ꢀ, ꢀCH ),
2
2
2
3

1
44
M. Schmidt et al. / Chemistry and Physics of Lipids 114 (2002) 139–147
2
.1.3.13. (4-Thiaicosyl) 2%-deoxy-i-
D
-glucopyra-
2.1.3.17. Hexadecyl 7-(2%,3%,4%,6%-tetra-O-acetyl-
i- -galactopyranosyloxy)-4-thiaheptanoic amide
noside (6f). MS (ES, positive ions): m/z 485.73
D
+
(
M+23) ; R (CHCl /MeOH 8:2) 0.67; yield
(7b). MS (ES, positive ions): m/z 740.95 (M+
f
3
+
7
1
6
6%; Anal. Calc. for C H O S: C, 64.89; H,
23) ; R (CHCl /EtO 8:2) 0.46; yield 80%; Anal.
25
50
5
f
3
2
0.89; S, 6.93. Found: C, 64.78; H, 10.94; S,
.87%.
Calc. for C H NO S: C, 60.23; H, 8.84; N, 1.95;
36 63 11
S, 4.47. Found: C, 60.12; H, 9.01; N, 1.87; S,
.32%.
4
2.1.3.14. (4-Thiaicosyl) 6%-deoxy-i-D-glucopyra-
noside (6g). MS (ES, positive ions): m/z 485.73
2.1.3.18. Hexadecyl 7-(i-D-galactopyranosyloxy)-
+
(
M+23) ; R (CHCl /MeOH 8:2) 0.72; yield
4-thiaheptanoic amide (7c). MS (ES, positive ions):
f
3
+
1
1
6
6%; Anal. Calc. for C H O S: C, 64.89; H,
0.89; S, 6.93. Found: C, 64.81; H, 10.92; S,
.87%.
m/z 572.80 (M+23) ; R (CHCl /MeOH 8:2)
25
50
5
f
3
0.69; yield 76%; Anal. Calc. for C H NO S: C,
28 55 7
61.17; H, 10.08; N, 2.55; S, 5.83. Found: C, 60.98;
H, 10.15; N, 2.72; S, 5.69%.
2.1.3.15. Hexadecyl 7-(i-D-galactopyranosyloxy)-
4
-thiaheptanoic amide (7). To a solution of 4c
(
0.01 mol) in 5 ml CHCl mercaptocarboxylic acid
3. Results and discussion
3
(
0.05 mol) was added. The mixture was stirred in
a quartz flask under argon atmosphere at room
temperature and irradiated at 254 nm for 2 h.
Detection of the quantitative reaction of double
bond was achieved by a solution of bromine in
MeOH. The mixture was diluted with water and
3.1. Synthesis of hexadecyl i-D-glycopyranosides
2
A range of hexadecyl b- -glycopyranosides 2
D
was synthesized by conventional 1,2-trans-glyco-
sylation of hexadecyl alcohol using the TMS-trifl-
ate method (Wilhelm et al., 1995) with the
CHCl , the organic phase was separated and dried
3
over Na SO . The filtered and evaporated residue
2
4
was purified by flash chromatography (petroleum
ether/EtOAc 8:2 v/v) to give 7a in good yield.
To a solution of 7a (0.01 mol) in 100 ml CCl4
N-hydroxysuccinimide (0.012 mol) was added and
the mixture was cooled at 0 °C. Then DCC (0.014
mol) was added and stirred for 12 h. The solid
corresponding
peracetylated
glycopyranose
derivatives 1 which either are commercially avail-
able or were obtained according to the literature
(Koizumi and Utamura, 1981). All of the glycol-
ipids were obtained in ordinary satisfying yield
after deacetylation of the corresponding peracety-
(
dicyclohexyl urea) was filtered and hexadecy-
lated lipid with NH –MeOH (Fig. 1).
3
lamine (0.01 mol) in 50 ml CH Cl was added to
2
2
the solution at room temperature which was
stirred for 4 h
3.2. Synthesis of (4-thiaicosyl)
i-D
-glycopyranosides 6
The organic phase was washed with water, sep-
arated and dried over Na SO . The residue ob-
The motive for these investigations is the rela-
2
4
tained after evaporation was deacetylated as
described earlier and then purified by flash chro-
matography (petroleum ether/EtOAc 8:2 v/v) to
give 7c in good yield.
tively low yields of conventional glycosylation
methods for the synthesis of glycolipids thus far
reported. Starting points were the good results of
perallylation (Kieburg et al., 1997) at the synthesis
of glycodendrimers (Roy et al., 2001). According
to the literature (Takano et al., 1990; Ew-
stigneewa et al., 1993) the preparation of allyl
glycopyranoside derivatives starting from the per-
acetylated sugar compounds by the use of cata-
2
.1.3.16. 7-(2%,3%,4%,6%-Tetra-O-acetyl-i-
D-galac-
topyranosyloxy)-4-thiaheptanoic acid (7a). MS
+
(
(
ES, positive ions): m/z 517.51 (M+23) ; R
f
petroleum ether/EtOAc 6:4) 0.18; yield 43%;
Anal. Calc. for C H O S: C, 48.58; H, 6.11; S,
lytic amounts of BF –etherate-complex as Lewis
2
0
30 12
3
6.48. Found: C, 48.46; H, 6.18; S, 6.52%.
acid afforded very good results concerning to the

M. Schmidt et al. / Chemistry and Physics of Lipids 114 (2002) 139–147
145
overall yield and the stereoselectivity with an
anomeric ratio of about 95:5. The divergent bibli-
ography concerning the reactant ratios (Takano et
al., 1990; Ewstigneewa et al., 1993) sets us to
optimize the reaction conditions with the result of
an optimal reactant ratio glycosyl acceptor/glyco-
deacetylation a range of glycolipids 6 was obtained
which are characterized by a long alkyl chain as
hydrophobic anchor, a sulfur-linked propyl spacer
and a terminal carbohydrate headgroup. The dif-
ferences between the unfunctionalized glycopyra-
noses
D-glucose, D-galactose, D-mannose and the
syl donor/BF –etherate-complex 1.5:1:1.1 and a
reaction time of 4 h.
The following photoaddition was achieved by
the exposure of the allyl glycosides 4 and hexade-
cyl thiol to radiation at 254 nm in a quartz flask
with almost quantitative yields (\95%). After
number of deoxy and partially O-methylated sugar
derivatives seem to have an influence in the aggre-
gation, e.g. the gauche-conformation of the alkyl
chain which can be determined by means of CꢀC
vibration measured by comparative Raman spec-
tral study (Fig. 2).
3
Fig. 1. Reaction pathway to the synthesis of compounds 2.
Fig. 2. Reaction pathway to the synthesis of compounds 3–5.

1
46
M. Schmidt et al. / Chemistry and Physics of Lipids 114 (2002) 139–147
Fig. 3. Reaction pathway to the synthesis of compound 7c.
3
.3. Synthesis of hexadecyl 7-(i-
D
-galacto-
preparation of amphiphilic molecules in excellent
yield. On the one hand a comparison between
glycolipids with identical carbohydrate headgroups
concerning the influence of the three different
hydrophobic anchors in the physicochemical be-
havior of the general lipid is under progress. On the
other hand the differences between the unfunction-
pyranosyloxy)-4-thiaheptanoic amide 7
Based on the excellent results of the addition of
the thiol functionality onto the alkenyl moiety of
4
using photochemical conditions an alternative
method for the preparation of spacered neoglycol-
ipids was searched for. According to the experience
of other authors (van Seeventer et al., 1997; Peer-
lings et al., 1998; Roy et al., 2001) on the synthesis
of glycodendrimeres the allyl derivative 4c was
converted with 3-mercaptopropionic acid into the
free acid derivative 7a. Introduction of the hydro-
phobic moiety on the terminal of hexadecyl amine
with N-hydroxysuccinimide/DCC to 7b followed
by deacetylation using Zemplen conditions af-
forded 7c in very good yields. This method for the
preparation of spacered neoglycolipids is a good
alternative to, e.g. ethyleneoxy groups because the
size of spacer can be varied by the use of different
mercaptocarboxylic acids (Fig. 3).
alized glycopyranoses
D-glucose, D-galactose, D-
mannose and the number of deoxy and partially
O-methylated sugar derivatives have an influence
on the aggregation, e.g. the gauche-conformation
of the alkyl chain. The polymorphism of the lipids
synthesized, the chain packing and the order/disor-
der of the hydrocarbon chains are going to be
studied by differential scanning calorimetry, X-ray
diffraction and Raman spectroscopy. Results of
these physicochemical investigations and further
biochemical recognition studies will be published
soon.
Acknowledgements
4. Conclusions
This work was supported by the Deutsche For-
With these methods a range of neoglycolipids
was synthesized which allows the stereoselective
schungsgemeinschaft
197).
(Sonderforschungsbereich

M. Schmidt et al. / Chemistry and Physics of Lipids 114 (2002) 139–147
147
tions: basis of glycobiology. Acc. Chem. Res. 28, 321–
27.
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