Large-scale synthesis of 6-deoxy-6-sulfonatomethyl glycosides and their application for novel synthesis of a heparinoid pentasaccharide trisulfonic acid of anticoagulant activity

Article abstract of DOI:10.1016/j.carres.2014.02.012

Multigram-scale syntheses of three 6-deoxy-6-sulfonatomethyl α-glucosides were accomplished via reactions of the corresponding primary triflate derivatives with the lithiated ethyl methanesulfonate. Chemoselective glycosylation reactions of different 6-C-sulfonatomethyl glucoside donors were studied. The sulfonic acid-containing building blocks were utilised in a novel [2+3] block synthesis of a trisulfonic acid isoster of the anticoagulant pentasaccharide idraparinux.

Full text of DOI:10.1016/j.carres.2014.02.012

Carbohydrate Research 388 (2014) 19–29
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Large-scale synthesis of 6-deoxy-6-sulfonatomethyl glycosides and
their application for novel synthesis of a heparinoid pentasaccharide
trisulfonic acid of anticoagulant activity
Erika Mezo a,b, Mihály Herczeg b, Dániel Eszenyi a,b, Anikó Borbás a,
⇑
}
a Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, PO Box 70, H-4010 Debrecen, Hungary
b Department of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 January 2014
Received in revised form 5 February 2014
Accepted 9 February 2014
Available online 18 February 2014
Multigram-scale syntheses of three 6-deoxy-6-sulfonatomethyl
a-glucosides were accomplished via
reactions of the corresponding primary triflate derivatives with the lithiated ethyl methanesulfonate.
Chemoselective glycosylation reactions of different 6-C-sulfonatomethyl glucoside donors were studied.
The sulfonic acid-containing building blocks were utilised in a novel [2+3] block synthesis of a trisulfonic
acid isoster of the anticoagulant pentasaccharide idraparinux.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Anticoagulation
Pentasaccharide
Sulfonic acid
Chemoselective glycosylation
Aglycon transfer
Uronic acids
1. Introduction
factor Xa inhibitors.6–10 Two pentasaccharide sulfonic acids
(3 and 4) and the reference compound 2 have been prepared until
Heparin is a linear sulfated polysaccharide that plays a crucial
role in maintaining the haemostatic state of blood. Binding to anti-
thrombin, a serine protease inhibitor, accelerates its inhibitory
activity against thrombin and factor Xa in the blood-coagulation
cascade.1 The anticoagulant properties of heparin have made it
an invaluable drug for prevention and treatment of thromboembo-
lic diseases.2 However, heparin therapy is limited to intravenous
administration and may be accompanied by side effects
(inflammation, bleeding, liver toxicity and heparin induced throm-
bocytopenia) due to the polyanionic and heterogeneous nature of
the polysaccharide obtained from animal organs.3 To develop syn-
thetic heparinoid anticoagulants with fewer adverse effects and a
better pharmacokinetic profile the antithrombin-binding DEFGH
pentasaccharide fragment of heparin and many simplified
analogues have been prepared. These research efforts led to the
synthetic antithrombotic drug Arixtra (fondaparinux, 1)4 as well
as to the non-glycosaminoglycan derivative idraparinux (2),5 both
possessing selective factor Xa inhibitory activities (Fig. 1).
now.10,11 Evaluation of the inhibitory activities of pentasaccharides
2–4 towards the blood-coagulation proteinase factor-Xa revealed
that the disulfonate analogue 3 displayed higher activity than idra-
parinux, however, introduction of the third sulfonic-acid moiety
(4) resulted in a notable decrease in anti-Xa activity.10 To gain dee-
per insight into the structure–activity relationship of the anticoag-
ulant action of the sulfonic acid derivatives we decided to prepare
a series of heparinoid pentasaccharides by systematic replacement
of the sulfate esters with a sodium sulfonatomethyl moiety, and
we also aimed at preparing compounds 3 and 4 in sufficient
amounts for detailed STD NMR studies of their interactions with
antithrombin. As a beginning of this work, we present here the
multigram-scale syntheses of 6-sulfonatomethyl-containing
mono- and disaccharides, useful for modular syntheses of the
planned pentasaccharide sulfonic acids, and application of the
new building blocks in a novel, [2+3] synthesis of the pentasaccha-
ride trisulfonic acid 4.
Our group has been dealing with the synthesis of bioisosteric
sulfonic acid analogues of idraparinux to obtain novel selective
2. Results and discussion
Previously we utilised free-radical addition of bisulfite to exo-
methylene derivatives for introducing the sulfonatomethyl group
onto primary or secondary positions of saccharides (i.e. 5?7,
⇑
Corresponding author. Tel.: +36 52512900/22475; fax: +36 52512914.
E-mail address: borbas.aniko@pharm.unideb.hu (A. Borbás).
http://dx.doi.org/10.1016/j.carres.2014.02.012
0008-6215/Ó 2014 Elsevier Ltd. All rights reserved.

}
20
E. Mezo et al. / Carbohydrate Research 388 (2014) 19–29
D
E
F
G
H
SO3Et
SO3Et
-
R
OSO3
O
c
d
-
a or b
O
NAPO
HO
-
O
OSO3
O
HO
BnO
OSO3
O
NAPO
BnO
COO-
O
5
HO
BnO
-OOC
OH
O
-O3SHN
O
O
BnO
R = I
BnO
18
BnO
17
O
HO
O
HO
OMe
OMe
-O3SO
OMe
-O3SHN
15
16
OH
-O3SHN
OMe
-O3SO
R = OTf
O
1
R3
O
SO3Et
OAc
O
Ref. 18
R2
R1
MeO
MeO
AcO
AcO
COO-
O
O
-OOC
NAPO
BnO
OMe
O
O
O
MeO
O
AcO
O
-O3SO
O
BnO
MeO
SEt
-O3SO
-O3SO
SEt
MeO
-O3SO
OMe
19
20
O
MeO
e
-
SO3Et
2
3
4
R
R
R
1 = R2 = R3 = OSO3
OH
O
O
1 = R2 = CH2SO3-, R3 = OSO3
-
PMP
g
b, c
O
O
O
PMBO
BnO
PMBO
BnO
1 = R2 = R3 = CH2SO3
-
RO
RO
BnO
23
BnO
24
SEt
SEt
SEt
21
R = H
Figure 1. Synthetic pentasaccharides with selective factor Xa inhibitory activity:
fondaparinux (1), idraparinux (2) and its sulfonatomethyl analogues 3 and 4.
f
22
R = Bn
SO3Et
OH
O
OTf
O
h
b
c
MeO
MeO
MeO
MeO
O
MeO
MeO
19
Scheme 1).6,8,12 As this method, requiring a peroxybenzoate catal-
ysis, is incompatible with the oxidisable thio aglycone, the synthe-
sis of the C6-sulfonatomethyl thioglycosides was accomplished by
Horner–Wadsworth–Emmons (HWE) reaction (8?10, 11?14).10
However, multistep transformation of compound 5 via addition
of the sulfite radical anion to the unsaturated heptoside 6 afforded
the glycosyl acceptor building block 7 with only 30% overall yield.6
Synthesis of the thioglycoside building block 1410 from the corre-
sponding 6-hydroxy derivative 11 using HWE olefination13 pro-
ceeded also with unsatisfyingly low 26% overall yield due to the
unexpected elimination side reaction14 that occurred in the oxida-
tion step, either Swern or Dess–Martin oxidation methods were
applied (Scheme 1). Thence, we considered both prior approaches
to be inefficient for large-scale synthesis of the 6-sulfonatometh-
yl-containing D and H glycosyl units.
MeO
MeO
26
MeO
27
SEt
SEt
SEt
25
Scheme 2. Synthesis of the sulfonatomethyl-containing glucosyl building blocks by
nucleophilic substitution. Reagents and conditions: (a) PPh3, I2, imidazole, toluene,
75 °C, 30 min, 90%; (b) Tf2O, py, CH2Cl2, ꢀ10 °C, 30 min; (c) n-BuLi, THF, CH3SO3Et,
ꢀ78 °C to ꢀ20 °C, 2.5 h, 26% from 15, 88% via 16 over two steps, 33% from 23 over
two steps, 88% via 26 over two steps; (d) DDQ, CH2Cl2–H2O (9:1), rt, 30 min 86%; (e)
(1) NaOMe, MeOH; (2) 4-methoxybenzaldehyde dimethyl acetal, p-toluenesulfonic
acid, reflux, 74%; (f) NaH, BnBr, DMF, 0 °C to rt, 90%; (g) LiAlH4–AlCl3 (3:1), CH2Cl2–
Et2O, 0 °C, 30 min, 83%; (h) (1) NaOMe, MeOH, (2) TrCl, py, (3) NaH, MeI, DMF, 0 °C
to rt, (4) AcOH, 67% over 4 steps.
product 17 with 26% yield (Scheme 2). We attempted to enhance
the reactivity of the alkylating agent by adding 1,3-dimethyltetra-
hydropyrimidin-2(1H)-one (dimethylpropyleneurea, DMPU) to the
reaction mixture that, however, did not lead to higher yield of 17.
As reaction of a a-lithio sulfonate ester with a primary carbohy-
drate iodide15 or triflate16 appeared in the literature as the most
straightforward way to introduce a sulfonatomethyl ester moiety
to O-glycosides, we decided the exploitation of this facile method
for improved synthesis of the glycosyl acceptor building block 7.
The primary iodide 15 prepared from 517 showed low reactivity to-
wards the lithiated ethyl methanesulfonate providing the desired
Reaction of the a-lithio sulfonate ester with the more reactive tri-
flate derivative 16 proceeded with high efficacy,18 therefore this
transformation was applied in ten-gram-scale to produce the
sulfonate ester 17 in excellent 88%. Selective demasking of the
4-OH group by oxidative cleavage of the 2-naphthylmethyl (NAP)
ether with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)19
SO3Me
c) NaHSO3
t-Bu-perbenzoate
(60%)
d) Amberlite IR 120 H+;
CH2N2 (Et2O)
a) oxidation
(91%)
OH
O
O
O
HO
BnO
NAPO
BnO
NAPO
BnO
b) Wittig
BnO
BnO
BnO
reaction
(67%)
OMe
OMe
OMe
(82%)
7
5
6
NAP: (2-naphthyl)methyl
SO3Et
SO3Et
O
OH
O
H
a) 97%
H
f) Pd/C, H2
(75%)
PMBO
BnO
SPh
O
PMBO
PMBO
BnO
SPh
SPh
BnO
e) HWE
reaction
(72%)
OBn
OBn
OBn
8
9
10
PMB: p-methoxybenzyl
SO3Et
O
O
O
e) 70%
f) 73%
MeO
MeO
SPh
MeO
MeO
SPh
OH
OMe
(50%)
+
OMe
a)
O
12
14
MeO
SPh
MeO
OMe
O
O
11
SPh
MeO
OMe
(36%)
13
Scheme 1. Prior syntheses of the 6-deoxy-6-sulfonatomethyl building blocks 7,6 1010 and 14.10

}
E. Mezo et al. / Carbohydrate Research 388 (2014) 19–29
21
Table 1
Syntheses of the DE disaccharide building block 30 by chemoselective glycosylations
SO3Et
SO3Et
O
SO3Et
O
ONAP
O
ONAP
O
O
MeO
MeO
Table 1
CH2Cl2
ONAP
O
HO
MeO
MeO
Me SiO
3 AcO
MeO
MeO
SPh
+
MeO
+
SPh
SPh
+
AcO
O
OAc
OAc
MeO
MeO
R
SPh
AcO
30
OAc
14 R = β-SPh
29
14
α,β
31
Br2
28
27
α
R = -Br
α
R = -SEt
Entry
R (Compound)
Promoter system (equiv)
T °C
Reaction time
Yield of 30 (%)
Byproduct
1
2
3
4
5
6
b-SPh (14)
NIS (1.1)-AgOTf (0.2)
AgOTf (1.5)
NIS (1.5)-TfOH (0.1)
NIS (1.5)-TMSOTf (0.2)
NIS (1.1)-AgOTf (0.2)
NIS (1.1)-AgOTf (0.2)
ꢀ75 to ꢀ15
ꢀ30
1.5 h
1.5 h
3 h
2 h
45 min
45 min
11
21
31
44
66
89b
14
14
a
a
,b (9%)
,b (6%)
a-Br (28)
a-SEt (27)
a-SEt (27)
a-SEt (27)
a-SEt (27)
ꢀ75 to ꢀ50
ꢀ75 to ꢀ55
ꢀ75 to ꢀ55
ꢀ75 to ꢀ65
Degradation productsa
31 (8%)
The compounds are represented by bold numbers in Table 1.
a
Not isolated.
b
The reaction was carried out in 13 mmol scale to produce 6.0 g of disaccharide 30.
furnished the glycosyl acceptor building block 18, the ethyl ester
counterpart of the previously prepared 7, with 86% yield.
The nucleophilic displacement approach was successfully
adapted for the synthesis of thioglucoside 20, the building block
F, as it has been reported very recently.18 It is important to note
subsequent [1+4] coupling. Although the stepwise elongation
approach proved to be efficient, this time a [DE+FGH] route to 4
was envisioned for two reasons. First, the block synthesis precludes
excessive synthetic steps at the tetrasaccharide level, and second,
the sulfonatomethyl-containing DE donor can be utilised in the
syntheses of further pentasaccharide mono-, and disulfonic acids.
Therefore, we decided to prepare disaccharide 30 as the new
non-glucuronide type disaccharide donor. We assumed that either
compound 14, used in prior synthesis of 4,10 or the newly prepared
27, both being armed thioglycosides, could be applied for chemo-
selective glycosylations22 of the disarmed thioglycoside 299 (Ta-
ble 1). When 14 and 29 were reacted in the presence of NIS and
AgOTf significant amounts of degradation products were observed
and the desired disaccharide 30 was isolated in a disappointingly
low 11% yield (Table 1, entry 1). Interestingly, the donor was recov-
that application of
a-thioglycoside 19 as the starting material
was crucial, because anchimeric assistance of the anomeric group
in the displacement of the triflate was observed with b-glyco-
sides.18,20 In order to cut down the cost of the synthesis of this
orthogonally protected glucose unit, the (2-naphthyl)methyl
(NAP) masking group at position C-4 was changed to p-methoxy-
benzyl ether, because synthesis of the 4-O-PMB-protected deriva-
tive 23 via reductive cleavage of the 4,6-O-(4-methoxy)
benzylidene derivative 22 is significantly cheaper than that of
the 4-O-NAP congener. Accordingly, the
a-thioglucoside 19,
produced stereoselectively in forty-gram-scale by our recently
published photoinduced hydrothiolation method,21 was converted
into 23 by routine transformations, involving Zemplén deacetyla-
tion followed by acetalation (21), benzylation (22) and regioselec-
tive opening of the 4,6-acetal ring with LiAlH4–AlCl3.
Unfortunately, the 4-O-PMB protection turned out to be inappro-
priate for the following two-step nucleophilic procedure. Besides
formation of the corresponding triflate, degradation was also
observed upon treatment of 23 with triflic anhydride and the sub-
sequent reaction with a-lithio sulfonate ester provided the desired
sulfonate ester 24 in a low, 33% yield over two steps.
Large scale synthesis of the terminal 6-sulfonatomethyl-con-
taining building block 27 was also accomplished by the above
nucleophilic substitution method. The starting a-thioglucoside 19
ered as an unseparable alpha/beta mixture 14
a
,b (
a
:b ꢁ 5:1),
revealing that the yield of disaccharide formation was decreased
by a competitive S-glycosylation reaction in which thiophenyl
aglycon was transferred from acceptor 29 to donor 14 through
the intermediate sulfonium ion II (Scheme 3).23 On the basis of
the mechanism of the aglycon transfer depicted in Scheme 3, gly-
cosylation on the sulfur atom of product 30 is also possible.23g
Therefore, the yield of the process could also be decreased by
destroying the product of the O-glycosylation reaction. We at-
tempted to improve the synthesis of disaccharide 30 by condensa-
tion of acceptor 29 with donor 28 obtained from thioglucoside 14
by bromination. Although compound 30 was formed with higher
yield, aglycon transfer to the detriment of the O-glycoside forma-
tion was also observed (Table 1, entry 2). The further experiments
were carried out with the newly prepared donor 27 (Table 1, en-
tries 3–6). Due to the high reactivity of the ethylthio glycoside
27, the condensation reactions could be conducted at low temper-
atures in all runs, which was beneficial for the O-glycosylation
reaction. The NIS-TfOH mediated glycosylation gave disaccharide
30 in 31% yield; significant amounts of degradation products were
also formed, probably owing to the long reaction time (Table 1, en-
try 3). Decreasing the reaction time and changing the promoter
system from NIS-TfOH to NIS-TMSOTf resulted in a slightly higher
yield of 30, however, the new byproduct 31 appeared in the reac-
tion mixture due to silylation of the acceptor by the TMSOTf cata-
lyst (Table 1, entry 4). The NIS-AgOTf mediated condensation
(Table 1, entry 5) turned out to be superior affording disaccharide
30 with 66% yield. Carrying out the reaction in large scale at
slightly lower reaction temperature led to more efficient
was transformed into 25 via Zemplén deacetylation, tritylation,
methylation and detritylation. Triflation of the primary free hydro-
xyl of thioglucoside 25 took place quantitatively, and subsequent
nucleophilic displacement of the triflate moiety of 26 with the a-
lithiosulfonate ester afforded 27 in 88% yield for two steps
(Scheme 2). The latter two-step procedure was carried out in
40 mmol scale to provide almost 13 g of the 6-sulfonatomethyl-
containing D building block 27.
Having the 6C-sulfonatomethyl-glucoside building blocks in
large scale in our hands, we started the synthesis of the pentasac-
charide trisulfonic acid 4. Previously, compound 4 was gained via
construction of an
L-iduronic-acid-containing trisaccharide
disulfonic acid as an FGH acceptor, and its elongation with a
non-oxidised precursor of the glucuronic acid unit E followed by
post-glycosidation oxidation at a tetrasaccharide level, and a

}
22
E. Mezo et al. / Carbohydrate Research 388 (2014) 19–29
SO3Et
29
O-glycosylation
O
MeO
MeO
30
14 27
,
28
or
MeO
I
29
S-glycosylation
SO3Et
ONAP
O
O
b
MeO
MeO
ONAP
O
HO
HO
MeO
O
AcO
14α,β +
S
AcO
Ph
O
OAc
O
a
NAPO
HO
OAc
CH3
IV
III
AcO
II
Scheme 3. Formation of aglycon transfer product 14
a,b during syntheses of disaccharide 30.
SO3Et
O
SO3Et
O
SO3Et
MeO
O
O
d
c
O
OR
MeO
MeO
BnO
BnO
O
HO
+
BnO
OMe
O
O
BnO
R
O
BnO
OMe
OAc
O
BnO
O
OMe
OAc
35 R = CH2OH
36
OAc
OH
e
O
Ph
32 R = Ac
33 R = C(NH)CCl3
18
34
Ph
a,b
R = COOMe
Scheme 4. Synthesis of the GH disaccharide acceptor 36. Reagents and conditions: (a) BnNH2, THF, rt, 5 h, 70%; (b) Cl3CCN, DBU, CH2Cl2, 0 °C, 1 h, 94%; (c) TMSOTf, CH2Cl2, 4 Å
MS, ꢀ40 °C to ꢀ15 °C, 1 h, 82%; (d) 70% aq TFA, CH2Cl2, 0 °C to rt, 5 h, 87%; (e) (1) TEMPO, BAIB, CH2Cl2, H2O, rt, 3 h, (2) CH2N2ꢂEt2O, THF, 24 h, 70%.
O-glycosylation to produce 6.0 g (89%) of the desired DE building
block (Table 1, entry 6).
During previous synthesis of pentasaccharides 3 and 4 the com-
mon FGH trisaccharide acceptor bearing a 6-sulfonatomethyl moi-
The 6-position of the penultimate glucose unit was unmasked by
oxidative de-O-(2-napthyl)methylation to produce 40 which was
transformed to 41 by TEMPO-(BAIB) oxidation24 followed by treat-
ment with ethereal diazomethane. The fully protected 41 was an
intermediate in the previous synthesis route of the pentasaccha-
ride trisulfonic acid 4. Transformation of 41 into 4, involving
deprotection steps and introduction of the methyl ether and sul-
fate ester functions were carried out according to the published
procedure.10
ety at units F and H has been built up from an L-iduronic acid and
two monosaccharide sulfonic acids via a [FG+H] coupling.10 How-
ever, that route had the drawback that conversion of the uronic-
and sulfonic-acid-containing FG disaccharide into a donor pro-
ceeded with low yield. To avoid this inefficient transformation,
now the sequence of the couplings was changed and the GH disac-
charide was prepared first.
For the synthesis of the GH unit 36, the L
-idose derivative 329
3. Conclusions
was converted to donor 33 by selective anomeric deacetylation
and subsequent trichloroacetimidoylation of the obtained
hemiacetal (Scheme 4). Condensation of 33 and acceptor 18 in
the presence of TMSOTf led to the stereoselective formation of
The straightforward nucleophilic approach provided easy access
to three 6-deoxy-6 sulfonatomethyl
a-glucosides from the corre-
sponding 6-OH derivatives in multigram scale. The low yields ob-
served with the 6-deoxy-6-iodo glucoside 15 and the 4-O-PMB
protected derivative 23 revealed that the nature of both the leaving
group at C-6 position and the protecting group at C-4 position is
crucial for the efficacy of the nucleophilic procedure.
During synthesis of disaccharide 30 by chemoselective glycosyl-
ation, the newly prepared ethyl 6-deoxy-6-C-(ethyl sulfonatom-
ethyl)-2,3,4-tri-O-methyl-1-thio-a-D-glucopyranoside 27 could be
applied efficiently as an armed donor. The failed chemoselective
glycosylations with the phenylthio glucoside 14 and glycosyl bro-
mide 28 can be explained by their lower reactivity. Activation of 14
and 28 required a higher activation temperature than that of 27, at
which temperature the chemoselectivity was eroded.
the a-linked disaccharide 34. As application of this building block
in future syntheses of pentasaccharide mono-, and disulfonic acids
was also planned, it was prepared in 10 mmol scale (6.6 g).
Removal of the benzylidene protecting group of the fully protected
34 by acidic hydrolysis afforded diol 35 which was subjected
to (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)-[bis(acetoxy)
iodo]benzene (BAIB) mediated selective oxidation24 followed by
treatment with ethereal diazomethane to yield the iduronide
acceptor 36 in 61% over the last three steps.
Next, NIS and TfOH promoted glycosylation of 36 with the eth-
ylthio glycoside donor 2018 proceeded with full
a-selectivity to
provide the trisaccharide disulfonic acid 37 with excellent 92%
yield (Scheme 5). Liberation of the 4-OH group of the terminal glu-
cose unit of 37 was accomplished by oxidative removal of the NAP-
group using DDQ as a reagent,19 furnishing the trisaccharide accep-
tor 38 in 79% yield. Condensation of 38 and the disaccharide donor
30 upon NIS-AgOTf activation afforded pentasaccharide 39, with
the required b-linkage between units E and F, in a yield of 65%.
Synthesis of the anticoagulant pentasaccharide trisulfonic acid
4 was accomplished via a new block-synthetic route involving an
improved synthesis of the
L-iduronic-acid-containing FGH trisac-
charide acceptor 38, its condensation with the disaccharide donor
30 and formation of the D-glucuronide residue at a pentasaccharide
level.

}
E. Mezo et al. / Carbohydrate Research 388 (2014) 19–29
23
SO3Me
O
were carried out in the positive reflectron mode using a BIFLEX
III mass spectrometer (Bruker, Germany) equipped with delayed-
ion extraction. The matrix solution was a saturated 2,4,6-trihy-
droxy-acetophenone (THAP) solution in MeCN. Elemental analyses
(C, H, S) were performed using an Elementar Vario MicroCube
instrument.
SO3Et
O
a
OMe
O
MeOOC
O
BnO
20 36
+
BnO
RO
BnO
OMe
AcO
BnO
O
37
R = NAP
b
38 R = H
4.2. General method A for introduction of the
trifluoromethanesulfonyl group (16, 24, 26)
30
+
c
SO3Et
SO3Et
O
To a solution of the appropriate alcohol (1 mmol) in dry CH2Cl2
(2 mL), dry pyridine (0.25 mL) was added. The stirred mixture was
cooled to ꢀ10 °C under argon and trifluoromethanesulfonic anhy-
dride (0.24 mL, 1.4 mmol) dissolved in CH2Cl2 (0.7 mL) was added.
After the complete disappearance of the starting material (30 min),
the reaction mixture was diluted with CH2Cl2 (25 mL) and washed
successively with H2O (15 mL), 1 M HCl (15 mL), H2O (15 mL), satd
aq NaHCO3 (15 mL) and H2O (15 mL). The organic phase was dried
and concentrated at 30 °C. The crude product was used for further
reaction without purification.
O
SO3Et
MeO
MeO
O
OMe
O
ONAP
O
MeOOC
O
BnO
MeO
O
BnO
O
OMe
BnO
AcO
OAc
BnO
O
AcO
39
SO3Et
d
SO3Et
O
MeO
MeO
SO3Et
O
O
OMe
O
OH
O
MeOOC
BnO
MeO
O
O
BnO
O
OMe
AcO
BnO
OAc
BnO
O
40
AcO
4.3. General method B for introduction of ethyl
sulfonatomethyl group from the appropriate triflate (17, 24, 27)
e
SO3Et
O
SO3Et
O
A solution of methanesulfonic acid ethyl ester (0.2 mL, 2 mmol)
in dry THF (5 mL) was cooled to ꢀ80 °C under argon and 2.5 M n-
BuLi (0.8 mL, 2 mmol) in n-hexane was added. After stirring at
ꢀ78 °C for 30 min, a solution of the corresponding triflate (1 mmol)
in dry THF (2.5 mL) was added dropwise. The reaction mixture was
stirred for 1.5 h while its temperature was raised to ꢀ20 °C. The
stirred mixture was quenched by the addition of satd aq NH4Cl
solution (10 mL) and diluted with EtOAc (30 mL). The organic
phase was washed successively with satd aq NH4Cl solution
(10 mL), H2O (10 mL), satd aq NaCl solution (10 mL), dried and
concentrated.
MeO
MeO
SO3Et
O
OMe
O
COOMe
O
MeOOC
O
BnO
MeO
O
O
BnO
OMe
AcO
BnO
OAc
BnO
O
AcO
41
Ref. 10
4
Scheme 5. Construction of the pentasaccharide trisulfonic acid 24 by 3+2 coupling
and post-glycosidation oxidation of the penultimate glucose unit into glucuronic
acid. Reagents and conditions: (a) NIS, TfOH, CH2Cl2, THF, 4 Å MS, ꢀ60 °C to ꢀ50 °C,
3 h, 92%; (b) DDQ, CH2Cl2–H2O (9:1), rt, 30 min, 79%; (c) NIS, AgOTf, CH2Cl2, 4 Å MS,
ꢀ20 °C to rt, 3 h (65%); (d) DDQ, CH2Cl2–H2O (9:1), rt, 45 min (84%); (e) (1) TEMPO,
BAIB, CH2Cl2, H2O, rt 5 h, (2) CH2N2ꢂEt2O, THF (62%).
4.4. General method C for removal of the (2-naphthyl)methyl
ether group (18, 38 and 40)
To a vigorously stirred solution of starting material (1 mmol) in
CH2Cl2/H2O (9:1, 10 mL) DDQ (1.5 mmol) was added. The reaction
mixture was stirred at room temperature for 30 min (18, 38) and
45 min (40), diluted with CH2Cl2 (30 mL), washed successively
with satd aq NaHCO3 solution (15 mL) and H2O (15 mL). The organ-
ic phase was dried and concentrated. The crude product was puri-
fied by column chromatography.
NMR and ITC studies of the interaction of compound 4 with
antithrombin, as well as utilisation of the sulfonatomethyl-
containing mono- and disaccharide building blocks in the synthe-
ses of further sulfonic acid isosters of idraparinux are in progress.
4. Experimental
4.1. General Information
4.5. General method D for TEMPO-BAIB oxidation and
subsequent esterification (36, 41)
Optical rotations were measured at room temperature with a
Perkin–Elmer 241 automatic polarimeter. TLC was performed on
Kieselgel 60 F254 (Merck) with detection by immersing into 5% eth-
anolic sulfuric acid solution followed by heating. Column chroma-
tography was performed on Silica gel 60 (Merck 0.063–0.200 mm).
Organic solutions were dried over MgSO4, and concentrated in vac-
uum. The 1H NMR (360 and 400 MHz) and 13C NMR (90.54 and
100.28 MHz) spectra were recorded with Bruker DRX-360 and
DRX-400 spectrometers at 25 °C. Chemical shifts are referenced
to Me4Si or DSS (0.00 ppm for 1H) and to the solvent signals (CDCl3:
77.00 ppm for 13C). The 1H and 13C NMR assignments have been
established from 1D NMR spectra and for compounds 30, 36 and
39 the proton-signal assignments were supported by analysis of
two-dimensional 1H–1H correlation spectra (COSY), as well as the
carbon-signal assignments by two-dimensional 13C–1H correlation
maps (HSQC). IR spectra were recorded on a Perkin–Elmer 16 PC
FTIR spectrometer. MALDI-TOF MS analyses of the compounds
To a vigorously stirred solution of the appropriate alcohol
(1 mmol) in CH2Cl2 (25 mL) and H2O (12.5 mL) were added TEMPO
(0.18 mmol) and BAIB (4 mmol), stirred for 3 h (36) and 5 h (41) at
room temperature. The reaction mixture was quenched by the
addition of 10% aq Na2S2O3 solution (20 mL). The mixture was then
extracted twice with CH2Cl2 (10 mL), and the combined organic
layers were dried, and concentrated. The crude uronic acid was dis-
solved in THF (3 mL) and treated with ethereal diazomethane at
0 °C. After complete disappearance of the uronic acid, the mixture
was concentrated.
4.6. Methyl 2,3-di-O-benzyl-6-deoxy-6-iodo-4-O-(20-
naphthyl)methyl-a-D-glucopyranoside (15)
Triphenyl phosphine (765 mg, 2.9 mmol), imidazole (397 mg,
5.8 mmol) and iodine (690 mg, 2.7 mmol) were added to the

}
E. Mezo et al. / Carbohydrate Research 388 (2014) 19–29
24
solution of 5 (1 g, 1.9 mmol) in dry toluene (16 mL). The stirred mix-
ture was heated and refluxed at 75 °C. After 30 min the reaction was
quenched by addition of a solution of NaHCO3 (650 mg, 7.7 mmol) in
H2O (8 mL) and was stirred for 5 min. Satd aq Na2S2O3 solution
(15 mL) was added to the stirred mixture and it was diluted with
EtOAc (50 mL). The organic phase was washed with H2O
(2 ꢃ 25 mL), dried and concentrated. Et2O (15 mL) was added to
the residue and the solution was placed in the refrigerator for 1 h.
The precipitated Ph3PO was filtered off and the filtrate was concen-
trated. The residue was purified by column chromatography to give
15 (1.09 g, 90%) as white crystals. Mp 55–59 °C; Rf 0.46 (8:2 n-hex-
by column chromatography (6:4 n-hexane–EtOAc) to give 18
(259 mg, 86%) as a colourless oil. Rf 0.34 (6:4 n-hexane/EtOAc);
½
a 2D5 +15.21 (c 0.72, CHCl3); 1H NMR (360 MHz, CDCl3) d 7.37–
ꢄ
7.23 (m, 10H, arom), 4.98 (d, J = 11.4 Hz, 1H, PhCH2), 4.74–4.69
(m, 2H, PhCH2), 4.62 (d, J = 12.1 Hz, 1H, PhCH2), 4.54 (d,
J = 3.4 Hz, 1H, H-1), 4.23 (q, J = 7.1 Hz, 2H, SO3CH2CH3), 3.72 (t,
J = 9.2 Hz, 1H, H-4), 3.57 (m, 1H, H-5), 3.45 (dd, J = 9.6, J = 3.4 Hz,
1H, H-2), 3.32 (s, 3H, OCH3), 3.29–3.15 (m, 2H, H-3, H-7a), 3.09
(m, 1H, H-7b), 2.72 (s, 1H, OH), 2.40–2.28 (m, 1H, H-6a), 1.95–
1.84 (m, 1H, H-6b), 1.34 (t, J = 7.1 Hz, 3H, SO3CH2CH3) ppm; 13C
NMR (90 MHz, CDCl3) d 138.6, 137.9 (2 ꢃ Cq arom), 128.4, 128.4,
127.9, 127.8, 127.7 (10C, arom), 97.9 (C-1), 81.0, 79.6, 73.4, 68.5
(C-2, C-3, C-4, C-5), 75.2, 72.9 (2 ꢃ PhCH2), 66.1 (SO3CH2CH3),
55.2 (OCH3), 46.5 (C-7), 25.9 (C-6), 15.0 (SO3CH2CH3) ppm; Anal.
Calcd for C99H118O27 (480.57): C, 59.98; H, 6.71; O, 26.63; S, 6.67.
Found: C, 60.06; H, 6.81; S, 6.55.
ane/EtOAc); ½a 2D5
ꢄ
+12.8 (c 0.17, CHCl3); 1H NMR (360 MHz, CDCl3)
d 7.84–7.76 (m, 3H, arom), 7.69 (s, 1H, arom), 7.50–7.43 (m, 2H,
arom), 7.41–7.25 (m, 11H, arom), 5.08 (d, J = 11.2 Hz, 1H, ArCH2),
5.02 (d, J = 10.9 Hz, 1H, ArCH2), 4.87–4.77 (m, 3H, H-1, 2 ꢃ ArCH2),
4.67 (d, J = 12.1 Hz, 1H, ArCH2), 4.62 (d, J = 3.6 Hz, 1H, H-1), 4.08–
4.02 (m, 1H) 3.56 (dd, J2,3 = 9.6, J1,2 = 3.6 Hz, 1H, H-2), 3.53–3.44
(m, 2H), 3.43–3.35 (m, 1H), 3.42 (s, 3H, OCH3), 3.32–3.28 (m, 1H),
ppm; 13C NMR (90 MHz, CDCl3) d 138.7, 138.2, 135.6, 133.4, 133.1
(5 ꢃ Cq arom), 128.6, 128.6, 128.4, 128.2, 128.1, 127.8, 126.8,
126.3, 126.1, 125.9 (17C, arom), 98.2 (C-1), 81.7, 81.6, 80.3, 69.42
(C-2, C-3, C-4, C-5) 75.9, 75.5, 73.5 (3 ꢃ ArCH2), 55.7 (OCH3), 7.9
(C-6) ppm; Anal. Calcd for C99H118O27 (484.32): C, 52.08; H, 5.20; I,
26.20; O, 16.52. Found: C, 51.92; H, 5.31.
4.10. Ethyl 4,6-O-(4-methoxybenzylidene)-1-thio-a-D-
glucopyranoside (21)
To the solution of compound 19 (22 g, 56.2 mmol) in MeOH
(100 mL) was added NaOMe (250 mg, 4.6 mmol) and the reaction
mixture was stirred for 1 h at room temperature. The reaction
was quenched by addition of Amberlite IR-120 (H+) resin. The
crude product (11.9 g) was dissolved in DMF (30 mL) and 4-
methoxybenzaldehyde dimethyl acetal (10.4 mL, 58.9 mmol) and
p-toluenesulfonic acid (149 mg, 0.87 mmol) were added. After 4 h
stirring at 50 °C on 100 mbar pressure, the mixture was concen-
trated. The residue was dissolved in CH2Cl2 (150 mL), washed suc-
cessively with satd aq NaHCO3 solution (30 mL), H2O (2 ꢃ 30 mL),
dried and concentrated. The residue was purified by crystallisation
from CH2Cl2 (40 mL) and n-hexane (80 mL) to give 21 (14.24 g, 74%
for 2 steps) as white crystals.
4.7. Methyl 2,3-di-O-benzyl-4-O-(20-naphthyl)methyl-6-O-
(trifluoromethanesulfonyl)-a-D-glucopyranoside (16)
Compound 5 (9.5 g, 18.5 mmol) was converted to 16 according
to general method A. The crude product was used for further reac-
tion without purification. Rf 0.78 (6:4 n-hexane/EtOAc).
4.8. Methyl 2,3-di-O-benzyl-6-deoxy-6-C-(ethyl
sulfonatomethyl)-4-O-(20-naphthyl)methyl-
a
-D
-
Mp 120–124 °C; Rf 0.45 (6:4 n-hexane/EtOAc); ½a D25
ꢄ
+134.5 (c
glucopyranoside (17)18
0.07, CHCl3); IR mmax (KBr) 3418, 2969, 2927, 1681, 1601, 1517,
1457, 1426, 1373, 1302, 1254, 1170, 1108, 1076, 1036, 979,
1036, 979, 830, 787, 634, 607 cmꢀ1 1H NMR (360 MHz, CDCl3) d
;
4.8.1. Starting from the appropriate 6-deoxy-6-iodide derivative
15
7.42 (d, J = 8.5 Hz, 2H, arom), 6.89 (d, J = 8.5 Hz, 2H, arom), 5.49
(s, 1H, ArCH), 5.39 (d, J = 5.3 Hz, 1H, H-1), 4.30–4.14 (m, 2H),
4.02–3.69 (m, 4H), 3.80 (s, 3H, OCH3), 3.48 (t, J = 9.2 Hz, 1H),
2.72–2.66 (m, 2H, SCH2CH3), 1.33 (t, J = 7.4 Hz, 3H, SCH2CH3,)
ppm; 13C NMR (90 MHz, CDCl3) d 160.0, 129.9 (2 ꢃ Cq arom),
127.8, 113.9, (2C, arom), 101.3 (PMPCH), 84.3 (C-1), 81.3, 78.8,
78.7, 62.8 (C-2, C-3, C-4, C-5), 75.2, 72.9, (2 ꢃ CH2Ph), 68.9 (C-6),
55.5 (OCH3), 26.1 (SCH2CH3), 15.2 (SCH2CH3) ppm; Anal. Calcd for
A
solution of methanesulfonic acid ethyl ester (325
l
L,
1,3-dimethyltetrahydropyrimidin-2(1H)-one
lL, 3.1 mmol) in dry THF (10 mL) was cooled to
3.1 mmol)
(DMPU) (375
and
ꢀ80 °C under argon and 2.5 M n-BuLi (1.25 mL, 3.1 mmol) in n-
hexane was added. After stirring at ꢀ78 °C for 30 min, a solution
of compound 15 (970 mg, 1.55 mmol) in dry THF (5 mL) was added
dropwise. The reaction mixture was stirred for 1.5 h while its tem-
perature was raised to ꢀ20 °C. The stirred mixture was quenched
by the addition of satd aq NH4Cl solution (15 mL) and diluted with
EtOAc (50 mL). The organic phase was washed successively with
satd aq NH4Cl solution (15 mL), H2O (15 mL), satd aq NaCl solution
(15 mL), dried and concentrated. The crude product was purified
by column chromatography (7:3 n-hexane–EtOAc) to give 17
(253 mg, 26%) as a colourless oil.
C99H118O27 (342.41): C, 56.12; H, 6.48; O, 28.04; S, 9.36. Found:
C, 56.17; H, 6.39; S, 9.42.
4.11. Ethyl 2,3-di-O-benzyl-4,6-O-(4-methoxybenzylidene)-1-
thio-a-D-glucopyranoside (22)
The solution of 21 (14 g, 40.9 mmol) in dry DMF was cooled to
0 °C under argon and 60% NaH (4.9 g, 0.12 mol) was added in por-
tions to the reaction. After 30 min benzyl bromide (11.7 mL,
98 mmol) was added to the mixture and stirred for 12 h. The reac-
tion was quenched with addition of MeOH and concentrated in va-
cuo. The residue was dissolved with CH2Cl2 (300 mL), washed
successively with satd aq NaHCO3 (100 mL) and H2O
(2 ꢃ 100 mL). The organic phase was dried and concentrated. The
residue was purified by crystallisation from EtOAc (25 mL) and n-
hexane (50 mL) to give 22 (19.24 g, 90%) as white crystals. Mp
4.8.2. Starting from the appropriate 6-O-triflate derivative 16
Compound 16 (9.7 mg, 15 mmol) was converted to 17 according
to general method B. The crude product was purified by column
chromatography (7:3 n-hexane–EtOAc) to give 17 (10.27 g, 88%)
as a colourless oil. The analytical data of compound 17 are consis-
tent with those are given in the literature.18
4.9. Methyl 2,3-di-O-benzyl-6-deoxy-6-C-(ethyl
86–91 °C; Rf 0.46 (8:2 n-hexane/EtOAc); ½a D25
ꢄ
+81.2 (c 0.12, CHCl3);
IR mmax (KBr) 3442, 3065, 3033, 2898, 2864, 1614, 1517, 1496,
sulfonatomethyl)-
a-
D-glucopyranoside (18)
1455, 1423, 1367, 1303, 1252, 1214, 1171, 1091, 1031, 959, 931,
Compound 17 (390 mg, 0.63 mmol) was converted to 18
according to general method C. The crude product was purified
822 cmꢀ1 1H NMR (360 MHz, CDCl3) d 7.44–7.21 (m, 12H, arom),
;
6.89 (d, J = 8.7 Hz, 2H, arom), 5.50 (s, 1H, PMPCH), 5.37 (d,

}
E. Mezo et al. / Carbohydrate Research 388 (2014) 19–29
25
J = 5.5 Hz, 1H, H-1), 4.88–4.67 (m, 4H, PhCH2), 4.31–4.17 (m, 2H),
3.91 (t, J = 9.1 Hz, 1H), 3.84–3.80 (m, 1H), 3.78 (s, 3H, OCH3), 3.71
(t, J = 9.7 Hz, 1H), 3.59 (t, J = 9.1 Hz, 1H), 2.61–2.47 (m, 2H, SCH2-
CH3), 1.27 (t, J = 7.4 Hz, 3H, SCH2CH3) ppm; 13C NMR (90 MHz,
CDCl3) d 160.0, 138.8, 137.9, 130.0 (4 ꢃ Cq arom), 128.4, 128.3,
128.1, 128.1, 128.0, 127.9, 127.6, 127.4, 113.6, (14C, arom), 101.3
(PMPCH), 84.1 (C-1), 81.9, 79.0, 78.9, 62.9 (C-2, C-3, C-4, C-5),
75.3, 72.8, (2 ꢃ CH2Ph), 68.9 (C-6), 55.3 (OCH3), 23.8 (SCH2CH3),
14.9 (SCH2CH3) ppm; Anal. Calcd for C99H118O27 (522.65): C,
68.94; H, 6.56; O, 18.37; S, 6.14. Found: C, 68.29; H, 6.52; S, 5.80.
(OCH3), 46.9 (C-7), 25.8 (C-6), 23.8 (SCH2CH3), 15.1 (SO3CH2CH3),
14.7 (SCH2CH3), ppm; Anal. Calcd for C99H118O27 (630.81): C,
62.83; H, 6.71; O, 20.29; S, 10.17. Found: C, 62.89; H, 6.62; S, 10.24.
4.14. Ethyl 2,3,4-tri-O-methyl-1-thio-a-D-glucopyranoside (25)
To a solution of 19 (40 g, 0.1 mol) in MeOH (200 mL) a catalytic
amount of NaOMe was added. After 2 h stirring, the mixture was
neutralised with Amberlite IR-120 (H+) to give the corresponding
tetrahydroxy derivative (22.8 g). To a solution of the crude product
(22.8 g) in pyridine (100 mL) TrCl (57 g, 0.2 mol) was added. The
mixture was stirred for 48 h at room temperature. After comple-
tion of the reaction, the mixture was concentrated in vacuo to give
the 6-O-trityl derivative (47.5 g) To the solution of the residue in
DMF (2 ꢃ 400 mL) at 0 °C were successively added 60% NaH
(40.77 g, 1.02 mol) and MeI (151 mL, 0.82 mol). After 1 h stirring
at this temperature, MeOH (2 ꢃ 45 mL) was added. The reaction
mixture was stirred for 15 min, and the solvents were evaporated.
A solution of the crude 2,3,4-tri-O-methyl-6-O-triphenylmethyl
derivative (56.2 g) in AcOH (80%, 400 mL) was stirred for 1 h at
30 °C. The mixture was then concentrated in vacuo and the residue
was purified by column chromatography to give 25 (18.15 g, 67%
4.12. Ethyl 2,3-di-O-benzyl-4-O-(4-methoxybenzyl)-1-thio-a-D-
glucopyranoside (23)
To a stirred solution of 22 (17 g, 32.5 mmol) in a mixture of dry
CH2Cl2 (300 mL) and dry Et2O (130 mL) LiAlH4 (5.55 g, 0.15 mol)
and a solution of AlCl3 (6.5 g, 48.8 mmol) in dry Et2O (100 mL)
were successively added under argon at 0 °C. When the TLC (7:3
n-hexane/EtOAc) indicated complete disappearance of the starting
material (30 min), the reaction mixture was cooled in an ice-bath,
the excess reagent decomposed by careful addition of EtOAc
(200 mL) and H2O (50 mL), and the mixture stirred for an addi-
tional 10 min. The obtained heterogeneous mixture containing a fi-
nely precipitated solid was filtered through a pad of Celite, and the
filter cake was washed with EtOAc (2 ꢃ 30 mL). The combined fil-
trates were transferred into a separating funnel and diluted with
EtOAc (50 mL), the layers were separated and the organic phase
was washed with H2O (3 ꢃ 50 mL), dried and concentrated. The
residue was purified by column chromatography (65:35 n-hex-
ane/EtOAc) to give 23 (14.18 g, 83%), as white crystals. Mp 47–
for 4 steps). Mp 38–41 °C; ½a D25
ꢄ
+270.21 (c 0.523, CHCl3); Rf 0.23
(98:2 CH2Cl2/CH3OH); Anal. Calcd for C88H110O27 (266.35): C,
49.60; H, 8.33; O, 30.03; S, 12.04. Found: C, 49.84; H, 8.11; S, 11.87.
4.15. Ethyl 2,3,4-tri-O-methyl-6-O-(trifluoromethanesulfonyl)-
1-thio-a-D-glucopyranoside (26)
Compound 25 (10.5 g, 39.5 mmol) was converted to 26 accord-
ing to general method A. The crude product (13.59 g) was used for
further reaction without purification. Rf 0.64 (6:4 n-hexane/EtOAc).
49 °C; Rf 0.33 (7:3 n-hexane/EtOAc); ½a D25
ꢄ
+112.1 (c 0.39, CHCl3);
NMR (360 MHz, CDCl3) d 7.40–7.24 (m, 10H, arom), 7.20 (d,
J = 8.6 Hz, 2H, arom), 6.84 (d, J = 8.6 Hz, 2H, arom), 5.34 (d,
J = 5.4 Hz, 1H, H-1), 4.95 (d, J = 10.9 Hz, 1H, ArCH2), 4.79 (dd,
J = 10.8, 2.7 Hz, 2H, ArCH2), 4.72 (d, J = 11.8 Hz, 1H, ArCH2), 4.64
(d, J = 11.7 Hz, 1H, ArCH2), 4.57 (d, J = 10.7 Hz, 1H, ArCH2), 4.07–
4.03 (m, 1H), 3.87 (t, J = 9.2 Hz, 1H), 3.80–3.66 (m, 3H), 3.76 (s,
3H, OCH3), 3.51 (t, J = 9.4 Hz, 1H), 2.60–2.42 (m, 2H, SCH2CH3),
1.76–1.68 (m, 1H, OH), 1.26 (t, J = 7.4 Hz, 3H, SCH2CH3) ppm; 13C
NMR (90 MHz, CDCl3) d 159.4, 138.9, 137.9, 130.4 (4 ꢃ Cq arom),
129.7, 128.5, 128.4, 128.1, 128.0, 127.9, 127.7, 114.0 (14C, arom),
83.1 (C-1), 82.5, 79.8, 77.0, 71.2 (C-2, C-3, C-4, C-5), 75.7, 74.7,
72.4 (3 ꢃ ArCH2), 62.0 (C-6), 55.3 (OCH3), 23.8 (SCH2CH3), 14.8
(SCH2CH3) ppm; Anal. Calcd for C99H118O27 (524.67): C, 68.68; H,
6.92; O, 18.30; S, 6.11. Found: C, 68.82; H, 6.77; S, 6.21.
4.16. Ethyl 6-deoxy-6-C-(ethyl sulfonatomethyl)-2,3,4-tri-O-
methyl-1-thio-a-D-glucopyranoside (27)
Compound 26 (13.59 g, 39.5 mmol) was converted to 27 accord-
ing to general method B. The crude product was purified by col-
umn chromatography to give 27 (12.87 g, 88% for two steps) as a
light brown oil; Rf 0.50 (6:4 n-hexane/EtOAc); ½a D25
ꢄ
+139.49 (c
3.27, CHCl3); IR mmax (KBr): 3635, 2936, 2835, 1445, 1352, 1174,
1089, 1006, 974, 920, 814, 643, 574, 529, 472 cmꢀ1
;
1H NMR
(360 MHz, CDCl3): 5.40 (d, J = 5.4 Hz 1H, H-1), 4.31 (q,
d
J = 7.1 Hz, 2H, SO3CH2CH3), 3.97–3.91 (m, 1H, J = 5.5 Hz, 9.6 Hz,
H-5), 3.59, 3.56, 3.48 (3 ꢃ s, 9H, 3 ꢃ OCH3), 3.45–3.41 (m, 1H, H-
2), 3.34–3.24 (m, 2H, H-4, H-7a), 3.13–3.05 (m, 1H, H-7b), 2.83
(t, 1H, J = 9.5 Hz, 8.8 Hz, H-3), 2.56–2.50 (m, 2H; SCH2CH3), 2.42–
2.32 (m, 1H; H-6a), 2.02–1.91 (m, 1H, H-6b), 1.42 (t, J = 7.1 Hz,
4.13. Ethyl 2,3-di-O-benzyl-6-deoxy-6-C-(ethyl
sulfonatomethyl)-4-O-(4-methoxybenzyl)-1-thio-a-D-
glucopyranoside (24)
3H; SO3CH2CH3), 1.29 (t, J = 7.4 Hz, 3H; SCH2CH3),13
C NMR
(90 MHz, CDCl3): d 83.5 (C-1), 83.2, 82.4, 81.3, 68.5 (C-2, C-3, C-4,
C-5), 66.0 (SO3CH2CH3), 60.6, 60.5, 57.9 (3 ꢃ OCH3), 46.9 (C-7),
25.8 (C-6), 23.8 (SCH2CH3), 14.9 (SO3CH2CH3), 14.5 (SCH2CH3)
ppm; MALDI-TOF (positive ion): m/z calcd for [M+Na]+ 395.12.
Found: 395.08. Anal. Calcd for C88H110O27 (372.50): C, 45.14; H,
7.58; O, 30.07; S, 17.22. Found: C, 44.97; H, 7.75; S, 17.43.
Compound 23 (14 g, 1.55 mmol) was converted to the corre-
sponding triflate according to general method A. The crude triflate
(17.3 g) was converted to 24 according to general method B. The
crude product was purified by column chromatography to give
24 (5.6 g, 33%) as a colourless oil. Rf 0.59 (7:3 n-hexane/EtOAc);
½
a 2D5 +95.17 (c 0.13, CHCl3); 1H NMR (360 MHz, CDCl3) d 7.40–
ꢄ
7.20 (m, 12H, arom), 6.85 (d, J = 8.6 Hz, 2H, arom), 5.28 (d,
J = 5.0 Hz, 1H, H-1), 4.95 (d, 1H, ArCH2), 4.83–4.61 (m, 4H, ArCH2),
4.54 (d, J = 10.7 Hz, 1H, ArCH2), 4.27–4.17 (m, 2H, SO3CH2CH3),
4.06–4.00 (m, 1H), 3.83–3.73 (m, 2H), 3.75 (s, 3H, OCH3), 3.19–
2.95 (m, 3H), 2.53–2.42 (m, 2H, SCH2CH3), 2.34–2.25 (m, 1H, H-
6a), 1.93–1.80 (m, 1H, H-6b), 1.34, 1.26 (2 ꢃ t, 6H, SCH2CH3, SO3-
CH2CH3) ppm; 13C NMR (90 MHz, CDCl3) d 159.4, 138.6, 137.7,
129.9 (4 ꢃ Cq arom), 129.8, 128.4, 128.4, 128.0, 127.9, 127.9,
127.6, 113.9 (14C, arom), 82.9 (C-1), 82.2, 80.3, 79.6, 68.7 (C-2, C-
3, C-4, C-5), 75.6, 74.7, 72.3 (3 ꢃ ArCH2), 66.0 (SO3CH2CH3), 55.2
4.17. Phenyl [6-deoxy-6-C-(ethyl sulfonatomethyl)-2,3,4-tri-O-
methyl-
naphthyl)methyl-1-thio-b-
deoxy-6-C-(ethyl sulfonatomethyl)-2,3,4-tri-O-methyl-1-thio-
-glucopyranoside (14
,b) and phenyl 2,3-di-O-acetyl-6-O-(20-
a-D
-glucopyranosyl]-(1?4)-2,3-di-O-acetyl-6-O-(20-
D-glucopyranoside (30), phenyl 6-
a
-
D
a
naphthyl)methyl-4-O-trimethylsilyl-1-thio-a-D-
glucopyranoside (31)
Method I (entry 1): To a solution of donor 1410 (200 mg,
0.47 mmol), and acceptor 299 (252 mg, 0.31 mmol) in dry CH2Cl2

}
E. Mezo et al. / Carbohydrate Research 388 (2014) 19–29
26
(10 mL), 4 Å molecular sieves (0.50 g) were added. The stirred mix-
added. The temperature was increased to ꢀ65 °C in 45 min. The
reaction mixture was quenched with Et3N (500 L), diluted with
ture was cooled to ꢀ75 °C under argon. After 30 min at this tem-
l
perature, NIS (116 mg, 0.52 mmol) dissolved in THF (155
l
L) and
L) were
added. The temperature was increased to ꢀ15 °C in 1.5 h. The reac-
tion mixture was quenched with Et3N (50 L), diluted with CH2Cl2
CH2Cl2 (300 mL) and filtered through a pad of Celite. The filtrate
was concentrated. The crude product was purified by column chro-
matography (55:45 n-hexane/EtOAc) to give 30 (6.02 g, 89%) as a
colourless syrup.
AgOTf (29 mg, 0.11 mmol) dissolved in toluene (155
l
l
(200 mL) and filtered through a pad of Celite. The filtrate was con-
centrated. The crude product was purified by column chromatog-
Compound 30: Rf 0.30 (55:45 n-hexane/EtOAc); ½a D25
ꢄ
+28.29 (c
0.48, CHCl3); IR mmax (KBr): 3444, 3052, 2933, 1754, 1441, 1359,
raphy (1:1 n-hexane/EtOAc) to give 30 (45 mg, 11%) and 14
a,b
1238, 1169, 1096, 1072, 1034, 997, 916, 820, 750 cmꢀ1 1H NMR
;
(17 mg, 9%) each as a colourless syrup.
Method II (entry 2): A solution of 14 (200 mg, 0.47 mmol) in dry
CH2Cl2 (3 mL) was cooled to 0 °C under argon. To the solution Br2
(CDCl3, 400 MHz): d7.87–7.75, 7.52–7.45, 7.27–7.21 (3 ꢃ m, 12H,
arom), 5.29 (t, J = 9.1 Hz, 1H, H-3), 5.00 (d, 1H, J = 3.1 Hz, H-10),
4.94 (t, J = 9.6 Hz, 1H, H-2), 4.80–4.69 (m, 3H, H-1, ArCH2), 4.08
(q, J = 7.1 Hz, 2H, SO3CH2CH3), 3.93 (t, J = 9.3 Hz, 1H, H-4), 3.88–
3.78 (m, 2H, H-6a, H-6b), 3.61–3.48 (m, 2H, H-5, H-50), 3.52, 3.49,
3.40 (3 ꢃ s, 9H; 3 ꢃ OCH3), 3.43–3.31 (m, 1H, H-30), 3.23–3.12 (m,
1H, H-7a0), 3.05–2.93 (m, 2H; H-7b0, H-20), 2.71 (t, J = 9.2 Hz, 1H,
H-40), 2.28–2.19 (m, 1H, H-6a0), 2.07, 2.02 (2 ꢃ s, 6H, COCH3),
1.93–1.79 (m, 1H, H-6b0), 1.27–1.23 (m, 3H, SO3CH2CH3) 13C NMR
(90 MHz, CDCl3): d169.4, 169.1 (2 ꢃ CO), 135.1, 132.9, 132.7,
131.6 (4 ꢃ Cq arom), 132.9, 129.0, 128.3, 128.2, 128.0, 127.8,
126.7, 126.2, 126.0, 125.9, (12C, arom), 96.7 (C-10), 84.9 (C-1),
83.0 (C-4), 82.2 (C-30), 81.5 (C-20), 78.8 (C-5), 75.3 (C-3), 73.9
(C-4), 73.3 (ArCH2), 70.2 (C-2), 69.0 (C-50), 67.7 (C-6), 65.7 (SO3CH2
CH3), 60.2, 58.7 (3 ꢃ CH3), 46.3 (C-70), 25.7 (C-60), 20.6, 20.4
(2 ꢃ CH3CO), 14.7 (SO3CH2CH3) ppm; MALDI-TOF (positive ion):
m/z calcd for [M+Na]+ 829.25. Found: 828.95. Anal. Calcd for
(24 lL) was added and stirred for 30 min. The reaction mixture
was concentrated at 30 °C and co-evaporated with toluene
(2 ꢃ 5 mL). The obtained glycosyl bromide and acceptor 29
(252 mg, 0.31 mmol) were dissolved in dry CH2Cl2 (10 mL) and
4 Å molecular sieves (0.50 g) were added. The solution was stirred
for 15 min at room temperature then further 15 min at –30 °C.
AgOTf (185 mg, 0.70 mmol) dissolved in toluene (900 lL) was
added and the mixture was allowed to warm up to room temper-
ature in 1.5 h. The reaction mixture was diluted with CH2Cl2
(40 mL) and filtered through a pad of Celite. The filtrate was
washed successively with aq NaHCO3 (15 mL) and H2O (15 mL).
The organic phase was dried and concentrated. The crude product
was purified by column chromatography (1:1 n-hexane/EtOAc) to
give 30 (55 mg, 14%) and 14a,b (12 mg, 6%).
Method III (entry 3): To a solution of acceptor 29 (250 mg,
0.50 mmol) and donor 27 (263 mg, 0.71 mmol) in dry CH2Cl2
(10 mL), 4 Å molecular sieves (0.50 g) were added. The stirred mix-
ture was cooled to ꢀ75 °C under argon. After 30 min at this tem-
C
88H110O27 (806.94): C, 58.05; H, 6.25; O, 27.76; S, 7.95. Found:
C, 57.87; H, 6.02; S, 8.10.
Compound 14 ,b: (
:b ꢁ 5:1) Rf 0.36 (6:4 n-hexane/EtOAc); IR
mmax (KBr): 3630, 3516, 2979, 2934, 2834, 1752, 1444, 1353,
1239, 1173, 1090, 1002, 915, 816, 642, 575, 528, 472 cmꢀ1 1H
NMR (360 MHz, CDCl3) d 7.46–7.49 (m, 2H, arom), 7.36–7.22 (m,
4H, arom), 5.78 (d, J = 5.3 Hz, 1H, H-1 ), 4.47 (d, J = 9.8 Hz, 0.20H,
a
a
perature, a mixture of NIS (174 mg, 0.78 mmol) and TfOH (29
l
L,
L) was added. After 3 h stirring
L) was added. The reaction mixture was di-
;
0.03 mmol) dissolved in THF (500
at ꢀ50 °C, Et3N (50
l
l
a
luted with CH2Cl2 (250 mL), washed successively with H2O
(50 mL), aq NaHCO3 (50 mL), H2O (60 mL), dried and concentrated.
The crude product was purified by column chromatography (55:45
n-hexane/EtOAc) to give 30 (165 mg, 31%,) as a colourless syrup.
Method IV (entry 4): To a solution of acceptor 29 (500 mg,
1.01 mmol) and donor 27 (525 mg, 1.40 mmol) in dry CH2Cl2
(20 mL), 4 Å molecular sieves (0.50 g) were added. The stirred mix-
ture was cooled to ꢀ75 °C under argon. After 20 min at this tem-
H-1b), 4.25–4.10 (m, 2.40H, SO3CH2CH3), 3.92 (dt, J = 9.8, 2.4 Hz,
1H), 3.64 (s, 3H, OCH3), 3.62 (s, 0.60H), 3.59–3.49 (m, 8.40H),
3.44 (t, J = 9.0 Hz, 1.20H), 3.23–3.13 (m, 1H, 0.60), 3.07–2.98 (m,
0.40H), 2.90–2.80 (m, 2.20H), 2.68–2.58 (m, 1H), 2.43–2.27 (m,
1.20H), 1.97–1.78 (m, 1.20H), 1.65 (s, 0.5H), 1.40–1.32 (m, 3.60H,
SO3CH2CH3); 13C NMR (90 MHz, MeOD) d 133.4 (1 ꢃ Cq arom),
131.4, 129.1, 127.2 (5C, arom), 84.7 (C-1a), 83.7, 83.4, 81.7, 69.4
(C-2, C-3, C-4, C-5), 66.1 (SO3CH2CH3), 61.0, 60.9, 58.3 (3 ꢃ OCH3),
46.6 (C-7), 25.7 (C-6), 15.0 (SO3CH2CH3); Anal. Calcd for C88H110O27
(420.54): C, 51.41; H, 6.71; O, 26.63; S, 15.25. Found: C, 51.27; H,
6.65; S, 15.27.
perature,
a
mixture of TMSOTf (36
lL, 0.20 mmol) and NIS
(349 mg, 1.55 mmol) in THF (500
lL) was added and the reaction
mixture was allowed to warm up to ꢀ55 °C in 2 h. The mixture
was diluted with CH2Cl2 (50 mL) washed successively with aq Na2-
S2O3 (15 mL), H2O (15 mL), aq NaHCO3 (15 mL) and H2O (15 mL),
dried and concentrated. The crude product was purified by column
chromatography (55:45 n-hexane/EtOAc) to give 30 (350 mg, 44%)
and 31 (45 mg, 8%) as a colourless syrup.
Compound 31: Rf 0.77 (6:4 n-hexane/EtOAc); IR mmax (KBr):
3056, 2925, 1754, 1583, 1509, 1478, 1440, 1371, 1237, 1050,
906, 876, 843, 748, 691, 608, 475 cmꢀ1; 1H NMR (360 MHz, CDCl3)
d 8.02–7.93, 7.69–7.59, 7.42–7.33 (3 ꢃ m, 12H, arom), 5.26 (t,
J = 9.2 Hz, 1H), 5.05 (t, J = 9.6 Hz, 1H), 4.95–4.84 (m, 3H), 4.03–
3.84 (m, 3H), 3.71–3.64 (m, 1H), 2.22, 2.19 (2 ꢃ s, 6H, 2 ꢃ COCH3),
0.21 (s, 9H, 3 ꢃ CH3) ppm; 13C NMR (90 MHz, CDCl3) d 170.2, 169.8
(2 ꢃ CO), 135.8, 133.4, 133.1, 132.4 (4 ꢃ Cq arom), 132.9, 129.0,
128.2, 128.1, 128.0, 127.8, 126.3, 126.2, 125.9, 125.8 (12C, arom),
85.7 (C-1), 80.5, 70.8, 69.3 (C-2, C-3, C-4, C-5), 73.7 (ArCH2), 68.8
(C-6), 21.2, 20.9 (2 ꢃ COCH3), 0.4 (3 ꢃ CH3) ppm; MALDI-TOF (po-
sitive ion): m/z calcd for [M+Na]+ 591.05. Found: 591.18. Anal.
Calcd for C88H110O27 (568.75): C, 63.35; H, 6.38; O, 19.69; S, 5.64;
Si, 4.94. Found: C, 63.42; H, 6.46; S, 5.58.
Method V (entry 5): To a solution of donor 27 (113 mg,
0.30 mmol), and acceptor 29 (100 mg, 0.20 mmol) in dry CH2Cl2
(10 mL), 4 Å molecular sieves (0.50 g) were added. The stirred mix-
ture was cooled to ꢀ75 °C under argon. After 30 min at this tem-
perature, NIS (75 mg, 0.33 mmol) dissolved in THF (100
l
L) and
L) were
added. The temperature was increased to ꢀ55 °C in 45 min. The
reaction mixture was quenched with Et3N (50 L), diluted with
AgOTf (19 mg, 0.07 mmol) dissolved in toluene (100
l
l
CH2Cl2 (100 mL) and filtered through a pad of Celite. The filtrate
was concentrated. The crude product was purified by column chro-
matography (55:45 n-hexane/EtOAc) to give 30 (106 mg, 66%).
4.18. 2-O-Acetyl-4,6-O-(benzylidene)-3-O-methyl-
a,b-L-
Method VI (entry 6): To
a
solution of donor 27 (5 g,
idopyranosyl-trichloroacetimidate (33 ,b)
a
13.42 mmol), and acceptor 29 (4.16 g, 8.39 mmol) in dry CH2Cl2
(190 mL), 4 Å molecular sieves (2.0 g) were added. The stirred mix-
ture was cooled to ꢀ75 °C under argon. After 30 min at this tem-
perature, NIS (3.32 g, 14.76 mmol) dissolved in THF (4.5 mL) and
AgOTf (828 mg, 3.22 mmol) dissolved in toluene (4.5 mL) were
To the solution of compound 32 (7.5 g, 20.47 mmol) in THF
(200 mL), benzylamine (8 mL, 71.7 mmol) was added. The reaction
mixture was stirred at room temperature for 5 h. The mixture was
poured on 1 M aq HCl (300 mL). The aqueous phase was extracted

}
E. Mezo et al. / Carbohydrate Research 388 (2014) 19–29
27
with EtOAc (3 ꢃ 150 mL). The combined organic phase was dried
J = 3.6 Hz, 1H, H-1), 4.33–4.23 (m, 3H), 3.86 (t, J = 9.4 Hz, 1H),
3.81–3.75 (m, 1H), 3.57–3.46 (m, 3H), 3.51, 3.34 (2 ꢃ s, 6H,
OCH3), 3.42–3.27 (m, 3H), 3.20–3.08 (m, 2H), 2.42–2.31 (m, 1H,
H-6a), 2.08 (s, 3H, COCH3), 2.04 (s, 1H, OH), 1.99–1.87 (m, 1H, H-
6b), 1.40 (t, J = 7.1 Hz, 3H, SO3CH2CH3) ppm; 13C NMR (90 MHz,
CDCl3) d 169.4 (CO), 138.2, 137.9 (2 ꢃ Cq arom), 128.6, 128.5,
128.2, 128.2, 128.0 (10C, arom), 100.1, 97.8 (C-1, C-10), 80.4, 79.7,
77.6, 76.5, 68.3, 67.6, 67.1, 67.1 (C-2, C-20, C-3, C-30, C-4, C-40, C-
5, C-50), 76.0, 73.5 (PhCH2), 66.2 (SO3CH2CH3), 62.7 (C-60), 58.3,
55.5 (2 ꢃ OCH3), 46.5 (C-7), 25.8 (C-6), 21.0 (COCH3), 15.2 (SO3CH2-
CH3) ppm; MALDI-TOF (positive ion): m/z calcd for [M+Na]+
721.25. Found: 721.26. Anal. Calcd for C88H110O27 (698.77): C,
56.72; H, 6.64; O, 32.05; S, 4.59. Found: C, 56.82; H, 6.57; S, 4.66.
and concentrated. The crude product was purified by column chro-
matography (9:1 CH2Cl2/acetone) to give an
a/b-mixture of the
appropriate hemiacetal (4.65 g, 70%) as a colourless syrup. The
solution of the crude product (4.59 g, 14.15 mmol) in dry CH2Cl2
(85 mL) was cooled to 0 °C and trichloroacetonitrile (28.1 mL,
0.28 mol) and DBU (550 lL, 0.85 mmol) were added. The reaction
mixture was stirred for 1 h then concentrated in vacuo at 30 °C.
The residue was purified by column chromatography (80:18:2 CH2-
Cl2/EtOAc/Et3N) to give 33a,b (6.25 g, 94%) as a colourless syrup; Rf
0.73 (8:2 CH2Cl2/EtOAc);
4.19. Methyl [2-O-acetyl-4,6-O-(benzylidene)-3-O-methyl-
a-L-
idopyranosyl]-(1?4)-2,3-di-O-benzyl-6-deoxy-6-C-(ethyl
sulfonatomethyl)-
a
-
D
-glucopyranoside (34)
4.21. Methyl [methyl (2-O-acetyl-3-O-methyl-
uronate]-(1?4)-2,3-di-O-benzyl-6-deoxy-6-C-(ethyl
sulfonatomethyl)- -glucopyranoside (36)
a-L-idopyranosyl)
To the solution of acceptor 18 (4.85 g, 10.1 mmol) and donor 33
(6.25 g, 13.3 mmol) in dry CH2Cl2 (200 mL), 4 Å molecular sieves
(4.5 g) were added. The stirred mixture was cooled to ꢀ40 °C under
argon. After 20 min at this temperature, TMSOTf (2.39 mL,
0.133 mmol) was added and the mixture was allowed to warm
up to ꢀ15 °C in 1 h. The mixture was diluted with CH2Cl2
(250 mL) washed successively with aq NaHCO3 (120 mL) and H2O
(120 mL), dried and concentrated. The crude product was purified
by column chromatography (6:4 n-hexane/EtOAc) to give 34
(6.58 g, 82%) as white crystals. Mp 119–124 °C; Rf 0.30 (6:4 n-hex-
a-D
Compound 35 (865 mg, 1.24 mmol) was converted to 36
according to general method D. The crude product was purified
by column chromatography to give 36 (627 mg, 70%) as a colour-
less oil. Rf 0.44 (6:4 n-hexane/acetone); ½a D25
ꢄ
+5.91 (c 1.00, CHCl3);
IR mmax (KBr): 3480, 2985, 2938, 2838, 1745, 1637, 1630, 1497,
1455, 1371, 1357, 1221, 1166, 1104, 1045, 1003 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 7.33–7.28 (m, 10H, arom), 5.13 (s, 1H, H-10),
4.96–4.93 (m, 2H, PhCH2, H-50), 4.88 (s, 1H, H-20), 4.85–4.80,
4.73–4.67, 4.58–4.52 (3 ꢃ m, 3H, PhCH2), 4.47 (s, 1H, H-1), 4.32–
4.27 (m, 2H, SO3CH2CH3), 3.94 (s, 1H, H-40), 3.85–3.74 (m, 2H, H-
3, H-5), 3.56–3.45 (m, 3H, H-2, H-30, H-4), 3.51, 3.49, 3.33 (3 ꢃ s,
9H, 3 ꢃ OCH3,), 3.37–3.27 (m, 1H, H-7a), 3.16–3.74 (m, 1H, H-7b),
2.71 (s, 1H, OH), 2.42–2.36 (m, 1H, H-6a), 2.07 (s, 3H, COCH3),
1.97–1.89 (m, 1H, H-6b), 1.40 (t, J = 7.0 Hz, 3H, SO3CH2CH3) ppm;
13C NMR (90 MHz, CDCl3) d 169.5, 168.9 (2 ꢃ CO), 138.6, 137.7
(2 ꢃ Cq arom), 128.3, 128.0, 127.8, 127.3, 127.0 (10C, arom), 97.6
(C-1), 97.5 (C-10), 80.2, 77.9, 76.5, (C-2, C-30, C-4), 79.1 (C-3),
74.9, 73.2 (2PhCH2), 68.1 (C-50), 67.8 (C-5), 66.9 (C-40), 66.6 (C-
20), 65.9 (SO3CH2CH3), 58.1, 55.4, 51.9 (3 ꢃ OCH3), 46.4 (C-7),
25.8 (C-6), 20.7 (COCH3), 15.0 (SO3CH2CH3) ppm; MALDI-TOF (po-
sitive ion): m/z calcd for [M+Na]+ 749.29. Found: 749.21. Anal.
Calcd for C88H110O27 (726.26): C, 56.19; H, 6.38; O, 33.02; S, 4.41.
Found: C, 56.04; H, 6.23; S, 4.56.
ane/EtOAc); ½a 2D5
ꢀ4.03 (c 0.59, CHCl3); IR mmax (KBr): 3444, 2983,
ꢄ
2935, 2907, 2837, 1747, 1637, 1628, 1508, 1497, 1454, 1397,
1370, 1356, 1237, 1168, 1139, 1101, 1046, 1005 cmꢀ1 1H NMR
;
(360 MHz, CDCl3) d 7.47–7.24 (m, 15H, arom), 5.33 (s, 1H, PhCH),
5.08 (d, J = 2.2 Hz, 1H, H-10), 5.04 (d, J = 10.8 Hz, 1H, PhCH2), 4.93
(dd, J = 4.5, 2.5 Hz, 1H, H-20), 4.78–4.62 (m, 3H, PhCH2), 4.51 (d,
J = 3.6 Hz, 1H, H-1), 4.28 (q, J = 7.1 Hz, J = 7.1 Hz, 2H, SO3CH2CH3),
3.92–3.72 (m, 5H), 3.54–3.43 (m, 3H), 3.49, 3.34 (2 ꢃ s, 6H,
2 ꢃ OCH3), 3.33–3.21 (m, 2H), 3.15–3.05 (m, 1H, H-7b), 2.43–2.31
(m, 1H, H-6a), 2.05 (s, 3H, COCH3), 1.97–1.85 (m, 1H, H-6b), 1.39
(t, J = 7.1 Hz, 3H, SO3CH2CH3) ppm; 13C NMR (90 MHz, CDCl3) d
170.11 (CO), 138.9, 138.1, 138.0 (4 ꢃ Cq arom), 129.0, 128.5,
128.3, 128.2, 128.1, 127.7, 127.6, 126.3 (15C, arom), 100.5 (PhCH),
98.1, 97.9 (C-1, C-10), 80.4, 79.6, 77.6, 77.1, 73.5, 68.4, 67.3 60.5, (C-
2, C-20, C-3, C-30, C-4, C-40, C-5, C-50), 75.5, 73.4 (2 ꢃ PhCH2), 69.2
(C-60), 66.1 (SO3CH2CH3), 58.3, 55.5 (2 ꢃ OCH3), 46.8 (C-7), 26.1
(C-6), 20.9 (COCH3), 15.2 (SO3CH2CH3) ppm; MALDI-TOF (positive
ion): m/z calcd for [M+Na]+ 809.28. Found: 809.30. Anal. Calcd for
4.22. Methyl [2,3-di-O-benzyl-4-O-(20-naphthyl)methyl-6-
deoxy-6-C-(ethyl sulfonatomethyl)-
[methyl (2-O-acetyl-3-O-methyl-
(1?4)-2,3-di-O-benzyl-6-deoxy-6-C-(ethyl sulfonatomethyl)-
-glucopyranoside (37)
a-D
-glucopyranosyl]-(1?4)-
C88H110O27 (786.88) C: 61.05; H, 6.40; O, 28.47; S, 4.07. Found:
a-L-idopyranosyl) uronate]-
C: 61.23; H, 6.44; S, 3.87.
a-
D
4.20. Methyl [2-O-acetyl-3-O-methyl-a-L-idopyranosyl]-(1?4)-
2,3-di-O-benzyl-6-deoxy-6-C-(ethyl sulfonatomethyl)-
glucopyranoside (35)
a
-
D
-
To a solution of acceptor 36 (700 mg, 0.96 mmol) and donor
2018 (940 mg, 1.45 mmol) in dry CH2Cl2 (30 mL), 4 Å molecular
sieves (0.50 g) were added. The stirred mixture was cooled to
ꢀ60 °C under argon. After 30 min at this temperature, a mixture
The solution of 34 (2.75 g, 3.5 mmol) in CH2Cl2 (75 mL) was
cooled to 0 °C, 70% aq trifluoroacetic acid (8.5 mL) was added and
the mixture was allowed to warm up to room temperature in
5 h. The reaction was quenched with addition of solid NaHCO3
(9.3 g, 0.11 mol), the mixture was diluted with CH2Cl2 (100 mL)
and washed with H2O (2 ꢃ 100 mL). The organic phase was dried
and concentrated. The crude product was purified by column chro-
matography by using first CH2Cl2-acetone (93:7) and then CH2Cl2-
MeOH (95:5) as the eluents to give 35 (2.13 g, 87%) as a colourless
of NIS (488 mg, 2.17 mmol) and TfOH (38 lL, 0.43 mmol) dissolved
in THF (1.2 mL) was added. After 3 h stirring at ꢀ50 °C, Et3N
(50 L) was added. The reaction mixture was diluted with CH2Cl2
l
(150 mL), washed successively with 10% aq Na2S2O3 solution
(20 mL). H2O (50 mL), aq NaHCO3 (50 mL), H2O (50 mL), dried
and concentrated. The crude product was purified by column chro-
matography (1:1 n-hexane/acetone) to give 37 (1.17 g, 92%,) as a
colourless syrup. Rf 0.42 (1:1 n-hexane/EtOAc); ½a D25
ꢄ
+15.51 (c
oil. ½a 2D5
ꢄ
+5.12 (c 3.25, CHCl3); Rf 0.39 (85:15 CH2Cl2/acetone); IR
mmax (KBr): 3466, 3061, 3031, 2937, 2906, 2837, 1743, 1497,
0.20, CHCl3); IR mmax (KBr): 3439, 3061, 3031, 2983, 2934, 1739,
1604, 1497, 1455, 1356, 1238, 1166, 1105, 1070, 1048, 1029,
1455, 1370, 1356, 1221, 1166, 1103, 1044, 1000, cmꢀ1
;
1H NMR
1001, 1070 cmꢀ1 1H NMR (360 MHz, CDCl3) d 8.01–7.82 (m, 4H,
;
(360 MHz, CDCl3) d 7.39–7.27 (m, 10H, arom), 5.04 (d, J = 10.4 Hz,
1H, PhCH2), 4.92 (s, 1H,H-20), 4.88 (d, 1H, J = 10.4 Hz, H-10), 4.79
(d, J = 12.0 Hz, 1H, PhCH2), 4.70–4.64 (m, 2H, PhCH2), 4.50 (d,
arom), 7.66–7.38 (m, 23H, arom), 5.41 (d, J = 1.0 Hz, 1H, H-10),
5.25–5.14 (m, 1H), 5.10 (d, J = 10.9 Hz, 2H, ArCH2), 5.05–4.90 (m,
7H), 4.90–4.79 (m, 2H), 4.73 (d, J = 12.0 Hz, 1H, ArCH2), 4.64 (d,

}
E. Mezo et al. / Carbohydrate Research 388 (2014) 19–29
28
J = 3.5 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H, SO3CH2CH3), 4.28 (q,
J = 7.0 Hz, 2H, SO3CH2CH3), 4.19–3.83 (m, 7H), 3.73–3.44 (m,
12H), 3.44–3.24 (m, 4H, 2 ꢃ H-7a,b), 2.62–2.52 (m, 1H), 2.47 (m,
1H), 2.22 (s, 3H, COCH3), 2.17–2.00 (m, 2H), 1.55 (t, J = 7.1 Hz,
3H, SO3CH2CH3), 1.41 (t, J = 7.0 Hz, 3H, SO3CH2CH3) ppm; 13C
NMR (90 MHz, CDCl3) d 170.1, 169.4 (2 ꢃ CO), 138.9, 138.4,
138.0, 138.0, 135.5, 133.2, 133.0 (7 ꢃ Cq arom), 128.6, 128.5,
128.2, 128.0, 127.9, 127.8, 127.7, 127.5, 127.3, 126.4, 126.2,
126.0, 125.7 (27C, arom), 98.7, 97.9, 97.8 (3 ꢃ C-1), 81.4, 81.1,
80.3, 79.4, 78.3, 76.6, 74.5, 69.6, 68.7, 68.1, 67.7 (12C, skeleton car-
bons), 75.4, 75.1, 75.0, 73.6, 73.4 (5 ꢃ ArCH2), 66.2, 66.1 (2 ꢃ SO3-
CH2CH3), 58.4, 55.5, 51.9 (3 ꢃ OCH3), 46.6, 46.4 (2 ꢃ C-7), 26.0,
25.9 (2 ꢃ C-6), 21.0 (COCH3), 15.1, 15.0 (2 ꢃ SO3CH2CH3) ppm;
MALDI-TOF (positive ion): m/z calcd for [M+Na]+ 1337.46. Found:
1337.25 Anal. Calcd for C88H110O27 (1315.50): C, 62.09; H, 6.28;
O, 26.76; S, 4.87. Found: C, 61.97; H, 6.15; S, 4.96.
successively with H2O (50 mL), aq NaHCO3 (50 mL), H2O (60 mL),
dried and concentrated. The crude product was purified by column
chromatography (93:7 CH2Cl2/acetone) to give 39 (813 mg, 65%,)
as a colourless syrup. Rf 0.31 (93:7 CH2Cl2/acetone); ½a D25
ꢄ
+29.85
(c 0.08, CHCl3); NMR (400 MHz, CDCl3) d 7.86–7.75 (m, 3H, arom),
7.65 (s, 1H, arom), 7.46 (m, 2H, arom), 7.36–7.13 (m, 21H, arom),
5.22–5.14 (m, 2H, H-3-E, H-1-G), 5.01–4.76 (m, 8H, H-1-D, H-2-E,
H-5-G, H-2-G, ArCH2), 4.76–4.62 (m, 4H, H-1-F, H-1-E, ArCH2),
4.57–4.51 (m, 4H, ArCH2), 4.48 (d, J = 3.5 Hz, 1H, H-1-H), 4.31–
4.25 (m, 4H, SO3CH2CH3), 4.09 (q, J = 7.1 Hz, 2H, SO3CH2CH3),
3.91–3.70 (m, 6H, H-4-E, H-4-G, H-3-F, H-3-H, H-5-H, H-5-F),
3.65 (t, J = 3.7 Hz, 1H, H-3-G), 3.55–3.42 (m, 4H, H-5-D, H-2-H,
H-6a,b-E), 3.53, 3.50, 3.49, 3.38, 3.33, 3.32 (6 ꢃ s, 18H, OCH3),
3.42–3.18 (m, 7H, H-4-F, H-2-F, H-4-H, H-3-D, H-5-E, 2 ꢃ H-7a),
3.15–3.03 (m, 3H, H-7a, 2 ꢃ H-7b), 2.92–2.82 (m, 2H, H-2-D,
H-7b), 2.66 (t, J = 9.2 Hz, 1 H, H-4-D), 2.42–2.82 (m, 1H, H-6a),
2.30–2.22 (m, 1H, H-6a), 2.16–2.12 (m, 1H, H-6a), 2.08, 2.01, 2.00
(3 ꢃ s, 9H, 3 ꢃ COCH3) 1.98–1.88 (m, 1H, H-6b), 1.84–1.73 (m,
2H, 2 ꢃ H-6b), ppm; 13C NMR (100 MHz, CDCl3) d 170.2, 169.8,
169.4 (4 ꢃ CO), 139.1, 138.9, 137.9, 137.8, 135.4, 133.3, 133.0
(7 ꢃ Cq arom), 128.4, 128.2, 128.1, 128.0, 127.9, 127.7, 127.4,
127.2, 127.1, 126.4, 126.4, 126.2, 125.9, 125.6 (27C, arom), 101.2
(C-1-E), 98.1 (C-1-F), 97.8 (C-1-H), 97.7 (C-1-G), 96.9 (C-1-D),
83.29 82.42, 82.05, 82.01, 80.28, 79.76, 79.47, 79.32, 78.36, 76.28,
75.20, 74.60, 74.5 74.00 72.64, 69.33, 69.06, 68.73 68.07, 67.46
(20C, skeleton carbons), 75.0, 74.4, 73.8, 73.5, 73.4 (5 ꢃ ArCH2),
66.2, 65.9 (3 ꢃ SO3CH2CH3), 60.6, 59.0, 58.3, 55.5, 51.9 (6 ꢃ OCH3),
46.7, 46.7, 46.5 (3 ꢃ C-7), 26.1, 26.0, 25.8 (3 ꢃ C-6), 21.0, 20.9, 20.7
(3 ꢃ COCH3), 15.1, 15.1 (3 ꢃ SO3CH2CH3) ppm; MALDI-TOF (posi-
tive ion): m/z calcd for [M+Na]+ 1893.65. Found: 1893.64. Anal.
Calcd for C88H110O27 (1872.07): C, 57.74; H, 6.35; O, 30.77; S,
5.14. Found: C, 57.67; H, 6.41; S, 5.20.
4.23. Methyl [2,3-di-O-benzyl-6-deoxy-6-C-(ethyl
sulfonatomethyl)-
a-
D-glucopyranosyl]-(1?4)-[methyl (2-O-
acetyl-3-O-methyl-a-L-idopyranosyl) uronate]-(1?4)-2,3-di-O-
benzyl-6-deoxy-6-C-(ethyl sulfonatomethyl)-a-D-
glucopyranoside (38)
Compound 37 (1.14 g, 0.87 mmol) was converted to 38 accord-
ing to the general method C. The crude product was purified by col-
umn chromatography to give 38 (805 mg, 79%) as a colourless oil.
Rf 0.37 (1:1 n-hexane/EtOAc); ½a D25
ꢄ
+23.57 (c 0.08, CHCl3); IR mmax
(KBr): 3525, 3031, 2935, 1740, 1606, 1497, 1455, 1369, 1355,
1234, 1166, 1107, 1053, 1029, 997, 919, cmꢀ1
;
1H NMR
(360 MHz, CDCl3) d 7.38–7.23 (m, 20H, arom), 5.23 (d, J = 2.7 Hz,
1H, H-10), 4.93–4.83 (m, 4H), 4.79 (dd, J = 7.9, 3.0 Hz, 2H), 4.74–
4.68 (m, 4H), 4.64 (d, J = 11.8 Hz, 1H, PhCH2), 4.56 (d, J = 12.0 Hz,
1H, PhCH2), 4.47 (d, J = 3.5 Hz, 1H), 4.27 (m, 4H, SO3CH2CH3),
3.91–3.87 (m, 1H), 3.82 (t, J = 9.2 Hz, 1H), 3.77–3.61 (m, 4H),
3.57–3.45 (m, 5H), 3.43–3.28 (m, 9H), 3.26–3.05 (m, 4H, 2 ꢃ
H-7a,b), 2.51 (d, J = 3.1 Hz, 1H, OH), 2.45–2.34 (m, 1H, H-6a),
2.34–2.21 (m, 1H, H-6a), 2.02 (s, 3H, COCH3), 1.99–1.87 (m, 2H,
2 ꢃ H-6b), 1.44–1.33 (m, 6H, SO3CH2CH3) ppm; 13C NMR
4.25. Methyl [2,3,4-tri-O-methyl-6-deoxy-6-C-(ethyl
sulfonatomethyl)-
a-
D-glucopyranosyl]-(1?4)-[2,3-di-O-acetyl-
b-D
-glucopyranosyl]-(1?4)-[2,3-di-O-benzyl-6-deoxy-6-C-(ethyl
sulfonatomethyl)-
acetyl-3-O-methyl-
a
a
-
-
D
-glucopyranosyl]-(1?4)-[methyl (2-O-
-idopyranosyl) uronate]-(1?4)-2,3-di-O-
L
(91 MHz, CDCl3)
d
170.06, 169.42 (2 ꢃ CO), 138.90, 138.49,
benzyl-6-deoxy-6-C-(ethyl sulfonatomethyl)-a-D-
glucopyranoside (40)
138.00, 137.89 (4 ꢃ Cq arom), 128.61, 128.56, 128.45, 128.14,
128.01, 127.95, 127.87, 127.82, 127.57, 127.27 (20C, arom),
98.75, 97.92, 97.83 (3 ꢃ C-1), 80.72, 80.15, 79.89, 79.37, 78.49,
76.91, 74.56, 73.39, 69.95, 69.32, 68.42, 68.12 (12C; skeleton car-
bons), 75.08, 73.46, 73.34 (PhCH2), 66.32, 66.19 (2 ꢃ SO3CH2CH3),
58.43, 55.52, 51.87 (3 ꢃ OCH3), 46.66, 46.26 (2 ꢃ C-7), 25.83
(2 ꢃ C-6), 20.97 (COCH3), 15.11 (2 ꢃ SO3CH2CH3) ppm; MALDI-
TOF (positive ion): m/z calcd for [M+Na]+ 1197.40. Found:
1197.34. Anal. Calcd for C88H110O27 (1175.31): C, 58.25; H, 6.35;
O, 29.95; S, 5.46. Found: C, 58.34; H, 6.21; S, 5.48.
Compound 39 (775 mg, 0.41 mmol) was converted to 40
according to general method C. The crude product was purified
by column chromatography to give compound 40 (600 mg, 84%)
as a colourless oil. Rf 0.20 (6:4 n-hexane/acetone); ½a D25
ꢄ
+32.32 (c
0.16, CHCl3); IR mmax (KBr): 3443, 2935, 1755, 1633, 1497, 1454,
1356, 1240, 1220, 1166, 1099, 1042, 919, 820, 740, 700,
593 cmꢀ1 1H NMR (360 MHz, CDCl3) d 7.41–7.19 (m, 20H, arom),
;
5.31–5.15 (m, 3H), 5.01 (d, J = 3.3 Hz, 1H), 4.96–4.51 (m, 12H),
4.48 (d, J = 3.4 Hz, 1H), 4.32–4.26 (m, 6H, 3 ꢃ SO3CH2CH3), 3.88–
3.62 (m, 7H), 3.55, 3.52, 3.49, 3.41, 3.33, 3.32 (6 ꢃ s, 18H,
6 ꢃ OCH3), 3.59–3.27 (m, 15H), 3.24–3.18 (m, 3H), 3.17–3.09 (m,
3H), 3.01 (dd, J = 9.7, 3.4 Hz, 1H), 2.73 (t, J = 9.2 Hz, 1H), 2.45–
2.21 (m, 3H), 2.07, 2.03, 2.02 (3 ꢃ s, 9H, 3 ꢃ COCH3), 2.15–1.83
(m, 4H), 1.44–1.38 (m, 9H, 3 ꢃ SO3CH2CH3), ppm; 13C NMR
(90 MHz, CDCl3) d 170.1, 169.8, 169.5 (4x CO), 138.9, 138.8,
137.9, 137.8 (4 ꢃ Cq arom), 128.5, 128.5, 128.4, 128.1, 128.0,
127.6, 127.4, 127.2, 126.1 (20C, arom), 100.8, 98.3, 97.8, 97.6,
96.7 (5 ꢃ C-1), 83.7, 82.7, 81.9, 81.6, 80.3, 79.3, 79.0, 78.3, 76.3,
75.2, 74.8, 74.1, 72.5, 72.2, 69.5, 69.2, 68.7, 68.0, 67.5 (20C, skeleton
carbons), 75.0, 74.5, 73.8, 73.4 (PhCH2), 66.1, 66.1 (3 ꢃ SO3CH2-
CH3), 60.7, 60.6, 59.3, 58.2, 55.5, 51.9 (6 ꢃ OCH3), 46.7, 46.6, 46.5
(3 ꢃ C-7), 26.3, 25.9, 25.4 (3 ꢃ C-6), 20.9, 20.9, 20.5 (3 ꢃ SO3CH2-
CH3), 15.1 (3 ꢃ COCH3) ppm; Anal. Calcd for C88H110O27
(1731.89): C, 54.79; H, 6.40; O, 33.26; S, 5.55. Found: C, 54.84; H,
6.52; S, 5.43.
4.24. Methyl [2,3,4-tri-O-methyl-6-deoxy-6-C-(ethyl
sulfonatomethyl)-
6-O-(20-naphthyl)methyl-b-
benzyl-6-deoxy-6-C-(ethyl sulfonatomethyl)-
glucopyranosyl]-(1?4)-[methyl (2-O-acetyl-3-O-methyl-
idopyranosyl) uronate]-(1?4)-2,3-di-O-benzyl-6-deoxy-6-C-
(ethyl sulfonatomethyl)- -glucopyranoside (39)
a-
D-glucopyranosyl]-(1?4)-[2,3-di-O-acetyl-
D-glucopyranosyl]-(1?4)-[2,3-di-O-
a-D-
a-L-
a
-D
To a solution of trisaccharide acceptor 38 (790 mg, 0.67 mmol)
and disaccharide donor 30 (825 mg, 1.01 mmol) in dry CH2Cl2
(26 mL), 4 Å molecular sieves (0.50 g) were added. The stirred mix-
ture was cooled to ꢀ60 °C under argon. After 30 min at this tem-
perature, NIS (340 mg, 1.51 mmol) dissolved in THF (300
l
L) and
L) were
L) was added. The
reaction mixture was diluted with CH2Cl2 (150 mL), washed
AgOTf (86 mg, 0.32 mmol) dissolved in toluene (300
added. After 3 h stirring at ꢀ20 °C, Et3N (50
l
l

}
E. Mezo et al. / Carbohydrate Research 388 (2014) 19–29
29
Meuleman, D. G.; Visser, A.; Vogel, G. M. T.; Damm, J. B. L.; Overklift, G. T.
Bioorg. Med. Chem. 1994, 2, 1267–1280.
6. Herczeg, M.; Lázár, L.; Borbás, A.; Lipták, A.; Antus, S. Org. Lett. 2009, 11, 2619–
2622.
7. Lázár, L.; Herczeg, M.; Fekete, A.; Borbás, A.; Lipták, A.; Antus, S. Tetrahedron
Lett. 2010, 51, 6711–6714.
4.26. Methyl [2,3,4-tri-O-methyl-6-deoxy-6-C-(ethyl
sulfonatomethyl)- -glucopyranosyl]-(1?4)-[methyl (2,3-di-
O-acetyl-b- -glucopyranosyl) uronate]-(1?4)-[2,3-di-O-benzyl-
6-deoxy-6-C-(ethyl sulfonatomethyl)-
(1?4)-[methyl (2-O-acetyl-3-O-methyl-
a-D
D
a
-
a
D
-glucopyranosyl]-
-idopyranosyl)
-L
8. Herczeg, M.; Lázár, L.; Mándi, A.; Borbás, A.; Komáromi, I.; Lipták, A.; Antus, S.
Carbohydr. Res. 2011, 346, 1827–1836.
uronate]-(1?4)-2,3-di-O-benzyl-6-deoxy-6-C-(ethyl
sulfonatomethyl)- -glucopyranoside (41)
}
9. Lázár, L.; Mezo, E.; Herczeg, M.; Lipták, A.; Antus, S.; Borbás, A. Tetrahedron
a-D
2012, 68, 7386–7399.
10. Herczeg, M.; Lázár, L.; Bereczky, Zs.; Kövér, K. E.; Timári, I.; Kappelmayer, J.;
Lipták, A.; Antus, S.; Borbás, A. Chem. Eur. J. 2012, 18, 10643–10652.
11. Herczeg, M.; Mezo, E.; Lázár, L.; Fekete, A.; Kövér, K. E.; Antus, S.; Borbás, A.
Compound 40 (600 mg, 0.35 mmol) was converted to 41
according to general method D. The crude product was purified
by column chromatography to give compound 41 (380 mg, 62%)
}
Tetrahedron 2013, 69, 3149–3158.
12. (a) Lázár, L.; Csávás, M.; Borbás, A.; Gyémánt, Gy.; Lipták, A. Arkivoc 2004, 7,
196–207; (b) Borbás, A.; Csávás, M.; Szilágyi, L.; Májer, G.; Lipták, A. J.
Carbohydr. Chem. 2004, 23, 133–146.
as a colourless oil. Rf 0.62 (9:1 CH2Cl2/acetone); ½a D25
ꢄ
+39.44 (c
0.04, CHCl3); NMR (360 MHz, CDCl3) d 7.36–7.14 (m, 20H, arom),
5.30–5.16 (m, 2H), 4.97–4.47 (m, 14H), 4.47 (d, J = 3.4 Hz, 1H),
4.33–4.24 (m, 6H), 3.86–3.60 (m, 7H), 3.58–3.06 (m, 12H), 3.55,
3.5, 3.48, 3.41, 3.33, 3.31 (6 ꢃ s, 21H, 7 ꢃ OCH3), 2.98 (dd, J = 9.7,
3.2 Hz, 1H), 2.70 (t, J = 9.2 Hz, 1H), 2.45–2.31 (m, 1H), 2.31–2.13
(m, 2H), 2.08, 2.02 (2 ꢃ s, 9H, 3 ꢃ COCH3), 2.10–1.74 (m, 3H),
1.43–1.38 (m, 9H, 3 ꢃ SO3CH2CH3) ppm; 13C NMR (90 MHz, CDCl3)
d 170.3, 169.7, 169.6, 169.5, 167.8 (5 ꢃ CO), 139.0, 138.9, 138.0,
137.7 (4 ꢃ Cq arom), 128.5, 128.3, 128.2, 128.0, 127.5, 127.3,
127.2, 126.8 (20C, arom), 101.4, 98.3, 97.9, 97.7, 97.2 (5 ꢃ C-1),
83.2, 82.6, 81.7, 80.3, 80.0, 79.4, 79.2, 78.3, 76.3, 75.3, 74.6, 74.4,
73.7, 72.0, 69.4, 68.9, 68.6, 68.1, 67.3 (20C, skeleton carbons),
75.1, 74.5, 73.8, 73.4 (4 ꢃ PhCH2), 66.2 (3 ꢃ SO3CH2CH3), 60.7,
60.7, 59.3, 58.3, 55.6, 52.7, 51.9 (7 ꢃ OCH3), 46.7, 46.5 (3 ꢃ C-7),
26.0, 25.8 (3 ꢃ C-6), 21.0, 20.8, 20.6 (3 ꢃ SO3CH2CH3), 15.2
(3 ꢃ COCH3) ppm; Anal. Calcd for C88H110O27 (1759.90): C, 54.60;
H, 6.30; O, 33.64; S, 5.47. Found: C, 54.66; H, 6.32; S, 5.57.
13. (a) Carretero, J. C.; Demillequand, M.; Ghosez, L. Tetrahedron 1987, 43, 5125–
5134; (b) Musicki, B.; Widlanski, T. S. Tetrahedron Lett. 1991, 32, 1267–1270;
(c) Jeanjean, A.; Gary-Bobo, M.; Nirdé, P.; Leiris, S.; Garcia, M.; Morère, A.
Bioorg. Med. Chem. Lett. 2008, 18, 6240–6243; (d) Franchini, L.; Compostella, F.;
Colombo, D.; Panza, L.; Ronchetti, F. J. Org. Chem. 2010, 75, 5363–5366.
14. Such an elimination reaction is well-known upon oxidation of 4-O-acyl or 4-O-
sulfonyl derivatives into dialdoses, but was surprising for 11 possessing a 4-O-
alkyl substituent. For oxidation of 4-O-acyl-6-OH derivatives, see: (a) Mackie,
D. M.; Perlin, A. S. Carbohydr. Res. 1972, 24, 67–85; (b) Jordan, A. M.; Osborn, H.
M. I.; Stafford, P. M.; Tzortzis, G.; Rastall, R. A. J. Carbohydr. Chem. 2003, 22,
705–717; For oxidation of 4-O-sulfonyl-6-OH derivative, see: (c) Vatele, J.-M.
Tetrahedron 1986, 42, 4443–4450.
15. Musicki, B.; Widlanski, T. S. J. Org. Chem. 1990, 55, 4231–4233.
16. Navidpour, L.; Lu, W.; Taylor, S. D. Org. Lett. 2006, 8, 5617–5620.
17. Borbás, A.; Szabó, Z. B.; Szilágyi, L.; Bényei, A.; Lipták, A. Tetrahedron 2002, 58,
5723–5732.
}
18. Herczeg, M.; Mezo, E.; Eszenyi, D.; Lázár, L.; Csávás, M.; Bereczki, I.; Antus, S.;
Borbás, A. Eur. J. Org. Chem. 2013, 5570–5573.
19. (a) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; Alderfer, J. L.; Matta, K. L.
Tetrahedron Lett. 2000, 41, 169–173; (b) Wright, J. A.; Yu, J.; Spencer, J. B.
Tetrahedron Lett. 2001, 42, 4033–4036.
20. Christina, A. E.; van der Es, D.; Dinkelaar, J.; Overkleeft, H. S.; van der Marel, G.
A.; Codée, J. D. C. Chem. Commun. 2012, 2686–2688.
Acknowledgements
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4650–4653.
22. Selected articles on chemoselective glycosylations, see: (a) Kaeothip, S.;
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Mydock, L. K.; Demchenko, A. V. J. Org. Chem. 2010, 75, 1095–1100; (c)
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van Boeckel, C. A. A.; van Boom, J. H.; van der Marel, G. A. Tetrahedron 2004, 60,
1057–1064; (e) Lahmann, M.; Oscarson, S. Can. J. Chem. 2002, 80, 889–893; (f)
Zhu, T.; Boons, G.-J. Org. Lett. 2001, 3, 4201–4203; (g) Boons, G.-J.; Geurtsen, R.;
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Angew. Chem., Int. Ed. 1994, 33, 2292–2294; (i) Veeneman, G. H.; Van Boom, J.
H. Tetrahedron Lett. 1990, 31, 6325–6328; (j) Fraser-Reid, B.; Wu, Z.; Udodong,
U. E.; Ottosson, H. J. Org. Chem. 1990, 50, 6068–6070.
23. Recent articles on aglycon transfer of thioglycosides, see: (a) Peng, P.; Xiong,
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The work was supported by the TÁMOP 4.2.4.A/2-11-1-2012-
0001 Project (National Excellence Program). The project is co-fi-
nanced by the European Union and the European Social Fund.
Financial support of the Hungarian Research Fund (OTKA K
105459 and K 109208) is also acknowledged.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.carres. 2014.
02.012.
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