Synthesis of 2-aminoethyl glycosides of chitooligosaccharides

Article abstract of DOI:10.1007/s11172-015-1250-6

2-Aminoethyl glycosides of chitotriose, chitopentaose, and chitoheptaose were synthesized. The successive extension of the oligosaccharide chain by two monosaccharide residues was carried out using a monosaccharide acceptor and a disaccharide donor, in which amino groups were protected by phthaloyl groups, benzyl moieties were used as a permanent protection for the hydroxy groups at C(3) and C(6), and acetyl or chloroacetyl groups were employed as a temporary protection for the hydroxy group at C(4).

Full text of DOI:10.1007/s11172-015-1250-6

Russian Chemical Bulletin, International Edition, Vol. 64, No. 12, pp. 2932—2941, December, 2015
2932
Synthesis of 2ꢀaminoethyl glycosides of chitooligosaccharides*
O. N. Yudina, Yu. E. Tsvetkov, and N. E. Nifantiev
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 8784. Eꢀmail: nen@ioc.ac.ru
2ꢀAminoethyl glycosides of chitotriose, chitopentaose, and chitoheptaose were syntheꢀ
sized. The successive extension of the oligosaccharide chain by two monosaccharide residues
was carried out using a monosaccharide acceptor and a disaccharide donor, in which amino
groups were protected by phthaloyl groups, benzyl moieties were used as a permanent protecꢀ
tion for the hydroxy groups at C(3) and C(6), and acetyl or chloroacetyl groups were employed
as a temporary protection for the hydroxy group at C(4).
Key words: chitin, chitooligosaccharides, 2ꢀaminoethyl glycosides, blockwise synthesis.
Chitin is a polysaccharide composed of βꢀ(1→4)ꢀ
Examples of the synthesis of rather large chitooligoꢀ
saccharides or their analogs with unacetylated amino
groups containing four to twelve monosaccharides were
described in the literature12—15 and have been recently
summarized in the review.16 These methods of synthesis
differ from each other in the type of Nꢀprotecting groups
used (phthaloyl,12,13 dimethylmaleoyl,14 or trichloroꢀ
acetyl15), as well as in the nature (thioglycoside,13,15 glycoꢀ
syl fluoride,13 or trichloroacetimidate12,14) and the size
(from monoꢀ15 to tetrasaccharides12) of glycosyl donors,
which were employed for the extension of the oligoꢀ
saccharide chain. In the present study, we report the blockꢀ
wise synthesis of 2ꢀaminoethyl glycosides of chitotriose,
chitopentaose, and chitoheptaose based on the extension
of the oligosaccharide chain of a disaccharide glycosyl
donor containing Nꢀphthaloyl protecting groups.
linked Nꢀacetylglucosamine units. This polysaccharide
together with cellulose are the most abundant natural orꢀ
ganic compounds. Chitin is an essential structural eleꢀ
ment of the exoskeleton of insects and crustaceans and
a major constituent of the cell wall of fungi,1 including such
clinically important pathogenic fungi as Candida albicans
and Aspergillus fumigatus.2 A contact of a pathogen with
the immune system of the host organism produces an imꢀ
mune response to surface polysaccharide antigens of the
fungal cell wall, such as mannan, αꢀ and βꢀ(1→3)ꢀgluꢀ
cans, galactomannans, and chitin. The detection of antiꢀ
bodies specific for fungal surface polysaccharide antigens,
including chitin, in the blood serum can be used for the
diagnosis of fungal infections.3 The reliable antibody deꢀ
tection requires samples of the corresponding polysacchaꢀ
ride antigens, which were isolated from natural sources, or
their oligosaccharide fragments, which can be prepared
via a synthetic route.
Results and Discussion
The present work was performed as a part of research
on the synthesis of oligosaccharide derivatives representꢀ
ing distinct structural fragments of surface polysaccharide
antigens of pathogenic fungi.4—9 The aim of this study is
to prepare 2ꢀaminoethyl glycosides of chitooligosacchaꢀ
rides — βꢀ(1→4)ꢀlinked oligoꢀNꢀacetylglucosamines conꢀ
taining three, five, and seven monosaccharide residues.
Such compounds are intended for use in the development
of enzyme immunoassay test systems (including those
based on chip technologies10) for the detection of polysacꢀ
charide mycoantigens and homologous antibodies, as well
as of glycoconjugate molecular systems11 for use as imꢀ
munogens to induce specific antichitin antibodies.
In order to synthesize the target compounds, we iniꢀ
tially intended (Scheme 1) to use thioglycoside donor 3, in
which the hydroxy groups at C(3) and C(6) are protected
by permanent benzyl groups, while the hydroxy group at
C(4) is protected by the temporary acetyl group.
However, the orthogonal glycosylation of thioglycoꢀ
side 2 (see Ref. 17) with trichloroacetimidate 1 (see
Ref. 18) in the presence of TMSOTf or BF3•Et2O affordꢀ
ed desired disaccharide 3 (see Ref. 19) in yields of not
higher than 25—30%. This synthesis gave thioglycoside 4
as the major product, which was generated via intermoꢀ
lecular transfer of the ethylthio group from acceptor 2
to activated donor 1 (the transfer of alkylꢀ and arylthio
groups in glycosylation reactions was considered in detail
in the review20).
* Dedicated to Academician of the Russian Academy of Sciences
N. S. Zefirov on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2932—2941, December, 2015.
1066ꢀ5285/15/6412ꢀ2932 © 2015 Springer Science+Business Media, Inc.

2ꢀAminoethyl glycosides
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015 2933
Scheme 1
Reagents and conditions: TMSOTf, CH2Cl2, –25 °C or BF3•Et2O, CH2Cl2, –40 °C.
Therefore, we synthesized the disaccharide glycosyl
donor by the glycosylation reaction of pꢀmethoxyphenyl
glycoside 5 (see Ref. 21) with thioglycoside 4,22 which
produced known disaccharide 6. Earlier, this disaccharide
has been synthesized12 by the reaction of imidate 1 with
acceptor 5. Then compound 6 was transformed into
imidate 7 using the described sequence of transformaꢀ
tions (Scheme 2), involving the removal of the anomeric
pꢀmethoxyphenyl group followed by the reaction of the
hemiacetal that formed with trichloroacetonitrile.12
Since it was necessary to synthesize the target chitoꢀ
oligosaccharides in the form of 2ꢀaminoethyl glycosides,
we employed 2ꢀazidoethyl glycoside 10 as the glycosyl
acceptor that served as the starting point for the extension
of the polysaccharide chain (see Schemes 3 and 4). The
azide group is stable under the conditions of removal of
the Nꢀphthaloyl group. This ensures the differentiation
between the amino groups in the glucosamine residues
and the aglycone.
The glycosylation of 2ꢀchloroethanol with thioglycoꢀ
side 8 (see Ref. 17) (Scheme 3) gave 2ꢀchloroethyl glycoꢀ
side 9. The latter was transformed into 2ꢀazidoethyl glyꢀ
coside 10 by the replacement of the chlorine atom with
the azide group. The reductive cleavage of the benzylidene
ring in compound 10 under the conditions described earliꢀ
er23 afforded target acceptor 11.
Then we proceeded to extend the oligoglucosamine
chain. The glycosylation of derivative 11 with imidate 7
in the presence of TMSOTf gave trisaccharide 12 in
good yield (Scheme 4). The spinꢀspin coupling constant
J1,2 = 7.9 Hz of the glucosamine residue B (the notation of
monosaccharide residues is given in Scheme 4) in the
1H NMR spectrum confirms the β configuration of the
glycosidic bond that formed. The removal of the acetyl
group in trisaccharide 12 with sodium methoxide in methꢀ
anol12 was rather inefficient due, apparently, to the comꢀ
petitive cleavage of the phthalimide ring.24 Therefore,
compound 12 was deacetylated with hydrogen chloride in
Scheme 2
MP is 4ꢀMeOC6H4.
Reagents, conditions, and yields: i. NIS, TfOH, 4 Å molecular sieves, CH2Cl2, –20 °C; ii. (NH4)2Ce(NO3)6, acetonitrile—toluene—
water (4 : 1 : 1), 0 °C, yield 90%; iii. CCl3CN, DBU, –20 °C, yield 96%.

2934
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015
Yudina et al.
Scheme 3
Reagents and conditions: i. NIS, TfOH, 4 Å molecular sieves, CH2Cl2, –20 °C; ii. NaN3, DMF, 60 °C; iii. H3B•NMe3, AlCl3,
H2O, THF.
a methanol—CH2Cl2 mixture. The reaction proceeded
slowly (the complete conversion of the starting acetate
was achieved in five—six days) and afforded trisaccharide
glycosyl acceptor 13 in moderate yield (70%). The further
glycosylation of glycosyl acceptor 13 with imidate 7 proꢀ
duced pentasaccharide 14 (86%), which was also subjectꢀ
ed to acidic deacetylation to form pentasaccharide accepꢀ
tor 15; however, the latter was obtained in a moderate
yield (57%).
Because of the long reaction time of acidic deacetylaꢀ
tion, which is inconvenient from a preparative point of
view, and a low yield of pentasaccharide glycosyl acceptor
15, we used the chloroacetyl group instead of the acetyl
group as a temporary protection of the hydroxy group at
C(4). For this purpose, glycosyl acceptor 5 was introꢀ
duced into the glycosylation reaction with thioglycoside
16,25 giving disaccharide 17 (Scheme 5), and the latter
was transformed into imidate 18 by means of the convenꢀ
tional removal of the pꢀmethoxyphenyl group and the reꢀ
action with trichloroacetonitrile in the presence of a base.
The glycosylation of trisaccharide acceptor 13 with
imidate 18 in the presence of TMSOTf produced penꢀ
tasaccharide 19. The removal of the chloroacetyl group in
19 by the treatment with thiourea proceeded much faster
than the removal of the acetyl group in acetylated analog
14 (8—10 h versus 6 days) and gave product 15 in higher
yield. The final step of the extension of the oligosacchaꢀ
ride chain via the glycosylation of pentasaccharide 15 with
imidate 18 afforded heptasaccharide 20 in 68% yield.
The protecting groups in oligomers 13, 14, and 20
were removed by means of the reaction sequence presentꢀ
ed in Scheme 6. The Nꢀphthaloyl protecting groups were
Scheme 4
Reagents and conditions: i. TMSOTf, 4 Å molecular sieves, CH2Cl2, –40 °C; ii. HCl, CH2Cl2, MeOH.

2ꢀAminoethyl glycosides
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015 2935
Scheme 5
CA is ClCH2C(O).
Reagents, conditions, and yields: i. NIS, TfOH, 4 Å molecular sieves, CH2Cl2, –20 °C; ii. (NH4)2Ce(NO3)6, 90% aqueous MeCN,
yield 61%; iii. CCl3CN, DBU, CH2Cl2, –20 °C, yield 85%; iv. TMSOTf, 4 Å molecular sieves, CH2Cl2, –40 °C; v. (H2N)2CS, 2,4,6ꢀ
collidine, EtOH—AcOEt (1 : 1), 70—80 °C.
removed by the treatment with hydrazine hydrate, and the
resulting oligosaccharides containing free amino groups
were treated with acetic anhydride in methanol to obtain
Nꢀacetylated oligosaccharides 21—23. Attempts to simulꢀ
taneously reduce the azide group and remove the benzyl
groups by the Pdꢀcatalyzed hydrogenation gave rise to
complex mixtures consiting, apparently, of partially benzꢀ
ylated amino derivatives. We failed to convert these comꢀ
pounds into the corresponding free oligosaccharides even
during a longer reaction time. This result is evidently attribꢀ
uted to the ability of amines to inhibit Oꢀdebenzylation.26
Therefore, the reduction of the azide group and the debenzꢀ
ylation were performed sequentially, using the temporary
protection of the amine that formed with the trifluoroꢀ
acetyl group. Earlier,27—29 we have employed a similar
approach.
in the presence of a base. The most efficient reduction was
observed in trisaccharide 21, the reduction was less effiꢀ
cient in pentasaccharide 22, whereas the reaction with
heptasaccharide 23 was not completed under these condiꢀ
tions even in the presence of a large excess of the reagent
during a long reaction time. The azide group in 23 was
more efficiently reduced by the treatment with triphenylꢀ
phosphine in aqueous THF31 or anhydrous SnCl2 and with
thiophenol in acetonitrile.32 2ꢀAminoethyl glycosides that
formed were subjected to Nꢀtrifluoroacetylation to obtain
derivatives 24—26. The removal of the benzyl groups in
compounds 24—26 by catalytic hydrogenolysis afforded
target chitooligosaccharides 27—29. It should be noted
that the efficiency of the aboveꢀdescribed sixꢀstep reaction
sequence, which was employed to remove the protecting
groups and convert the azide group into amine, substanꢀ
tially decreased with increasing length of the oligosacchaꢀ
ride chain. Thus, the transformations of protected oligoꢀ
mers 13 and 14 to free 2ꢀaminoethyl glycosides 27 and 28
The azide group was reduced under the conditions,
which we have proposed recently,30 including the treatꢀ
ment with 1,4ꢀdithiothreitol (DTT) in aqueous acetonitrile

2936
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015
Yudina et al.
Scheme 6
n = 1 (21, 24, 27), 2 (22, 25, 28), 3 (23, 26, 29)
Reagents and conditions: i. H2NNH2•H2O, EtOH, reflux; ii. Ac2O, MeOH; iii. DTT, Pri2NH, 75% aqueous MeCN or Ph3P, 90%
aqueous THF, 60 °C, or SnCl2, PhSH, Et3N, MeCN; iv. CF3COOEt, Et3N, MeOH; v. H2, Pd/C, MeOH; vi. 1 M aqueous NaOH,
aqueous MeOH.
(CDCl3) in the case of protected derivatives. The 1H NMR
proceeded in satisfactory overall yields (37 and 22%,
spectra were measured using signals of residual undeuterated
respectively). By contrast, the reaction of heptasaccharide
CHCl3 (δH 7.27) as the internal standard; the 13C NMR spectra,
20 gave product 29 in a total yield of only 3.4%, the main
using the signal of CDCl3 (δ 77.0). The spectra of unprotected
C
loss being in the step of the catalytic debenzylation of
intermediate 26.
oligosaccharides were recorded in heavy water (D2O) with aceꢀ
tone (δ 2.225, δ 31.45) as the internal standard. The assignꢀ
H
C
The structures of oligomers 27—29 were confirmed by
1H and 13C NMR spectroscopic data, which are in good
agreement with the NMR spectra of chitooligosacchaꢀ
rides published earlier.33,34 The results of application of
the newly synthesized ligands in the synthesis of glycoꢀ
conjugates and biochemical investigations will be described
elsewhere.
ment of the signals was made by means of 2D correlation techꢀ
niques (COSY, TOCSY, and HSQC). In the description of the
NMR spectra, monosaccharide residues are denoted with Latin
letters (A, B, C, etc.) beginning with the reducing end of an
oligosaccharide (see Scheme 4).
Highꢀresolution mass spectra were recorded on a Bruker
micrOTOF II instrument.
Glycosylation reactions were performed in anhydrous solvents
under a dry argon atmosphere. Prior to the reaction, molecular
sieves were activated for 2 h at 180 °C using a vacuum oil pump.
pꢀMethoxyphenyl 4ꢀOꢀacetylꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀ
phthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeꢀ
oxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranoside (6). Molecular sieves 4 Å
(0.4 mg) were added to a solution of thioglycoside 4 (217 mg,
0.38 mmol) and glycosyl acceptor 5 (160 mg, 0.27 mmol) in
dichloromethane (4 mL). The mixture was stirred for 1.5 h and
then cooled to –20 °C, after which NIS (122 mg, 0.54 mmol)
was added, the mixture was stirred for 10 min, and TfOH (11.3 μL,
0.11 mmol) was added. The mixture was stirred for 20 min at
–20 °C, triethylamine (50 μL) was added, and the mixture was
diluted with dichloromethane (30 mL) and filtered through celite.
The precipitate was washed with dichloromethane (20 mL). The
combined filtrates were washed with a 1 M aqueous Na2S2O3
solution and a saturated aqueous NaHCO3 solution, dried with
Na2SO4, and concentrated. The residue was chromatographed
on silica gel (toluene—acetone, 6 : 1) to isolate disaccharide 6 in
a yield of 270 mg (90%). 1H NMR (600 MHz, CDCl3), δ, charꢀ
acteristic signals): 5.47 (d, 1 H, HA(1), J1,2 = 8.4 Hz); 5.36 (d, 1 H,
HB(1), J1,2 = 8.3 Hz); 5.18 (t, 1 H, HB(4), J = 9.4 Hz); 3.66 (s, 3 H,
CH3O); 1.94 (s, 3 H, OCOCH3) (cf. Refs 12, 35). 13C NMR
(150 MHz, CDCl3), δ: 169.6 (CH3CO); 167.5 (ArCON); 155.3,
Experimental
All reactions were performed in solvents purified by standard
procedures; TfOH, TMSOTf, NIS, DBU, and trichloroacetonitrile
(Acros) were used as purchased. Thin layer chromatography was
performed on Kieselgel 60 F254 silica gel plates (Merck). The
spots of compounds were visualized using UV radiation and by
spraying with an orcinol solution (180 mg of orcinol in a mixture
of 85 mL of water, 10 mL of orthophosphoric acid, and 5 mL of
ethanol) followed by heating at ~150 °C. Column chromatoꢀ
graphy was carried out on silica gel 60 (40—63 μm, Merck). Gel
chromatography of protected oligosaccharides was performed
using BioꢀBeads SꢀX1 and Bio Beads SꢀX3 (Bio Rad) in toluene.
Gel chromatography of free oligosaccharides was carried out on
a Fractogel TSK HWꢀ40(S) column (1.5×90 cm) in 0.1 M acetic
acid; the eluate was analyzed using a Knauer Kꢀ2401 differential
flow refractometer. The optical rotation was measured using
a JASCO Pꢀ2000 digital polarimeter (Japan) at room temperature
(20—25 °C) in chloroform in the case of protected derivatives or
in water in the case of free oligosaccharides.
The NMR spectra were recorded at 25 °C on Bruker AMXꢀ400
and Bruker Avance 600 instruments in deuterochloroform

2ꢀAminoethyl glycosides
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015 2937
150.9, 138.5—137.8, 134.1—133.6, 131.7, 129.0—127.0, 123.7,
123.3, 118.6, 114.2 (Ar); 97.5 (CA(1)); 97.2 (CB(1)); 76.9 (CB(3));
76.8 (CA(3)); 76.3 (CA(4)); 74.7 (CA(4)); 74.5, 73.9, 73.6 (3 PhCH2);
73.5 (CB(5)); 72.7 (CB(4), PhCH2); 69.5 (CB(6)); 68.0 (CA(6));
56.2 (CB(2)); 55.6 (CA(2)); 55.5 (CH3O); 20.9 (CH3CO).
CDCl3), δ: 168.3 (ArCON); 138.2, 137.7, 133.8, 129.1—127.5,
123.3 (Ar); 98.5 (C(1)); 78.8 (C(3)); 74.4 (CH2Ph); 74.1 (C(5));
74.0 (C(4)); 73.8 (CH2Ph); 70.7 (C(6)); 68.2 (CH2CH2N3); 55.4
(C(2)); 50.5 (CH2CH2N3). MS (ESI), m/z: 576.2457 [M + NH4]+.
Calculated for C30H38N6NaO7: 576. 2443.
2ꢀAzidoethyl 3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ2ꢀdeoxyꢀ2ꢀphthalꢀ
imidoꢀβꢀDꢀglucopyranoside (10). 2ꢀChloroethanol (47 μL, 0.7 mmol)
and 4 Å molecular sieves (200 mg) were added to a solution of
compound 8 (150 mg, 0.28 mmol) in dichloromethane (2 mL).
The mixture was stirred at room temperature for 1 h and cooled
to –20 °C. Then NIS (126 mg, 0.56 mmol) was added, the mixꢀ
ture was stirred for 30 min, and TfOH (15 μL, 0.17 mmol) was
added. The reaction mixture was stirred for 45 min at –20 °C,
after which triethylamine (50 μL) was added. The mixture was
diluted with dichloromethane (20 mL) and filtered through celite.
The precipitate was washed with dichloromethane (30 mL). The
filtrate was washed with a 1 M aqueous Na2S2O3 solution and
a saturated aqueous NaHCO3 solution, dried with Na2SO4, and
concentrated. The residue was chromatographed on silica gel
(toluene—AcOEt, 95 : 5) to obtain chloroethyl glycoside 9 in
a yield of 150 mg (90%). Sodium azide (165 mg, 2.5 mmol) was
added to a solution of derivative 9 in DMF (5 mL). The mixture
was vigorously stirred for 19 h at 60 °C, cooled, diluted with
water (20 mL), and extracted with ethyl acetate (3×20 mL). The
combined extracts were washed with water and a saturated aqueous
NaCl solution, dried with Na2SO4, and concentrated. The silica
gel column chromatography (toluene—AcOEt, 95 : 5) of the resꢀ
idue gave azidoethyl glycoside 10 in a yield of 118 mg (79%),
[α]D +34.4 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3), δ:
7.66—6.79 (m, 14 H, Phth, 2 Ph); 5.55 (s, 1 H, CHPh); 5.21
(d, 1 H, H(1), J1,2 = 8.5 Hz); 4.72 (d, 1 H, CH2Ph, J = 12.3 Hz);
4.42 (d, 1 H, CH2Ph); 4.37—4.30 (m, 2 H, H(3), H(6a)); 4.18
(dd, 1 H, H(2), J2,3 = 10.4 Hz); 3.86 (m, 1 H, OCH2CH2N3);
3.78 (t, 1 H, H(6b), J = 10.2 Hz); 3.75 (t, 1 H, H(4), J = 9.1 Hz);
3.56 (m, 1 H, H(5)); 3.52 (m, 1 H, OCH2CH2N3); 3.23 (m, 1 H,
OCH2CH2N3); 3.08 (m, 1 H, OCH2CH2N3). 13C NMR (100 MHz,
CDCl3), δ: 133.8, 129.1—127.5, 123.3 (Ar); 101.4 (CHPh);
99.1 (C(1)); 83.1 (C(4)); 74.7 (C(3)); 74.2, (CH2Ph); 68.8
(C(6)); 68.5 (OCH2CH2N3); 66.3 (C(5)); 55.7 (C(2)); 50.5
(CH2CH2N3). MS (ESI), m/z: 579.1842 [M + Na]+. Calculated
for C30H28N4NaO7: 579.1850.
2ꢀAzidoethyl 3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀ
glucopyranoside (11). To a solution of compound 10 (98 mg,
0.163 mmol) in THF (3 mL), BH3•NMe3 (48 mg, 0.65 mmol)
was added. The mixture was cooled to 0 °C, and then AlCl3 (130 mg,
0.98 mmol) was added. The mixture was allowed to warm to
room temperature (~25 °C), water (6 μL) was added, and the
mixture was stirred for 16 h and then cooled to 0 °C. Water
(1.5 mL) and 1 M HCl (1.5 mL) were added to the mixture, and
the resulting mixture was extracted with AcOEt (3×20 mL). The
combined extracts were washed with water and a saturated aqueous
NaCl solution, dried with Na2SO4, and concentrated. The silica
gel column chromatography (toluene—AcOEt, 95 : 5) gave
glucopyranoside 11 in a yield of 84 mg (92%), [α]D +26.1 (c 1,
CHCl3). 1H NMR (600 MHz, CDCl3), δ: 7.66—6.89 (m, 14 H,
Phth, 2 Ph); 5.17 (d, 1 H, H(1), J1,2 = 8.1 Hz); 4.66 (d, 1 H,
CH2Ph, J = 12.3 Hz); 4.58 (d, 1 H, CH2Ph, J = 12.0 Hz); 4.51
(d, 1 H, CH2Ph); 4.47 (d, 1 H, CH2Ph); 4.14 (m, 2 H, H(2),
H(3)); 3.85 (m, 1 H, OCH2CH2N3); 3.80—3.68 (m, 3 H, H(4),
2 H(6)); 3.58 (m, 1 H, H(5)); 3.50 (m, 1 H, OCH2CH2N3); 3.25,
3.05 (both m, 2 H, OCH2CH2N3). 13C NMR (150 MHz,
2ꢀAzidoethyl 4ꢀOꢀacetylꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalꢀ
imidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀ
phthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeꢀ
oxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranoside (12). A mixture of imiꢀ
date 7 (218 mg, 0.19 mmol) and glycosyl acceptor 11 (89 mg,
0.16 mmol) was once coevaporated with anhydrous toluene, dried
using a vacuum oil pump for 2 h, and dissolved in dichloroꢀ
methane (3 mL). Then 4 Å molecular sieves (200 mg) were
added. The mixture was stirred for 1 h at room temperature and
cooled to –40 °C, after which TMSOTf (6 μL, 0.03 mmol) was
added. The mixture was stirred for 30 min at –40 °C, diluted
with dichloromethane (40 mL), and filtered through celite. The
precipitate was washed on a filter with dichloromethane (20 mL).
The combined filtrates were washed with a saturated aqueous
NaHCO3 solution, dried with Na2SO4, and concentrated. The
silica gel column chromatography (toluene—AcOEt, 4 : 1) gave
trisaccharide 12 in a yield of 188 mg (76%) as a white foam, [α]D
+35.5 (c 1, CHCl3). 1H NMR (600 MHz, CDCl3), δ: 7.77—6.68
(m, 42 H, 3 Phth, 6 Ph); 5.33 (d, 1 H, HC(1), J1,2 = 8.3 Hz); 5.16
(t, 1 H, HC(4), J = 9.3 Hz); 5.12 (d, 1 H, HB(1), J1,2 = 7.9 Hz);
5.00 (m, 1 H, HA(1)); 4.90 (d, 1 H, CH2Ph, J = 12.5 Hz); 4.76
(d, 1 H, CH2Ph, J = 13.0 Hz); 4.61 (d, 1 H, CH2Ph, J = 11.9 Hz);
4.56 (d, 1 H, CH2Ph, J = 12.2 Hz); 4.51—4.44 (m, 4 H, HC(3),
CH2Ph); 4.41—4.36 (m, 4 H, CH2Ph); 4.33 (d, 1 H, CH2Ph,
J = 12.0 Hz); 4.29 (dd, 1 H, HC(2), J1,2 = 10.7 Hz); 4.23—4.13
(m, 3 H, HB(4), HB(3), HB(2)); 4.10—4.04 (m, 3 H, HA(4),
HA(3), HA(2)); 3.80 (m, 1 H, OCH2CH2N3); 3.54 (m, 2 H,
HC(5), HC(6a)); 3.48 (br.d, HA(6a), J6a,6b = 10.7 Hz); 3.44 (m, 2 H,
HC(6b), OCH2CH2N3); 3.39 (br.d, HB(6a), J6a,6b = 10.7 Hz);
3.35 (dd, 1 H, HA(6b), J6b,5 = 4.1 Hz); 3.28 (m, 1 H, HA(5));
3.25 (m, 1 H, OCH2CH2N3); 3.15 (dd, 1 H, HB(6b), J6b,5 = 3.1 Hz);
3.04 (m, 1 H, OCH2CH2N3); 2.93 (m, 1 H, HB(5)); 1.91 (s, 3 H,
OCOCH3). 13C NMR (150 MHz, CDCl3), δ: 169.7 (CH3CO);
168.2, 167.5 (ArCON); 138.7—137.7, 134.0—133.4, 129.0—127.7,
123.5—123.0 (Ar); 98.2 (CA(1)); 97.1 (CC(1)); 96.7 (CB(1)); 76.9
(CC(3)); 76.8 (CB(3)); 76.62 (CA(3)); 76.0 (CB(4)); 75.5 (CA(4));
74.60 (2 C, CH2Ph, CA(5)); 74.37 (2 C, CH2Ph, CB(5)); 73.9
(CH2Ph); 73.5 (CH2Ph); 73.1 (CC(5)); 72.7 (CC(4)); 72.6
(CH2Ph); 72.3 (CH2Ph); 69.5 (CC(6)); 68.1 (CB(6)); 67.9
(OCH2CH2N3); 67.0 (CA(6)); 56.6 (CB(2)); 56.2 (CC(2)); 55.5
(CA(2)); 50.3 (CH2CH2N3). MS (ESI), m/z: 1565.5476 [M + Na]+.
Calculated for C88H82N6NaO20: 1565.5483.
2ꢀAzidoethyl 3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀ
glucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀ
βꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalꢀ
imidoꢀβꢀDꢀglucopyranoside (13). A solution of HCl in methanol,
which was prepared by mixing acetyl chloride (0.1 mL) and
methanol (2.3 mL) at 0 °C, was added to a solution of trisacchaꢀ
ride 12 (76 mg, 0.05 mmol) in dichloromethane (1.5 mL) at
~20 °C. The mixture was allowed to stand for 5 days at room
temperature (~25 °C), volatile components were evaporated,
and HCl was removed by coevaporation with toluene. The silica
gel column chromatography (toluene—AcOEt, 4 : 1) gave comꢀ
pound 13 in a yield of 52 mg (70%), [α]D 0 (c 0.6, CHCl3).
1H NMR (400 MHz, CDCl3), δ: 7.85—6.57 (m, 42 H, 3 Phth,
6 Ph); 5.21 (d, 1 H, HC(1), J1,2 = 8.4 Hz); 5.02 (m, 1 H, HB(1));

2938
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015
Yudina et al.
4.90 (m, 1 H, HA(1)); 4.76—4.68 (m, 3 H, CH2Ph); 4.50—4.27
(m, 9 H, CH2Ph); 4.18 (dd, 1 H, HC(3), J3,4 = 8.4 Hz, J3,2
HCl in methanol, which was prepared by mixing acetyl chloride
(50 μL) and methanol (1 mL) at 0 °C, was added to a solution of
pentasaccharide 14 (41 mg, 0.012 mmol) in dichloromethane
(1 mL) at ~25 °C. The resulting solution was allowed to stand for
6 days at room temperature (~25 °C), volatile components were
evaporated, and HCl was removed by coevaporation with toluꢀ
ene. The silica gel column chromatography (toluene—AcOEt,
4 : 1) gave monohydroxy derivative 15 in a yield of 23 mg (57%),
[α]D +10.7 (c 1, CHCl3). 1H NMR (600 MHz, CDCl3), δ:
7.85—6.65 (m, 70 H, 5 Phth, 10 Ph); 5.26 (d, 1 H, Hz, HE(1),
J1,2 = 8.4 Hz); 5.06 (d, 1 H, H(1), J1,2 = 7.7 Hz); 5.03 (m, 2 H,
2 H(1)); 4.95 (m, 1 H, H(1)); 4.82—4.69 (m, 5 H, CH2Ph);
4.52—4.33 (m, 15 H, CH2Ph); 4.26—4.22 (m, 2 H, HE(3), H(4));
4.19—3.98 (m, 12 H, HA(2,3), HB(2,3), HC(2,3), HD(2,3),
HE(2), 3 H(4)); 3.81—3.76 (m, 2 H, HE(4), OCH2CH2N3); 3.65
(dd, 1 H, H(6), J6,5 = 4.1 Hz, J6a,6b = 9.8 Hz); 3.47 (dd, 1 H,
H(6), J6,5 = 6.2 Hz, J6a,6b = 9.8 Hz); 3.43—3.27 (m, 7 H, HE(5),
5 H(6), OCH2CH2N3); 3.24—3.19 (m, 2 H, H(5), OCH2CH2N3);
3.13 (dd, 1 H, H(6), J6,5 = 2.9 Hz, J6a,6b = 10.7 Hz); 3.05—2.98
(m, 3 H, 2 H(6), OCH2CH2N3); 2.85—2.78 (m, 3 H, 3 H(5)).
13C NMR (150 MHz, CDCl3), δ: 168.1, 167.6 (ArCON);
138.8—121.7 (Ar); 98.1 (C(1)); 96.8, 96.7, 96.6, 95.6 (4 C(1));
78.4 (CE(3)); 77.2—76.7 (4 C(3)); 75.6—75.3 (5 C(4)); 74.6—74.2
(6 CH2Ph, 4 C(5)); 73.7 (CH2Ph); 72.6—72.2 (3 CH2Ph, CE(5));
71.1 (C(6)); 68.1 (C(6)); 67.9 (OCH2CH2N3); 67.1 (3 C(6));
56.6, 56.1, 55.4 (5 C(2)); 50.3 (CH2CH2N3). MS (ESI), m/z:
=
= 10.6 Hz); 4.14—3.95 (m, 5 H, HC(2), HB(2), HA(2), HA(3),
HB(3)); 3.74—3.67 (m, 2 H, OCH2CH2N3, HC(4)); 3.59 (dd, 1 H,
HC(6a), J6a,5 = 4.4 Hz, J6a,6b = 10.0 Hz); 3.45—3.23 (m, 6 H,
HA(6a), HA(6b), HC(6b), HC(5), HB(6a), OCH2CH2N3);
3.19—3.08 (m, 3 H, HA(5), HB(6b), OCH2CH2N3); 2.83 (m, 1 H,
HB(5)). 13C NMR (100 MHz, CDCl3), δ: 168.3, 167.6 (ArCON);
138.9—137.6, 134.0—131.9, 129.1—126.8, 123.6—123.1 (Ar);
98.3 (CA(1)); 97.0 (CC(C)); 96.8 (CB(1)); 76.8 (2 C, CC(3),
CB(3)); 75.6 (3 C, CA(4), CB(4), CC(4)); 74.7 (CA(5)); 74.5, 74.4
(4 C, 3 CH2Ph, CB(5)); 73.8 (CC(5)); 72.7 (2 C, 2 CH2Ph); 72.4
(CH2Ph); 71.2 (CC(6)); 68.2 (CA(6)); 68.0 (OCH2CH2N3);
67.3 (CB(6)); 56.7 (CB(2)), 56.2 (CC(2)); 55.6 (CA(2)); 50.4
(OCH2CH2N3). MS (ESI), m/z: 1523.5370 [M + Na]+. Calcuꢀ
lated for C86H80N6NaO19: 1523.5373.
2ꢀAzidoethyl 4ꢀOꢀacetylꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalꢀ
imidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀ
phthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeꢀ
oxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ
2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀ
benzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranoside (14). A mixꢀ
ture of imidate 7 (45 mg, 0.04 mmol) and glycosyl acceptor 13
(50 mg, 0.03 mmol) was once coevaporated with anhydrous tolꢀ
uene, dried using a vacuum oil pump for 2 h, and dissolved in
dichloromethane (1 mL). Then 4 Å molecular sieves (100 mg)
were added. The mixture was stirred for 1 h at room temperature
and then cooled to –40 °C, after which TMSOTf (1.3 μL,
0.007 mmol) was added. The mixture was stirred for 30 min at
–40 °C, diluted with dichloromethane (40 mL), and filtered
through a layer of celite. The precipitate was washed on a filter
with dichloromethane (20 mL). The combined filtrates were
washed with a saturated aqueous NaHCO3 solution, dried with
Na2SO4, and concentrated. Pentasaccharide 14 was isolated in
a yield of 70 mg (86%) by silica gel column chromatography of the
1239.4741 [M + 2 NH4]2+. Calculated for C142H138N10O31
1239.4759.
:
B. 2,4,6ꢀCollidine (47 μL, 0.35 mmol) and thiourea (12 mg,
0.16 mmol) were added to a solution of compound 19 (81 mg,
0.032 mmol) in a mixture of EtOH (1 mL) and AcOEt (1 mL).
The mixture was stirred for 9 h at 75—80 °C, cooled, and
concentrated. The residue was dissolved in dichloromethane
(50 mL). The resulting solution was washed with 1 M HCl and
water, dried with Na2SO4, and concentrated. The silica gel colꢀ
umn chromatography gave 61 mg (78%) of compound 15, which
was identical, according to the 1H and 13C NMR spectra, to the
sample synthesized by the method A.
1
residue (toluene—AcOEt, 9 : 1). H NMR (600 MHz, CDCl3),
δ: 7.88—6.65 (m, 70 H, 10 Ph, 5 Phth); 5.31 (d, 1 H, HE(1),
J1,2 = 8.3 Hz); 5.14 (t, 1 H, HE(4), J = 9.3 Hz); 5.08 (d, 1 H, H(1),
J1,2 = 8.2 Hz); 5.06—5.03 (m, 2 H, 2 H(1)); 4.98 (m, 1 H, H(1));
4.61—4.25 (m, 22 H, 10 CH2Ph, HE(2), HE(3)); 4.21—4.03
(m, 12 H, HA(2,3,4), HB(2,3,4), HC(2,3,4), HD(2,3,4)); 3.78
(m, 1 H, OCH2CH2N3); 3.54—3.50 (m, 2 H, HE(5), H(6));
3.45—3.40 (m, 3 H, 2 H(6), OCH2CH2N3); 3.36—3.29 (m, 3 H,
3 H(6)); 3.25—3.20 (m, 2 H, HA(5), OCH2CH2N3); 3.11 (dd, 1 H,
H(6), J6,5 = 2.7 Hz, J6a,6b = 10.9 Hz); 3.06—3.00 (m, 3 H, H(6),
OCH2CH2N3); 2.87—2.80 (m, 3 H, HB(5), HC(5), HD(5)); 1.90
(s, 3 H, OCOCH3). 13C NMR (150 MHz, CDCl3), δ: 169.6
(CH3CO); 168.1, 168.0, 167.5 (ArCON); 138.7—123.1 (Ar); 98.3
(C(1)); 97.0 (CE(1)); 96.72 (C(1)); 96.66 (C(1)); 95.6 (C(1));
77.2—76.6 (4 C, CA(3), CB(3), CC(3), CD(3)); 75.9—75.2 (4 C,
CA(4), CB(4), CC(4), CD(4)); 74.6—74.1 (7 CH2Ph, CE(3),
4 C(5)); 73.1 (CE(5)); 72.8 (CE(4)); 72.6—72.2 (3 CH2Ph);
69.4—67.0 (5 C(6), OCH2CH2N3); 56.6—55.4 (5 C(2)); 50.23
(CH2CH2N3); 20.8 (OCOCH3). MS (ESI), m/z: 1265.4410
[M + 2 Na]2+. Calculated for C144H132N8NaO32: 1265.4366.
2ꢀAzidoethyl 3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀ
glucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀ
βꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalꢀ
imidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀ
phthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeꢀ
oxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranoside (15). A. A solution of
4ꢀMethoxyphenyl 3,6ꢀdiꢀOꢀbenzylꢀ4ꢀOꢀchloroacetylꢀ2ꢀdeꢀ
oxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ
2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranoside (17). A mixture of
thioglycoside 16 (225 mg, 0.37 mmol) and glycosyl acceptor 5
(162 mg, 0.27 mmol) was once coevaporated with anhydrous
toluene, dried using a vacuum oil pump for 2 h, and dissolved in
dichloromethane (5 mL). Then 4 Å molecular sieves (500 mg)
were added. The mixture was stirred for 1 h at room temperature
and cooled to –20 °C, after which NIS (140 mg, 0.62 mmol) was
added. The mixture was stirred for 10 min, TfOH (11 μL,
0.124 mmol) was added, and the mixture was stirred for 20 min
at –20 °C. Then the reaction was terminated by adding Et3N
(20 μL). The mixture was diluted with dichloromethane (20 mL)
and filtered through celite. The precipitate was washed on
a filter with dichloromethane (30 mL). The combined filtrates
were washed with a 1 M aqueous Na2S2O3 solution and water,
dried with Na2SO4, and concentrated. The gel chromatography
of the residue using Bio Beads SꢀX3 gave disaccharide 17 in
1
a yield of 275 mg (89%), [α]D +25.1 (c 0.3, CHCl3). H NMR
(600 MHz, CDCl3), δ: 7.73—6.56 (m, 32 H, 2 Phth, 4 CH2Ph,
4ꢀMeOC6H4); 5.46 (d, 1 H, HA(1), J1,2 = 8.5 Hz); 5.34 (d, 1 H,
HB(1), J1,2 = 8.4 Hz); 5.22 (t, 1 H, HB(4), J = 9.3 Hz); 4.83 (d, 1 H,
CH2Ph, J = 12.3 Hz); 4.59 (d, 1 H, CH2Ph, J = 12.2 Hz);

2ꢀAminoethyl glycosides
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015 2939
[α]D +21.5 (c 1, CHCl3). 1H NMR (600 MHz, CDCl3), δ:
4.55—4.51 (m, 3 H, HB(3), CH2Ph); 4.48—4.41 (m, 5 H,
CH2Ph); 4.39—4.36 (m, 2 H, HA(2), CH2Ph); 4.32 (dd, 1 H,
HB(2), J2,3 = 10.6 Hz); 4.27—4.22 (m, 1 H, HA(3), HA(4)); 3.74,
3.71 (both d, 2 H, CH2Cl, J = 14.7 Hz); 3.67 (s, 3 H, CH3O);
3.58—3.49 (m, 4 H, HB(5), HA(6a), 2 HB(6)); 3.46—3.42 (m, 2 H,
HA(6b), HA(5)). 13C NMR (150 MHz, CDCl3), δ: 167.8 (ArCON);
166.1 (ClCH2CO); 155.4, 150.9, 137.8—114.2 (Ar); 97.5 (CA(1));
97.2 (CB(1)); 76.7 (CA(3)); 76.5 (CB(3)); 76.3 (CA(4)); 74.7
(CB(4)); 74.60 (CB(5)); 74.5 (CH2Ph); 74.2, 73.6, 72.7 (3 CH2Ph);
72.4 (CA(5)); 69.6 (CB(6)); 67.9 (CA(6)); 56.2 (CA(2)); 55.6
(CB(2)); 55.5 (CH3O); 40.6 (CH2Cl). MS (ESI), m/z: 1165.3474
[M + Na]+. Calculated for C65H59ClN2NaO15: 1165.3496.
3,6ꢀDiꢀOꢀbenzylꢀ4ꢀOꢀchloroacetylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀ
βꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalꢀ
imidoꢀβꢀDꢀglucopyranosyl trichloroacetimidate (18). Ammonium
cerium nitrate (576 mg, 1.05 mmol) was added to a solution of
disaccharide 17 (243 mg, 0.21 mmol) in 90% aqueous acetoꢀ
nitrile (2 mL) at 0 °C. The reaction mixture was stirred for 2 h,
diluted with AcOEt (50 mL), washed with water and a saturated
aqueous NaCl solution, dried with Na2SO4, and concentrated.
The residue was purified by silica gel column chromatography
(toluene—AcOEt, 4 : 1) to obtain hemiacetal in a yield of 134 mg
(61%). Trichloroacetonitrile (82 μL, 0.8 mmol) was added to
a solution of this product (110 mg, 0.106 mmol) in dichloroꢀ
methane (1 mL), the mixture was cooled to –20 °C, and then
DBU (0.7 μL, 0.005 mmol) was added. The mixture was stirred
for 2 h at –20 °C and concentrated. The residue was chromatoꢀ
graphed on a silica gel column (toluene—AcOEt, 96 : 4) to obꢀ
tain imidate 18 in a yield of 105 mg (85%), [α]D +48.0 (c 0.6,
CHCl3). 1H NMR (600 MHz, CDCl3), δ: 8.34 (s, 1 H, NH);
7.74—6.69 (m, 70 H, 5 Phth, 10 Ph); 5.33 (d, 1 H, HE(1), J1,2
=
= 8.1 Hz); 5.22 (t, 1 H, HE(4), J = 8.7 Hz); 5.11 (d, 1 H, H(1),
J1,2 = 8.0 Hz); 5.07 (m, 2 H, 2 H(1)); 4.98 (m, 1 H, H(1));
4.89—4.74 (m, 4 H, CH2Ph); 4.59—4.33 (m, 16 H, H(3), H(4),
CH2Ph); 4.30—4.25 (m, 3 H, HE(2), CH2Ph); 4.22—4.16 (m, 4 H,
2 H(2), H(3), H(4)); 4.15—4.08 (m, 8 H, 2 H(2), 3 H(3), 3 H(4));
3.81 (m, 1 H, OCH2CH2N3); 3.69 (br.s, 2 H, CH2Cl); 3.54—3.20
(m, 10 H, OCH2CH2N3, 2 H(5), 3 H(6), OCH2CH2N3). 13C NMR
(150 MHz, CDCl3), δ: 168.1, 167.9, 167.5 (ArCON); 166.0
(OCOCH2Cl); 133.8—123.0 (Ar); 98.1 (CE(1)); 97.0, 96.6, 96.55,
96.5 (4 C(1)); 76.8, 76.6 (4 C(3)); 75.9—75.2 (4 C(4)); 74.8—74.1
(7 CH2Ph CE(3), 4 C(5)); 73.5—72.1 (3 CH2Ph, CE(4), CE(5));
69.6—67.0 (5 C(6), OCH2CH2N3); 56.6—55.4 (5 C(2)); 50.2
(CH2CH2N3); 40.5 (CH2Cl). MS (ESI), m/z: 1277.4610
[M + 2 NH4]2+. Calculated for C144H139ClN10O32: 1277.4617.
2ꢀAzidoethyl 3,6ꢀdiꢀOꢀbenzylꢀ4ꢀOꢀchloroacetylꢀ2ꢀdeoxyꢀ2ꢀ
phthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeꢀ
oxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ
2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀ
benzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀ
diꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ
3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranosylꢀ
(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranoꢀ
side (20). Heptasaccharide 20 was synthesized from donor 18
(22 mg, (0.019 mmol) and glycosyl acceptor 15 (38 mg, 0.016 mmol)
as described above for compound 19. The product was isoꢀ
lated by gel permeation chromatography using Bio Beads SꢀX1
in toluene, the yield was 37 mg (68%), [α]D +19.4 (c 1, CHCl3).
1H NMR (600 MHz, CDCl3), δ: 7.74—6.64 (m, 98 H, 7 Phth,
14 Ph); 5.29 (d, 1 H, HG(1), J1,2 = 8.4 Hz); 5.19 (t, 1 H, HG(4),
J = 8.9 Hz); 5.06 (d, 1 H, H(1), J1,2 = 8.1 Hz); 5.03—4.98
(m, 4 H, 4 H(1)); 4.96 (d, 1 H, H(1), J1,2 = 8.4 Hz); 4.85 (d, 1 H,
CH2Ph, J = 12.5 Hz); 4.79—4.69 (m, 6 H, CH2Ph); 4.57—4.08
(m, 27 H, HG(3), CH2Ph, HG(2), H(2), H(3), H(4)); 4.07—3.98
(m, 16 H, 5 H(2), 5 H(3), 6 H(4)); 3.80—3.76 (m, 1 H,
CH2CH2N3); 3.67 (br.s, 2 H, CH2Cl); 3.47—3.38 (m, 4 H,
OCH2CH2N3, 2 H(6), H(5)); 3.34—3.21 (m, 8 H, OCH2CH2N3,
6 H(6), H(5)); 3.08 (br.d, 1 H, H(6), J = 11.0 Hz); 3.02—2.97
(m, 5 H, CH2CH2N3, 4 H(6)); 2.83—2.72 (m, 5 H, 5 H(5)).
13C NMR (150 MHz, CDCl3), δ: 168.1, 167.9, 167.5 (ArCON);
166.1 (OCOCH2Cl); 138.8—123.0 (Ar); 98.1 (CG(1)); 97.0, 96.6
(2 C(1)); 96.5 (4 C(1)); 77.0—74.9 (7 C(3), 7 C(4)); 74.6—72.1
(14 CH2Ph, 6 C(5)); 69.7—67.0 (7 C(6), OCH2CH2N3); 56.8—55.4
(7 C(2)); 50.4 (OCH2CH2N3); 40.6 (CH2Cl). MS (ESI), m/z:
7.83—6.71 (m, 28 H, 2 Phth, 4 Ph); 6.16 (d, 1 H, HA(1), J1,2
=
= 8.8 Hz); 5.27 (d, 1 H, HB(1), J1,2 = 8.3 Hz); 5.14 (m, 1 H,
HB(4)); 4.77 (d, 1 H, CH2Ph, J = 12.5 Hz); 4.54—4.15 (m, 12 H,
CH2Ph, HA(2), HB(2), HA(3), HB(3), HA(4)); 3.63 (s, 2 H,
CH2Cl); 3.55—3.32 (m, 6 H, HA(5), HB(5), 2 HA(6), 2 HB(6)).
13C NMR (150 MHz, CDCl3), δ: 167.5 (ArCON); 166.2
(OCOCH2Cl); 160.9 (OC(=NH)CCl3); 138.5—123.4 (Ar); 97.0
(CB(1)); 94.1 (CA(1)); 76.4, 75.5 (3 C); 74.8, 74.6, 74.3, 73.7,
72.8, 72.6 (4 CH2Ph, CA(3), CB(3), CA(4), CB(4), CA(5), CB(5));
69.7, 67.8 (CA(6), CB(6)); 56.3, 54.6 (CA(2), CB(2)); 40.7
(OCOCH2Cl). MS (ESI), m/z: 1202.2160 [M + Na]+. Calculatꢀ
ed for C60H53Cl4N3NaO14: 1202.2174.
2ꢀAzidoethyl 3,6ꢀdiꢀOꢀbenzylꢀ4ꢀOꢀchloroacetylꢀ2ꢀdeoxyꢀ2ꢀ
phthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ2ꢀdeꢀ
oxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀbenzylꢀ
2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀdiꢀOꢀ
benzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ3,6ꢀ
diꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀphthalimidoꢀβꢀDꢀglucopyranoside (19).
A mixture of imidate 18 (95 mg, 0.084 mmol) and glycosyl acꢀ
ceptor 13 (105 mg, 0.07 mmol) was once coevaporated with
anhydrous toluene, dried using a vacuum oil pump for 2 h, and
dissolved in dichloromethane (2 mL). Then 4 Å molecular sieves
(200 mg) were added. The mixture was stirred for 1 h at room
temperature and cooled to –40 °C, after which TMSOTf (2.6 μL,
0.014 mmol) was added. The mixture was stirred for 30 min at
–40 °C, diluted with dichloromethane (30 mL), and filtered
through celite. The precipitate was washed with dichloromethane
(20 mL). The combined filtrates were washed with a saturated
NaHCO3 solution, dried with Na2SO4, and concentrated.
The gel permeation chromatography of the residue using Bio
Beads SꢀX3 gave pentasaccharide 19 in a yield of 103 mg (58%),
1748.6256 [M + 2 NH4]2+. Calculated for C200H189ClN12O44
1748.6299.
:
2ꢀAminoethyl 2ꢀacetamidoꢀ2ꢀdeoxyꢀβꢀDꢀglucopyranosylꢀ
(1→4)ꢀ2ꢀacetamidoꢀ2ꢀdeoxyꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ2ꢀacetꢀ
amidoꢀ2ꢀdeoxyꢀβꢀDꢀglucopyranoside (27). Hydrazine hydrate
(0.5 mL) was added to a solution of trisaccharide 13 (73 mg,
0.049 mmol) in EtOH (5 mL). The resulting mixture was reꢀ
fluxed for 3 h and then cooled. The solvent was evaporated, and
the residue was dried using a vacuum oil pump for 2 h. Then
Ac2O (0.3 mL) was added to a solution of the residue in methaꢀ
nol (5 mL), the mixture was allowed to stand for 20 min, the
solvent was evaporated, and the residue was chromatographed
on a silica gel column (chloroform—methanol, 95 : 5) to obtain
Nꢀacetylated trisaccharide 21 (55 mg). Then DTT (20 mg,
0.13 mmol) and diisopropylamine (5.3 μL, 0.044 mmol) were
added to a solution of this product in aqueous acetonitrile (3 : 1,

2940
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015
Yudina et al.
1.2 mL). The resulting solution was allowed to stand for 24 h at
room temperature (~25 °C). The solvent was evaporated, water
was removed by coevaporation with toluene, the residue was
dissolved in methanol (2 mL), and then one drop of triethylꢀ
amine and CF3COOEt (22 μL, 0.22 mmol) were added. After
2.5 h, the mixture was coevaporated with toluene and the resiꢀ
due was chromatographed on a silica gel column (toluene—aceꢀ
tone gradient, from 4 : 1 to 1 : 1) to obtain 2ꢀtrifluoroacetamidoꢀ
ethyl glycoside 24 (33 mg). The latter was dissolved in methanol
(1.5 mL), 10% Pd/C (20 mg) was added, and the mixture was
stirred under a hydrogen atmosphere for 2.5 h. The catalyst was
filtered off through celite and washed with 80% aqueous methaꢀ
nol (20 mL). The combined filtrates were concentrated, the resꢀ
idue was dissolved in 80% aqueous methanol (1 mL), and then
1 M NaOH was added to pH ~10. After 2 h, AcOH was added
until the mixture was neutral, the solvent was evaporated, and
the residue was chromatographed using Fractogel TSK HWꢀ40.
After freezeꢀdrying from water, trisaccharide 27 was obtained in
a yield of 12.4 mg (37% overall yield for six steps), [α]D –21.2
(c 0.7, H2O). 1H NMR (600 MHz, D2O), δ: 4.57 (d, 2 H, 2 H(1),
J1,2 = 8.3 Hz); 4.54 (d, 1 H, H(1), J1,2 = 8.3 Hz); 4.03 (m, 1 H,
OCH2CH2NH2); 3.92—3.82 (m, 4 H, 3 H(6a), OCH2CH2NH2);
3.78—3.59 (m, 10 H, 3 H(2), 3 H(6b), 2 H(3), 2 H(4)); 3.57—3.45
(m, 5 H, H(3), H(4), 3 H(5)); 3.25—3.15 (m, 2 H, CH2CH2NH2);
2.05 (s, 6 H, 2 CH3CO); 2.03 (s, 3 H, CH3CO); 1.92 (s, 1 H,
~0.3 CH3COO–). 13C NMR (150 MHz, D2O), δ: 176.1, 175.8
(NHCOCH3); 102.7, 102.5, 102.1 (3 C(1)); 80.5, 80.4 (2 C(4));
77.1, 75.7 (3 C(5)); 74.7, 73.5, 73.4 (3 C(3)); 70.9 (CC(4)); 67.0
(OCH2CH2NH2); 61.8, 61.2 (3 C(6)); 56.8, 56.2, 56.0 (3 C(2));
40.6 (OCH2CH2NH2); 23.4, 23.3 (COCH3). MS (ESI), m/z:
693.2794 [M + Na]+. Calculated for C26H46N4NaO16: 693.2801.
2ꢀAminoethyl 2ꢀacetamidoꢀ2ꢀdeoxyꢀβꢀDꢀglucopyranosylꢀ
(1→4)ꢀ2ꢀacetamidoꢀ2ꢀdeoxyꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ2ꢀacetꢀ
amidoꢀ2ꢀdeoxyꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ2ꢀacetamidoꢀ2ꢀdeꢀ
oxyꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ2ꢀacetamidoꢀ2ꢀdeoxyꢀβꢀDꢀglucoꢀ
pyranoside (28). Hydrazine hydrate (0.5 mL) was added to
a solution of pentasaccharide 14 (82 mg, 0.033 mmol) in EtOH
(5 mL). The mixture was refluxed for 12 h, the solvent was
evaporated, and the residue was dried using a vacuum oil pump
at 50 °C for 2 h. The product was dissolved in methanol (5 mL),
Ac2O (0.3 mL) was added, and the solution was allowed to stand
for 1 h and then concentrated to dryness. The residue was chroꢀ
matographed on a silica gel column (chloroform—methanol,
95 : 5) to obtain Nꢀacetylated pentasaccharide 22 (50 mg). The
product was dissolved in aqueous acetonitrile (3 : 1, 1.2 mL),
DTT (11 mg, 0.072 mmol) and diisopropylamine (5 μL,
0.036 mmol) were added, and the solution was allowed to stand
for 4 days at room temperature (~25 °C). The solvent was evapoꢀ
rated, water was removed by coevaporation with toluene, and
the residue was dissolved in methanol (1 mL). Then one drop of
triethylamine and CF3COOEt (21 μL, 0.18 mmol) were added.
After 3 h, the mixture was coevaporated with toluene, and the
residue was chromatographed on a silica gel column (toluene—
acetone, 2 : 1) to obtain trifluoroacetamidoethyl glycoside 25
(28 mg). The latter was dissolved in methanol (3 mL), 10% Pd/C
(20 mg) was added, and the mixture was stirred under a hydroꢀ
gen atmosphere for 5 h. The catalyst was filtered through celite
and washed with 50% aqueous methanol (20 mL). The comꢀ
bined filtrates were concentrated, and then 1 M NaOH was addꢀ
ed to a solution of the residue in water (1 mL) to pH ~10. The
solution was allowed to stand for 3 h at room temperature,
neutralized with AcOH, and concentrated. The residue was subꢀ
jected to gel permeation chromatography on TSK HWꢀ40, and
the product was freezeꢀdried from water to obtain pentasacchaꢀ
ride 28 in a yield of 8 mg (22% overall yield for six steps), [α]D
–17.8 (c 0.5, H2O). 1H NMR (600 MHz, D2O), δ: 4.61—4.57
(m, 4 H, 4 H(1)); 4.56 (d, 1 H, H(1), J1,2 = 8.4 Hz); 4.06 (m, 1 H,
OCH2CH2NH2); 3.95—3.84 (m, 6 H, 5 H(6a), OCH2CH2NH2);
3.80—3.62 (m, 18 H, 5 H(2), 5 H(6b), 4 H(3), 4 H(4)); 3.58—3.46
(m, 7 H, H(3), H(4), 5 H(5)); 3.27—3.17 (m, 2 H, OCH2CH2NH2);
2.08 (s, 3 H, CH3CO); 2.07 (s, 9 H, 3 CH3CO); 2.06 (s, 3 H,
CH3CO). 13C NMR (150 MHz, D2O), δ: 175.8 (NHCOCH3);
102.7, 102.5, 102.1 (5 C(1)); 80.3, 80.1 (4 C(4)); 77.1 (CE(5));
75.8, 75.7 (4 C(5)); 74.6 (CE(3)); 73.5, 73.3, 73.2 (4 C(3)); 70.9
(CE(4)); 67.0 (OCH2CH2NH2); 61.7, 61.1 (5 C(6)); 56.8, 56.3,
56.0 (5 C(2)) 40.6 (CH2CH2NH2); 23.3 (COCH3). MS (ESI),
m/z: 1099.4371 [M + Na]+. Calculated for C42H72N6NaO26
:
1099.4388.
2ꢀAminoethyl 2ꢀacetamidoꢀ2ꢀdeoxyꢀβꢀDꢀglucopyranosylꢀ
(1→4)ꢀ2ꢀacetamidoꢀ2ꢀdeoxyꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ2ꢀacetꢀ
amidoꢀ2ꢀdeoxyꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ2ꢀacetamidoꢀ2ꢀdeꢀ
oxyꢀβꢀDꢀglucopyranosylꢀ(1→4)ꢀ2ꢀacetamidoꢀ2ꢀdeoxyꢀβꢀDꢀglucoꢀ
pyranosylꢀ(1→4)ꢀ2ꢀacetamidoꢀ2ꢀdeoxyꢀβꢀDꢀglucopyranosylꢀ
(1→4)ꢀ2ꢀacetamidoꢀ2ꢀdeoxyꢀβꢀDꢀglucopyranoside (29). Hydrꢀ
azine hydrate (0.5 mL) was added to a solution of heptasacchaꢀ
ride 20 (69 mg, 0.02 mmol) in EtOH (5 mL). The mixture was
refluxed for 16 h, the solvent was evaporated, and the residue
was dried using a vacuum oil pump at 50 °C for 2 h. The product
was treated with a solution of Ac2O (0.3 mL) in methanol (1 mL)
for 1 h at room temperature. The mixture was concentrated and
then subjected to silica gel column chromatography (chloroꢀ
form—methanol, 97 : 3) to obtain 43 mg of Nꢀacetylated heptaꢀ
saccharide 23. The further reduction of the azide group was
performed by two methods.
Method A. Triphenylphosphine (3.2 mg, 0.012 mmol) was
added to a solution of 2ꢀazidoethyl glycoside 23 (19.6 mg,
0.007 mmol) in 90% aqueous THF (0.5 mL). The mixture was
stirred for 21 h at 60 °C. The solvent was evaporated, and the
residue was chromatographed on a silica gel column (chloroꢀ
form—methanol, from 97 : 3 to 1 : 1). The product was dissolved
in methanol (0.5 mL) and treated with CF3COOEt (0.1 mL) in
the presence of one drop of triethylamine for 2 h. Trifluoroacetꢀ
amidoethyl glycoside 26 (10.7 mg) was isolated by silica gel colꢀ
umn chromatography (chloroform—methanol, 97 : 3).
Method B. A solution (65 μL), which was prepared by mixꢀ
ing SnCl2 (18.2 mg), thiophenol (39 μL), triethylamine (40 μL),
and acetonitrile (0.6 mL), was added to a solution of 2ꢀazidoꢀ
ethyl glycoside 23 (19.7 mg, 0.007 mmol) in acetonitrile (100 μL).
The mixture was stirred for 16 h at room temperature (~25 °C),
the solvent was evaporated, 2 M NaOH (3 mL) was added to the
residue, and the resulting solution was extracted with dichloroꢀ
methane (3×10 mL). The combined extracts were dried with
Na2SO4 and concentrated. 2ꢀAminoethyl glycoside was subjectꢀ
ed to trifluoroacetylation, and the product was isolated as deꢀ
scribed in the method A. The yield of trifluoroacetamidoethyl
glycoside 26 was 8.4 mg.
The products prepared by the methods A and B were subjectꢀ
ed to hydrogenolysis in methanol (0.5 mL) in the presence of
Pd/C (5 mg) for 24 h and then treated with 1 M NaOH, as
described above for compound 28. The product was isolated by
gel chromatography on TSK HWꢀ40. After freezeꢀdrying from
water, heptasaccharide 29 was obtained in yield of 1 mg (3.4%),

2ꢀAminoethyl glycosides
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015 2941
[α]D –25.8 (c 0.08, H2O). 1H NMR (600 MHz, D2O), δ:
4.61—4.57 (m, 6 H, 6 H(1)); 4.56 (d, 1 H, H(1), J1,2 = 8.4 Hz);
4.04 (m, 1 H, OCH2CH2NH2); 3.95—3.83 (m, 8 H, 7 H(6a),
OCH2CH2NH2); 3.80—3.61 (m, 26 H, 7 H(2), 6 H(3), 6 H(4),
7 H(6b)); 3.59—3.46 (m, 9 H, H(3), H(4), 7 H(5)); 3.18 (m, 2 H,
CH2CH2NH2); 2.08 (s, 3 H, CH3CO); 2.07 (s, 15 H, 5 CH3CO);
2.06 (s, 3 H, CH3CO); 1.92 (s, 1 H, ~0.3 CH3COO–). 13C NMR
(150 MHz, D2O), δ: 175.8 (NHCOCH3); 102.7, 102.4, 102.1
(7 C(1)); 80.4, 80.2 (6 C(4)); 77.1 (CG(5)); 75.7 (6 C(5)); 74.6
(CG(3)); 73.5, 73.3 (6 C(3)); 70.9 (CG(4)); 67.5 (OCH2CH2NH2);
61.8, 61.1 (7 C(6)); 56.8, 56.2, 56.0 (7 C(2)); 40.7 (CH2CH2NH2);
23.3 (COCH3). MS (ESI), m/z: 1505.5968 [M + Na]+. Calculatꢀ
ed for C58H98N8NaO36: 1505.5976.
13. O. Kanie, Y. Ito, T. Ogawa, J. Am. Chem. Soc., 1994, 116,
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This study was financially supported by the Russian
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Received July 20, 2015;
in revised form September 9, 2015