Synthesis of neoglycolipids based on D-lactose

Article abstract of DOI:10.1134/S1070428009020031

A synthesis was performed of amphiphilic D-lactose derivatives differing by the length and number of aliphatic chains. The compounds may be applied to the carbohydrate modification of phosphatidylcholine liposomes.

Full text of DOI:10.1134/S1070428009020031

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 2, pp. 173−177. © ©Pleiades Publishing, Ltd., 2009.
Original Russian Text © ©L.Yu. Gur’eva, U.A. Budanova, Yu.L. Sebyakin, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 2,
pp. 186−190.
Synthesis of Neoglycolipids Based on D-Lactose
L. Yu. Gur’eva, U.A. Budanova, and Yu. L. Sebyakin
Lomonosov Moscow State Academy of Fine Chemical Engineering,
Moscow, 119571 Russia
e-mail: C-221@yandex.ru
Received December 14, 2007
Abstract—A synthesis was performed of amphiphilic D-lactose derivatives differing by the length and number of
aliphatic chains. The compounds may be applied to the carbohydrate modification of phosphatidylcholine
liposomes.
DOI: 10.1134/S1070428009020031
Recently the research in the field of carbohydrate
chemistry was aimed mainly on designing and preparation
of artificial analogs of glycoconjugates containing natural
structural and functional elements. Synthetic carbohydrate
frameworks may possess properties similar to natural
compounds, may simulate various biological processes
or their stages, can be used in biochemical research
involving isolation of lectins from natural sources, the
study of their specificity, preparation of antibodies to
carbohydrate determinants of desired structure, to serve
as vectors of selective transport of biologically active
substances into cells, and also be employed as sorbents
in affine chromatography. Therewith the carbohydrate
derivatives of low molecular weight can be obtained in
preparative amounts in good yield by simpler procedures
14 carbon atoms long, and to those containing oleic acid
residues [7–10]. In the synthesis of neoglycolipids VII
and XVI we used lauric acid (C ) and tetradecanol (C ).
12
14
Compound VII was prepared along Scheme 1.
Amidoalcohol IV was obtained from ethanolamine (III)
and lauroyl chloride (II) in the presence of triethylamine.
The subsequent reaction of 2-hydroxyethyldodecylamide
(
IV) with D-lactose octaacetate (V) was carried out in
dichloromethane for 12 h at room temperature and was
catalyzed by boron trifluoride etherate [11]. On removing
the protective groups by treating with 0.1M sodium
methylate solution in methanol we obtained (2-dodecyl-
amido)ethyl-β-D-lactoside (VII) in 94% yield.
The structure of compounds VI and VII were
1
1
confirmed by H, IR, and mass spectra. In the H NMR
spectrum of compound VI signals appeared from the
protons of acetyl and aliphatic groups, ethylene fragment,
and carbohydrate skeleton. The signal of anomeric proton
[
1–4].
The goal of this study was the preparation of neoglyco-
lipids VII and XVI that might be used in the composition
of mixed liposomes for directional transport of pharma-
ceuticals and genetic material to desired target organs.
The choice of the carbohydrate fragment in our study
was due to the presence of a terminal galactosyl residue
recognizable for membrane lectins of the cell surface
specific thereto [5, 6].
1
H was observed as a doublet with the chemical shift
4
.51–4.53 ppm (J 7.4 Hz) indicating the β-configuration
1,2
of the anomeric center. No signal of the α-anomer was
1
seen in the H NMR spectrum of compound VI. In the
IR spectrum of glycoside VII the absorption bands of
hydroxy groups and of amide moiety were observed. The
mass spectrum of target compound VII contained the
The hydrophobic component of synthetic amphiphiles
is commonly composed of saturated or unsaturated
aliphatic chains containing from 8 to 18 carbon atoms.
The study of the effect of the chain length on the trans-
fection efficiency in experiments both in vitro and in vivo
revealed that the highest activity was inherent to com-
pounds containing saturated hydrophobic chains 12 and
molecular ion peak of m/z 589.2 (I 4.2%).
rel
Glycopolyaminoacidic derivative of D-lactose XVI was
prepared along Scheme 2. The initial hydrophobic
fragment of the amphiphile XI was obtained by
esterification of L-glutamic acid (VIII) with tetradecanol
(
IX) in the presence of p-toluenesulfonic acid followed
173

174
GUR’EVA et al.
Scheme 1.
NH CH CH OH
2
2
2
O
III
CH (CH ) C
CH (CH ) CONHCH CH OH
3
2 10
3
2 10
2
2
Cl
II
IV
OAc
OAc
O
OAc
OAc
SOCl2
O
OAc
O
OAc
OH
CH (CH ) COOH
3
2 10
OAc
OAc
I
V
OAc
OCH CH NHCO(CH ) CH
2 2 2 10
OAc
3
OH
OH
OAc
OH
OCH CH NHCO(CH )
2 2 2 10
CH3
O
O
O
O
O
OAc
OAc
OH
O
OAc
OAc
OH
OH
VI
VII
Scheme 2.
HOCOCH2
n-TsOH
14 29
C H OCOCH2
CH2
HOCOCHNH2
VIII
C H OH
CH2
1
4 29
IX
C H OCOCHNH Ts
14
29
3
X
14 29
C H OCOCH2
C H OCOCH
1
4
29
2
O
O
NaHCO3
O
XII
CH2
CH2
C H OCOCHNH
2
C H OCOCHNHCO(CH ) COOH
14 29
2 2
1
4
29
XIII
XI
O
OAc
OAc
OAc
O
OAc
OAc
O
OAc
OAc
OAc O
OAc
OAc
O
O OAc
ON
O
O
OAc
O
OAc
OH
OAc XIV
OAc
OH
V
CH COOC H
2
14 29
OH
OH
O
CH2
OH
O
ONH2
O
OH
N H H O
O ONHCO(CH ) CONHCHCOOC H
2
4
2
2 2 14 29
O
XIII
OH
OH
OH
O
OH
OH
OH
OH
OH
XV
XVI
by the treatment of the arising salt X with 5% solution of
sodium hydrogen carbonate [12]. The obtained chromato-
graphically pure compound XI without further purification
was treated with succinic anhydride in order to react it
further with D-lactose derivative.
aliphatic chains, L-glutamic acid residue, and also the
signals of the methylene groups of the succinic acid
residue as a multiplet at 3.59–3.70 ppm. In the IR spec-
trum of compound XIII absorption bands were observed
belonging to the hydroxy and ester groups, and also to
two amide bands.
The structure of compound XIII possessing a free
1
carboxy group was confirmed by H and IR spectra. The
β-Aminolactoside XV [13] was obtained by treating
the D-lactose octaacetate (V) with N-hydroxysuccinimide
1
H NMR spectrum contained the proton signals from the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009

SYNTHESIS OF NEOGLYCOLIPIDS BASED ON D-LACTOSE
175
under acid catalysis followed by reacting the obtained
compound XIV with hydrazine hydrate.
substances containing free amino groups were developed
with a 5% ninhydrin solution followed by heating at 50–
8
0°C. The substances containing N-hydroxysuccinimide
The target N-substituted amino-β-D-lactoside XVI
was obtained by treating compound XV with the diester
of L-glutamic acid XIII in DMF in the presence of
dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine
in 50% yield [14]. The IR spectrum of compound XVI
contained absorption bands of hydroxy and ester groups,
and also bands amide I and II. The mass spectrum
group were visualized by a specific developer for N
hydroxysuccinimides [15].
Lauroyl chloride (II). A mixture of 1 g (5 mmol) of
lauric acid (I), 1 ml (14 mmol) of thionyl chloride, and 1
drop of DMF was heated at 88°C on an oil bath for 2 h.
Excess SOCl was distilled off in a vacuum (10 mm Hg)
2
contained the molecular ion peak of m/z 976.5 (I 2%).
at the bath temperature 25°C [16]. Yield 1.1 g (99%).
Compound II was used in further stage of the synthesis
without additional purification.
rel
The synthesized neoglycolipids VII and XVI were
applied to the preparation of mixed phosphatidylcholine
dispersions at the ratio phosphatidylcholine–glycoside
N-(2-Hydroxyethyl)dodecylamide (IV). A solution
of 0.22 ml (5.5 mmol) of ethanolamine and 0.61 g (6 mmol)
of triethylamine in 10 ml of anhydrous dichloromethane
was cooled to –10°C, 1.1 g (5 mmol) of compound II
was added, and the mixture was kept for 30 min at room
temperature. The separated precipitate was filtered off
and washed with dichloromethane, and the solvent was
removed in a vacuum. The reaction product was purified
by column chromatography (eluent system G). Yield
95:5. The modified liposomes are considerably more stable
than the control phosphatidylcholine liposomes. At the
storage of water dispersions of mixed liposomes for 24 h
at room temperature no precipitation of aggregates was
observed.
Hence we performed a synthesis of two amphiphiles
based on D-lactose that could be used for preparation of
carbohydrate-containing transport system and for further
biochemical investigations.
0
.6 g (50%), colorless crystals, R 0.41 (Ε), mp 78–79°C
f
–1
(
(
CH Cl ). IR spectrum (mull in mineral oil), cm : 3300
NH), 3250 (OH), 1640 (C=O), 1540 (NH), 1465, 1460,
2 2
EXPERIMENTAL
1
380, 710 (CH), 1050 (C–N).
1H NMR spectra were registered on a pulse spec-
trometer Bruker WM-200 at operating frequency
00 MHz from solutions in deuterochloroform. IR spectra
were recorded on a spectrophotometer Shimadzu IR-435
from thin films or mulls in mineral oil. Electron-impact
mass spectra were measured on a Finnigan Polaris Q
instrument, ionizing chamber temperature 150°C, ionizing
electrons energy 70 eV. The melting points were
determined on a Bo¸tius heating block.
N-{2-[4-O-(2,3,4,6-Tetra-O-acetyl-β-D-galacto-
pyranosyl)-2,3,6-tri-O-acetyl-β-D-glycopyrano-
sido]ethyl}dodecylamide (VI). To solution of 0.76 g
2
(
1.1 mmol) octaacetyl-β-D-lactose (V) in 10 ml of
anhydrous dichloromethane was added 0.16 ml (1.2 mmol)
of boron trifluoride etherate.After 15 min into the reaction
mixture was added 0.3 g (1.2 mmol) of compound IV,
and the mixture was left standing for 12 h at room
temperature. On completion of the reaction the mixture
was neutralized with 25% ammonia solution till pH 7,
washed with water (3×100 ml), the organic layer was
dried with anhydrous sodium sulfate, the solvent was
distilled off in a vacuum, and the reaction product was
purified by column chromatography (eluent system H).
The thin-layer chromatography was performed on
Sorbfil plates (Krasnodar, Russia) using the following
eluent systems: chloroform–methanol, 3:1 (A), chloro-
form–methanol, 9:1 (B), chloroform–methanol, 12:1 (C),
chloroform–ethanol, 5:1 (D), toluene–acetonitrile, 3:1 (E),
toluene–ethyl acetate, 3:1 (F), toluene–ethyl acetate, 5:1
G), acetone–petroleum ether, 1:5 (H), acetone–petroleum
ether, 3:1 (I), ethyl acetate–petroleum ether, 3:1 (J),
acetone–methanol, 1:1 (K).
Yield 0.3 g (30%), colorless oily substance, R 0.48 (eluent
f
–1
system I). IR spectrum (thin film), cm : 3300 (NH), 1750
(
(
(
C=O), 1640 (C=O), 1530 (NH), 2845, 1460, 1375, 710
CH), 1050 (C–N), 1210 (C–O), 1160–1035 (4 bands,
1
carbohydrate skeleton). H NMR spectrum (CDCl ), δ,
3
The preparative TLC was carried out on silica gel
L5/40 μm (Czechia), the column chromatography, on silica
gel L40/100 μ (Czechia).
ppm: 0.86–0.91 t (3H, CH ), 1.26 s (16H, CH ), 1.98 s,
3
2
2
1
.06 s, 2.07 s, 2.13 s, 2.17 s, 2.18 s, 2.19 s (21H, COCH3),
.60–1.64 t (2H, COCH CH ), 2.67 m (2H,
2
2
The spot visualizing at TLC was performed in iodine
vapor or by heating over the flame of a spirit-lamp. The
COCH CH ), 3.75–3.82 t (2H, NCH ), 3.86–3.91 t (2H,
2
2
2
6
5
5'
OCH ), 4.12–4.19 m (4H, H , H , H ), 4.47–4.50 t (2H,
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009

176
GUR’EVA et al.
1
'
1
–1
H , J 8.0 Hz), 4.51–4.53 t (2H, H , J 7.4 Hz), 4.46–
(mull in mineral oil), cm : 3390 (OH), 3290 (NH), 2960,
1
,2
1,2
6
'
2
2'
4
5
5
.53 m (2H, H ), 4.85–4.99 m (2H, H , H ), 5.10–
.22 m (2H, H , H ), 5.36–5.39 m (2H, H , H ), 5.89–
.92 t (1H, NH).
1465,1375, 715 (CH), 1730, 1720 (C=O), 1640 (C=O,
NH), 1389 (C–N). H NMR spectrum (CDCl ), δ, ppm:
0.83–0.92 t (6H, CH ), 1.15–1.40 s (44H, CH ), 1.50–
3
4'
3'
4
1
3
3
2
N-{2-[4-O-(β-D-Galactopyranosyl)-β-D-glyco-
1.70 m (4H, β-CH2CH2OCO), 2.35–2.42 m (2H, β-CH2),
2.62–2.77 m (2H, δ-CH ), 3.59–3.70 m (4H, CH CO),
pyranosido]ethyl}dodecylamide (VII). To a solution
of 0.3 g of compound VI in 3 ml of methanol was added
at room temperature while stirring 0.75 ml of freshly
obtained 0.1 M solution of sodium methylate in methanol
till pH 8. After 20 min the solution was treated with ion-
exchange resin KU-2 till pH 7, the resin was filtered off,
the solvent was distilled off in a vacuum. Yield 0.2 g
2
2
4.03–4.08 t (2H, α-CH OCO), 4.10–4.15 t (2H, α-
2
CH OCO), 4.57–4.64 m (1H, CH).
2
N-[4-O-(2,3,4,6-Tetra-O-acetyl-β-D-galacto-
pyranosyl)-2,3,6-tri-O-acetyl-β -D-glyco-
pyranosido]succinimide (XIV). To a solution of 5 g
(
7.4 mmol) of octaacetyl-β-D-lactose (V) in 22 ml of
(
(
(
94%), R 0.45 (eluent system A), mp 146–147°C
f
anhydrous dichloromethane was added 1 ml (8.1 mmol)
of boron trifluoride etherate. After 15 min the reaction
mixture was treated with 0.93 g (8.1 mmol) of N-hy-
droxysuccinimide and left standing for 12 h at room
temperature. On completion of the reaction the mixture
was neutralized with 25% ammonia solution till pH 7
and washed with water (5 × 100 ml). The organic layer
was dried, the solvent was distilled off in a vacuum, the
residue was subjected to column chromatography (eluent
-1
MeOH). IR spectrum (mull in mineral oil), cm : 3280
NH), 3250 (OH), 1630 (C=O), 1560 (NH), 2890, 1324,
7
00 (CH), 1210–1060 (4 bands, carbohydrate skeleton).
+
Mass spectrum, m/z (I , %): 589.2 (4.2) [M] , 399.2
rel
(
1
(
18.9), 280.1 (19.9), 279.1 (100), 206.1 (25), 191.2 (70),
63.2 (23.8), 147.1 (39.8), 111.1 (44.5), 85.1 (57.9), 71.0
68), 57.1 (89.1).
Ditetradecyl L-glutamate (XI). A mixture of 2.3 g
15.6 mmol) of L-glutamic acid (VIII), 10 g (46.9 mmol)
(
system J). Yield 2.4 g (43%), colorless crystals, R 0.42
f
of tetradecanol (IX), and 4.15 g (15.6 mmol) finely
dispersed in a mortar p-toluenesulfonic acid was heated
on an oil bath at 110°C for 1.5 h. The completion of the
reaction was determined by the disappearance of the
L-glutamic acid; then the reaction mixture was cooled to
room temperature and recrystallized from acetone. The
precipitate was filtered off, dissolved in 100 ml of
chloroform, washed with 5% solution of sodium hydrogen
carbonate (5×35 ml), with water till pH 7, and dried with
sodium sulfate. The solvent was removed in a vacuum.
(
[
eluent system B), mp 90–91°C (EtOH) (92.5–93.7°C
1
17]). H NMR spectrum (CDCl ), δ, ppm: 1.90 s,
3
1
2
3
4
4
.99 s, 2.00 s, 2.02 s, 2.04 s, 2.06 s, 2.09 s (21H, COCH ),
3
5
.73 s (4H, CH CH ), 3.72–3.78 m (1H, H ), 3.86–
.91 m (1H, H ), 4.05–4.23 m (4H, H , H ), 4.41–
2
2
5
'
6
6'
4
1'
.45 d.d (1H, H ), 4.53–4.56 d (1H, H , J 7.9 Hz),
1,2
3
'
1
.94–4.98 d.d (1H, H ), 5.06–5.10 d (1H, H ,
2
2'
3
J1,2 6.3 Hz), 5.14–5.22 m (2H, H , H , H ), 5.33–5.35 d.d
(
C H NO . Calculated, %: C 49.12; H 5.36; N 1.91.
4
’
1H, H ). Found, %: C 48.97; H 5.43; N 2.09.
Yield 10 g (96%), colorless amorphous substance, R 0.53
30 39
20
f
(
eluent system E). IR spectrum (mull in mineral oil),
[4-O-(β-D-Galactopyranosyl)-β-D-glycopyrano-
syl]oxyamine (XV). To a solution of 100 mg (0.1 mmol)
of compound XIV in 15 ml of ethanol was added 1.65 ml
(0.95 mmol) of hydrazine hydrate. The mixture was left
standing at room temperature for 24 h. The reaction
progress was monitored by TLC (eluent system K). On
completion of the reaction the excess hydrazine hydrate
and the solvent were removed in a vacuum. The reaction
product was purified by recrystallization from ethanol.
Yield 0.03 g (33%), Rf 0.6 (eluent system K), mp 138–
–1
cm : 3450 (NH), 2926, 2904, 1450, 1375, 700 (CH), 1736
(
C=O), 1172 (C–N), 1145, 1028 (C–O).
The obtained chromatographically pure compound XI
without further purification was used in the next reaction
stage.
3
-[1,3-Di(tetradecyloxycarbonyl)propylcar-
bamoyl]propanoic acid (XIII). To a solution of 1.53 g
2.8 mmol) of ester XI in 20 ml of toluene was added
.29 g (2.8 mmol) of succinic anhydride XII, and the
(
0
–1
mixture was stirred for 12 h at room temperature. Toluene
was distilled off in a vacuum, the residue was dissolved
in 50 ml of chloroform, washed with 0.1 N HCl, with
water till pH 7, and dried. The solvent was removed in
139°C (EtOH). IR spectrum (mull in mineral oil), cm :
3340 (OH), 3320 (NH), 2920 (CH), 1638 (NH), 1435,1356
(CH), 1212 (C–O), 1114–1035 (C–O, 4 bands, carbo-
1
hydrate skeleton). H NMR spectrum (D O), δ, ppm:
2
3
2
2'
3'
a vacuum. Yield 1.6 g (91%), colorless crystals, R 0.4
3.41 d.d (1H, H ), 3.53–3.69 m (3H, H , H , H ), 3.76–
3.81 m (1H, H , H ), 3.88 d (1H, H ), 4.07–4.18 m (2H,
f
6
6'
4'
(eluent system C), mp 33–34°C (CH C H ). IR spectrum
3
6
5
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009

SYNTHESIS OF NEOGLYCOLIPIDS BASED ON D-LACTOSE
177
5
5'
4
1
H , H ), 4.24 m (1H, H ), 4.34 d (1H, H , J 8.0 Hz),
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1'
4
.92 d (1H, H , J 7.5 Hz).
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–1
1
1
650 (C=O), 1572 (NH), 2902, 2870, 1370, 700 (CH),
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rel
1
(100), 515.2 (59.5), 232.2 (45), 219.2 (56.1), 189.1 (100),
1
1
79.1 (23), 149.1 (51.9), 147.1 (81.8), 111.0 (55), 97.0
(
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1
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0
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009