Synthesis of neoglycolipids for the development of non-viral gene delivery systems

Article abstract of DOI:10.1007/s11172-010-0389-4

Synthesis of lipid conjugates with galactose as a targeting ligand intended for the development of non-viral systems for the targeted delivery of nucleic acids into hepatocytes is described. 3,4-Diethoxycyclobut-3-ene-1,2-dione (diethyl squarate) was used

Full text of DOI:10.1007/s11172-010-0389-4

Russian Chemical Bulletin, International Edition, Vol. 59, No. 12, pp. 2281—2289, December, 2010
2281
Synthesis of neoglycolipids for the development
of nonꢀviral gene delivery systems
E. V. Shmendel´, M. A. Maslov, N. G. Morozova, and G. A. Serebrennikova
M. V. Lomonosov Moscow State Academy of Fine Chemical Tehnology,
86 prosp. Vernadskogo, 119571 Moscow, Russian Federation.
Fax: + (495) 936 8901. Eꢀmail: mamaslov@mail.ru
Synthesis of lipid conjugates with galactose as a targeting ligand intended for the developꢀ
ment of nonꢀviral systems for the targeted delivery of nucleic acids into hepatocytes is described.
3,4ꢀDiethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀdione (diethyl squarate) was used to bind the galactose moiety
to the lipid component.
Key words: neoglycolipids, galactose, targeting ligand, 3,4ꢀdiethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀ
dione (diethyl squarate), hepatocytes.
Gene therapy is based on the corrections of genetic
disorders and curing diseases caused by them by introducꢀ
tion of molecules of therapeutic DNA into the defective
cells. For the successful treatment, it is necessary to proꢀ
vide efficient delivery of these DNA into the target cells
and their prolonged functioning.1 At present, cationic
liposomes are extensively studied as prospective systems
for the DNA delivery.2—4 The DNA incorporated into
a lipid membrane becomes unavailable for the destructive
action of cell enzymes, whereas liposomes themselves are
noninfectious and nonimmunogenic.5
Unfortunately, liposomal DNA delivery systems do not
possess cell specificity. Therefore, the liposomal surface is
modified with ligands specific to receptors on the surface
of target cells to overcome this shortcoming.6—10
Thus hepatocytes expose asialoglycoprotein recepꢀ
tors on their surface11,12 specific to glycoproteins, as well
as to other molecules containing galactose groups.13 Thereꢀ
fore, modification of liposomes or their lipid components
with galactose residues can be used to solve the problem of
specific transport of biologically active compounds into
hepatocytes, in particular, for elimination of genetic disꢀ
orders of liver cells and curing various pathologies and
diseases caused by them.14
ents, compounds containing tetradecyl residues provide
the best delivery of DNA to cells,15,16 therefore, 1,2ꢀdiꢀOꢀ
tetradecylꢀracꢀglycerol has been used as a hydrophobic
component. To study the effect of the lipid conjugate strucꢀ
ture on the transfection activity, the galactose residue was
bound to the dialkylglycerol molecule with spacers of varꢀ
ious length and nature. The structure of a spacer group can
affect the lypophilic—hydrophilic balance of the moleꢀ
cule, which determines the structureꢀforming properties
of glycolipid conjugates. In the case of extended oligomeꢀ
thylene spacers, the lypophilic—hydrophilic balance can
be disturbed, since spacers of this type tend to arrange
close to the alkyl chains of the diglyceride disturbing the
stability of lipid aggregates and approximating the galacꢀ
tose residues to the surface of liposomes. The shortening
of a spacer group decreases availability of the targeting
ligand for the receptors on the surface of the target cells.
On the contrary, incorporation of a long hydrophilic oligoꢀ
oxamethylene spacer into the molecule of a lipid conjuꢀ
gate will make the galactose residue remote from the lipoꢀ
some surface. Carbamoyl linker has been chosen to conꢀ
nect the lipid component to the spacer groups, which proꢀ
vides the optimum combination of stability and toxicity of
the lipid conjugate.17
The present work deals with the synthesis of lipid conꢀ
jugates with galactose as a targeting ligand, which are
meant to be used for the development of vectors for targetꢀ
ed delivery of nucleic acids to hepatocytes.
Molecular constructions developed by us, in addition
to the "targeting" carbohydrate residues, include a dialkylꢀ
glycerol component, which is intended for the incorporaꢀ
tion of the conjugate into liposomes and functions as an
anchor that fixes the carbohydrate unit. It is known that
among lipids with the longꢀchain hydrocarbon substituꢀ
The strategy for obtaining galactoseꢀcontaining lipids
is based on the use of 3,4ꢀdiethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀ
dione (diethyl squarate), which first has been used in the
synthesis of neoglycopeptides.18 Being a chemoselective
reagent, which reacts with primary amino groups, diethyl
squarate is also used in the synthesis of carbohydrate19 and
peptide20 conjugates.
The binding of the galactose residue to a spacer group
was performed by glycosylation of 6ꢀ(tertꢀbutoxycarbonylꢀ
amino)hexanol with 2,3,4,6ꢀtetraꢀOꢀacetylꢀαꢀDꢀgalactoꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2225—2233, December, 2010.
1066ꢀ5285/10/5912ꢀ2281 © 2010 Springer Science+Business Media, Inc.

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Shmendel´ et al.
Scheme 1
Reagents and conditions: (a) BocNH(CH2)6OH, CdCO3, C6H6, 80 °C; (b) 4 M HCl, dioxane, 0 °C.
pyranosyl bromide (1) under conditions of the modified
Koenigs—Knorr method21 using CdCO3 as a promoter
(Scheme 1). Glycoside 2 was isolated by column chromatoꢀ
graphy on silica gel in 43% yield. Its H NMR spectrum
exhibits a signal for the anomeric proton with the chemical
To bind the lipid component to the spacer fragꢀ
ments of various length and type, we performed preꢀ
liminarily the reaction of 1,2ꢀdiꢀOꢀtetradecylꢀracꢀglyꢀ
cerol (4) with 4ꢀnitrophenyl chloroformate in the presꢀ
ence of Et3N (Scheme 2). Carbonate 5 was obtained
in 96% yield. The reaction of activated hydrophobic
1
shift δH 4.37 and the spinꢀspin coupling constant J1,2
=
= 7.9 Hz and the 13C NMR spectrum contains a signal for the
anomeric carbon atom at δC 100.78, which indicates the
βꢀconfiguration of the glycosidic bond. tertꢀButoxycarboꢀ
nyl protecting group was removed with 4 M hydrogen chloꢀ
ride in dioxane to obtain compound 3 in 97% yield.
component 5 with monoꢀBocꢀprotected diamines
6a—f, obtained by the previously described method,22
led to compounds 7a—f. Variations in the reaction
time and temperature allowed us to increase the yields of
compounds 7a—f to 75—97%. Removal of the Bocꢀproꢀ
Scheme 2
Reagents and conditions: (a) 4ꢀNO2C6H4OCOCl, Et3N, 24 °C; (b) NH2XNHBoc (6a—f), Et3N, 24—45 °C; (c) 4 M HCl, dioxane,
0 °C; (d) 3,4ꢀdiethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀdione, Et3N, 24 °C; (e) 3, Et3N, 24—40 °C; (f) MeONa/MeOH, 24 °C.

Synthesis of neoglycolipids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
2283
molecular sieves 4 Å, and after 15 min 2,3,4,6ꢀtetraꢀOꢀacetylꢀαꢀ
Dꢀgalactopyranosyl bromide26 (1) (0.927 g, 2.25 mmol) were
added. The reaction mixture was refluxed for 5 h, filtered, the
solvent was evaporated in vacuo. The product was isolated by
column chromatography; elution with the toluene—EtOAc (6 : 1)
solvent system afforded compound 2 (0.525 g, 43%) as a crystalꢀ
tecting groups afforded amino derivatives 8a—f in
89—94% yields.
Coupling of glycerol (8a—f) and galactose (3) derivaꢀ
tives containing terminal NH2 groups was performed by
the successive substitution of the ethoxy groups in diethyl
squarate. First, we performed its reaction with compounds
8a—f in the presence of Et3N. Compounds 9a—f were
isolated by column chromatography on silica gel in
72—99% yields. Subsequent reaction of compounds 9a—f
with the carbohydrate component 3 in the presence of
Et3N led to conjugates 10a—f in 50—89% yields. It should
be noted that an increase in the reaction time and the use
of an excess of galactoside 3 (1.8 equiv.) resulted in the
increase in the yields of compounds 10a—f. Removal of
the acetyl groups was performed by the Zemplén proceꢀ
dure (treatment with 0.1 M methanolic MeONa), to give
the target galactoseꢀcontaining lipids 11a—f in high yields.
To confirm the structures of compounds 11a—f and assign
the signals for the protons of the carbohydrate residue,
we used twoꢀdimensional homonuclear correlation NMR
spectroscopy (1H,1HꢀCOSY). The structures of conjugates
11a—f were confirmed by the mass spectrometric data,
as well.
27
lizing oil, [α]D –4.95 (c 0.5, CHCl3). MS, m/z (Irel (%)):
570.307 [M + Na]+ (100). Calculated for C25H41NO12: 547.263
1
[M]+. H NMR, δ: 1.21—1.33 (m, 4 H, (CH2)2); 1.37 (s, 9 H,
C(Me)3); 1.35—1.44 (m, 2 H, NHCH2CH2); 1.45—1.57 (m, 2 H,
OCH2CH2); 1.91, 1.98, 1.99, 2.08 (all s, 3 H each, 4 MeCO);
2.96—3.10 (m, 2 H, NHCH2); 3.40 (dt, 1 H, OCHHa, J = 6.8 Hz,
J = 9.5 Hz); 3.77—3.86 (m, 2 H, H(5) Gal, OCHHb); 4.06 (dd, 1 H,
J = 6.9 Hz, J = 11.1 Hz) and 4.12 (dd, 1 H, both H(6) Gal,
J = 6.6 Hz, J = 11.1 Hz); 4.37 (d, 1 H, H(1) Gal, J = 7.9 Hz);
4.40—4.50 (m, 1 H, CONH); 4.94 (dd, 1 H, H(3) Gal, J = 3.4 Hz,
J = 10.5 Hz); 5.13 (dd, 1 H, H(2) Gal, J = 7.9 Hz, J = 10.5 Hz);
5.31 (dd, 1 H, H(4) Gal, J = 1.1 Hz, J = 3.4 Hz). 13C NMR, δ:
10.38, 13.47, 20.02, 20.10, 20.11, 20.19, 22.41, 23.17, 24.95,
25.90, 27.85, 28.35, 28.75, 29.45, 29.79, 38.16, 60.70, 66.50,
67.58, 68.36, 69.51, 70.02, 70.39, 100.78, 155.40, 168.50, 169.61,
169.71, 169.83.
(6ꢀAminohexyl)ꢀ2,3,4,6ꢀtetraꢀOꢀacetylꢀβꢀDꢀgalactopyranoꢀ
side hydrochloride (3). A solution of hydrogen chloride in diꢀ
oxane (4 M, 5 mL) was added to a solution of compound 2 (0.315 g,
0.575 mmol) in CH2Cl2 (10 mL) cooled to 0 °C. After 1 h, the
solvents were evaporated in vacuo, the product was isolated by
column chromatography; elution with the CHCl3—MeOH
(10 : 1) → (5 : 1) solvent system afforded compound 3 (0.271 g,
In conclusion, using 3,4ꢀdiethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀ
dione as the chemoselective coupling reagent we succeedꢀ
ed in obtaining galactoseꢀcontaining lipids for the targetꢀ
ed delivery of nucleic acids to hepatocytes.
27
97%) as a crystallizing oil, [α]D –1.5 (c 1, CHCl3). MS, m/z
(Irel (%)): 448.242 [M – HCl + H]+ (100). Calculated for
C20H34NO10: 448.218 [M – HCl + H]+. 1H NMR, δ: 1.20—1.70
(m, 8 H, (CH2)4); 1.92, 1.98, 2.00, 2.09 (all s, 3 H each,
4 MeCO); 2.75—2.86 (m, 2 H, CH2NH2); 3.41 (dd, 1 H, OCHHa,
J = 7.1 Hz, J = 8.9 Hz); 3.76—3.88 (m, 2 H, H(5) Gal, OCHHb);
4.06 (dd, 1 H, J = 6.9 Hz, J = 11.2 Hz) and 4.13 (dd, 1 H,
both H(6) Gal, J = 6.6 Hz, J = 11.2 Hz); 4.39 (d, 1 H, H(1) Gal,
J = 7.9 Hz); 4.96 (dd, 1 H, H(3) Gal, J = 3.4 Hz, J = 10.5 Hz);
5.13 (dd, 1 H, H(2) Gal, J = 7.9 Hz, J = 10.5 Hz); 5.32 (dd, 1 H,
H(4) Gal, J = 1.1 Hz, J = 3.4 Hz). 13C NMR, δ: 11.35, 14.04,
20.52, 20.61, 20.63, 20.69, 20.78, 22.57, 25.16, 26.08, 27.37,
28.35, 29.03, 29.61, 30.24, 31.50, 31.84, 34.59, 36.42, 39.77,
61.16, 66.99, 67.01, 68.89, 69.75, 70.52, 70.84, 77.20, 101.18,
169.41, 170.09, 170.20, 170.33.
Experimental
Distilled solvents were used in the work (Khimmed, Reaꢀ
khim), as well as 6ꢀ(tertꢀbutoxycarbonylamino)hexanol, 4ꢀnitroꢀ
phenyl chloroformate (Aldrich), 3,4ꢀdiethoxycyclobutꢀ3ꢀeneꢀ
1,2ꢀdione (Acros), and Et3N (Merck). Benzene was refluxed
over metallic Na and distilled directly before the reaction;
CH2Cl2 and Et3N were refluxed over CaH2 and distilled.
1,2ꢀDiꢀOꢀtetradecylꢀracꢀglycerol (4) was obtained according to
the known procedure.23 BocꢀProtected diamines 6a—f were obꢀ
tained as described for Nꢀtertꢀbutoxycarbonylꢀ1,4ꢀdiaminoꢀ
butane (6a).22
Thinꢀlayer chromatography was performed on Kieselgel
60 F254 plates (Merck). Visualization of compounds on the chroꢀ
matographic plates was performed by treatment with chlorine
and then with a benzidine solution,24 the Dragendorff reagent,24
or phosphormolybdic acid—cerium(IV) sulfate with subsequent
heating,25 and under the UV light (254 nm). Column chromatoꢀ
graphy was performed on Kieselgel 60 silica gel (40—63 μm,
Merck). 1H and 13C NMR spectra were recorded on a Bruker
DPX 300 pulse Fourierꢀspectrometer in CDCl3 using SiMe4 as
an internal standard, if not stated otherwise. Mass spectra were
obtained on a Bruker Ultraflex timeꢀofꢀflight mass spectrometer
using laserꢀdesorption ionizaition and 2,5ꢀdihydroxybenzoic acid
as a matrix.
racꢀ1ꢀOꢀ(4ꢀNitrophenyloxycarbonyl)ꢀ2,3ꢀdiꢀOꢀtetradecylꢀ
glycerol (5). A solution of 4ꢀnitrophenyl chloroformate (1.55 g,
7.69 mmol) in anhydrous CH2Cl2 (20 mL) was added dropwise
to a solution of 1,2ꢀdiꢀOꢀtetradecylꢀracꢀglycerol (4) (2.42 g,
4.99 mmol) and anhydrous Et3N (1.4 mL) in anhydrous CH2Cl2
(20 mL) over 30 min. The reaction mixture was stirred for 11 h at
24 °C, washed with 3% aqueous HCl (20 mL) and brine (3×20 mL)
to pH 7, dried with Na2SO4, filtered, and concentrated in vacuo.
The product was isolated by column chromatography in toluene
to obtain compound 5 (3.11 g, 96%) as a crystallizing oil. MS,
m/z (Irel (%)): 672.622 [M + Na]+ (100). Calculated for C38H67NO7:
649.492 [M]+. 1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me, J = 6.9 Hz);
1.15—1.30 (m, 44 H, 2 (CH2)11Me); 1.44—1.57 (m, 4 H,
2 OCH2CH2); 3.38 (t, 2 H, OCH2CH2, J = 6.6 Hz); 3.43 (dd, 1 H,
J = 6.3 Hz, J = 10.0 Hz) and 3.49 (dd, 1 H, OCH2CH, J = 4.9 Hz,
J = 10.0 Hz); 3.52 (t, 2 H, OCH2CH2, J = 6.6 Hz); 3.61—3.69
(m, 1 H, OCH2CH); 4.25 (dd, 1 H, J = 5.9 Hz, J = 11.3 Hz) and
[6ꢀ(tertꢀButoxycarbonylamino)hexyl]ꢀ2,3,4,6ꢀtetraꢀOꢀacetylꢀ
βꢀDꢀgalactopyranoside (2). To a solution of 6ꢀ(tertꢀbutoxyꢀ
carbonylamino)hexanol (0.5 g, 2.30 mmol) in anhydrous benzꢀ
ene (50 mL), cadmium carbonate (0.721 g, 4.18 mmol), ground

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Shmendel´ et al.
4.39 (dd, 1 H, CH2OC(O), J = 3.8 Hz, J = 11.3 Hz); 7.29—7.35
(m, 2 H) and 8.18—8.24 (m, 2 H, Ar).
30.08, 30.16, 32.07, 40.73, 41.18, 64.32, 70.57, 70.73, 71.92,
77.02, 79.17, 156.12, 156.54.
racꢀ1ꢀOꢀ{Nꢀ[4ꢀ(tertꢀButoxycarbonylamino)butyl]}carbamoylꢀ
2,3ꢀdiꢀOꢀtetradecylglycerol (7a). A solution of compound 5
(1.04 mmol) and anhydrous Et3N (2.89 mmol) in anhydrous
CH2Cl2 (8 mL) was added to a solution of Nꢀtertꢀbutoxycarbonꢀ
ylꢀ1,4ꢀdiaminobutane 6a (1.72 mmol) in anhydrous CH2Cl2
(12 mL) with stirring. The mixture was heated for 30 h at 45 °C.
After the starting compound 5 disappeared from the reaction
mixture, it was washed with 3% aq. HCl (10 mL) and brine
(4×10 mL) to pH 7, dried with Na2SO4, filtered, the solvent was
evaporated in vacuo. The product was isolated by column chroꢀ
matography in the toluene—EtOAc (20 : 1 → 10 : 1) solvent sysꢀ
tem to obtain compound 7a (0.628 g, 86%) as a crystallizing oil.
Found (%): C, 70.28; H, 12.05; N, 4.03. C41H82N2O6. Calculatꢀ
racꢀ1ꢀOꢀ{Nꢀ[12ꢀ(tertꢀButoxycarbonylamino)dodecyl]}carbꢀ
amoylꢀ2,3ꢀdiꢀOꢀtetradecylglycerol (7d). NꢀtertꢀButoxycarbonylꢀ
1,12ꢀdiaminododecane (6d) (0.465 g, 1.55 mmol), compound 5
(0.638 g, 0.982 mmol), Et3N (0.4 mL, 2.89 mmol), 45 °C, 6.5 h,
toluene—EtOAc (20 : 1). Compound 7d (0.663 g, 83%) was obꢀ
tained as a crystallizing oil. Found (%): C, 71.92; H, 12.33;
N, 3.59. C49H98N2O6•1/2 H2O. Calculated (%): C, 71.74; H,
12.16; N, 3.41. 1H NMR, δ: 0.80 (t, 6 H, 2 (CH2)11Me, J = 6.7 Hz);
1.12—1.30 (m, 60 H, 2 (CH2)11Me, (CH2)8); 1.38—1.54 (m, 17 H,
2 OCH2CH2, 2 NHCH2CH2, C(Me)3); 2.98—3.15 (m, 4 H,
2 NHCH2); 3.32—3.43 (m, 4 H, OCH2CH2, OCH2CH);
3.44—3.57 (m, 3 H, OCH2CH2, OCH2CH); 4.02 (dd, 1 H,
J = 5.4 Hz, J = 11.5 Hz) and 4.12 (dd, 1 H, CH2OC(O),
J = 4.2 Hz, J = 11.5 Hz); 4.43—4.56 (m, 1 H, CONH); 4.70
(br.t, 1 H, CONH, J = 5.5 Hz). 13C NMR, δ: 14.25, 22.82,
26.15, 26.21, 26.60, 26.89, 28.56, 29.42, 29.49, 29.62, 29.78,
29.82, 30.10, 32.04, 40.09, 41.20, 64.29, 70.48, 70.69, 71.88,
76.95, 79.21, 156.24, 156.51.
racꢀ1ꢀOꢀ{Nꢀ[12ꢀ(tertꢀButoxycarbonylamino)ꢀ4,9ꢀdioxadoꢀ
decyl]}carbamoylꢀ2,3ꢀdiꢀOꢀtetradecylglycerol (7e). NꢀtertꢀButꢀ
oxycarbonylꢀ4,9ꢀdioxaꢀ1,12ꢀdiaminododecane (6e) (0.552 g,
1.81 mmol), compound 5 (0.708 g, 1.09 mmol), Et3N (0.45 mL,
3.25 mmol), 24 °C, 5 h, toluene—EtOAc (4 : 1). Compound 7e
(0.861 g, 97%) was obtained as a crystallizing oil. MS, m/z
(Irel (%)): 837.839 [M + Na]+ (100). Calculated for C47H94N2O8:
814.701 [M]+. 1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me, J = 6.7 Hz);
1.19—1.30 (m, 44 H, 2 (CH2)11Me); 1.36 (s, 9 H, C(Me)3);
1.42—1.52 (m, 4 H, 2 OCH2CH2); 1.53—1.61 (m, 4 H,
2 OCH2CH2); 1.63—1.75 (m, 4 H, 2 OCH2CH2); 3.10—3.26
(m, 4 H, 2 NHCH2); 3.31—3.44 (m, 12 H, 5 OCH2CH2,
OCH2CH); 3.45—3.58 (m, 3 H, OCH2CH2, OCH2CH); 4.01
(dd, 1 H, J = 5.4 Hz, J = 11.5 Hz) and 4.12 (dd, 1 H, CH2OC(O),
J = 4.4 Hz, J = 11.5 Hz); 4.80—4.92 (m, 1 H, CONH);
4.97—5.10 (m, 1 H, CONH). 13C NMR, δ: 13.90, 22.47, 25.84,
25.90, 26.23, 28.22, 29.15, 29.30, 29.82, 31.71, 38.58, 38.95,
63.98, 68.77, 69.01, 70.28, 70.39, 70.52, 70.59, 71.56, 76.70,
78.89, 155.80, 156.20.
racꢀ1ꢀOꢀ{Nꢀ[13ꢀ(tertꢀButoxycarbonylamino)ꢀ4,7,10ꢀtrioxaꢀ
tridecyl]}carbamoylꢀ2,3ꢀdiꢀOꢀtetradecylglycerol (7f). NꢀtertꢀButꢀ
oxycarbonylꢀ4,7,10ꢀtrioxaꢀ1,13ꢀdiaminotridecane (6f) (0.705 g,
2.20 mmol), compound 5 (0.720 g, 1.11 mmol), Et3N (0.45 mL,
3.25 mmol), 24 °C, 3 h, toluene—EtOAc (4 : 1). Compound 7f
(0.884 g, 96%) was obtained as a crystallizing oil. MS, m/z
(Irel (%)): 853.858 [M + Na]+ (100). Calculated for C47H94N2O9:
830.696 [M]+. 1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me, J = 6.7 Hz);
1.15—1.30 (m, 44 H, 2 (CH2)11Me); 1.36 (s, 9 H, C(Me)3);
1.42—1.54 (m, 4 H, 2 OCH2CH2); 1.63—1.75 (m, 4 H,
2 OCH2CH2); 3.10—3.26 (m, 4 H, 2 NHCH2); 3.32—3.42
(m, 4 H, OCH2CH2, OCH2CH); 3.44—3.60 (m, 15 H,
7 OCH2CH2, OCH2CH); 4.01 (dd, 1 H, J = 5.4 Hz, J = 11.4 Hz)
and 4.11 (dd, 1 H, CH2OC(O), J = 4.3 Hz, J = 11.4 Hz);
4.87—5.00 (m, 1 H, CONH); 5.09—5.22 (m, 1 H, CONH)).
13C NMR, δ: 13.90, 22.47, 25.84, 25.90, 28.24, 29.15, 29.30,
29.48, 29.83, 31.71, 38.34, 38.74, 63.95, 69.16, 69.36, 70.04,
70.31, 70.38, 71.56, 76.72, 155.84, 156.26.
1
ed (%): C, 70.44; H, 11.82; N, 4.01. H NMR, δ: 0.81 (t, 6 H,
2 (CH2)11Me, J = 6.8 Hz); 1.17—1.25 (m, 44 H, 2 (CH2)11Me);
1.43 (s, 9 H, C(Me)3); 1.40—1.55 (m, 8 H, 2 OCH2CH2,
2 NHCH2CH2); 3.00—3.17 (m, 4 H, 2 NHCH2); 3.33—3.59
(m, 7 H, 2 OCH2CH2, OCH2CH); 4.01 (dd, 1 H, J = 5.3 Hz,
J = 11.5 Hz) and 4.13 (dd, 1 H, CH2OC(O), J = 4.2 Hz,
J = 11.5 Hz); 4.49—4.55 (m, 1 H, CONH); 4.65—4.77 (m, 1 H,
CONH). 13C NMR, δ: 14.29, 22.83, 26.18, 26.24, 27.42, 27.52,
28.55, 29.50, 29.64, 29.79, 29.83, 30.16, 32.06, 40.30, 40.80,
64.40, 70.55, 70.74, 71.92, 77.00, 79.35, 156.13, 156.57.
Compounds 7b—f were obtained similarly (below, the amounts
of the starting reactants, reaction temperature, reaction time,
eluent for chromatography, the yields, and physicochemical
characteristics of compounds obtained are given).
racꢀ1ꢀOꢀ{Nꢀ[6ꢀ(tertꢀButoxycarbonylamino)hexyl]}carbamoylꢀ
2,3ꢀdiꢀOꢀtetradecylglycerol (7b). NꢀtertꢀButoxycarbonylꢀ1,6ꢀdiꢀ
aminohexane (6b) (0.349 g, 1.61 mmol), compound 5 (0.610 g,
0.939 mmol), Et3N (0.4 mL, 2.89 mmol), 45 °C, 20 h, toluene.
Compound 7b (0.553 g, 81%) was obtained as a crystallizing oil.
Found (%): C, 70.81; H, 12.10; N, 3.76. C43H86N2O6. Calculatꢀ
1
ed (%): C, 71.03; H, 11.92; N, 3.85. H NMR, δ: 0.78 (t, 6 H,
2 (CH2)11Me, J = 6.9 Hz); 1.14—1.28 (m, 48 H, 2 (CH2)11Me,
(CH2)2); 1.30—1.56 (m, 17 H, 2 OCH2CH2, 2 NHCH2CH2,
CMe3); 2.93—3.10 (m, 4 H, 2 NHCH2); 3.30—3.55 (m, 7 H,
2 OCH2CH2, OCH2CH); 4.03 (dd, 1 H, J = 5.5 Hz, J = 11.3 Hz)
and 4.15 (dd, 1 H, CH2OC(O), J = 4.2 Hz, J = 11.3 Hz);
4.48—4.60 (m, 1 H, CONH); 4.66—4.80 (m, 1 H, CONH).
13C NMR, δ: 14.24, 22.80, 26.01, 26.14, 26.21, 27.43, 29.48,
29.63, 29.78, 29.82, 30.11, 32.03, 40.47, 63.55, 64.29, 70.52,
70.71, 71.21, 76.95, 77.58, 79.06, 156.12, 156.61.
racꢀ1ꢀOꢀ{Nꢀ[8ꢀ(tertꢀButoxycarbonylamino)octyl]}carbamoylꢀ
2,3ꢀdiꢀOꢀtetradecylglycerol (7c). NꢀtertꢀButoxycarbonylꢀ1,8ꢀdiꢀ
aminooctane (6c) (0.359 g, 1.47 mmol), compound 5 (0.620 g,
0.954 mmol), Et3N (0.4 mL, 2.89 mmol), 45 °C, 30 h, toluꢀ
ene—EtOAc (20 : 1 → 10 : 1). Compound 7c (0.543 g, 75%) was
obtained as a crystallizing oil. Found (%): C, 71.45; H, 12.25;
N, 3.52. C45H90N2O6. Calculated (%): C, 71.57; H, 12.01; N,
3.71. 1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me, J = 6.9 Hz);
1.17—1.27 (m, 52 H, 2 (CH2)11Me, (CH2)4); 1.38 (s, 9 H,
C(Me)3); 1.40—1.59 (m, 8 H, 2 OCH2CH2, 2 NHCH2CH2);
2.98—3.13 (m, 4 H, 2 NHCH2); 3.33—3.44 (m, 4 H, OCH2CH2,
OCH2CH); 3.46—3.59 (m, 3 H, OCH2CH2, OCH2CH); 4.02
(dd, 1 H, J = 5.4 Hz, J = 11.5 Hz) and 4.13 (dd, 1 H, CH2OC(O),
J = 4.1 Hz, J = 11.5 Hz); 4.39—4.57 (m, 1 H, CONH); 4.70
(br.t, 1 H, CONH, J = 5.6 Hz). 13C NMR, δ: 14.25, 22.82,
26.19, 26.24, 26.79, 26.84, 28.57, 29.31, 29.50, 29.64, 29.84,
racꢀ1ꢀOꢀ[Nꢀ(4ꢀAminobutyl)]carbamoylꢀ2,3ꢀdiꢀOꢀtetradecylꢀ
glycerol hydrochloride (8a). A solution of hydrogen chloride in
dioxane (4 M, 5 mL) was added to a solution of compound 7a
(0.295 mmol) in CH2Cl2 (7 mL) cooled to 0 °C with stirring.

Synthesis of neoglycolipids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
2285
After 4 h, the solvents were evaporated, and compound 8a (0.167 g,
89%) was isolated by chromatography in the CHCl3—MeOH
(12 : 1) solvent system as a crystallizing oil. Found (%): C, 67.93;
H, 12.06; N, 4.48. C36H75ClN2O4. Calculated (%): C, 68.05;
H, 11.90; N, 4.41. 1H NMR, δ: 0.82 (t, 6 H, 2 (CH2)11Me,
J = 6.7 Hz); 1.15—1.32 (m, 44 H, 2 (CH2)11Me); 1.42—1.67
(m, 6 H, 2 OCH2CH2, NHCH2CH2); 1.70—1.89 (m, 2 H,
NH2CH2CH2); 2.96 (t, 2 H, CH2NH2, J = 7.3 Hz); 3.09—3.20
(m, 2 H, NHCH2); 3.33—3.60 (m, 7 H, 2 OCH2CH2, OCH2CH);
4.01 (dd, 1 H, J = 5.4 Hz, J = 11.4 Hz) and 4.11 (dd, 1 H,
CH2OC(O), J = 4.3 Hz, J = 11.4 Hz); 5.35—5.48 (m, 1 H,
CONH). 13C NMR, δ: 13.54, 22.11, 24.37, 25.47, 25.54, 26.21,
28.80, 28.97, 29.10, 29.44, 31.36, 39.07, 39.64, 63.68, 69.83,
70.07, 71.25, 76.29, 156.07.
1 H, CH2OC(O), J = 4.1 Hz, J = 11.5 Hz); 4.70 (br.t, 1 H,
CONH, J = 5.8 Hz). 13C NMR, δ: 14.25, 22.81, 26.15, 26.21, 26.60,
26.89, 27.86, 29.09, 29.41, 29.49, 29.62, 29.78, 29.82, 30.10,
32.04, 40.08, 41.20, 64.23, 70.48, 70.69, 71.88, 76.95, 156.51.
racꢀ1ꢀOꢀ[Nꢀ(12ꢀAminoꢀ4,9ꢀdioxadodecyl)]carbamoylꢀ2,3ꢀ
diꢀOꢀtetradecylglycerol hydrochloride (8e). Compound 8e (0.223 g,
90%) was obtained from compound 7e (0.269 g, 0.330 mmol)
(3 h, CHCl3—MeOH (15 : 1)) as a crystallizing oil. MS, m/z
(Irel (%)): 715.756 [M – HCl + H]+ (100). Calculated for
C42H87N2O6: 715.656 [M – HCl + H]+. 1H NMR, δ: 0.81
(t, 6 H, 2 (CH2)11Me, J = 6.7 Hz); 1.10—1.32 (m, 44 H,
2 (CH2)11Me); 1.42—1.64 (m, 8 H, 4 OCH2CH2); 1.65—1.77
(m, 2 H, OCH2CH2); 1.86—1.98 (m, 2 H, OCH2CH2); 3.03—3.15
(m, 2 H, NH2CH2); 3.16—3.26 (m, 2 H, NHCH2); 3.32—3.68
(m, 15 H, 6 OCH2CH2, OCH2CH); 4.00 (dd, 1 H, J = 5.4 Hz,
J = 11.5 Hz) and 4.10 (dd, 1 H, CH2OC(O), J = 4.3 Hz,
J = 11.5 Hz); 5.45 (t, 1 H, CONH, J = 5.4 Hz). 13C NMR, δ:
13.54, 22.10, 25.46, 25.53, 25.73, 25.76, 27.44, 28.78, 28.94,
29.06, 29.12, 29.44, 31.34, 38.39, 38.55, 63.59, 68.15, 68.44,
69.88, 70.04, 70.53, 71.20, 76.32, 155.90.
racꢀ1ꢀOꢀ[Nꢀ(13ꢀAminoꢀ4,7,10ꢀtrioxatridecyl)]carbamoylꢀ
2,3ꢀdiꢀOꢀtetradecylglycerol hydrochloride (8f). Compound 8f
(0.232 g, 93%) was obtained from compound 7f (0.270 g,
0.325 mmol) (3 h, CHCl3—MeOH (15 : 1)) as a crystallizing oil.
Rf 0.55 (К). MS, m/z (Irel (%)): 731.763 [M – HCl + H]+ (100).
Calculated for C42H87N2O7: 731.651 [M – HCl + H]+.
1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me, J = 6.7 Hz); 1.10—1.32
(m, 44 H, 2 (CH2)11Me); 1.46—1.54 (m, 4 H, 2 OCH2CH2);
1.68—1.78 (m, 2 H, OCH2CH2); 1.89—2.03 (m, 2 H, OCH2CH2);
3.03—3.15 (m, 2 H, NH2CH2); 3.16—3.26 (m, 2 H, NHCH2);
3.32—3.68 (m, 19 H, 7 OCH2CH2, OCH2CH); 4.00 (dd, 1 H,
J = 5.4 Hz, J = 11.5 Hz) and 4.10 (dd, 1 H, CH2OC(O),
J = 4.4 Hz, J = 11.5 Hz); 5.45 (br.t, 1 H, CONH, J = 5.4 Hz).
13C NMR, δ: 13.54, 22.11, 25.47, 25.53, 26.26, 28.78, 28.94,
29.07, 29.12, 29.72, 29.44, 31.34, 38.00, 39.19, 63.13, 63.64,
68.39, 69.31, 69.56, 69.86, 70.04, 71.21, 76.29, 156.19.
racꢀ1ꢀOꢀ{Nꢀ[4ꢀNꢀ(4ꢀEthoxyꢀ1,2ꢀdioxocyclobutꢀ3ꢀenyl)aminoꢀ
butyl]}carbamoylꢀ2,3ꢀdiꢀOꢀtetradecylglycerol (9a). Triethylꢀ
amine (0.1 mL) and 3,4ꢀdiethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀdione
(0.153 mmol) were sequentially added to a solution of comꢀ
pound 8a (0.076 mmol) in CHCl3 (2 mL), and the mixture was
stirred for 4 h at 24 °C. The solvent was evaporated in vacuo, the
product was isolated by column chromatography; elution with
CHCl3 → CHCl3—MeOH (70 : 1) solvent system afforded
compound 9a (44.2 mg, 80%) as a crystallizing oil. MS, m/z
(Irel (%)): 745.384 [M + Na]+ (100). Calculated for C42H78N2O7:
722.581 [M]+. 1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me, J = 6.7 Hz);
1.15—1.30 (m, 44 H, 2 (CH2)11Me); 1.35—1.66 (m, 11 H,
2 OCH2CH2, 2 NHCH2CH2, OCH2Me); 3.07—3.19 (m, 2 H,
NHCH2); 3.31—3.68 (m, 9 H, 2 OCH2CH2, NHCH2, OCH2CH);
4.01 (dd, 1 H, J = 5.6 Hz, J = 11.4 Hz) and 4.12 (dd, 1 H,
CH2OC(O), J = 4.0 Hz, J = 11.5 Hz); 4.64—4.75 (m, 2 H,
OCH2Me); 4.80—4.93 (m, 1 H, CONH); 6.85—7.02 (m, 1 H,
NH). 13C NMR, δ: 13.52, 15.27, 22.10, 25.46, 25.52, 26.34,
27.08, 28.78, 28.92, 29.05, 29.11, 29.43, 31.34, 39.75, 43.76,
63.80, 69.16, 69.77, 70.02, 71.21, 76.25, 156.00, 171.86, 176.89,
182.06, 189.01.
Compounds 8b—f were obtained similarly (below, the amounts
of compounds 7b—f, reaction time, eluent for chromatography,
the yields and physicochemical characteristics of compounds
obtained are given).
racꢀ1ꢀOꢀ[Nꢀ(6ꢀAminohexyl)]carbamoylꢀ2,3ꢀdiꢀOꢀtetradecylꢀ
glycerol hydrochloride (8b). Compound 8b (0.181 g, 90%) was
obtained from compound 7b (0.220 g, 0.303 mmol) (2 h,
CHCl3—MeOH (15 : 1)) as a crystallizing oil. Found (%):
C, 66.83; H, 12.13; N, 4.25. C38H79ClN2O4•H2O. Calculated (%):
C, 66.97; H, 11.98; N, 4.11. 1H NMR, δ: 0.81 (t, 6 H,
2 (CH2)11Me, J = 6.7 Hz); 1.13—1.38 (m, 48 H, 2 (CH2)11Me,
(CH2)2); 1.40—1.55 (m, 6 H, 2 OCH2CH2, NHCH2CH2);
1.63—1.80 (m, 2 H, NH2CH2CH2); 2.85—3.00 (m, 2 H, CH2NH2);
3.02—3.13 (m, 2 H, NHCH2); 3.30—3.70 (m, 7 H, 2 OCH2CH2,
OCH2CH); 4.00 (dd, 1 H, J = 5.3 Hz, J = 11.5 Hz) and 4.10
(dd, 1 H, CH2OC(O), J = 4.3 Hz, J = 11.5 Hz); 5.02 (br.t, 1 H,
CONH, J = 5.6 Hz). 13C NMR, δ: 14.28, 22.84, 26.04, 26.18,
26.25, 27.47, 29.52, 29.67, 29.82, 29.85, 30.14, 32.07, 39.89,
40.84, 43.07, 61.76, 64.33, 70.55, 70.75, 71.25, 71.93, 72.42,
76.99, 156.64.
racꢀ1ꢀOꢀ[Nꢀ(8ꢀAminooctyl)]carbamoylꢀ2,3ꢀdiꢀOꢀtetradeꢀ
cylglycerol hydrochloride (8c). Compound 8c (0.184 g, 92%) was
obtained from compound 7c (0.219 g, 0.290 mmol) (4 h,
CHCl3—MeOH (15 : 1)) as a crystallizing oil. Found (%):
C, 69.43; H, 12.30; N, 4.13. C38H79ClN2O4. Calculated (%):
C, 69.47; H, 12.10; N, 4.05. 1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me,
J = 6.7 Hz); 1.11—1.34 (m, 52 H, 2 (CH2)11Me, (CH2)4);
1.35—1.57 (m, 6 H, 2 OCH2CH2, NHCH2CH2); 1.62—1.80
(m, 2 H, NH2CH2CH2); 2.82—3.00 (m, 2 H, CH2NH2);
3.02—3.14 (m, 2 H, NHCH2); 3.33—3.70 (m, 7 H, 2 OCH2CH2,
OCH2CH); 4.01 (dd, 1 H, J = 5.3 Hz, J = 11.5 Hz) and 4.12 (dd,
1 H, CH2OC(O), J = 4.1 Hz, J = 11.5 Hz); 4.72—4.84 (m, 1 H,
CONH). 13C NMR, δ: 13.90, 22.48, 25.84, 25.90, 26.15, 26.35,
27.33, 28.58, 28.70, 29.15, 29.30, 29.45, 29.49, 29.66, 29.81,
31.71, 39.76, 40.81, 63.99, 66.87, 70.25, 70.40, 71.58, 72.07,
76.68, 156.23.
racꢀ1ꢀOꢀ[Nꢀ(12ꢀAminododecyl)]carbamoylꢀ2,3ꢀdiꢀOꢀtetraꢀ
decylglycerol hydrochloride (8d). Compound 8d (0.217 g, 94%)
was obtained from compound 7d (0.251 g, 0.309 mmol) (2 h,
CHCl3—MeOH (15 : 1)) as a crystallizing oil. MS, m/z (Irel (%)):
711.814 [M – HCl + H]+ (100). Calculated for C44H91N2O4:
711.698 [M – HCl + H]+. 1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me,
J = 6.7 Hz); 1.10—1.33 (m, 60 H, 2 (CH2)11Me, (CH2)8);
1.35—1.57 (m, 6 H, 2 OCH2CH2, NHCH2CH2); 1.59—1.78
(m, 2 H, NH2CH2CH2); 2.81—2.98 (m, 2 H, CH2NH2);
3.02—3.14 (m, 2 H, NHCH2); 3.29—3.63 (m, 7 H, 2 OCH2CH2,
OCH2CH); 4.02 (dd, 1 H, J = 5.4 Hz, J = 11.5 Hz) and 4.13 (dd,
Compounds 9b—f were obtained similarly (below, the amounts
of compounds 8b—f and 3,4ꢀdiethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀdione,
the yields, and physicochemical characteristics of compounds
obtained are given).

2286
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
Shmendel´ et al.
racꢀ1ꢀOꢀ{Nꢀ[6ꢀNꢀ(4ꢀEthoxyꢀ1,2ꢀdioxocyclobutꢀ3ꢀenyl)aminoꢀ
hexyl]}carbamoylꢀ2,3ꢀdiꢀOꢀtetradecylglycerol (9b). Compound
9b (84 mg, 97%) was obtained from compound 8b (76.4 mg,
0.115 mmol) and 3,4ꢀdiethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀdione (34 μL,
0.230 mmol) as a crystallizing oil. 1H NMR, δ: 0.81 (t, 6 H,
2 (CH2)11Me, J = 6.7 Hz); 1.12—1.35 (m, 48 H, 2 (CH2)11Me,
(CH2)2); 1.36—1.62 (m, 11 H, 2 OCH2CH2, 2 NHCH2CH2,
OCH2Me); 3.02—3.12 (m, 2 H, NHCH2); 3.32—3.62 (m, 9 H,
2 OCH2CH2, NHCH2, OCH2CH); 4.01 (dd, 1 H, J = 5.4 Hz,
J = 11.5 Hz) and 4.12 (dd, 1 H, CH2OC(O), J = 4.1 Hz,
J = 11.5 Hz); 4.61—4.83 (m, 3 H, OCH2Me, CONH); 6.86—7.07
(m, 1 H, NH). 13C NMR, δ: 13.52, 15.28, 22.10, 25.29, 25.46,
25.51, 28.77, 28.91, 29.26, 29.43, 29.81, 31.33, 40.18, 44.04, 63.67,
69.81, 70.00, 71.19, 76.27, 155.94, 171.86, 176.82, 182.03, 189.07.
racꢀ1ꢀOꢀ{Nꢀ[8ꢀNꢀ(4ꢀEthoxyꢀ1,2ꢀdioxocyclobutꢀ3ꢀenyl)aminoꢀ
octyl]}carbamoylꢀ2,3ꢀdiꢀOꢀtetradecylglycerol (9c). Compound 9c
(115 mg, 96%) was obtained from compound 8c (106.0 mg,
0.153 mmol) and 3,4ꢀdiethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀdione (45.4 μL,
0.306 mmol) as a crystallizing oil. 1H NMR, δ: 0.80 (t, 6 H,
2 (CH2)11Me, J = 6.7 Hz); 1.10—1.29 (m, 52 H, 2 (CH2)11Me,
(CH2)4); 1.33—1.62 (m, 11 H, 2 OCH2CH2, 2 NHCH2CH2,
OCH2Me); 3.02—3.14 (m, 2 H, NHCH2); 3.29—3.61 (m, 9 H,
2 OCH2CH2, NHCH2, OCH2CH); 4.01 (dd, 1 H, J = 5.5 Hz,
J = 11.5 Hz) and 4.12 (dd, 1 H, CH2OC(O), J = 4.2 Hz,
J = 11.5 Hz); 4.60—4.85 (m, 3 H, OCH2Me, CONH). 13C NMR,
δ: 13.50, 15.25, 22.07, 25.44, 25.49, 25.65, 25.99, 28.34, 28.46,
28.75, 28.89, 29.05, 29.08, 29.29, 29.41, 29.89, 31.31, 40.38,
44.20, 63.59, 68.97, 69.80, 69.96, 71.14, 76.27, 155.85, 171.89,
176.73, 181.95, 189.14.
racꢀ1ꢀOꢀ{Nꢀ[12ꢀNꢀ(4ꢀEthoxyꢀ1,2ꢀdioxocyclobutꢀ3ꢀenyl)ꢀ
aminododecyl]}carbamoylꢀ2,3ꢀdiꢀOꢀtetradecylglycerol (9d).
Compound 9d (133 mg, 99%) was obtained from compound 8d
(120.4 mg, 0.161 mmol) and 3,4ꢀdiethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀ
dione (47.6 μL, 0.322 mmol) as a crystallizing oil. MS, m/z
(Irel (%)): 857.520 [M + Na]+ (100). Calculated for C50H94N2O7:
834.706 [M]+. 1H NMR, δ: 0.80 (t, 6 H, 2 (CH2)11Me, J = 6.7 Hz);
1.12—1.32 (m, 60 H, 2 (CH2)11Me, (CH2)8); 1.34—1.62 (m, 11 H,
2 OCH2CH2, 2 NHCH2CH2, OCH2Me); 3.03—3.14 (m, 2 H,
NHCH2); 3.30—3.64 (m, 9 H, 2 OCH2CH2, NHCH2, OCH2CH);
4.01 (dd, 1 H, J = 5.5 Hz, J = 11.5 Hz) and 4.13 (dd, 1 H,
CH2OC(O), J = 4.1 Hz, J = 11.5 Hz); 4.61—4.78 (m, 3 H,
OCH2Me, CONH); 6.74—6.96 (m, 1 H, NH). 13C NMR, δ:
13.52, 15.26, 22.09, 25.46, 25.51, 25.73, 26.14, 28.51, 28.65, 28.77,
28.91, 29.10, 29.42, 29.99, 31.33, 40.48, 44.28, 63.59, 68.98,
69.81, 69.99, 71.17, 76.28, 155.83, 171.87, 176.74, 182.03, 189.07.
racꢀ1ꢀOꢀ{Nꢀ[12ꢀNꢀ(4ꢀEthoxyꢀ1,2ꢀdioxocyclobutꢀ3ꢀenyl)ꢀ
aminoꢀ4,9ꢀdioxadodecyl]}carbamoylꢀ2,3ꢀdiꢀOꢀtetradecylglycerol
(9e). Compound 9e (88.3 mg, 72%) was obtained from comꢀ
pound 8e (109.5 mg, 0.146 mmol) and 3,4ꢀdiethoxycyclobutꢀ3ꢀ
eneꢀ1,2ꢀdione (43 μL, 0.290 mmol) as a crystallizing oil.
1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me, J = 6.7 Hz); 1.09—1.29
(m, 44 H, 2 (CH2)11Me); 1.32—1.62 (m, 11 H, 4 OCH2CH2,
OCH2Me); 1.59—1.75 (m, 2 H, OCH2CH2); 1.75—1.86 (m, 2 H,
OCH2CH2); 3.15—3.25 (m, 2 H, NHCH2); 3.31—3.55 (m, 17 H,
6 OCH2CH2, NHCH2, OCH2CH); 4.01 (dd, 1 H, J = 5.5 Hz,
J = 11.5 Hz) and 4.12 (dd, 1 H, CH2OC(O), J = 4.2 Hz,
J = 11.5 Hz); 4.61—4.75 (m, 2 H, OCH2Me); 5.02—5.12 (m, 1 H,
CONH); 6.74—6.97 (m, 1 H, NH). 13C NMR, δ: 13.51, 15.25,
22.08, 25.45, 25.51, 25.80, 25.87, 28.76, 28.91, 29.09, 29.43,
31.32, 38.51, 42.60, 63.61, 68.03, 68.32, 68.87, 69.86, 69.99,
70.12, 70.39, 71.17, 76.29, 155.85, 171.94, 176.56, 182.45, 188.56.
racꢀ1ꢀOꢀ{Nꢀ[13ꢀNꢀ(4ꢀEthoxyꢀ1,2ꢀdioxocyclobutꢀ3ꢀenyl)ꢀ
aminoꢀ4,7,10ꢀtrioxatridecyl]}carbamoylꢀ2,3ꢀdiꢀOꢀtetradecylꢀ
glycerol (9f). Compound 9f (108 mg, 86%) was obtained from
compound 8f (112.7 mg, 0.147 mmol) and 3,4ꢀdiethoxycyclobutꢀ
3ꢀeneꢀ1,2ꢀdione (43.4 μL, 0.294 mmol) as a crystallizing oil.
1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me, J = 6.7 Hz); 1.09—1.29
(m, 44 H, 2 (CH2)11Me); 1.32—1.55 (m, 7 H, 2 OCH2CH2,
OCH2Me); 1.64—1.75 (m, 2 H, CH2(11)); 1.75—1.86 (m, 2 H,
CH2(12)); 3.14—3.28 (m, 2 H, NHCH2); 3.31—3.66 (m, 21 H,
8 OCH2CH2, NHCH2, OCH2CH); 4.01 (dd, 1 H, J = 5.5 Hz,
J = 11.5 Hz) and 4.11 (dd, 1 H, CH2OC(O), J = 4.3 Hz,
J = 11.5 Hz); 4.61—4.78 (m, 2 H, OCH2Me); 5.02—5.27 (m, 1 H,
CONH); 6.95—7.10 (m, 1 H, NH). 13C NMR, δ: 13.51, 15.25,
22.08, 25.45, 25.51, 28.76, 28.91, 29.05, 29.09, 29.43, 31.32,
38.51, 42.64, 63.61, 68.71, 68.79, 69.64, 69.74, 69.89, 69.97,
71.17, 76.29, 155.89, 172.06, 176.34, 182.53, 188.42.
3ꢀ[6ꢀ(2,3,4,6ꢀTetraꢀOꢀacetylꢀβꢀDꢀgalactopyranosyloxy)ꢀ
hexyl]aminoꢀ4ꢀ{4ꢀ[racꢀ2,3ꢀbis(tetradecyloxy)propoxycarbonylꢀ
amino]butyl}aminocyclobutꢀ3ꢀeneꢀ1,2ꢀdione (10a). A mixture of
compound 3 (0.077 mmol) and Et3N (0.1 mL) in CHCl3 (4 mL)
was added to a solution of compound 9a (0.042 mmol) in CHCl3
(2 mL) and the mixture was kept for 36 h at 24 °C. The solvents
were evaporated in vacuo, the product was isolated by column
chromatography; elution with a CHCl3—MeOH (70 : 1 → 50 : 1)
solvent system afforded compound 10a (41.8 mg, 89%) as a crysꢀ
28
tallizing oil, [α]D –5.36 (c 0.5, CHCl3). MS, m/z (Irel (%)):
1147.026 [M + Na]+ (100). Calculated for C60H105N3O16
:
1123.749 [M]+. 1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me, J = 6.7 Hz);
1.11—1.35 (m, 48 H, 2 (CH2)11Me, (CH2)2); 1.40—1.68 (m, 12 H,
3 OCH2CH2, 3 NHCH2CH2); 1.92, 1.98, 1.99, 2.08 (all s,
3 H each, 4 MeCO); 3.08—3.20 (m, 2 H, NHCH2); 3.30—3.69
(m, 12 H, 2 OCH2CH2, 2 NHCH2, OCH2CH, OCHHa);
3.76—3.89 (m, 2 H, H(5) Gal, OCHHb); 3.96—4.16 (m, 4 H,
H(6) Gal, CH2OC(O)); 4.39 (d, 1 H, H(1) Gal, J = 7.9 Hz);
4.96 (dd, 1 H, H(3) Gal, J = 3.4 Hz, J = 10.5 Hz); 5.10 (dd, 1 H,
H(2) Gal, J = 7.8 Hz, J = 10.5 Hz); 5.17 (br.t, 1 H, CONH,
J = 6.3 Hz); 5.33 (dd, 1 H, H(4) Gal, J = 0.9 Hz, J = 3.4 Hz);
6.89—7.02 (m, 1 H, NH); 7.04—7.17 (m, 1 H, NH). 13C NMR,
δ: 13.53, 20.00, 20.07, 20.10, 20.25, 22.10, 24.99, 25.47, 25.52,
25.60, 26.41, 27.07, 28.78, 28.94, 29.08, 29.46, 30.54, 31.34,
43.41, 43.96, 60.59, 63.99, 66.48, 68.48, 69.60, 69.77, 70.03,
70.09, 70.29, 71.23, 76.26, 100.79, 156.36, 167.14, 167.46,
169.11, 169.50, 169.62, 169.86, 181.93, 182.10.
Compounds 10b—f were obtained similarly (below, the
amounts of compounds 9b—f and compound 3, reaction temꢀ
perature, reaction time, the yields, and physicochemical charꢀ
acteristics of compounds obtained are given).
3ꢀ[6ꢀ(2,3,4,6ꢀTetraꢀOꢀacetylꢀβꢀDꢀgalactopyranosyloxy)ꢀ
hexyl]aminoꢀ4ꢀ{6ꢀ[racꢀ2,3ꢀbis(tetradecyloxy)propoxycarbonylꢀ
amino]hexyl}aminocyclobutꢀ3ꢀeneꢀ1,2ꢀdione (10b). Compound
10b (56.4 mg, 74%) was obtained from compound 9b (49.7 mg,
0.069 mmol) and compound 3 (39.9 mg, 0.082 mmol) (24 °C,
34 h) as a crystallizing oil, [α]D28 –4.06 (c 1, CHCl3). Found (%):
C, 64.64; H, 9.59; N, 3.47. C62H109N3O16. Calculated (%):
C, 64.61; H, 9.53; N, 3.65. 1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me,
J = 6.7 Hz); 1.10—1.37 (m, 52 H, 2 (CH2)11Me, 2 (CH2)2);
1.38—1.63 (m, 12 H, 3 OCH2CH2, 3 NHCH2CH2); 1.91, 1.98,
1.99, 2.07 (all s, 3 H each, 4 MeCO); 3.04—3.15 (m, 2 H,
NHCH2); 3.28—3.68 (m, 12 H, 2 OCH2CH2, 2 NHCH2,
OCH2CH, OCHHa); 3.75—3.90 (m, 2 H, H(5) Gal, OCHHb);
3.95—4.19 (m, 4 H, H(6) Gal, CH2OC(O)); 4.39 (d, 1 H, H(1)

Synthesis of neoglycolipids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
2287
Gal, J = 7.9 Hz); 4.95 (dd, 1 H, H(3) Gal, J = 3.4 Hz, J = 10.5 Hz);
4.96—5.05 (m, 1 H, CONH); 5.10 (dd, 1 H, H(2) Gal, J = 7.9 Hz,
J = 10.5 Hz); 5.33 (dd, 1 H, H(4) Gal, J = 1.1 Hz, J = 3.4 Hz);
6.85—7.16 (m, 2 H, 2 NH). 13C NMR, δ: 13.52, 19.99, 20.07,
20.09, 20.23, 22.08, 24.79, 24.98, 25.05, 25.46, 25.51, 25.62,
28.77, 28.92, 29.07, 29.11, 29.23, 29.44, 30.10, 30.58, 31.33,
39.93, 43.40, 43.92, 60.59, 63.99, 66.47, 68.44, 69.57, 69.72,
70.01, 70.08, 70.30, 71.22, 76.25, 100.76, 156.34, 167.29, 167.53,
169.04, 169.49, 169.63, 169.84, 181.93, 182.04.
(40 °C, 37 h) as a crystallizing oil, [α]D28 –3.7 (c 1, CHCl3). MS,
m/z (Irel (%)): 1263.169 [M + Na]+ (100). Calculated for
C66H117N3O18: 1239.833 [M]+. 1H NMR, δ: 0.81 (t, 6 H,
2 (CH2)11Me, J = 6.7 Hz); 1.09—1.37 (m, 48 H, 2 (CH2)11Me,
(CH2)2); 1.39—1.63 (m, 12 H, 5 OCH2CH2, NHCH2CH2);
1.64—1.75 (m, 2 H, OCH2CH2)); 1.76—1.87 (m, 2 H, OCH2CH2);
1.91, 1.98, 1.99, 2.08 (all s, 3 H each, 4 MeCO); 3.14—3.26
(m, 2 H, NHCH2); 3.29—3.73 (m, 20 H, 6 OCH2CH2, 2 NHCH2,
OCH2CH, OCHHa); 3.76—3.89 (m, 2 H, H(5) Gal, OCHHb);
4.00 (dd, 1 H, CH2OC(O), J = 5.5 Hz, J = 11.3 Hz); 4.04—4.16
(m, 3 H, H(6) Gal, CH2OC(O)); 4.39 (d, 1 H, H(1) Gal, J = 7.9 Hz);
4.95 (dd, 1 H, H(3) Gal, J = 3.4 Hz, J = 10.5 Hz); 5.11 (dd, 1 H,
H(2) Gal, J = 7.9 Hz, J = 10.5 Hz); 5.05—5.18 (m, 1 H, CONH);
5.32 (dd, 1 H, H(4) Gal, J = 1.1 Hz, J = 3.4 Hz); 6.72—6.89
(m, 2 H, 2 NH). 13C NMR, δ: 13.52, 19.99, 20.06, 20.09, 20.22,
22.09, 24.97, 25.45, 25.50, 25.61, 25.78, 25.87, 28.76, 28.91,
29.06, 29.10, 29.42, 30.62, 30.68, 31.32, 38.41, 41.49, 43.85,
60.61, 63.82, 66.48, 67.49, 68.05, 68.41, 69.56, 69.73, 70.01,
70.13, 70.32, 71.23, 76.27, 100.78, 156.04, 167.28, 167.55,
169.00, 169.51, 169.64, 169.82, 182.11, 182.27.
3ꢀ[6ꢀ(2,3,4,6ꢀTetraꢀOꢀacetylꢀβꢀDꢀgalactopyranosyloxy)ꢀ
hexyl]aminoꢀ4ꢀ{8ꢀ[racꢀ2,3ꢀbis(tetradecyloxy)propoxycarbonylꢀ
amino]octyl}aminocyclobutꢀ3ꢀeneꢀ1,2ꢀdione (10c). Compound
10c (75.9 mg, 85%) was obtained from compound 9c (58.7 mg,
0.075 mmol) and compound 3 (37.1 mg, 0.077 mmol) (24 °C, 48 h)
as a crystallizing oil, [α]D28 1.02 (c 1, CHCl3). MS, m/z (Irel (%)):
1203.016 [M + Na]+ (100). Calculated for C64H113N3O16
:
1179.812 [M]+. 1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me,
J = 6.7 Hz); 1.09—1.35 (m, 56 H, 2 (CH2)11Me, (CH2)2,
(CH2)4); 1.36—1.64 (m, 12 H, 3 OCH2CH2, 3 NHCH2CH2);
1.91, 1.98, 1.99, 2.08 (all s, 3 H each, 4 MeCO); 3.00—3.11
(m, 2 H, NHCH2); 3.32—3.64 (m, 12 H, 2 OCH2CH2, 2 NHCH2,
OCH2CH, OCHHa); 3.80 (dt, 1 H, OCHHb, J = 6.1 Hz,
J = 9.3 Hz); 3.84 (dt, 1 H, H(5) Gal, J = 1.1 Hz, J = 6.8 Hz);
3.96—4.18 (m, 4 H, H(6) Gal, CH2OC(O)); 4.39 (d, 1 H, H(1)
Gal, J = 7.9 Hz); 4.89—4.98 (m, 1 H, CONH); 4.96 (dd, 1 H,
H(3) Gal, J = 3.4 Hz, J = 10.5 Hz); 5.10 (dd, 1 H, H(2) Gal,
J = 7.9 Hz, J = 10.5 Hz); 5.33 (dd, 1 H, H(4) Gal, J = 1.1 Hz,
J = 3.4 Hz); 6.82—7.10 (m, 2 H, 2 NH). 13C NMR, δ: 13.53,
20.00, 20.07, 20.11, 20.25, 22.10, 25.01, 25.47, 25.51, 25.64,
25.77, 25.91, 28.48, 28.78, 28.93, 29.08, 29.12, 29.35, 29.44,
30.53, 30.57, 31.34, 40.45, 43.94, 60.60, 66.47, 68.47, 69.60,
69.74, 70.02, 70.07, 70.30, 71.22, 76.26, 100.79, 156.23, 167.28,
167.50, 169.09, 169.50, 169.63, 169.85, 181.94, 182.07.
3ꢀ[6ꢀ(2,3,4,6ꢀTetraꢀOꢀacetylꢀβꢀDꢀgalactopyranosyloxy)ꢀ
hexyl]aminoꢀ4ꢀ{13ꢀ[racꢀ2,3ꢀbis(tetradecyloxy)propoxycarbonylꢀ
amino]ꢀ4,7,10ꢀtrioxatridecyl}aminocyclobutꢀ3ꢀeneꢀ1,2ꢀdione
(10f). Compound 10f (46.8 mg, 50%) was obtained from comꢀ
pound 9f (84.1 mg, 0.100 mmol) and compound 3 (35.9 mg,
28
0.074 mmol) (40 °C, 43 h) as a crystallizing oil, [α]D –2.95
(c 0.5, CHCl3). MS, m/z (Irel (%)): 1279.200 [M + Na]+ (100).
Calculated for C66H117N3O19: 1255.828 [M]+. 1H NMR, δ: 0.81
(t, 6 H, 2 (CH2)11Me, J = 6.7 Hz); 1.09—1.36 (m, 48 H,
2 (CH2)11Me, (CH2)2); 1.40—1.59 (m, 8 H, 3 OCH2CH2,
NHCH2CH2); 1.64—1.75 (m, 2 H, OCH2CH2); 1.77—1.87
(m, 2 H, OCH2CH2); 1.91, 1.98, 1.99, 2.08 (all s, 3 H each,
4 MeCO); 3.14—3.25 (m, 2 H, NHCH2); 3.30—3.74 (m, 24 H,
8 OCH2CH2, 2 NHCH2, OCH2CH, OCHHa); 3.80 (dt, 1 H,
OCHHb, J = 6.3 Hz, J = 9.5 Hz); 3.84 (dt, 1 H, H(5) Gal,
J = 1.1 Hz, J = 6.7 Hz); 4.00 (dd, 1 H, CHHaOC(O), J = 5.6 Hz,
J = 11.3 Hz); 4.07 (dd, 1 H, J = 6.7 Hz, J = 11.1 Hz) and 4.11
(dd, 1 H, both H(6) Gal, J = 6.7 Hz, J = 11.1 Hz); 4.11 (dd, 1 H,
CHHbOC(O), J = 3.9 Hz, J = 11.3 Hz); 4.39 (d, 1 H, H(1) Gal,
J = 7.9 Hz); 4.95 (dd, 1 H, H(3) Gal, J = 3.4 Hz, J = 10.5 Hz);
5.11 (dd, 1 H, H(2) Gal, J = 7.9 Hz, J = 10.5 Hz); 5.12—5.19
(m, 1 H, CONH); 5.32 (dd, 1 H, H(4) Gal, J =1.1 Hz, J = 3.4 Hz);
6.51—6.61 (m, 1 H, NH); 6.61—6.76 (m, 1 H, NH). 13C NMR,
δ: 13.53, 20.00, 20.07, 20.10, 20.22, 22.09, 24.95, 25.46, 25.51,
25.58, 28.76, 28.92, 29.05, 29.06, 29.10, 29.44, 29.95, 30.75,
31.32, 31.33, 38.10, 42.00, 43.77, 60.63, 63.83, 66.49, 68.39,
68.51, 68.96, 69.40, 69.56, 69.64, 69.70, 69.76, 70.02, 70.34,
71.24, 76.25, 100.79, 156.11, 167.27, 167.63, 168.97, 169.54,
169.66, 169.84, 182.26, 182.49.
3ꢀ[6ꢀ(2,3,4,6ꢀTetraꢀOꢀacetylꢀβꢀDꢀgalactopyranosyloxy)ꢀ
hexyl]aminoꢀ4ꢀ{12ꢀ[racꢀ2,3ꢀbis(tetradecyloxy)propoxycarbonylꢀ
amino]dodecyl}aminocyclobutꢀ3ꢀeneꢀ1,2ꢀdione (10d). Compound
10d (78.7 mg, 52%) was obtained from compound 9d (103 mg,
0.123 mmol) and compound 3 (50.2 mg, 0.104 mmol) (24 °C,
10 h) as a crystallizing oil, [α]D28 –7.3 (c 0.5, CHCl3). Found (%):
C, 66.06; H, 9.84; N, 3.56. C68H121N3O16. Calculated (%):
C, 66.04; H, 9.86; N, 3.40. 1H NMR, δ: 0.81 (t, 6 H, 2 (CH2)11Me,
J = 6.7 Hz); 1.08—1.35 (m, 64 H, 2 (CH2)11Me, (CH2)2,
(CH2)8); 1.35—1.64 (m, 12 H, 3 OCH2CH2, 3 NHCH2CH2);
1.91, 1.98, 1.98, 2.07 (all s, 3 H each, 4 MeCO); 3.00—3.14
(m, 2 H, NHCH2); 3.27—3.71 (m, 12 H, 2 OCH2CH2, 2 NHCH2,
OCH2CH, OCHHa); 3.74—3.90 (m, 2 H, H(5) Gal, OCHHb);
3.95—4.18 (m, 4 H, H(6) Gal, CH2OC(O)); 4.39 (d, 1 H, H(1)
Gal, J = 7.9 Hz); 4.83 (br.t, 1 H, CONH, J = 5.6 Hz); 4.96 (dd,
1 H, H(3) Gal, J = 3.4 Hz, J = 10.5 Hz); 5.09 (dd, 1 H, H(2)
Gal, J = 7.9 Hz, J = 10.5 Hz); 5.32 (dd, 1 H, H(4) Gal, J = 1.1 Hz,
J = 3.4 Hz); 7.27—7.52 (m, 2 H, 2 NH). 13C NMR, δ: 13.52,
19.98, 20.05, 20.07, 20.21, 22.09, 25.01, 25.45, 25.50, 25.67,
25.96, 26.19, 28.71, 28.76, 28.90, 29.05, 29.10, 29.42, 30.58,
30.66, 31.32, 40.51, 44.00, 44.10, 60.56, 63.73, 66.45, 68.42,
69.54, 69.79, 69.99, 70.01, 70.30, 71.18, 76.28, 100.76, 156.00,
167.19, 167.45, 168.94, 169.49, 169.61, 169.79, 181.61, 181.85.
3ꢀ[6ꢀ(2,3,4,6ꢀTetraꢀOꢀacetylꢀβꢀDꢀgalactopyranosyloxy)ꢀ
hexyl]aminoꢀ4ꢀ{12ꢀ[racꢀ2,3ꢀbis(tetradecyloxy)propoxycarbonylꢀ
amino]ꢀ4,9ꢀdioxadodecyl}aminocyclobutꢀ3ꢀeneꢀ1,2ꢀdione (10e).
Compound 10e (52.6 mg, 57%) was obtained from compound 9e
(88.3 mg, 0.103 mmol) and compound 3 (36.1 mg, 0.075 mmol)
3ꢀ[6ꢀ(βꢀDꢀGalactopyranosyloxy)hexyl]aminoꢀ4ꢀ{4ꢀ[racꢀ2,3ꢀ
bis(tetradecyloxy)propoxycarbonylamino]butyl}aminocyclobutꢀ3ꢀ
eneꢀ1,2ꢀdione (11a). A solution of MeONa in MeOH (0.1 M,
0.5 mL) was added to a solution of compound 10a (0.024 mmol)
in CH2Cl2 (3 mL). After 40 min, the reaction mixture was neuꢀ
tralized with the ionꢀexchange resin Dowex 50×8 (H+), filtered,
the solvent was evaporated in vacuo. The product was isolated by
column chromatography; elution with the CH2Cl2—MeOH
(10 : 1) solvent system afforded compound 11a (20.9 mg, 93%)
25
as a crystallizing oil, [α]D 0.3 (c 2, CHCl3—CH3OH, 1 : 1).
MS, m/z (Irel (%)): 978.953 [M + Na]+ (100). Calculated for
1
C52H97N3O12: 955.707 [M]+. H NMR (Pyꢀd5), δ: 0.81 (t, 6 H,

2288
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
Shmendel´ et al.
2 (CH2)11Me, J = 6.7 Hz); 1.10—1.39 (m, 48 H, 2 (CH2)11Me,
(CH2)2); 1.40—1.79 (m, 12 H, 3 OCH2CH2, 3 NHCH2CH2);
3.22—3.34 (m, 2 H, NHCH2); 3.36—3.46 (m, 2 H, NHCH2);
3.55 (dt, 1 H, CHHa, J = 6.5 Hz, J = 9.0 Hz); 3.57—3.77 (m, 8 H,
2 OCH2CH2, NHCH2, OCH2CH); 3.78—3.87 (m, 1 H,
OCH2CH); 3.92—4.02 (m, 2 H, H(5) Gal, OCHHb); 4.07 (dd, 1 H,
H(3) Gal, J = 3.4 Hz, J = 9.5 Hz); 4.33 (dd, 1 H, H(2) Gal,
J = 7.7 Hz, J = 9.5 Hz); 4.34—4.38 (m, 2 H, H(6) Gal); 4.41 (dd,
1 H, CHHaOC(O), J = 5.6 Hz, J = 11.3 Hz); 4.49 (dd, 1 H, H(4)
Gal, J = 0.9 Hz, J = 3.4 Hz); 4.50 (dd, 1 H, CHHbOC(O),
J = 4.6 Hz, J = 11.3 Hz); 4.64 (d, 1 H, H(1) Gal, J = 7.7 Hz);
7.86—8.23 (m, 3 H, 3 NH). 13C NMR, δ: 14.94, 23.61, 26.69,
26.98, 27.17, 27.21, 28.05, 29.85, 30.29, 30.49, 30.51, 30.60,
30.64, 30.66, 30.83, 31.30, 32.17, 32.81, 41.56, 44.77, 44.97,
63.12, 70.26, 71.01, 71.25, 71.79, 72.44, 73.29, 75.94, 77.51,
78.41, 105.88, 158.13, 169.68, 169.77, 184.77.
7.84 (t, 1 H, CONH, J = 5.4 Hz); 7.91—8.20 (m, 2 H, 2 NH).
13C NMR, δ: 14.58, 23.24, 26.32, 26.66, 26.80, 26.83, 27.00,
27.43, 29.75, 29.78, 29.92, 30.10, 30.13, 30.23, 30.26, 30.29,
30.44, 30.74, 30.93, 31.87, 32.14, 32.44, 41.72, 44.63, 44.83,
69.89, 70.64, 70.86, 71.42, 72.05, 72.89, 75.52, 77.10, 78.06,
105.49, 149.80, 150.16, 150.51, 169.32, 169.40, 184.38.
3ꢀ[6ꢀ(βꢀDꢀGalactopyranosyloxy)hexyl]aminoꢀ4ꢀ{12ꢀ[racꢀ
2,3ꢀbis(tetradecyloxy)propoxycarbonylamino]dodecyl}aminoꢀ
cyclobutꢀ3ꢀeneꢀ1,2ꢀdione (11d). Compound 11d (44.2 mg, 95%)
was obtained from compound 10d (54.1 mg, 0.044 mmol) as
26
a crystallizing oil, [α]D –2.85 (c 1, CHCl3—CH3OH, 1 : 1).
MS, m/z (Irel (%)): 1091.094 [M + Na]+ (100). Calculated for
C60H113N3O12: 1067.832 [M]+. 1H NMR (CDCl3—CD3OD
(6 : 1)), δ: 0.80 (t, 6 H, 2 (CH2)11Me, J = 6.7 Hz); 1.08—1.36
(m, 64 H, 2 (CH2)11Me, (CH2)2, (CH2)8); 1.37—1.62 (m, 12 H,
3 OCH2CH2, 3 NHCH2CH2); 2.99—3.09 (m, 2 H, NHCH2);
3.32—3.58 (m, 15 H, 2 OCH2CH2, 2 NHCH2, OCH2CH,
CHHa, H(2) Gal, H(3) Gal, H(5) Gal); 3.72 (dd, 2 H, H(6) Gal,
J = 2.2 Hz, J = 5.8 Hz); 3.82 (dt, 1 H, OCHHb, J = 6.4 Hz,
J = 9.5 Hz); 3.84—3.90 (m, 1 H, H(4) Gal); 4.00 (dd, 1 H,
J = 5.3 Hz, J = 11.5 Hz) and 4.09 (dd, 1 H, CH2OC(O), J = 5.4 Hz,
J = 11.5 Hz); 4.15 (d, 1 H, H(1) Gal, J = 7.5 Hz); 5.32—5.40
(m, 1 H, CONH); 7.89—7.91 (m, 2 H, 2 NH). 13C NMR, δ:
13.33, 21.97, 24.58, 25.07, 25.30, 25.36, 25.77, 26.09, 28.56,
28.61, 28.65, 28.78, 28.89, 28.94, 28.98, 29.23, 30.02, 30.46,
30.82, 31.22, 36.00, 40.26, 43.28, 43.77, 60.70, 63.31, 63.32,
68.35, 69.08, 69.63, 69.94, 70.64, 71.14, 72.80, 73.81, 76.18,
102.66, 156.16, 167.06, 167.35, 181.41, 181.57.
Compounds 11b—f were obtained similarly (below, the
amounts of compounds 10b—f, the yields, and physicochemical
characteristics of compounds obtained are given).
3ꢀ[6ꢀ(βꢀDꢀGalactopyranosyloxy)hexyl]aminoꢀ4ꢀ{6ꢀ[racꢀ2,3ꢀ
bis(tetradecyloxy)propoxycarbonylamino]hexyl}aminocyclobutꢀ3ꢀ
eneꢀ1,2ꢀdione (11b). Compound 11b (20.4 mg, 98%) was obꢀ
tained from compound 10b (24.4 mg, 0.021 mmol) as a crysꢀ
25
tallizing oil, [α]D –4.12 (c 1, CHCl3—CH3OH, 1 : 1). MS,
m/z (Irel (%)): 1007.009 [M + Na]+ (100). Calculated for
C54H101N3O12: 983.738 [M]+. 1H NMR (Pyꢀd5), δ: 0.80 (t, 6 H,
2 (CH2)11Me, J = 6.7 Hz); 1.09—1.39 (m, 52 H, 2 (CH2)11Me,
2 (CH2)2); 1.39—1.62 (m, 12 H, 3 OCH2CH2, 3 NHCH2CH2);
3.17—3.28 (m, 2 H, NHCH2); 3.35—3.44 (m, 2 H, NHCH2);
3.53 (dt, 1 H, OCHHa, J = 6.5 Hz, J = 9.5 Hz); 3.58—3.71 (m, 8 H,
2 OCH2CH2, NHCH2, OCH2CH); 3.75—3.87 (m, 1 H,
OCH2CH); 3.91—4.00 (m, 2 H, H(5) Gal, OCHHb); 4.06 (dd, 1 H,
H(3) Gal, J = 3.4 Hz, J = 9.5 Hz); 4.31 (dd, 1 H, H(2) Gal,
J = 7.6 Hz, J = 9.5 Hz); 4.32—4.37 (m, 2 H, H(6) Gal); 4.42 (dd,
1 H, CHHaOC(O), J = 5.6 Hz, J = 11.3 Hz); 4.48 (dd, 1 H, H(4)
Gal, J = 1.0 Hz, J = 3.4 Hz); 4.51 (dd, 1 H, CHHbOC(O),
J = 4.4 Hz, J = 11.3 Hz); 4.63 (d, 1 H, H(1) Gal, J = 7.6 Hz);
7.80—7.88 (m, 1 H, 1 CONH); 7.91—8.14 (m, 2 H, 2 NH).
13C NMR, δ: 14.94, 23.30, 26.37, 26.68, 26.75, 26.86, 26.89,
27.10, 29.97, 30.17, 30.19, 30.29, 30.32, 30.35, 30.51, 30.72,
30.99, 31.90, 32.17, 32.49, 41.62, 44.66, 44.75, 62.80, 64.87,
69.94, 70.69, 70.93, 71.48, 72.12, 72.98, 75.63, 77.22, 78.12,
105.57, 157.78, 169.43, 184.49, 184.52.
3ꢀ[6ꢀ(βꢀDꢀGalactopyranosyloxy)hexyl]aminoꢀ4ꢀ{12ꢀ[racꢀ
2,3ꢀbis(tetradecyloxy)propoxycarbonylamino]ꢀ4,9ꢀdioxadodecyl}ꢀ
aminocyclobutꢀ3ꢀeneꢀ1,2ꢀdione (11e). Compound 11e (26 mg,
83%) was obtained from compound 10e (36.4 mg, 0.029 mmol)
as a crystallizing oil, [α]D27 –3.55 (c 1, CHCl3—CH3OH, 1 : 1).
MS, m/z (Irel (%)): 1095.060 [M + Na]+ (100). Calculated for
C58H109N3O14: 1071.791 [M]+. 1H NMR (Pyꢀd5), δ: 0.80 (t, 6 H,
2 (CH2)11Me, J = 6.7 Hz); 1.10—1.39 (m, 48 H, 2 (CH2)11Me,
(CH2)2); 1.41—1.63 (m, 12 H, 6 OCH2CH2); 1.80—1.98 (m, 4 H,
OCH2CH2, NHCH2CH2); 3.19—3.32 (m, 4 H, 2 NHCH2);
3.33—3.71 (m, 15 H, 5 OCH2CH2, NHCH2, OCH2CH, CHHa);
3.73—3.88 (m, 3 H, OCH2CH2, OCH2CH); 3.90—4.01 (m, 2 H,
H(5) Gal, OCHHb); 4.06 (dd, 1 H, H(3) Gal, J = 3.4 Hz,
J = 9.5 Hz); 4.32 (dd, 1 H, H(2) Gal, J = 7.6 Hz, J = 9.4 Hz);
4.35 (d, 2 H, H(6) Gal, J = 6.0 Hz); 4.41 (dd, 1 H, CHHaOC(O),
J = 5.6 Hz, J = 11.4 Hz); 4.47 (dd, 1 H, H(4) Gal, J = 1.1 Hz,
J = 3.4 Hz); 4.51 (dd, 1 H, CHHbOC(O), J = 4.7 Hz, J = 11.4 Hz);
4.63 (d, 1 H, H(1) Gal, J = 7.7 Hz); 7.91 (t, 1 H, CONH,
J = 5.0 Hz); 7.99—8.27 (m, 2 H, 2 NH). 13C NMR, δ: 14.94,
23.61, 26.69, 27.03, 27.17, 27.20, 27.56, 30.29, 30.48, 30.50,
30.60, 30.63, 30.66, 30.82, 31.30, 31.43, 32.26, 32.77, 32.80,
39.50, 42.58, 44.99, 63.12, 65.19, 68.66, 69.25, 70.24, 71.00,
71.23, 71.54, 71.78, 72.43, 73.29, 75.95, 77.54, 78.41, 105.88,
158.10, 169.78, 169.82, 184.84, 184.92.
3ꢀ[6ꢀ(βꢀDꢀGalactopyranosyloxy)hexyl]aminoꢀ4ꢀ{8ꢀ[racꢀ2,3ꢀ
bis(tetradecyloxy)propoxycarbonylamino]octyl}aminocyclobutꢀ3ꢀ
eneꢀ1,2ꢀdione (11c). Compound 11c (51.8 mg, 85%) was obꢀ
tained from compound 10c (70.9 mg, 0.060 mmol) as a crystalꢀ
26
lizing oil, [α]D –3.72 (c 1, CHCl3—CH3OH, 1 : 1). MS, m/z
(Irel (%)): 1034.891 [M + Na]+ (100). Calculated for C56H105N3O12
:
1011.770 [M]+. 1H NMR (Pyꢀd5), δ: 0.80 (t, 6 H, 2 (CH2)11Me,
J = 6.7 Hz); 1.02—1.39 (m, 56 H, 2 (CH2)11Me, (CH2)2,
(CH2)4); 1.41—1.65 (m, 12 H, 3 OCH2CH2, 3 NHCH2CH2);
3.21—3.33 (m, 2 H, NHCH2); 3.34—3.44 (m, 2 H, NHCH2);
3.52 (dt, 1 H, CHHa, J = 6.5 Hz, J = 8.7 Hz); 3.56—3.74 (m, 8 H,
2 OCH2CH2, NHCH2, OCH2CH); 3.76—3.87 (m, 1 H,
OCH2CH); 3.89—4.00 (m, 2 H, H(5) Gal, OCHHb); 4.05 (dd, 1 H,
H(3) Gal, J = 3.4 Hz, J = 9.5 Hz); 4.29 (dd, 1 H, H(2) Gal,
J = 7.7 Hz, J = 9.5 Hz); 4.33 (d, 2 H, H(6) Gal, J = 6.0 Hz); 4.41
(dd, 1 H, CHHaOC(O), J = 5.6 Hz, J = 11.4 Hz); 4.47 (dd, 1 H,
H(4) Gal, J = 1.1 Hz, J = 3.5 Hz); 4.51 (dd, 1 H, CHHbOC(O),
J = 4.3 Hz, J = 11.6 Hz); 4.62 (d, 1 H, H(1) Gal, J = 7.7 Hz);
3ꢀ[6ꢀ(βꢀDꢀGalactopyranosyloxy)hexyl]aminoꢀ4ꢀ{13ꢀ[racꢀ
2,3ꢀbis(tetradecyloxy)propoxycarbonylamino]ꢀ4,7,10ꢀtrioxaꢀ
tridecyl}aminocyclobutꢀ3ꢀeneꢀ1,2ꢀdione (11f). Compound 11f
(23 mg, 80%) was obtained from compound 10f (33.9 mg,
27
0.027 mmol) as
a
crystallizing oil, [α]D
–3.92 (c 1,
CHCl3—CH3OH, 1 : 1). MS, m/z (Irel (%)): 1111.103 [M + Na]+
(100). Calculated for C58H109N3O15: 1087.786 [M]+. H NMR
1
(Pyꢀd5), δ: 0.80 (t, 6 H, 2 (CH2)11Me, J = 6.7 Hz); 1.09—1.39
(m, 48 H, 2 (CH2)11Me, (CH2)2); 1.41—1.62 (m, 8 H,

Synthesis of neoglycolipids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
2289
4 OCH2CH2); 1.78—1.96 (m, 4 H, OCH2CH2, NHCH2CH2);
3.34—3.70 (m, 23 H, 7 OCH2CH2, 3 NHCH2, OCH2CH,
CHHa); 3.72—3.86 (m, 3 H, OCH2CH2, OCH2CH); 3.91—4.02
(m, 2 H, H(5) Gal, OCHHb); 4.06 (dd, 1 H, H(3) Gal, J = 3.4 Hz,
J = 9.5 Hz); 4.32 (dd, 1 H, H(2) Gal, J = 7.7 Hz, J = 9.5 Hz);
4.35 (d, 2 H, H(6) Gal, J = 6.0 Hz); 4.41 (dd, 1 H, CHHaOC(O),
J = 5.6 Hz, J = 11.4 Hz); 4.45—4.56 (m, 2 H, H(4) Gal,
CHHbOC(O)); 4.64 (d, 1 H, H(1) Gal, J = 7.7 Hz); 7.89 (t, 1 H,
CONH, J = 5.6 Hz); 7.96—8.19 (m, 2 H, 2 NH). 13C NMR, δ:
14.58, 23.24, 26.33, 26.67, 26.81, 26.84, 29.92, 30.11, 30.14,
30.23, 30.26, 30.29, 30.45, 30.93, 30.97, 31.90, 32.25, 32.44,
39.05, 42.16, 44.63, 62.76, 64.83, 68.74, 69.31, 69.88, 70.62,
70.83, 70.87, 71.05, 71.07, 71.42, 72.07, 72.92, 75.60, 77.19,
78.05, 105.53, 157.74, 169.41, 164.44, 184.48, 184.56.
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This work was financially supported by the Russian
Foundation for Basic Research (Project No. 09ꢀ03ꢀ00874a).
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Received October 28, 2010;
in revised form November 24, 2010