Blockwise synthesis of a pentasaccharide structurally related to the mannan fragment from the Candida albicans cell wall corresponding to the antigenic factor 6

Article abstract of DOI:10.1007/s11172-015-1251-5

A spacer-armed pentasaccharide structurally related to a fragment of the mannan from the cell wall of the fungus Candida albicans and corresponding to the antigenic factor 6 has been synthesized. This compound, comprising two α-(1→2)- and three β-(1→2)-li

Full text of DOI:10.1007/s11172-015-1251-5

Russian Chemical Bulletin, International Edition, Vol. 64, No. 12, pp. 2942—2948, December, 2015
2942
Blockwise synthesis of a pentasaccharide structurally related
to the mannan fragment from the Candida albicans
cell wall corresponding to the antigenic factor 6
A. A. Karelin,a Yu. E. Tsvetkov,a E. Paulovi ová,b L. Paulovi ová,b and N. E. Nifantieva
aN. 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
bInstitute of Chemistry, Slovak Academy of Sciences,
Bratislava, Slovakia
A spacerꢀarmed pentasaccharide structurally related to a fragment of the mannan from the
cell wall of the fungus Candida albicans and corresponding to the antigenic factor 6 has been
synthesized. This compound, comprising two αꢀ(1→2)ꢀ and three βꢀ(1→2)ꢀlinked mannose
residues, was prepared by glycosylation of a selectively protected αꢀ(1→2)ꢀdimannoside bearꢀ
ing an aglycone spacer and a free OH group at atom C(2´) with a βꢀ(1→2)ꢀtrimannoside
glycosyl donor. The successful synthesis evidences that large βꢀ(1→2)ꢀoligomannoside donor
blocks can be used for the preparation of oligosaccharides including extended sequences of
repeating βꢀ(1→2)ꢀlinked mannose residues.
Key words: Candida albicans, mannan, βꢀoligomannosides, antigenic factor 6, blockwise
synthesis, βꢀmannosylation.
The present work is a continuation of our studies on
dues, is bonded by its reducing end to the side chain
through a phosphate group12 (structure 1). This structural
type is called as an acidꢀlabile βꢀ(1→2)ꢀoligomannoside
and corresponds to the antigenic factor 5 (see Ref. 13). In
the second case, the short (1—4 residues) βꢀ(1→2)ꢀlinked
oligomannosides is bonded by a glycoside bond to αꢀ(1→2)ꢀ
oligomannoside chains at atom O(2) of the terminal manꢀ
nose unit14 (structure 2). This type of βꢀ(1→2)ꢀoligomanꢀ
noside is called an acidꢀstable and corresponds to the antiꢀ
genic factor 6 (see Ref. 13). The acidꢀlabile βꢀ(1→2)ꢀ
oligomannoside chains are a component of the mannan of
the serotypes related to serogroups A and B, whereas the
acidꢀstable βꢀ(1→2)ꢀoligomannoside is an antigen specific
for serotypes of serogroup A.
Apart from Candida albicans serogroup A, the oligoꢀ
saccharide structure of type 2 corresponding to the antiꢀ
genic factor 6 were found in mannans of other Candida
species (for example, in C. tropicalis, C. glabrata, C. stellaꢀ
toidea, C. lusitaniae, and C. kefyr15). βꢀ(1→2)ꢀOligomanꢀ
noside chains of mannan play an important role in pathoꢀ
genesis of candidiasis. Thus, it was found that they were
involved in the first stage of development of an infectious
process, namely, the adhesion of Candida to the cells of
a host organism.16 Animal models were used to demonstrate
that the antibodies specific to βꢀ(1→2)ꢀoligomannosides
possess protective properties against different types of
the synthesis1—4 and immunological properties5—9 of
oligosaccharides related to fragments of the mannan from
the cell wall of the fungi of the genus Candida. The yeastꢀ
like fungi Candida albicans are part of the microflora of the
skin, mucous membranes, and the gastrointestinal tract of
healthy human, however, in people with weakened imꢀ
mune systems, they can cause superficial and deep canꢀ
didiasis.10 The cell wall of the fungi of the genus Candida
is first to be involved in the interaction with the host orꢀ
ganism and is responsible for the antigenic reaction, adheꢀ
sion, and cellꢀcell interactions.11
Mannan is the major surface polysaccharide antigen of
the cell wall of Candida, which is a carbohydrate part of
the mannoprotein with a combꢀlike structure.12 Mannan
is based on the αꢀ(1→6)ꢀlinked main chain, with relativeꢀ
ly short side oligomannoside chains attached to the sepaꢀ
rate mannose residues through the αꢀ(1→2)ꢀbonds. These
chains can contain αꢀ(1→2)ꢀ, αꢀ(1→3)ꢀ, αꢀ(1→6)ꢀ, and
βꢀ(1→2)ꢀlinked mannose residues. These are the mannan
side chains which in the first place determine the antigenic
specificity of the fungi of the genus Candida.
The βꢀ(1→2)ꢀlinked mannose residues are part of the
composition of two types of antigenic structures of manꢀ
nan from Candida. In the first case, the βꢀ(1→2)ꢀoligoꢀ
mannoside containing from two to seven mannose resiꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2942—2948, December, 2015.
1066ꢀ5285/15/6412ꢀ2942 © 2015 Springer Science+Business Media, Inc.

Synthesis of a pentasaccharide
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015 2943
chain by only one monosaccharide unit, the case of
the direct βꢀmannosylation also permits more efficient
blockwise method of assembly of βꢀ(1→2)ꢀoligomannoꢀ
sides. Separate examples when the blockwise method uses
βꢀ(1→2)ꢀdimannoside donor blocks are described in the
literature.23,24
In the present work, we describe a blockwise synthesis
of a pentamannoside corresponding to the antigenic facꢀ
tor 6 and containing three βꢀ and two αꢀlinked mannose
residues, using direct βꢀmannosylation. One of the purꢀ
poses of this work is to study a possibility of using donor
blocks for the preparation of βꢀ(1→2)ꢀoligomannosides,
which are larger than the dimannosides mentioned above.
Results and Discussion
Known thiomannoside 3 was used as the starting comꢀ
pound for the assembly of a trimannoside glycosyl donor
block. It was obtained in two steps from free thioglycoside 4
(see Ref. 37) through the initial setting of the 4,6ꢀOꢀbenzꢀ
ylidene group37 and subsequent regioselective 3ꢀOꢀbenzylꢀ
ation of derivative 5 through the intermediate 2,3ꢀdibutylꢀ
stannylene derivative38 (Scheme 1).
Scheme 1
candidiasis,17—19 whereas the immunization with the conꢀ
jugate of synthetic βꢀ(1→2)ꢀtrimannoside with the C. alꢀ
bicans cell wall peptide protects from infection with a lethal
dose of a live fungal culture.20,21
There are literature reports on the synthesis of oligoꢀ
saccharides of type 2, in which from one to three βꢀ(1→2)ꢀ
linked mannose residues are attached to the only αꢀlinked
mannose residue22—25 or to αꢀ(1→2)ꢀmannobioside.26,27
The main problem, which was necessary to solve in the
process of their synthesis, was βꢀmannosylation, which is
regarded as one of the most challenging cases of glycoꢀ
sylation.28 At the present time, there are known two genꢀ
eral approaches to the solution of the problem of stereoꢀ
selective βꢀmannosylation. The first method is indirect
and based on the initial βꢀglucosylation and subsequent
inversion of configuration of atom C(2) in the glucose
residue in the reaction product. This approach was used to
obtain a number of βꢀ(1→2)ꢀoligomannosides,29,30 includꢀ
ing those corresponding to the antigenic factor 6 (see Refs
22 and 26). The second approach is based on the direct
βꢀmannosylation with conformationally rigid 4,6ꢀOꢀbenzꢀ
ylideneꢀprotected mannosyl donors,31—33 usually thioꢀ
glycosides or glycosyl sulfoxides. Though the mechanism
of βꢀstereocontrol in this type of glycosylation reactions is
still in dispute (cf. Ref. 33 and Ref. 34), this approach was
successfully used for the preparation of both homoꢀβꢀ
(1→2)ꢀoctamannoside35,36 and the structures of type 2
(see Refs 23, 24, and 27). In contrast to the first approach,
which allows the building up a βꢀ(1→2)ꢀoligomannoside
MBn = nꢀCH3OC6H4CH2
Reagents, conditions, and yields: i. PhCHO, HCOOH, 49% yield
(see Ref. 37); ii. 1) Bu2SnO, MeOH, reflux; 2) BnBr, DMF,
110 °C, 80% yield (see Ref. 38); iii. 1) Bu2SnO, MeOH, reflux;
2) BnBr, CsF, DMF, 20 °C, 74% yield; iv. PhCH(OMe)2, CSA,
MeCN, 84% yield; v. MBnCl, NaH, Bu4NI, DMF, 75% yield
(see Ref. 36); vi. mꢀCPBA, CH2Cl2, –78 → –20 °C, 84% yield
(see Ref. 36).

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Karelin et al.
The main disadvantage of this method for the preparaꢀ
tion of compound 3 is the low yield of 4,6ꢀmonoacetal 5
because of the competitive formation of a 2,3 : 4,6ꢀbisaceꢀ
tal. As a result, the total yield of the conversion 4 → 5 → 3
is below 40%. We used a reversed sequence of the introꢀ
duction of protecting groups into thioglycoside 4. Regiꢀ
oselective benzylation of compound 4 through a dibutylꢀ
stannylene derivative led to 3ꢀbenzyl ether 6 in 74% yield.
Further introduction of 4,6ꢀOꢀbenzylidene group into comꢀ
pound 6 because of the impossibility to form 2,3ꢀacetal
proceeded without complications and led to derivative 3
in 84% yield (the overall yield for the conversion 4 → 6 → 3
was 62%). The conversion of compound 3 to pꢀmethoxyꢀ
benzyl ether 7 and its oxidation to sulfoxide 8, which
was further used as a glycosyl donor in the assembly of
βꢀ(1→2)ꢀtrimannoside, was carried out according to the
procedure described earlier.36
newly formed glycoside bond in trimannosides 11 and 12
was also inferred from the signal positions for atom H(5)
in the terminal mannose residues in the 1H NMR spectra.
Thus, in the case of βꢀanomer 11, the signal for atom
H(5) resonated at δ 3.49, whereas in αꢀanomer it was
found in the group of signals at δ ~4.35.
The synthesis was finalized by the condensation of
βꢀ(1→2)ꢀtrimannoside donor 11 with disaccharide acꢀ
ceptor 13 described by us earlier.1 There are contradictoꢀ
ry literature data on the influence of mannosylation
conditions on its stereochemical result, especially conꢀ
cerning the order of mixing the reagents. In the works,31—33
it was shown that the high βꢀselectivity of mannosylaꢀ
tion can be reached by a preliminary lowꢀtemperature
activation of the mannosyl donor with subsequent addiꢀ
tion of an acceptor. At the same time, in the work34 it
was demonstrated that 4,6ꢀbenzylideneꢀprotected manꢀ
nosyl trichloroacetimidate secured the βꢀselectivity of
mannosylation without preliminary activation, which
turned out to be virtually the same as that observed
with its preactivation. Taking into account the latter
result, the glycosylation of acceptor 13 with thioglycoꢀ
side 11 was carried out without preliminary activation of
the donor, i.e., by the addition of a catalytic amount of
TfOH to a mixture of compounds 11, 13, and NIS
(Scheme 3).
The βꢀmannosylation product, pentasaccharide 14,
was obtained in 41% yield. The βꢀconfiguration of the
newly formed glycoside bond was inferred from the highꢀ
field position of the signal for atom H(5) of the mannose
residue C (δ 2.77) in the 1H NMR spectrum of pentasacꢀ
charide 14. This means that even without preliminary acꢀ
tivation of the donor, the glycosylation with trisacchaꢀ
ride 11 leads to the βꢀlinked mannoside. This result also
confirms a possibility of using βꢀ(1→2)ꢀoligomannosyl
donor blocks (larger than dimannoside units) for the
Glycosylation of derivative 3 with sulfoxide 8 was efꢀ
fected under conditions of a preꢀactivation of the donor
upon treatment with Tf2O in the presence of 2,6ꢀdiꢀtertꢀ
butylpyridine (DTBP) with subsequent addition of accepꢀ
tor 3 (Scheme 2). It is believed33 that the preactivation of
the donor results in the formation of a covalent αꢀmannosyl
triflate, the further SN2ꢀlike reaction of which with glycoꢀ
syl acceptor secures the high βꢀselectivity of glycosylation.
The glycosylation gave βꢀdimannoside 9 in 59% yield.
The βꢀconfiguration of the newly formed glycoside bond
was confirmed by a highꢀfield position of the signal for
atom H(5) in the mannose residue at the nonreducing end
1
(δ 3.37)33 in the H NMR spectrum. The removal of the
pꢀmethoxybenzyl group in compound 9 upon treatment
with DDQ gave disaccharide glycosyl acceptor 10 in high
yield. The glycosylation of compound 10 with sulfoxide 8
proceeded less efficiently and led to βꢀ(1→2)ꢀtrimannoꢀ
side 11 in 40% yield. Apart from that, the αꢀlinked prodꢀ
uct 12 was isolated in 16% yield. The configuration of the
Scheme 2
Reagents, conditions, and yields: i. 1) Tf2O, DTBP, MS 4 Å, CH2Cl2, –80 °C; 2) 8, CH2Cl2, –80 → +10 °C, 59% yield for 9, 40% yield
for 11; ii. DDQ, CHCl3—water, 91% yield.

Synthesis of a pentasaccharide
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015 2945
Scheme 3
Reagents, conditions, and yields: i. NIS, TfOH, MS 4 Å, CH2Cl2, –40 → –10 °C, 41% yield; ii. H2, Pd(OH)2/C, MeOH—EtOAc,
20 °C; iii. aqueous NaOH, 47% yield.
nal standard for 1H NMR spectra, the signal of CDCl3 (δC 77.0)
preparation of oligosaccharides containing large enough
βꢀ(1→2)ꢀoligomannoside sequences.
was a reference for 13C NMR spectra. Spectra of unprotected
oligosaccharides were recorded in heavy water (D2O), using acꢀ
The benzyl and the benzylidene groups in protected
etone as an internal standard (δ 2.225, δ 31.45). The signals
H
C
pentasaccharide 14 were removed by catalytic hydrogenolꢀ
ysis, the Nꢀtrifluoroacetyl group was removed by alkaline
hydrolysis. The thus obtained free pentamannoside 3ꢀaminoꢀ
propylglycoside (15) will be used further for the preparaꢀ
tion of immunogens by the conjugation with protein
carriers, coating antigens for enzymeꢀlinked immunoꢀ
sorbent assay labeled molecular probes, and other bioꢀ
molecular systems.39
were assigned using procedures of 2D correlation spectroscopy
COSY, TOCSY, ROESY, and HSQC. In the description of NMR
spectra, the monosaccharide moieties starting from the reducing
end of the oligosaccharide are designated in Latin letters (A, B,
C, etc.) (see Scheme 3).
Electrospray ionization (ESI) high resolution mass spectra
were recorded on a Bruker micrOTOF II instrument.
Glycosylation reactions were carried out in anhydrous solꢀ
vents under dry argon. Molecular sieves before use in the reacꢀ
tion were activated for 2 h at 180 °C in vacuo, using an oil pump.
Ethyl 3ꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀmannopyranoside (6). The reꢀ
agent Bu2SnO (1.25 g, 5.0 mmol) was added to a solution of
thioglycoside 4 (1.15 g, 5.13 mmol) in anhydrous MeOH (20 mL).
The reaction mixture was refluxed until a homogeneous solution
was formed (~3 h). Then the solvent was evaporated, the residue
was dried in vacuo, using an oil pump. Cesium fluoride (935 mg,
6.16 mmol) and benzyl bromide (0.673 mL, 5.64 mmol) were
added to a solution of the product obtained in anhydrous DMF
(20 mL). The reaction mixture was stirred for 16 h at ~20 °C,
then filtered through a layer of silica gel, which was washed with
ethyl acetate. The filtrate was concentrated and then twice coꢀ
concentrated with toluene. The residue was dried in vacuo, using
an oil pump. 3ꢀBenzyl ether 6 (1.17 g, 74%) was isolated
by column chromatography in ethyl acetate, colorless syrup,
[α]D +114.4 (c 1, CH3OH). 1H NMR (600 MHz, CDCl3), δ:
7.43—7.27 (m, 5 H, Ph); 5.25 (d, 1 H, H(1), J1,2 = 1.5 Hz); 4.71
(d, 1 H, PhCH2, J = 11.8 Hz); 4.64 (d, 1 H, PhCH2); 4.04 (dd, 1 H,
H(2), J2,3 = 3.2 Hz); 3.92 (m, 1 H, H(5)); 3.84—3.79 (m, 2 H,
H(4), H(6a)); 3.74 (dd, 1 H, H(6b), J5,6 = 5.7 Hz, J6a,6b = 11.9 Hz);
3.56 (dd, 1 H, H(3), J3,4 = 9.3 Hz); 2.66 (m, 1 H, SCH2CH3);
2.58 (m, 1 H, SCH2CH3); 1.27 (t, 3 H, SCH2CH3, J = 7.4 Hz).
13C NMR (125 MHz, CDCl3), δ: 129.4, 129.3, 128.8 (Ph);
Experimental
All the reactions were carried out in the solvents purified
according to the standard procedures. The reagents TfOH, Tf2O,
NIS (Acros), and DTBP (Aldrich) were used without additional
purification. Thinꢀlayer chromatography was carried out on Kieꢀ
selgel 60 F254 plates with silica gel (Merck), compounds were
visualized under UV light or by spraying with a solution of orciꢀ
nol (180 mg of orcinol in a mixture of water (85 mL), 85%
aqueous orthophosphoric acid (10 mL), and 95% aqueous ethaꢀ
nol (5 mL)) with subsequent heating at ~150 °C. Column chroꢀ
matography was carried out on Silica gel 60 (40—63 μm, Merck),
gelꢀchromatography of free oligosaccharides was carried out on
a column with a TSK HWꢀ40(S) gal (1.5×90 cm) in 0.1 M acetic
acid, the eluate was analyzed using a Knauer Кꢀ2401 flow reꢀ
fractometer. Optical rotation was measured on a JASCO Pꢀ2000
digital polarimeter (Japan) at ~20 °C in methanol or chloroform
(in the case of protected derivatives) and in water (in case of free
oligosaccharide).
NMR spectra of protected derivatives were recorded on
a Bruker Avance 600 spectrometer in CDCl3 at 25 °C. The signal
of residual nondeuterated CHCl3 (δH 7.27) were used as an interꢀ

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Karelin et al.
86.1 (C(1)); 80.9 (C(3)); 75.1 (C(5)); 72.8 (PhCH2); 70.9 (C(2));
68.1 (C(4)); 62.9 (C(6)); 25.9 (SCH2CH3); 15.4 (SCH2CH3).
Found: m/z 353.0818 [M + K]+. C15H22O4KS. Calculated:
353.0820.
Ethyl (3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀβꢀDꢀmannopyranosyl)ꢀ
(1→2)ꢀ3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ1ꢀthioꢀαꢀDꢀmannopyranoꢀ
side (10). Water (0.2 mL) and DDQ (46 mg, 0.2 mmol) were
added to a solution of dimannoside 9 (145 mg, 0.168 mmol) in
chloroform (2 mL). The reaction mixture was stirred for 1.5 h,
then diluted with chloroform, washed with saturated aqueous
NaHCO3, and concentrated. Derivative 10 (114 mg, 91%) was
isolated by column chromatography (toluene—ethyl acetate,
10 : 1 → 6 : 1) as a colorless syrup, [α]D +5.4 (c 1, CHCl3).
1H NMR (600 MHz, CDCl3), δ: 7.55—7.28 (m, 20 H, 4 Ph);
5.58 (s, 1 H, PhCH); 5.51 (s, 1 H, PhCH); 5.35 (s, 1 H, H(1)A);
4.89 (d, 1 H, PhCH2, J = 12.2 Hz); 4.83—4.78 (m, 3 H, H(1)B,
2 PhCH2); 4.76 (d, 1 H, PhCH2, J = 11.8 Hz); 4.50 (d, 1 H,
H(2)A, J2,3 = 3.2 Hz); 4.35—4.29 (m, 2 H, H(4)B, H(6b)); 4.25—4.17
(m, 4 H, H(2)B, H(4)A, H(5)A, H(6a)A); 3.97 (dd, 1 H, H(3)A,
J2,3 = 3.2 Hz, J3,4 = 8.6 Hz); 3.84—3.78 (m, 2 H, H(6b)A,
H(6b)B); 3.74 (dd, 1 H, H(3)B, J2,3 = 3.9 Hz, J3,4 = 9.0 Hz); 3.45
(m, 1 H, H(5)B); 2.65 (m, 2 H, SCH2CH3); 1.32 (t, 3 H,
SCH2CH3, J = 7.4 Hz). 13C NMR (150 MHz, CDCl3), δ: 138.2,
138.1, 137.6, 137.5, 128.9—127.7, 126.1 (Ar); 101.5 (PhCH);
101.4 (PhCH); 97.6 (C(1)B); 83.0 (C(1)A); 78.9 (C(4)A); 78.6
(C(4)B); 76.3 (C(3)B); 74.8 (C(3)A); 74.6 (C(2)A); 72.6 (PhCH2);
72.4 (PhCH2); 69.6 (C(2)B); 68.7 (C(6)A); 68.5 (C(6)B); 66.9
(C(5)B); 64.5 (C(5)A); 25.5 (SCH2CH3); 15.0 (SCH2CH3).
Found: m/z 760.3146 [M + NH4]+. C42H50O10NS. Calculated:
760.3150.
Ethyl [3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ2ꢀOꢀ(pꢀmethoxybenzꢀ
yl)ꢀβꢀDꢀmannopyranosyl]ꢀ(1→2)ꢀ(3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylidꢀ
eneꢀβꢀDꢀmannopyranosyl)ꢀ(1→2)ꢀ3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylidꢀ
eneꢀ1ꢀthioꢀαꢀDꢀmannopyranoside (11) and ethyl [3ꢀOꢀbenzylꢀ4,6ꢀ
Oꢀbenzylideneꢀ2ꢀOꢀ(pꢀmethoxybenzyl)ꢀαꢀDꢀmannopyranosyl]ꢀ
(1→2)ꢀ(3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀβꢀDꢀmannopyranosyl)ꢀ
(1→2)ꢀ3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ1ꢀthioꢀαꢀDꢀmannopyranoꢀ
side (12). Molecular sieves 4 Å (150 mg) and DTBP (80 μL,
0.36 mmol) were added to a solution of sulfoxide 8 (96 mg,
0.18 mmol) in CH2Cl2 (1 mL). The resulting mixture was stirred
for 30 min at ~20 °C, then cooled to –80 °C, followed by the
addition of Tf2O (30 μL, 0.22 mmol). The reaction mixture was
stirred for 5 min, then a solution of dimannoside 10 (95 mg,
0.13 mmol) in CH2Cl2 (1.5 mL) was added dropwise, the stirring
was continued for 40 min at –80 °C. Then, the temperature of
the reaction mixture was gradually increased to +10 °C over
~1 h, and the reaction was stopped by the addition of triethylꢀ
amine (0.2 mL). This mixture was diluted with chloroform, filꢀ
tered through a layer of celite, the celite was washed with chloroꢀ
form. The combined filtrates were washed with water and conꢀ
centrated. β-Product 11 (61 mg, 40%) and aꢀproduct 12 (24 mg,
16%) were isolated by column chromatography (toluene—ethyl
acetate, 15 : 1 → 10 : 1).
Ethyl 3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ1ꢀthioꢀαꢀDꢀmannopyrꢀ
anoside (3). Benzaldehyde dimethyl acetal (0.29 mL, 1.9 mmol)
and CSA (40 mg) were added to a solution of thioglycoside 6
(400 mg, 1.27 mmol) in anhydrous acetonitrile (5 mL). The
mixture was allowed to stand at ~20 °C until the full conversion
of the starting compound 6, then triethylamine (0.1 mL) was
added, the solvent was evaporated. Compound 3 was isolated
(427 mg, 84%) by column chromatography (toluene—ethyl aceꢀ
tate, 20 : 1) as a colorless syrup. 1H NMR (400 MHz, CDCl3), δ:
7.51—7.46, 7.40—7.28 (both m, 10 H, 2 Ph); 5.61 (s, 1 H, PhCH);
5.36 (s, 1 H, H(1)); 4.85 (d, 1 H, PhCH2, J = 11.7 Hz); 4.69 (d, 1 H,
PhCH2, J = 11.8 Hz); 4.26—4.20 (m, 2 H, H(5), H(6a)); 4.14
(t, 1 H, H(4), J = 9.3 Hz); 4.10 (d, 1 H, H(2), J2,3 = 3.1 Hz);
3.92—3.85 (m, 2 H, H(3), H(6b)); 2.69—2.52 (m, 2 H, SCH2CH3);
1.28 (t, 3 H, SCH2CH3, J = 7.4 Hz). 13C NMR (100 MHz,
CDCl3), δ: 137.5, 137.7, 128.9, 128.5, 128.2, 128.0, 127.8, 126.0
(Ph); 101.6 (PhCH); 84.1 (C(1)); 79.1 (C(4)); 75.8 (C(3)); 73.1
(ArCH2); 71.4 (C(2)); 68.6 (C(6)); 63.8 (C(5)); 24.9 (SCH2CH3);
14.8 (SCH2CH3). According to the NMR spectral data, the prodꢀ
uct obtained was identical to derivative 3 described in the work.38
Ethyl [3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ2ꢀOꢀ(pꢀmethoxybenzꢀ
yl)ꢀβꢀDꢀmannopyranosyl]ꢀ(1→2)ꢀ3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ
1ꢀthioꢀαꢀDꢀmannopyranoside (9). Molecular sieves 4 Å (300 mg)
and DTBP (0.18 mL, 0.815 mmol) were added to a solution of
sulfoxide 8 (228 mg, 0.424 mmol) in CH2Cl2 (2 mL). The resultꢀ
ing mixture was stirred for 30 min at ~20 °C, then cooled to
–80 °C, followed by the addition of Tf2O (69 μL, 0.51 mmol).
After 5 min, a solution of thioglycoside 3 (131 mg, 0.326 mmol)
in CH2Cl2 (1 mL) was added dropwise to the reaction mixture.
The mixture was stirred for 1 h at –80 °C, then the temperature
was gradually elevated to +10 °C over 1 h. The reaction mixture
was neutralized with triethylamine (0.3 mL), diluted with chloroꢀ
form, and filtered through a layer celite. The celite was washed
with chloroform, the combined filtrates were washed with water
and concentrated. Disaccharide 9 (159 mg, 59%) was isolated by
column chromatography (toluene—ethyl acetate, 20 : 1) as a colorꢀ
less syrup, [α]D –27.9 (c 1, CHCl3). 1H NMR (600 MHz,
CDCl3), δ: 7.55—7.28 (m, 22 H, 4 Ph, pꢀCH3OC6H4); 6.88—6.84
(m, 2 H, pꢀCH3OC6H4); 5.65 (s, 1 H, PhCH); 5.54 (s, 1 H,
PhCH); 5.36 (s, 1 H, H(1)A); 5.02 (d, 1 H, ArCH2, J = 11.8 Hz);
4.95 (d, 1 H, ArCH2, J = 11.8 Hz); 4.80 (d, 1 H, ArCH2,
J = 12.0 Hz); 4.77—4.73 (m, 2 H, ArCH2); 4.69 (s, 1 H, H(1)B);
4.66 (d, 1 H, ArCH2, J = 12.5 Hz); 4.39 (d, 1 H, H(2)A,
J2,3 = 3.1 Hz); 4.32—4.24 (m, 4 H, H(4)B, H(5)A, H(6a)A,
H(6a)B); 4.17 (t, 1 H, H(4)A, J = 9.8 Hz); 4.04 (d, 1 H, H(2)B,
J2,3 = 3.1 Hz); 3.97 (dd, 1 H, H(3)A, J2,3 = 3.1 Hz, J3,4 = 9.8 Hz);
3.91 (t, 1 H, H(6b)B, J = 10.2 Hz); 3.83 (t, 1 H, H(6b)A, J= 11.6 Hz);
3.78 (s, 3 H, OCH3); 3.65 (dd, 1 H, H(3)B, J2,3 = 3.1 Hz,
J3,4 = 9.8 Hz); 3.37 (m, 1 H, H(5)B); 2.67 (m, 2 H, SCH2CH3);
1.31 (t, 3 H, SCH2CH3, J = 7.4 Hz). 13C NMR (125 MHz,
CDCl3), δ: 159.2, 138.6, 138.4, 137.5, 130.6, 130.2, 128.9—126.1,
113.6 (Ar); 101.7 (PhCH); 101.4 (PhCH); 99.9 (C(1)B); 82.7
(C(1)A); 78.9 (C(4)A); 78.5 (C(4)B); 77.7 (C(3)B); 76.2 (C(2)A);
75.6 (C(2)B); 74.5 (C(3)A); 74.2 (ArCH2); 72.3 (ArCH2); 71.4
(ArCH2); 68.7 (C(6)A); 68.5 (C(6)B); 67.8 (C(5)B); 64.7 (C(5)A);
55.2 (OCH3); 25.6 (SCH2CH3); 15.0 (SCH2CH3). Found: m/z
863.3457 [M + H]+. C50H54O11S. Calculated: 863.3460.
Compound 11, a colorless syrup, [α]D –56.1 (c 1, CHCl3).
1H NMR (600 MHz, CDCl3), δ: 7.57—7.19 (m, 32 H, 6 Ph,
pꢀCH3OC6H4); 6.81—6.77 (m, 2 H, pꢀCH3OC6H4); 5.65 (s, 1 H,
PhCH); 5.59 (s, 1 H, PhCH); 5.46 (s, 1 H, PhCH); 5.39 (s, 1 H,
H(1)A); 5.18 (s, 1 H, H(1)C); 4.93 (d, 1 H, PhCH2, J = 12.0 Hz);
4.90 (d, 1 H, PhCH2, J = 12.8 Hz)); 4.84 (d, 1 H, PhCH2,
J = 12.6 Hz)); 4.74 (s, 1 H, H(1)B); 4.71 (d, 1 H, PhCH2,
J = 12.0 Hz)); 4.69 (d, 1 H, PhCH2, J = 12.0 Hz)); 4.63 (d, 1 H,
PhCH2, J = 12.2 Hz); 4.50 (d, 1 H, PhCH2, J = 11.6 Hz); 4.47—4.43
(m, 4 H, H(2)A, H(2)B, H(2)C, PhCH2); 4.42—4.37 (m, 2 H,
H(6a)B, H(6a)C); 4.31—4.24 (m, 3 H, H(4)C, H(5)A, H(6a)A);
4.14 (t, 1 H, H(4)B, J = 9.5 Hz); 4.05—3.96 (m, 3 H, H(3)A,

Synthesis of a pentasaccharide
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015 2947
H(4)A, H(6b)C); 3.85—3.79 (m, 2 H, H(6b)A, H(6b)B); 3.73 (dd,
1 H, H(3)B, J2,3 = 2.9 Hz, J3,4 = 9.8 Hz); 3.68 (s, 3 H, OCH3);
3.59 (dd, 1 H, H(3)C, J2,3 = 3.0 Hz, J3,4 = 9.3 Hz); 3.49 (m, 1 H,
H(5)C); 3.43 (m, 1 H, H(5)B); 2.69 (m, 2 H, SCH2CH3); 1.43
(t, 3 H, SCH2CH3, J = 7.4 Hz). 13C NMR (150 MHz, CDCl3),
δ: 158.8, 138.6, 138.7, 138.2, 137.6, 137.4, 137.1, 131.5, 129.6—126.1,
125.3, 126.0, 113.4 (Ar); 103.0 (C(1)C); 102.1 (PhCH); 101.7
(PhCH); 100.3 (PhCH); 98.7 (C(1)B); 82.1 (C(1)A); 79.3 (C(3)C);
79.2 (C(4)A); 78.3 (C(4)B); 78.2 (C(4)C); 76.2 (C(2)); 75.8
(C(3)B); 75.7 (C(2)); 75.1 (C(2)); 74.8 (C(3)A); 74.5 (PhCH2);
72.2 (PhCH2); 71.7 (PhCH2); 71.1 (PhCH2); 68.8 (2C, C(6)B,
C(6)C); 68.7 (C(6)A); 68.0 (C(5)C); 67.9 (C(5)B); 64.4 (C(5)A);
55.1 (OCH3); 25.6 (SCH2CH3); 14.9 (SCH2CH3). Found: m/z
1225.4584 [M + Na]+. C70H74O16NaS. Calculated: 1225.4590.
Compound 12, a colorless syrup, [α]D –7.9 (c 1, CHCl3).
1H NMR (600 MHz, CDCl3), δ: 7.59—7.19 (m, 32 H, 6 Ph,
pꢀCH3OC6H4); 6.82—6.79 (m, 2 H, pꢀCH3OC6H4); 5.69 (s, 1 H,
PhCH); 5.63 (s, 1 H, PhCH); 5.60 (s, 1 H, H(1)C); 5.39 (s, 1 H,
H(1)A); 5.36 (s, 1 H, PhCH); 4.88 (d, 1 H, PhCH2, J = 11.8 Hz);
4.78—4.73 (m, 2 H, 2 PhCH2); 4.69 (d, 1 H, PhCH2, J = 12.4 Hz);
4.66 (s, 1 H, H(1)B); 4.55 (s, 2 H, 2 PhCH2); 4.46 (dd, H(6a)C,
J5,6 = 4.9 Hz, J6a,6b = 10.0 Hz); 4.42 (d, 1 H, PhCH2, J = 11.9 Hz);
4.38 (d, 1 H, H(2)B, J = 1.6 Hz); 4.37—4.33 (m, 2 H, H(2)A,
H(5)C); 4.31—4.25 (m, H(4)C, H(6a)B); 4.25—4.15 (m, 3 H,
H(3)C, H(4)A, H(5)A); 4.09 (t, H(4)B, J = 9.5 Hz); 4.05—4.02
(m, 2 H, H(2)C, H(6a)A); 3.95—3.87 (m, 3 H, H(3)A, H(6b)A,
H(6b)C); 3.78—3.73 (m, 5 H, H(3)B, H(6b)B, OCH3); 3.39 (m, 1 H,
H(5)B); 2.70—2.58 (m, 2 H, SCH2CH3); 1.32 (t, 3 H, SCH2CH3,
J = 7.4 Hz). 13C NMR (150 MHz, CDCl3, δ: 159.1, 139.1,
138.9, 137.9, 137.6, 137.5, 137.4, 130.4, 129.7—127.1, 126.1,
126.0, 125.9, 113.6 (Ar); 101.6 (PhCH); 101.5 (PhCH); 100.6
(PhCH); 99.3 (C(1)C); 99.2 (C(1)B); 83.1 (C(1)A); 79.6 (C(4)C);
79.0 (C(3)B); 78.9 (C(4)B); 77.6 (C(4)A); 76.8 (C(2)A); 76.7
(C(2)C); 76.4 (C(3)C); 74.5 (C(3)A); 73.5 (PhCH2); 73.4 (PhCH2);
72.9 (C(2)B); 72.7 (PhCH2); 70.8 (PhCH2); 68.7 (C(6)C); 68.4
(C(6)B); 67.8 (C(6)A); 67.6 (C(5)B); 64.7 (C(5)A); 64.4 (C(5)C);
55.2 (OCH3); 25.3 (SCH2CH3); 14.9 (SCH2CH3). Found: m/z
1241.4325 [M + K]+. C70H74O16KS. Calculated: 1241.4329.
3ꢀTrifluoroacetamidopropyl [3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylidꢀ
eneꢀ2ꢀOꢀ(pꢀmethoxybenzyl)ꢀβꢀDꢀmannopyranosyl]ꢀ(1→2)ꢀ(3ꢀOꢀ
benzylꢀ4,6ꢀOꢀbenzylideneꢀβꢀDꢀmannopyranosyl)ꢀ(1→2)ꢀ(3ꢀOꢀ
benzylꢀ4,6ꢀOꢀbenzylideneꢀβꢀDꢀmannopyranosyl)ꢀ(1→2)ꢀ(3,4,6ꢀ
triꢀOꢀbenzylꢀαꢀDꢀmannopyranosyl)ꢀ(1→2)ꢀ3,4,6ꢀtriꢀOꢀbenzylꢀαꢀ
Dꢀmannopyranoside (14). Molecular sieves 4 Å (125 mg) were
added to a solution of thioglycoside 11 (55 mg, 0.046 mmol) and
acceptor 13 (39 mg, 0.034 mmol) in CH2Cl2 (2.5 mL). The
mixture was stirred for 30 min at ~20 °C and cooled to –10 °C,
followed by the addition of NIS (20 mg, 0.094 mmol) and stirꢀ
ring for another 10 min. Then, the temperature was reduced to
–40 °C and TfOH (3 μL, 0.034 μmol) was added. The temperaꢀ
ture of the reaction mixture was gradually elevated to –10 °C
over 40 min. The stirring was continued at this temperature until
the reagents were completely consumed (TLC monitoring). The
reaction was stopped by addition of triethylamine (0.1 mL), the
mixture was diluted with chloroform and filtered through a layer
of celite, the celite was washed with chloroform, the combined
filtrates were washed with 1 M aqueous Na2S2O3, the organic
layer was concentrated. Pentasaccharide 14 (30 mg, 41%) was
isolated by column chromatography (toluene—ethyl acetate,
6 : 1) as a colorless syrup, [α]D –60.9 (c 1, CHCl3). 1H NMR
(600 MHz, D2O), δ: 7.54—6.94 (m, 62 H, 12 Ph, pꢀCH3OC6H4);
6.82 (br.s, 1 H, NH); 6.73—6.59 (m, 2 H, pꢀCH3OC6H4); 5.60
(s, 1 H, PhCH); 5.44 (s, 1 H, PhCH); 5.40 (s, 1 H, PhCH); 5.27
(s, 1 H, H(1)D); 5.13 (d, H(1)B, J1,2 = 1.8 Hz); 5.06 (s, 1 H,
H(1)E); 4.93 (d, 1 H, PhCH2, J = 12.1 Hz); 4.84 (d, 1 H, PhCH2,
J = 10.9 Hz); 4.78 (d, H(1)A, J1,2 = 1.1 Hz); 4.77—4.66 (m, 4 H,
PhCH2); 4.64—4.45, (m, 9 H, H(2)E, 8 PhCH2); 4.45—4.33
(m, 6 H, H(2)C, H(2)D, H(6a)D, 3 PhCH2); 4.32—4.22 (m, 3 H,
H(2)B, H(6a)E, PhCH2); 4.22—4.09 (m, 3 H, H(1)C, H(4)E,
H(6a)C); 4.08—4.00 (m, 2 H, H(2)A, H(4)D); 3.93 (t, 1 H,
H(6b)E, J5,6 = J6a,6b = 10.3 Hz); 3.89—3.62 (m, 13 H, H(3)A,
H(3)B, H(4)A, H(4)B, H(4)C, H(5)A, H(5)B, H(6a)A, H(6a)B,
H(6b)A, H(6b)C, H(6b)D, OCH2CH2CH2N); 3.62—3.50 (m, 6 H,
H(3)D, H(3)E, H(6b)B, OCH3); 3.50—3.43 (m, 2 H, H(5)D,
OCH2CH2CH2N); 3.43—3.32 (m, 2 H, H(5)E, OCH2CH2ꢀ
CH2N); 3.32—3.24 (m, 2 H, H(3)C, OCH2CH2CH2N); 2.76
(m, 1 H, H(5)C); 1.78 (m, 2 H, OCH2CH2CH2N). 13C NMR
(150 MHz, D2O, δ: 158.8, 156.9, 138.8—137.3, 131.7, 129.9—127.1,
126.3, 113.5 (Ar); 103.7 (C(1)E); 102.2 (PhCH); 101.4 (C(1)D);
101.4 (PhCH); 99.2 (C(1)A); 99.1 (C(1)C); 98.7 (C(1)B); 80.5
(C(3)A); 79.4 (C(3)E); 78.7 (C(4)C); 78.5 (C(4)D); 78.4 (C(4)E);
77.9 (C(3)B); 77.2 (C(3)D); 76.7 (C(2)D); 75.7 (2 C, C(2)E,
C(3)C); 75.2 (2 C, PhCH2); 75.0 (C(4)A); 74.8 (C(4)B); 74.5
(C(2)A); 74.4 (PhCH2); 73.8 (PhCH2); 73.6 (PhCH2); 73.4
(PhCH2); 72.9 (C(2)C); 72.4 (C(5)A); 72.2 (PhCH2); 71.7
(C(2)B); 71.5 (C(5)B); 71.2 (PhCH2); 70.7 (PhCH2); 70.6
(PhCH2); 69.3 (C(6)A); 68.7 (2 C, C(6)D, C(6)E); 68.6 (2 C,
C(6)B, C(6)C); 67.9 (2 C, C(5)D, C(5)E); 67.1 (C(5)C);
66.1 (OCH2CH2CH2N); 55.1 (OCH3); 38.2 (OCH2CH2CH2N);
28.3 (OCH2CH2CH2N). Found: m/z 2214.8503 [M + K]+.
C127H133F3KNO28. Calculated: 2214.8520.
3ꢀAminopropyl βꢀDꢀmannopyranosylꢀ(1→2)ꢀβꢀDꢀmannopyrꢀ
anosylꢀ(1→2)ꢀβꢀDꢀmannopyranosylꢀ(1→2)ꢀαꢀDꢀmannopyranoꢀ
sylꢀ(1→2)ꢀαꢀDꢀmannopyranoside, acetate (15). A 20% Pd(OH)2/C
(30 mg) was added to a solution of protected pentamannoside 14
(30 mg, 0.014 mmol) in a mixture of methanol (1 mL) and ethyl
acetate (1 mL). The mixture obtained was stirred in the hydroꢀ
gen atmosphere for 3 days. Then, the reaction mixture was dilutꢀ
ed with methanol, the catalyst was filtered through celite, thorꢀ
oughly washed with aqueous methanol (1 : 1). The combined
filtrates were concentrated, NaOH (3 mg, 0.078 mmol) was addꢀ
ed to a solution of the residue in water (1 mL), after 3 h the
solution was neutralized with acetic acid and concentrated. The
product was isolated by gelꢀchromatography as an acetate and
lyophilized from water to obtain pentasaccharide 15 (6 mg, 47%),
[α]D –16.5 (c 0.4, water). 1H NMR (600 MHz, D2O), δ: 5.13
(s, 1 H, H(1)B); 5.06 (s, 1 H, H(1)A); 4.92 (s, 2 H, H(1)D, H(1)E);
4.84 (s, 1 H, H(1)C); 4.40 (d, 1 H, H(2)D, J2,3 = 2.7 Hz); 4.27
(br.s, 1 H, H(2)B); 4.24 (d, 1 H, H(2)C, J2,3 = 3.1 Hz); 4.14 (d, 1 H,
H(2)E, J2,3 = 2.8 Hz); 3.99 (br.s, 1 H, H(2)A); 3.94—3.82 (m, 8 H,
H(3)A, H(3)B, H(6a)A, H(6a)B, H(6a)C, H(6a)D, H(6a)E,
OCH2CH2CH2N); 3.77—3.64 (m, 8 H, H(3)C, H(4)A, H(5)B,
H(6b)A, H(6b)B, H(6b)C, H(6b)D, H(6b)E); 3.63—3.54 (m, 7 H,
H(3)D, H(3)E, H(4)B, H(4)D, H(4)E, H(5)A, OCH2CH2CH2N);
3.50 (t, 1 H, H(4)C, J = 9.7 Hz); 3.41—3.33 (m, 3 H, H(5)C,
H(5)D, H(5)E); 3.12 (m, 2 H, OCH2CH2CH2N); 1.98 (m, 2 H,
OCH2CH2CH2N); 1.90 (s, 3 H, CH3COO–). 13C NMR (150 MHz,
D2O), δ: 102.5, 102.2 (2 C, C(1)E, C(1)D); 101.5 (C(1)B); 100.4
(C(1)C); 99.5 (C(1)A); 80.6 (C(2)C); 79.9 (C(2)A); 79.6 (C(2)D);
79.3 (C(2)B); 77.6 (C(5)D); 77.4 (2 C, C(5)C, C(5)E); 74.5
(C(5)B); 74.2 (C(3)E); 74.1 (C(3)D); 73.5 (C(5)A); 73.1 (C(3)C);
71.6 (C(2)E); 71.4 (C(3)B); 70.5 (C(3)A); 68.7 (C(4)E); 68.4

2948
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 12, December, 2015
Karelin et al.
(C(4)C); 68.2 (2 C, C(4)A, C(4)D); 68.0 (C(4)B); 66.2 (OCH2ꢀ
CH2CH2N); 62.4, 62.2, 62.1, 61.9 (5 C, C(6)A, C(6)B, C(6)C,
C(6)D, C(6)E); 38.7 (OCH2CH2CH2N); 27.9 (OCH2CH2CH2N);
16. Y. Fukazawa, K. Kagaya, M. Suzuki, T. Shinoda, in Fungal
Cells in Biodefense Mechanism, Eds S. Suzuki reaction,
M. Suzuki, Saikon Publishing Co, Tokyo, 1996, p. 17.
17. Y. Han, T. Kanbe, R. Cherniak, J. E. Cutler, Infect. Immun.,
1997, 65, 4100.
24.6 (CH3COO–). Found: m/z 886.3384 [M + H]+. C33H60NO26
.
Calculated: 886.3398.
18. Y. Han, J. E. Cutler, Infect. Immun., 1995, 63, 2714.
19. J. H. Lee, E. C. Jang, Y. Han, Arch. Pharm. Res., 2011,
34, 399.
This work was financially supported by the Russian
Science Foundation (Project No. 14ꢀ50ꢀ00126).
20. H. Xin, S. Dziadek, D. R. Bundle, J. E. Cutler, Proc. Nat.
Acad. Sci. USA, 2008, 105, 13526.
21. H. Xin, J. Cartmell, J. J. Bailey, S. Dziadek, D. R. Bundle,
J. E. Cutler, PLoS One, 2012, 7, e35106.
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in revised form October 9, 2015