Novel syntheses of Idraparinux, the anticoagulant pentasaccharide with indirect selective factor Xa inhibitory activity

Article abstract of DOI:10.1016/j.tet.2013.02.076

Idraparinux, the fully O-sulfated, O-methylated, heparin-related pentasaccharide possessing selective factor Xa inhibitory activity, was prepared by two novel synthetic pathways. Each route was based on a 2+3 block synthesis utilizing the same l-iduronic acid-containing trisaccharide acceptor, which was glycosylated with either a glucuronide disaccharide donor or its non-oxidized precursor. The latter route, involving the oxidation of the glucose unit into d-glucuronic acid at a pentasaccharide level proved to be much more efficient, providing the target pentasaccharide in a reasonable overall yield.

Full text of DOI:10.1016/j.tet.2013.02.076

Tetrahedron 69 (2013) 3149e3158
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel syntheses of Idraparinux, the anticoagulant pentasaccharide
with indirect selective factor Xa inhibitory activity
a
,
b
a
,
c
a
,
b
a
d
ꢀ
}
ꢀ
ꢀ ꢀ ꢀ
ꢀ
€ ꢀ
Mihaly Herczeg , Erika Mezo , Laszlo Lazar , Aniko Fekete , Katalin E. Kover ,
b
a,c,
*
ꢀ
ꢀ
ꢀ
Sandor Antus , Aniko Borbas
a Research Group for Carbohydrates of the Hungarian Academy of Sciences, H-4010 Debrecen, PO Box 94, Hungary
b Department of Organic Chemistry, University of Debrecen, H-4010 Debrecen, PO Box 20, Hungary
c Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, H-4010 Debrecen, PO Box 70, Hungary
d Department of Inorganic and Analytical Chemistry, University of Debrecen, H-4010 Debrecen, PO Box 21, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Idraparinux, the fully O-sulfated, O-methylated, heparin-related pentasaccharide possessing selective
Received 13 November 2012
Received in revised form 7 February 2013
Accepted 22 February 2013
Available online 26 February 2013
factor Xa inhibitory activity, was prepared by two novel synthetic pathways. Each route was based on
a 2þ3 block synthesis utilizing the same
glycosylated with either a glucuronide disaccharide donor or its non-oxidized precursor. The latter route,
involving the oxidation of the glucose unit into -glucuronic acid at a pentasaccharide level proved to be
much more efficient, providing the target pentasaccharide in a reasonable overall yield.
Ó 2013 Elsevier Ltd. All rights reserved.
L-iduronic acid-containing trisaccharide acceptor, which was
D
Keywords:
Blood coagulation
Heparinoid pentasaccharide
D
-Glucuronic acid
L-Iduronic acid
Glycosylation
1. Introduction
and exerts efficacy after daily administration in various thrombotic
conditions.3 This fully synthetic pentasaccharide is now a drug in
the USA and Europe under the name Arixtra.
The anticoagulant properties of heparin, the highly sulfated
member of the glycosaminoglycan family, have made it an invalu-
able drug for the prophylaxis and initial treatment of thrombosis.1
These properties arise from its ability to accelerate the inhibitory
activity of antithrombin (AT), a serine protease inhibitor that blocks
thrombin and factor Xa in the blood-coagulation cascade.2 How-
ever, heparin therapy also has several undesirable characteristics,
such as low bioavailability after subcutaneous administration,
a poor pharmacokinetic profile, and risk of bleeding and liver tox-
icity, that are associated with its polyanionic and heterogeneous
nature.3 Fondaparinux (1) and Idraparinux (2) are synthetic ana-
logues of the AT-binding pentasaccharide domain of heparin rep-
resenting a new class of antithrombotic agents, which specifically
activate antithrombin to inhibit factor Xa and not thrombin in the
coagulation cascade.4
Idraparinux4b,6 (2) is a synthetic analogue of Fondaparinux in
which the N-sulfates are replaced by O-sulfates and the hydroxyl
groups are methylated. Idraparinux binds to AT significantly
stronger than Fondaparinux through hydrophobic interactions and
also exhibits superior anti Xa-activity and a longer half-life allow-
ing once-a-week administration. The efficacy of Idraparinux was
proven in clinical studies with patients suffering from venous
thromboembolism or atrial fibrillation. However, due to major
bleeding events during treatment for more than six months the
development of Idraparinux was stopped.7 Notwithstanding, be-
cause of the feasible synthesis and specific activity, Idraparinux can
serve both as a lead and a reference compound for further de-
velopment of selective factor Xa inhibitors.
In the frame of our ongoing research aimed at the synthesis of
sulfonic acid-containing pentasaccharides with anticoagulant ac-
tivity, Idraparinux was chosen as a lead structure.8e12 To obtain
a reference compound for the structural and biological evaluation
of our derivatives, the synthesis of Idraparinux was also envisaged
in our laboratory. Two prior synthetic routes to Idraparinux have
been published. The first synthesis, involving glycosylation of
Fondaparinux is practically identical to the AT-binding penta-
saccharide sequence in heparin (referred to as DEFGH).5 It en-
hances the antithrombin mediated factor Xa inactivation 300-fold,
* Corresponding author. Tel.: þ36 52512900/22475; fax: þ36 52512914; e-mail
ꢀ
a GHl-iduronide-acceptor with a D-glucuronic acid-containing EF
addresses: borbas.aniko@pharm.unideb.hu, borbasa@puma.unideb.hu (A. Borbas).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.076

3150
M. Herczeg et al. / Tetrahedron 69 (2013) 3149e3158
donor and a subsequent [DþEFGH] coupling, was accomplished by
Westerduin et al. in 1994.6 Fifteen years later Chen and Yu de-
veloped a new [DEFþGH] route to 2.13 The common feature in these
syntheses was the application of non-oxidized precursors of the
uronic acids to construct disaccharide building blocks, and their
oxidation was achieved at disaccharide levels. Herein we report two
novel syntheses of Idraparinux, each based upon a [DEþFGH] block
synthesis utilizing the same trisaccharide acceptor, which was
coupled to either a glucuronide disaccharide donor or its non-
oxidized precursor (Fig. 1).
out in a 3:2 mixture of CH2Cl2 and Et2O at 0 ꢀC. After a routine
benzylation, donor 7 was ready to react with the -iduronic acid
acceptor 8, whose synthesis has been published recently.12
It is well-established that the condensation of a -glucopyr-
anoside donor bearing a nonparticipating group at position C2, and
either an -idose or an -iduronic acid acceptor proceeds with high
stereoselectivity to give the
-linked product.4e6,17 It is also well-
L
D
L
L
a
known that glycosyl donors and acceptors of low reactivity bene-
fit the formation of the more thermodynamically favoured prod-
uct.18 On the basis of these results, full
a-selectivity was expected
Fig. 1. Synthetic pentasaccharides with selective factor Xa inhibitory activity: Fondaparinux (1) and Idraparinux (2).
2. Results and discussion
during glycosylation of the relatively inactive uronate acceptor 8
with the glucoside donor 7. Surprisingly, condensation of com-
pounds 7 and 8 provided the corresponding disaccharide 11 as a 3:1
mixture of the a- and the b-coupled products, which turned out to
be inseparable. Hoping that the two diastereoisomers could be
separated at a trisaccharide level, the next transformations were
The target compound is built up of O-sulfated and O-methylated
glucosides and fully O-methylated uronic acids, bound to each
other with alternating 1,2-cis and 1,2-trans glycosidic linkages. Our
first approach was based on the formation of the uronic acids at
a monosaccharide level, thus precluding excessive synthetic steps
at oligosaccharide levels. The hydroxyls meant to be methylated
were masked in the form of acetates, whereas benzyl groups were
introduced to mask the hydroxyls that were to be sulfated. This
protecting group strategy was employed to ensure the stereo-
control in the glycosylation steps.
According to the retrosynthetic analysis shown in Fig. 2, the
glycosidic bond was disconnected between the E and F units pro-
viding the disaccharide donor 3 and the trisaccharide acceptor 4.
The synthesis of donor 3 has been described recently, the key step
in its preparation being the stereoselective glycosylation of an
uronate acceptor with a phenylthio-glucoside donor.11 Of the two
carried out with the
a/b-mixture. Selective deacetylation of the
anomeric position with benzylamine (12) and subsequent reaction
with trichloroacetonitrile in the presence of (1,8-diazabicyclo[5.4.0]
undec-7-ene) DBU took place smoothly affording the disaccharide
donor 5
component diastereoisomeric mixture of donor 5
coside acceptor 620 in the presence of TMSOTf proceeded stereo-
selectively to form the needed -glycosidic bond between units G
and H. Fortunately, the obtained mixture of 4 and 4 was separable
a,b
in 60% overall yield.19 Condensation of the four-
a,b and the glu-
a
b
by column chromatography furnishing the required FGH tri-
saccharide 4 in 61% yield. Due to the auspicious side reaction of
cleavage of the p-methoxybenzyl protecting group upon slightly
acidic conditions of the glycosylation, compound 4 could be used
directly as an acceptor in the next coupling reaction.
interglycosidic linkages of the
L-iduronic acid-containing tri-
saccharide 4, the more challenging 1,2-cis bond between units F
and G was intended to be prepared first.
Condensation of the uronic acid-containing donor 311 and the
trisaccharide acceptor 4 upon trimethylsilyl triflate activation
provided the desired pentasaccharide 13 in 46% yield. Next, the
The synthesis of the thioglucoside building block 7, possessing
C4-(4-methoxy)benzyl as a temporary protecting group, started
from phenyl 2,3-di-O-benzyl-4,6-O-(4-methoxy)benzylidene-1-
ꢀ
fully protected 13 was subjected to Zemplen deacetylation to lib-
thio-
b
-D
-glucopyranoside 914 (Scheme 1). Regioselective cleavage
erate the hydroxyls, which had to be methylated, to obtain 14. It
of the 4,6-O-acetal ring using the LiAlH4/AlCl3 reagent combina-
tion15 in a 3:1 ratio (forming AlH3)16 resulted in exclusively the 6-
OH derivative 10. Noteworthy, the ratio of the applied solvents
turned out to be crucial on the efficacy of the reaction. Attempts to
reductively cleave the (4-methoxy)benzylidene acetal in a 1:1
mixture of CH2Cl2 and Et2O failed at 0 ꢀC, while increasing the
temperature led to ring cleavage and degradation. Fortunately, fast
and complete reaction was observed when the reaction was carried
was found in this laboratory that sodium hydride mediated
methylation led to b-elimination of the base-sensitive uronic acid
residues.10,11 Therefore, to avoid the strongly basic conditions,
freshly prepared silver(I) oxide was used to assist the ether-
ification21 of 14 affording the desired 15 in 60% yield. Deprotection
of the carboxylic ester functions by saponification gave the diso-
dium salt 16 and subsequent demasking of the hydroxyls meant to
be sulfated by catalytic hydrogenolysis furnished 17 in high yield.

M. Herczeg et al. / Tetrahedron 69 (2013) 3149e3158
3151
Fig. 2. Retrosynthetic analysis of compound 2.
Scheme 1. Synthesis the trisaccharide acceptor 4. Reagents and conditions: (a) LiAlH4/AlCl3 (3:1); CH2Cl2/Et2O (3:2), 0 ꢀC, 30 min (87%); (b) BnBr, NaH, DMF (80%); (c) NIS, TfOH,
ꢀ
CH2Cl2, 4 A MS, ꢁ40 ꢀC, 1 h (68%); (d) BnNH2, THF, rt, 4 h (66%); (e) CCl3CN, DBU, CH2Cl2, 0 C, 30 min (91%); (f) TMSOTf, CH2Cl2, 4 A MS, ꢁ20 ꢀC, 30 min (61% for 4, 22% for 4
b).
ꢁ
ꢁ
Simultaneous O-sulfation at seven positions was achieved in one
step using excess SO3$Et3N to give, after treatment with Dowex Naþ
ion-exchange resin, target compound 2 in 73% yield (Scheme 2).
Because of the low reactivity of the glucuronide disaccharide
donor 3, its coupling with the trisaccharide acceptor 4 proceeded
with moderate yield. To increase the overall yield of our target
compound 2, another synthetic pathway was also elaborated to
construct the pentasaccharide skeleton. The new approach was
based on the application of the non-oxidized precursor of the
glucuronic acid in the [3þ2] coupling reaction, and formation of the
carboxylic function at a pentasaccharide level. Compound 1811 was
chosen as the new non-glucuronide type donor, bearing a 2-
naphthylmethyl group to temporarily protect the hydroxyl to be
oxidized. Condensation of 18 and the trisaccharide acceptor 4 upon
NIS/AgOTf activation provided the pentasaccharide 19 in 77% yield.
ꢀ
Zemplen deacetylation followed by silver(I) oxide assisted

3152
M. Herczeg et al. / Tetrahedron 69 (2013) 3149e3158
Scheme 2. [3þ2] Block synthesis of the pentasaccharide by using the glucuronide disaccharide donor 3. Reagents and conditions: (a) TMSOTf, CH2Cl2, 4 A MS, ꢁ10 ꢀC to rt, 2 h
(46%); (b) NaOMe, MeOH, rt, 24 h (77%); (c) MeI, Ag2O, DMF, rt, 4 days (60%); (d) 0.2 M NaOH, MeOH, THF, rt, 36 h (57%); (e) H2 (10 bar), Pd/C (10%), EtOH, rt, 24 h (80%); (f) SO3$Et3N,
DMF, rt, 24 h (73%).
ꢁ
methylation furnished 21, the fully protected derivative possessing
all of the required methyl ether substituents.
The first assembly of the pentasaccharide involving condensa-
tion of the trisaccharide acceptor 4 and the glucuronide di-
saccharide donor 3 provided the target compound, however, with
moderate yield due to the low efficacy of the glycosylation reaction.
Significant improvement was achieved in the synthesis when the
non-glucuronide disaccharide donor of higher reactivity (18) was
employed in the [2þ3] coupling step and the glucuronide unit was
created at a pentasaccharide level. The main advantage of the
second approach resides in the shorter and much more efficient
synthesis of the non-glucuronide donor 18 compared to the glu-
curonide donor 3.11
Selective removal of the 2-naphthylmethyl protecting group was
achieved by oxidative cleavage using DDQ as a reagent22 to afford 22
in 73% yield. The carboxylic function of unit E was formed by (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl TEMPO-based oxidation using
[bis(acetoxy)iodo]benzene (BAIB) as co-oxidant23 providing the
monosodium salt23. Then, hydrolysisoftheL-iduronicacidesterwith
sodium hydroxide resulted in the formation of disodium salt 16,
whichwasanintermediateinthefirstsynthesisrouteof2(Scheme3).
3. Conclusion
4. Experimental
In summary, two novel syntheses of Idraparinux have been ac-
complished, both employing the
trisaccharide acceptor 4 as the common building block. The syn-
thesis of this trisaccharide turned out to be challenging. The
iduronic acid-containing FG unit was formed, unexpectedly, as
a 3:1 mixture of the - and -coupled disaccharides, and, because of
the very similar chromatographic behaviour, the isomers could not
be separated. Therefore, the next transformations including
anomeric deacetylation, imidate formation and coupling reaction
with acceptor 6 were carried out with diastereoisomeric mixtures.
Fortunately, all of these reactions proceeded with high yield and
the key FGH building block 4 could be isolated in an acceptable
overall yield and also in sufficient amount.
L
-iduronic acid-containing FGH
4.1. General information
L-
Optical rotations were measured at room temperature with
a PerkineElmer 241 automatic polarimeter. TLC was performed on
Kieselgel 60 F254 (Merck) with detection by immersing into 5%
ethanolic sulfuric acid solution followed by heating. Column
chromatography was performed on Silica gel 60 (Merck
0.063e0.200 mm), Sephadex LH-20, and Sephadex G-25 (Sigma-
a
b
eAldrich, Bead size 25e100 mm). Organic solutions were dried over
MgSO4, and concentrated in vacuum. The 1H NMR (360, 400 and
500 MHz) and 13C NMR (90.54, 100.28, 125.76 MHz) spectra were
recorded with Bruker DRX-360, DRX-400 and Avance II 500

M. Herczeg et al. / Tetrahedron 69 (2013) 3149e3158
3153
Scheme 3. Improved synthesis of the fully methylated pentasaccharide 16. Reagents and conditions: (a) NIS, AgOTf, CH2Cl2, 4 A MS, ꢁ20 ꢀC to rt, 3 h (77%); (b) NaOMe, MeOH, rt,
ꢁ
24 h (99%); (c) MeI, Ag2O, DMF, rt, 36 h (51%); (d) DDQ, CH2Cl2/H2O (9:1), rt, 30 min (73%); (e) TEMPO, BAIB, CH2Cl2, H2O, rt 5 h (68%); (f) 0.5 M NaOH, MeOH, THF, rt, 6 h (85%).
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,
CD3OD: 49.15 ppm for 13C). IR spectra were recorded on a Per-
kineElmer 16 PC FTIR spectrometer. MALDI-TOF MS analyses of the
compounds 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 satd 2,4,6-
trihydroxy-acetophenone (THAP) solution in MeCN. Elemental
analyses (C, H, S) were performed using an Elementar Vario
MicroCube instrument.
obtained heterogeneous mixture containing a finely precipitated
solid was filtered through a pad of Celite, and the filter cake was
washed with EtOAc (2ꢂ5 mL). The combined filtrates were trans-
ferred into a separating funnel and diluted with EtOAc (50 mL), the
layers were separated and the organic phase was washed with H2O
(3ꢂ50 mL), dried and concentrated. The residue was purified by
silica gel chromatography (95:5 CH2Cl2/EtOAc) to give 10 (500 mg,
87%), as white needles; mp 141e143 ꢀC (from MeOH); [
a
]
25 ꢁ0.8 (c
D
0.10, CHCl3); Rf 0.38 (95:5 CH2Cl2/EtOAc); IR nmax (KBr): 3322, 3058,
3029, 2905, 2345, 1944, 1879, 1612, 1585, 1515, 1401, 1358, 1253,
1130, 1062, 1040, 988, 824, 742, 695, 649, 621, 558, 536, 499 cmꢁ1
;
4.2. Phenyl 2,3-di-O-benzyl-4-O-(4-methoxybenzyl)-1-thio-
-glucopyranoside (10)
b-
1H NMR (CDCl3, 360 MHz):
d¼7.52e6.81 (m, 19H, arom), 4.92e4.86
D
(m, 3H, CH2Ph), 4.78e4.56 (m, 4H, CH2Ph, H-1), 3.87e3.83 (m, 1H),
3.73 (s, 3H, OCH3), 3.70e3.64 (m, 2H), 3.56 (t, 1H, J 9.3 Hz), 3.47 (t,
1H, J 9.3 Hz), 3.38e3.33 (m, 1H), 2.25 (t, 1H, J 6.5 Hz, OH) ppm; 13C
To a stirred solution of 914 (570 mg, 0.997 mmol) in a mixture of
dry CH2Cl2 (9 mL) and dry Et2O (3 mL), LiAlH4 (171 mg, 4.50 mmol)
and a solution of AlCl3 (200 mg, 1.50 mmol) in dry Et2O (3 mL) were
successively added under argon at 0 ꢀC. When the TLC (95:5 CH2Cl2/
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 (20 mL), and H2O
(5 mL), and the mixture stirred for an additional 10 min. The
NMR (CDCl3, 90 MHz):
d
¼159.2, 138.2, 137.7, 133.4, 129.8 (5ꢂCq
arom), 131.7, 129.7, 128.9, 128.4, 128.3, 128.1, 127.6. 127.5, 113.7 (19C,
arom), 87.4 (C-1), 86.4, 80.9, 79.2, 77.1 (C-2, C-3, C-4, C-5), 75.6,
75.4, 74.6 (3ꢂCH2Ph), 61.8 (C-6), 55.1 (OCH3) ppm; MALDI-TOF
(positive ion): m/z calcd for [MþNa]þ 595.21. Found: 595.15. Anal.
Calcd for C34H36O6S (572.71): C, 71.30; H, 6.34; S, 5.60. Found: C,
71.61; H, 6.39; S, 5.53.

3154
M. Herczeg et al. / Tetrahedron 69 (2013) 3149e3158
4.3. Phenyl 2,3,6,-tri-O-benzyl-4-O-(4-methoxybenzyl)-1-
thio- -glucopyranoside (7)
for 4 h. The reaction was quenched in aq 1 M HCl (10 mL), extracted
with CH2Cl2 (3ꢂ50 mL), and the organic phase was washed with
H2O (10 mL), aq NaHCO3 (10 mL) and H2O (10 mL), dried and
concentrated. Column chromatography (9:1 n-hexane/acetone)
b-D
To a solution of 10 (4.60 g, 8.04 mmol) in DMF (38 mL) at 0 ꢀC
NaH (60%, 386 mg, 9.65 mmol) was added. After 30 min stirring at
this temperature, BnBr (1.19 mL, 10.04 mmol) was added, and the
reaction mixture was allowed to warm up to room temperature.
After completion of the reaction (4 h), MeOH (10 mL) was added.
The reaction mixture was stirred for 15 min, then the solvents were
evaporated. The residue was diluted with CH2Cl2 (300 mL), washed
with H2O (3ꢂ100 mL), dried and concentrated. The crude product
was purified by silica gel chromatography (6:4 n-hexane/EtOAc) to
gave 12 (810 mg, 66%) as a colourless oil; [
a
]
D
25 þ0.2 (c 0.15, CHCl3);
Rf 0.40 (6:4 n-hexane/acetone); 1H NMR (CDCl3, 360 MHz):
d
¼7.45e6.75 (m, 68H, arom), 4.98e4.18 (m, 36H), 4.09e3.76 (m,
11H), 3.72, 3.71, 3.69, 3.68 (4ꢂs, 20H, 8ꢂOCH3), 3.64e3.32 (m, 20H),
2.62 (s, 2H, 4ꢂOH), 2.08, 2.05, 1.99 (3ꢂs, 7H, 4ꢂCH3) ppm; 13C NMR
(CDCl3, 90 MHz):
d¼170.6, 170.1, 169.8, 169.7, 169.3, 169.2, 159.0,
158.6 (8ꢂCO), 139.9, 139.5, 139.4, 138.3, 138.1, 137.8, 137.7, 137.6,
130.5, 130.4, 129.8 (20ꢂCq arom), 129.3e113.3 (76C, arom), 105.2,
give 7 (4.26 g, 80%) as a white powder; mp: 74e79 ꢀC (from ace-
104.9, 99.9, 99.6, 99.3, 95.1 (C-1a,b a,b), 85.2, 84.5, 84.0, 83.5,
; C-10
25
tone/MeOH); [
a
]
ꢁ0.4 (c 0.22, CHCl3); Rf 0.72 (6:4 n-hexane/
81.9, 81.5, 81.3, 79.3, 78.5, 77.2, 75.7, 75.2, 74.9, 74.4, 74.2, 73.4, 70.9,
70.8, 70.1, 69.5, 68.6 (skeleton carbons), 75.6, 75.4, 75.1, 74.3, 73.9,
73.5, 73.2, 72.8 (16ꢂCH2Ph), 69.0, 67.7 (4ꢂC-6), 59.3, 58.1, 57.9, 54.9,
52.2, 51.9, 51.7 (8ꢂOCH3), 21.2, 21.0 (4ꢂCH3) ppm; MALDI-TOF
(positive ion): m/z calcd for [MþNa]þ 839.32. Found: 839.27. Anal.
Calcd for C45H52O14 (816.34): C, 66.16; H, 6.42. Found: C, 66.22; H,
6.49.
D
EtOAc); IR nmax (KBr): 3087, 3058, 3030, 2901, 1947, 1879, 1805,
1734,1654,1613,1359,1254,1066, 993, 823, 735, 695, 652, 603, 560,
520 cmꢁ1; 1H NMR (CDCl3, 360 MHz):
d
¼7.58e6.80 (m, 24H, arom),
4.88e4.54 (m, 9H, H-1, 4ꢂCH2Ph), 3.73 (s, 3H, OCH3), 3.75e3.48 (m,
6H, H-2, H-3, H-4, H-5, H-6a,b) ppm; 13C NMR (CDCl3, 90 MHz):
d
¼138.3, 138.1, 137.9, 133.7, 130.0 (6ꢂCq arom), 131.7, 129.5, 128.7,
128.4, 128.3, 128.2, 128.1, 127.8, 127.6, 127.5, 127.4, 127.3, 113.7 (24C,
arom), 87.3 (C-1), 86.6, 80.6, 78.9, 77.3 (C-2, C-3, C-4, C-5), 75.6,
75.3, 74.6, 73.2 (4ꢂCH2Ph), 68.8 (C-6), 55.1 (OCH3) ppm; MALDI-
TOF (positive ion): m/z calcd for [MþNa]þ 685.26. Found: 685.23.
Anal. Calcd for C41H42O6S (662.83): C, 74.29; H, 6.39; S, 4.84. Found:
C, 74.32; H, 6.44; S, 4.86.
4.6. Methyl [2,3,6-tri-O-benzyl-4-O-(4-methoxybenzyl)-
glucopyranosyl]-(1/4)-2-O-acetyl-3-O-methyl-1-O-tri-
a,b-D-
chloroacetimidoyl-a,b-L-idopyranosyluronate (5a,b)
A solution of 12 (780 mg, 1.00 mmol) in dry CH2Cl2 (14 mL) was
cooled to 0 ꢀC, trichloroacetonitrile (1.80 mL, 18.0 mmol) and DBU
4.4. Methyl [2,3,6-tri-O-benzyl-4-O-(4-methoxybenzyl)-
a
,
b-D
-
(35 mL, 0.234 mmol) were added. After stirring for 30 min, the
glucopyranosyl]-(1/4)-1,2-di-O-acetyl-3-O-methyl-
pyranosyluronate (11)
b
-
L
-ido-
mixture was concentrated under reduced pressure, and purified by
column chromatography (6:4 n-hexane/acetoneþ1% Et3N) to give
5a
,b
(830 mg, 91%) as a colourless syrup; [
a]
25 ꢁ0.3 (c 0.12, CHCl3);
D
To a solution of 8 (678 mg, 2.21 mmol) and phenylthio-glucoside
Rf 0.59 (6:4 n-hexane/acetone, containing 1% of Et3N); MALDI-TOF
(positive ion): m/z calcd for [MþNa]þ 982.23. Found: 982.32.
Anal. Calcd for C47H52Cl3NO14 (959.25): C, 58.72; H, 5.45. Found: C,
58.89; H, 5.63.
ꢁ
7 (2.20 g, 3.32 mmol) in dry CH2Cl2 (60 mL), 4 A molecular sieves
(1.00 g) were added. The stirred mixture was cooled to ꢁ45 ꢀC
under argon. After 30 min at this temperature, a mixture of NIS
(971 mg, 4.31 mmol) and TfOH (88 mL, 0.990 mmol) dissolved in
THF (2.3 mL) was added. After 2 h stirring at ꢁ10 ꢀC, Et3N (500
m
L)
4.7. Methyl (2,3,6-tri-O-benzyl-
(methyl 2-O-acetyl-3-O-methyl-
(1/4)-2,3,6-tri-O-benzyl- -glucopyranoside (4) and methyl
(2,3,6-tri-O-benzyl- -glucopyranosyl)-(1/4)-(methyl 2-O-
acetyl-3-O-methyl- -idopyranosyluronate)-(1/4)-2,3,6-tri-
O-benzyl- -glucopyranoside (4
a
-
D
-glucopyranosyl)-(1/4)-
was added. The reaction mixture was diluted with CH2Cl2 (250 mL),
and filtered through a pad of Celite. The filtrate was washed suc-
cessively with 10% aq Na2S2O3 (60 mL), H2O (60 mL), aq NaHCO3
(60 mL), H2O (60 mL), dried and concentrated. The crude product
was purified by silica gel chromatography (1. 6:4 n-hexane/EtOAc;
a-L-idopyranosyluronate)-
a-D
b-D
a-L
a
-D
b)
2. 99:1 CH2Cl2/MeOH) to give 11 (1.30 g, 68%,
a
/
b
w3:1) as a col-
25
ourless syrup; [
EtOAc); IR nmax (KBr): 3028, 2931, 1763, 1740, 1611, 1513, 1452, 1366,
1302, 1247, 1218, 1137, 1065, 960, 821, 771, 698, 605, 528 cmꢁ1 1H
NMR (CDCl3, 360 MHz):
¼7.40e6.78 (m, 26H, arom), 6.01 (d, 0.3H,
J 1.5 Hz, H-1 ), 5.97 (d, 1H, J 1.5 Hz, H-1 ), 4.96e4.38 (m, 14H),
a]
þ1.8 (c 0.07, CHCl3); Rf 0.38 (6:4 n-hexane/
To a solution of 620 (268 mg, 0.570 mmol) and disaccharide
D
ꢁ
donor 5
a,
b
(830 mg, 0.860 mmol) in dry CH2Cl2 (22 mL), 4 A mo-
;
lecular sieves (1.00 g) were added. The stirred mixture was cooled
d
to ꢁ20 ꢀC under argon. After 20 min at this temperature, TMSOTf
b
a
(21 mL, 0.079 mmol) in CH2Cl2 (780 mL) was added. After stirring at
4.17e4.15 (m, 0.3H), 4.05e4.01 (m, 0.3H), 3.91e3.82 (m, 3.3H), 3.77
(s, 3H, OCH3), 3.76e3.71 (m, 1.3H), 3.69 (s, 0.9H, OCH3), 3.68e3.64
(m, 8H), 3.59e3.46 (m, 5.6H), 2.12e2.08 (m, 8H, COCH3) ppm; 13C
ꢁ10 ꢀC for 2 h, Et3N (200
mL) was added and the reaction mixture
was concentrated. The crude product was purified by silica gel
chromatography (55:45 n-hexane/EtOAc) to give 4 (400 mg, 61%)
NMR (CDCl3, 90 MHz):
159.4e113.6 (38C, arom), 105.2 (C-1
89.9 (C-1 ), 84.7, 82.4, 81.8, 79.6, 77.5, 77.2, 76.3, 75.6, 74.9, 74.8,
d
¼170.7, 170.3, 168.8, 168.7, 168.0 (6ꢂCO),
and 4
b
(144 mg, 22%). Compound 4: colourless syrup; [
a
]
25 þ2.3 (c
D
b
), 100.1 (C-1’ ), 90.1 (C-1 ),
a
b
0.10, CHCl3); Rf 0.52 (55:45 n-hexane/EtOAc); IR nmax (KBr): 3028,
a
2927, 1735, 1496, 1452, 1369, 1218, 1102, 1045, 770, 739, 697 cmꢁ1
;
71.3, 69.8, 66.6, 66.3 (16C, skeleton carbons), 75.8, 75.4, 74.3, 73.8,
73.5 (6ꢂCH2Ph), 69.3, 68.0 (2ꢂC-60), 58.5, 55.2, 52.4 (3ꢂOCH3), 21.2,
20.9 (2ꢂCH3) ppm; MALDI-TOF (positive ion): m/z calcd for
[MþNa]þ 881.34. Found: 881.32. Anal. Calcd for C47H54O15 (858.35):
C, 65.72; H, 6.34. Found: C, 65.79; H, 6.35.
1H NMR (CDCl3, 400 MHz):
d
¼7.34e7.20 (m, 30H, arom), 5.19 (d, 1H,
J1 ,2 2.3 Hz, H-10), 4.90e4.87 (m, 3H, CH2Ph, H-100), 4.85e4.64 (m,
7H), 4.58e4.47 (m, 6H, 2ꢂCH2Ph, H-1), 3.91e3.89 (m, 2H, H-4, H-
40), 3.86e3.83 (m, 1H, H-3), 3.81e3.78 (m, 1H, H-500), 3.72e3.62 (m,
7H, H-400, H-30, H-300, H-5, H-6a,b, H-600a), 3.57e3.51 (m, 2H, H-600b,
H-2), 3.48e3.44 (m, 1H, H-200), 3.38, 3.36, 3.33 (3ꢂs, 9H, 3ꢂOCH3),
2.49 (s, 1H, OH), 1.92 (s, 3H, CH3) ppm; 13C NMR (CDCl3, 100 MHz):
0
0
4.5. Methyl [2,3,6-tri-O-benzyl-4-O-(4-methoxybenzyl)-a,b-D-
glucopyranosyl]-(1/4)-2-O-acetyl-3-O-methyl-
anosuronate (12)
a
,
b
-
L
-idopyr-
d
¼169.8, 169.2 (2ꢂCO), 138.9, 138.6, 137.9, 137.8, 137.7 (5ꢂCq arom),
128.3e126.8 (30C, arom), 98.9 (C-100), 97.9 (C-1), 97.6 (C-10), 80.7 (C-
30), 79.8 (C-3), 79.6 (C-2), 79.2 (C-200), 76.6 (C-300), 74.9, 74.6 (C-4, C-
40), 71.0 (C-400), 70.5 (C-500), 69.9 (C-5), 68.9 (C-50), 68.6 (C-20), 74.8,
73.4, 73.2, 72.9 (6ꢂCH2Ph), 69.1 (C-600), 68.2 (C-6), 58.6, 55.0, 51.5
To a solution of 11 (1.30 g, 1.51 mmol) in THF (10 mL), BnNH2
(580 L, 5.30 mmol) was added. The reaction mixture was stirred
m

M. Herczeg et al. / Tetrahedron 69 (2013) 3149e3158
3155
(3ꢂOCH3), 20.8 (CH3) ppm; MALDI-TOF (positive ion): m/z calcd for
1752, 1496, 1452, 1365, 1218, 1101, 1039, 908, 771, 698 cmꢁ1
;
1H
¼7.38e7.24 (m, 35H, arom), 5.43 (d, 1H, J
[MþNa]þ 1165.48. Found: 1165.53. Anal. Calcd for C65H74O18
NMR (CDCl3, 360 MHz):
d
(1142.49): C, 68.29; H, 6.52. Found: C, 68.37; H, 6.51.
3.5 Hz), 5.15 (s, 1H), 4.97e4.94 (m, 2H), 4.80e4.75 (m, 2H),
4.65e4.45 (m, 13H), 4.35 (d, J 7.5 Hz, 1H), 3.98e3.85 (m, 7H),
3.82e3.64 (m, 9H), 3.63e3.25 (m, 5H), 3.61, 3.55, 3.50, 3.49, 3.43,
3.37, 3.33, 3.28 (8ꢂs, 24H, 8ꢂOCH3), 3.20e3.12 (m, 4H), 2.13 (s, 2H,
Compound 4
b
: colourless syrup; [
a
]
25 þ148.5 (c 0.07, CHCl3); Rf
D
0.44 (55:45 n-hexane/EtOAc); 1H NMR (CDCl3, 360 MHz):
d
¼7.38e7.19 (m, 30H, arom), 5.12 (s, 1H, H-10), 4.98e4.57 (m, 14H,
6ꢂCH2Ph, H-1, H-50), 4.39 (d, 1H, J1 ,2 7.6 Hz, H-100), 3.98e3.93 (m,
2H), 3.87e3.76 (m, 5H), 3.72e3.54 (m, 5H), 3.48e3.24 (m, 3H), 3.36,
3.34, 3.26 (3ꢂs, 9H, 3ꢂOCH3), 2.45 (s, 1H, OH), 1.90 (s, 3H,
2ꢂOH) ppm; 13C NMR (CDCl3, 90 MHz):
¼169.6, 168.3 (2ꢂCO),
d
00 00
139.9, 138.7, 137.9, 137.8, 137.5, 137.3, 137.1 (7ꢂCq arom),
128.4e126.7 (35C, arom), 102.6, 100.7, 97.7, 96.4, 95.5 (5ꢂC-1), 84.7,
82.9, 81.3, 80.0, 79.5, 78.6, 77.7, 74.4, 74.3, 74.1, 73.9, 71.4, 70.5, 70.2,
69.9, 66.8, 65.8 (20C, skeleton carbons), 75.0, 73.4, 73.2, 73.1
(7ꢂCH2Ph), 68.5, 67.7, 67.6 (3ꢂC-6), 60.5, 60.2, 59.7, 58.8, 57.6, 54.9,
52.1, 51.7 (8ꢂOCH3) ppm; MALDI-TOF (positive ion): m/z calcd for
[MþNa]þ 1621.68. Found: 1621.57. Anal. Calcd for C87H106O28
(1598.69): C, 65.32; H, 6.68. Found: C, 65.25; H, 6.60.
CH3) ppm; 13C NMR (CDCl3, 90 MHz):
d
¼169.8, 169.5 (2ꢂCO), 138.8,
138.3, 137.8, 137.7, 137.6 (5ꢂCq arom), 128.4e126.8 (30C, arom),
104.9 (C-100), 97.8, 97.5 (C-1, C-10), 83.8, 81.3, 79.9, 79.7, 75.7, 74.2,
73.9, 73.5, 71.2, 69.9, 66.8, 66.7 (12C, skeleton carbons), 75.4, 74.8,
74.2, 73.5, 73.3, 73.2 (6ꢂCH2Ph), 70.3 (C-600), 68.6 (C-6), 58.1, 55.0,
51.7 (3ꢂOCH3), 21.0 (CH3) ppm; MALDI-TOF (positive ion): m/z
calcd for [MþNa]þ 1165.48. Found: 1165.53. Anal. Calcd for
C65H74O18 (1142.49): C, 68.29; H, 6.52. Found: C, 68.71; H, 6.87.
4.10. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
a
-
D
-glucopyr-
-glucopyr-
-D-glucopyr-
anosyl)-(1/4)-(methyl 2,3-di-O-methyl-
anosyluronate)-(1/4)-(2,3,6-tri-O-benzyl-
anosyl)-(1/4)-(methyl 2,3-di-O-methyl-
b-
D
4.8. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(methyl 2-O-acetyl-3-O-methyl-
anosyluronate)-(1/4)-(2,3,6-tri-O-benzyl- -glucopyr-
anosyl)-(1/4)-(methyl 2-O-acetyl-3-O-methyl-
a
-D
-glucopyr-
a
b-
D-glucopyr-
a
-
L-
a
-
D
idopyranosyluronate)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyr-
anoside (15)
a
-L-
idopyranosyluronate)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyr-
anoside (13)
To a solution of 14 (160 mg, 0.100 mmol) in DMF (3 mL) at room
temperature were successively added freshly prepared Ag2O
To a solution of trisaccharide acceptor 4 (340 mg, 0.297 mmol)
and disaccharide donor 311 (421 mg, 0.599 mmol) in dry CH2Cl2
(185 mg, 0.798 mmol, 4 equiv/OH) and MeI (25 mL, 0.400 mmol,
2 equiv/OH). After 4 days stirring at this temperature, the mixture
was diluted with CH2Cl2, filtered through a pad of Celite and the
filtrate was concentrated under reduced pressure. The crude
ꢁ
(15 mL), 4 A molecular sieves (1.00 g) were added. The stirred
mixture was cooled to ꢁ10 ꢀC under argon. After 20 min at this
temperature, TMSOTf (11
mL, 0.060 mmol) in CH2Cl2 (300
mL) was
product was purified by silica gel chromatography (1:1 n-hexane/
25
added and the mixture was allowed to warm up to 10 ꢀC in 2 h. The
mixture was diluted with CH2Cl2 (200 mL) washed successively
with H2O (60 mL), aq NaHCO3 (60 mL) and H2O (60 mL), dried and
concentrated. The crude product was purified by silica gel chro-
matography (1:1 n-hexane/EtOAc) to give 13 (228 mg, 46%) as
EtOAc) to give 15 (97 mg, 60%) as a colourless syrup; [
a]
þ6.6 (c
D
0.08, CHCl3); Rf 0.42 (1:1 n-hexane/EtOAc); IR nmax (KBr): 3460,
2932, 2360,1748,1496,1453,1363,1265,1218,1102,1077,1038, 909,
772, 698, 673, 602, 563 cmꢁ1
;
1H NMR (CDCl3, 360 MHz):
d
¼7.36e7.20 (m, 35H, arom), 5.44 (d, 1H, J 3.5 Hz), 5.29 (d, 1H, J
a colourless syrup; [
EtOAc); IR nmax (KBr): 3435, 3061, 3029, 2930, 1751, 1496, 1453,
a
]
25 þ5.8 (c 0.11, CHCl3); Rf 0.35 (1:1 n-hexane/
5.6 Hz), 5.12 (d,1H, J 3.2 Hz), 4.95e4.54 (m,12H), 4.49e4.41 (m, 4H),
4.27 (d, 1H, J 7.8 Hz), 3.92e3.78 (m, 10H), 3.75e3.64 (m, 6H),
3.60e3.29 (m, 5H), 3.63, 3.57, 3.53, 3.48, 3.46, 3.44, 3.43, 3.37 (10ꢂs,
30H, 10ꢂOCH3), 3.19e3.11 (m, 2H), 2.98e2.92 (m, 2H) ppm; 13C
D
1370, 1227, 1157, 1102, 1075, 1040, 911, 844, 822, 738, 698, 605,
560 cmꢁ1; 1H NMR (CDCl3, 360 MHz):
d
¼7.49e7.39 (m, 35H, arom),
5.49 (s, 1H), 5.32 (s, 1H), 5.10e4.45 (m, 18H), 4.24e4.14 (m, 2H),
4.08e4.01 (m, 4H), 3.83, 3.77, 3.65, 3.59, 3.57, 3.52, 3.48, 3.47 (8ꢂs,
24H, 8ꢂOCH3), 3.83e3.47 (m, 17H), 3.36e3.30 (m, 2H), 2.09 (s, 6H,
NMR (CDCl3, 90 MHz):
d¼169.6, 168.5 (2ꢂCO), 139.0, 138.9, 138.2,
138.0, 137.7 (7ꢂCq arom), 128.5e126.9 (35C, arom), 102.9, 99.9, 98.7,
98.1, 96.6 (5ꢂC-1), 85.3, 83.8, 83.4, 83.1, 81.4, 80.5, 80.1, 79.3, 78.7,
78.4, 77.5, 76.5, 75.5, 74.3, 72.4, 70.8, 70.5, 70.1 (20C, skeleton car-
bons), 73.5, 73.4, 73.2, 72.7 (7ꢂCH2Ph), 67.9, 67.7, 67.2 (3ꢂC-6),
60.6, 60.2, 60.1, 59.1, 55.2, 52.1, 51.4 (10ꢂOCH3) ppm; MALDI-TOF
(positive ion): m/z calcd for [MþNa]þ 1649.71. Found: 1649.71.
Anal. Calcd for C89H110O28 (1626.72): C, 65.67; H, 6.81. Found: C,
65.53; H, 6.72.
2ꢂCH3) ppm; 13C NMR (CDCl3, 90 MHz):
¼169.8,169.2,168.5,167.8
d
(4ꢂCO), 138.7, 138.0, 137.8, 137.6, 137.3 (7ꢂCq arom), 128.4e126.6
(35C, arom), 100.0, 99.1, 97.6, 97.3, 96.6 (5ꢂC-1), 83.0, 82.8, 81.2,
79.6, 79.5, 79.2, 78.7, 78.5, 76.4, 74.8, 74.5, 74.3, 72.0, 70.6, 69.8, 68.7,
68.0 (20C, skeleton carbons), 73.3, 73.1, 73.0 (7ꢂCH2Ph), 67.8, 67.5,
66.7 (3ꢂC-6), 60.3, 60.1, 58.7, 58.3, 54.8, 52.0, 51.5 (8ꢂOCH3), 20.7,
20.5 (2ꢂCH3) ppm; MALDI-TOF (positive ion): m/z calcd for
[MþNa]þ 1705.70. Found: 1705.78. Anal. Calcd for C91H110O30
(1682.71): C, 64.91; H, 6.58. Found: C, 64.82; H, 6.50.
4.11. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(sodium 2,3-di-O-methyl- -glucopyr-
anosyluronate)-(1/4)-(2,3,6-tri-O-benzyl- -glucopyr-
anosyl)-(1/4)-(sodium 2,3-di-O-methyl-
a-D-glucopyr-
b-D
a-D
4.9. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(methyl 3-O-methyl- -glucopyr-
anosyluronate)-(1/4)-(2,3,6-tri-O-benzyl- -glucopyr-
anosyl)-(1/4)-(methyl 3-O-methyl-
a
-D
-glucopyr-
a-L-
b-D
idopyranosyluronate)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyr-
anoside (16)
a
-
D
a-L-
idopyranosyluronate)-(1/4)-2,3,6-tri-O-benzyl-
anoside (14)
a
-
D
-glucopyr-
Compound 15 (90 mg, 0.055 mmol) was dissolved in MeOH/THF
(1:1, 4 mL) and treated with 0.2 M aq NaOH solution (1 mL). After
24 h stirring at room temperature the TLC showed complete con-
version of the carboxylic esters into sodium salts. The mixture was
neutralized with acetic acid, concentrated in vacuo, and the residue
To a solution of 13 (228 mg, 0.135 mmol) in MeOH (5 mL)
a catalytic amount of NaOMe (10 mg, 0.185 mmol) was added. After
24 h stirring, the mixture was neutralized with Amberlite IR-120 Hþ
ion-exchange resin, filtered, and concentrated. The crude product
was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to
25
give 16 (52 mg, 57%) as a colourless syrup; [
a
]
þ6.3 (c 0.03,
D
was purified by silica gel chromatography (9:1 CH2Cl2/acetone) to
MeOH); Rf 0.38 (95:5 CH2Cl2/MeOH); IR nmax (KBr): 2919, 2359,
1219, 1026, 772, 673 cmꢁ1 1H NMR (CD3OD, 360 MHz):
¼7.37e7.21 (m, 35H, arom), 5.41 (d, 1H, J 3.6 Hz), 5.21 (d, 1H, J
25
give 14 (160 mg, 77%) as a colourless syrup; [
a
]
þ5.2 (c 0.11,
;
D
CHCl3); Rf 0.47 (9:1 CH2Cl2/acetone); IR nmax (KBr): 3475, 2929,
d

3156
M. Herczeg et al. / Tetrahedron 69 (2013) 3149e3158
5.5 Hz), 5.08 (d, 1H, J 3.4 Hz), 4.99 (d, 1H, J 10.8 Hz), 4.89e4.40 (m,
16H), 4.02e3.95 (m, 2H), 3.88e3.63 (m, 12H), 3.61e3.30 (m, 2H),
3.58, 3.52, 3.48, 3.45, 3.41, 3.36, 3.33 (8ꢂs, 24H, 8ꢂOCH3),
(m, 1H, H-2-G), 3.37e3.29 (m, 3H, H-4-D, H-2-D, H-2-E) ppm; these
data are consistent with those are given in the literature;6 13C NMR
(D2O,125 MHz):
d
¼173.9,173.7 (2ꢂCO),102.4 (C-1-E),101.7 (C-1-G),
3.29e2.94 (m, 9H) ppm; 13C NMR (CD3OD, 90 MHz):
d¼140.3, 139.8,
98.2 (C-1-H), 97.2 (2C, C-1-D, C-1-F), 86.0 (C-3-E), 83.6 (C-2-E), 82.8
(C-3-D), 81.2 (C-2-D), 79.0 (C-4-D), 78.1 (C-2-G), 76.9 (C-3-H), 76.8
(C-3-G), 76.6 (C-5-F), 76.5 (C-3-F), 76.4 (C-2-H), 75.9 (2C, C-2-F, C-4-
H), 75.2 (C-4-E), 74.6 (C-4-G), 74.3 (C-4-F), 70.8 (C-5-F), 70.0 (C-5-
D), 69.9 (C-5-H), 69.7 (C-5-G), 67.2, 66.8, 66.5 (3ꢂC-6), 61.4, 61.1,
60.9, 60.4, 59.8, 58.9, 56.2 (8ꢂOCH3) ppm; ESI-MS (negative ion):
m/z found: 817.9 [Mꢁ4Naþ2H]2ꢁ, 537.6 [Mꢁ5Naþ2H]3ꢁ. Anal.
Calcd for C38H55Na9O49S7 (1727.18): C, 26.43; H, 3.27; S, 13.00.
Found: C, 25.94; H, 3.56; S, 11.99.
139.7, 139.6, 139.4 (7ꢂCq arom), 129.8e128.3 (35C, arom), 104.1,
101.1, 99.0, 97.9 (5ꢂC-1), 86.9, 85.5, 84.4, 83.1, 81.1, 81.0, 80.4, 80.3,
78.6, 77.8, 76.8, 72.1, 71.9, 71.7 (20C, skeleton carbons), 76.6, 76.2,
74.6, 74.5, 74.1 (7ꢂCH2Ph), 69.6, 69.4, 69.0 (3ꢂC-6), 61.2, 61.1, 60.9,
60.7, 60.3, 59.8, 55.6 (8ꢂOCH3) ppm; MALDI-TOF (positive ion): m/z
calcd for [MþNa]þ 1621.69. Found: 1621.65. Anal. Calcd for
C87H104Na2O28 (1642.65): C, 63.57; H, 6.38. Found: C, 63.60; H, 6.41.
The title compound was also prepared, analogously as described
above, from 23 to give, after silica gel chromatography, 16 (73 mg,
85%) as a colourless syrup.
4.14. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(2,3-di-O-acetyl-6-O-(2-naphthyl)methyl-
glucopyranosyl)-(1/4)-(2,3,6-tri-O-benzyl- -glucopyr-
anosyl)-(1/4)-(methyl 2-O-acetyl-3-O-methyl- -idopyr-
-glucopyrano-
a-D-glucopyr-
b-D-
4.12. Methyl (2,3,4-tri-O-methyl-
(sodium 2,3-di-O-methyl- -glucopyranosyluronate)-(1/4)-
-glucopyranosyl)-(1/4)-(sodium 2,3-di-O-methyl-
idopyranosyluronate)-(1/4)- -glucopyranoside (17)
a-
D-glucopyranosyl)-(1/4)-
a-D
b-D
a-L
(a
-D
a
-L-
anosyluronate)-(1/4)-2,3,6-tri-O-benzyl-a-D
a-
D
side (19)
Compound 16 (100 mg, 0.061 mmol) was dissolved in 96% EtOH/
AcOH (19:1, 5 mL), and Pd/C (10%, 44 mg) was added and stirred in
an autoclave under a H2 atmosphere (at 10 bar) for 24 h. The cat-
alyst was filtered off through a pad of Celite and the filtrate was
concentrated under reduced pressure. The crude product was pu-
To a solution of trisaccharide 4 (380 mg, 0.332 mmol), and di-
saccharide 18 (391 mg, 0.494 mmol) in dry CH2Cl2 (12 mL), 4 A
ꢁ
molecular sieves (1.00 g) were added. The stirred mixture was
cooled to ꢁ20 ꢀC under argon. After 30 min at this temperature, NIS
(134 mg, 0.594 mmol) dissolved in THF (300 mL) and AgOTf (31 mL,
rified by Sephadex LH-20 column chromatography eluting with
0.120 mmol) dissolved in toluene (100
mL) were added. After 3 h
25
MeOH to give 17 (49 mg, 80%) as a colourless syrup; [
a
]
þ8.5 (c
stirring at 0 ꢀC, pyridine (50
mL) was added. The reaction mixture
D
0.03, MeOH); Rf 0.35 (7:6:1 CH2Cl2/MeOH/H2O); 1H NMR (D2O,
360 MHz):
was diluted with CH2Cl2 (200 mL), and filtered through a pad of
Celite. The filtrate was washed successively with 10% aq Na2S2O3
(50 mL), H2O (50 mL), aq NaHCO3 (50 mL), H2O (50 mL), dried and
concentrated. The crude product was purified by silica gel chro-
matography (1:1 n-hexane/EtOAc) to give 19 (465 mg, 77%) as
d
¼5.46 (d, 1H, J 3.5 Hz), 5.12 (d, 1H, J 3.6 Hz), 5.05 (s, 1H),
4.69 (s, 1H), 4.56 (d, 1H, J 7.8 Hz), 4.19 (s, 1H), 3.90e3.69 (m, 14H),
3.65, 3.64, 3.63, 3.56, 3.54, 3.52, 3.51, 3.41 (8ꢂs, 24H, 8ꢂOCH3),
3.59e3.51 (m, 6H), 3.48e3.45 (m, 1H), 3.35e3.23 (m, 4H) ppm; 13C
NMR (D2O, 90 MHz):
d
¼175.9,175.6 (2ꢂCO),103.1,100.1,100.0, 96.9,
a colourless syrup; [
EtOAc); IR nmax (KBr): 3440, 3061, 3028, 2930, 1952, 1753, 1633,
a
]
25 þ4.3 (c 0.12, CHCl3); Rf 0.42 (1:1 n-hexane/
D
96.7 (5ꢂC-1), 86.6, 84.0, 82.6, 81.6, 79.4, 79.2, 78.5, 78.3, 77.2, 76.6,
75.0, 72.7, 72.5, 72.3, 71.7, 71.6, 71.5, 70.1 (20C, skeleton carbons),
61.5, 61.2, 60.7, 60.4, 59.9, 59.6, 58.9, 55.9 (8ꢂOCH3), 61.1, 60.5
(3ꢂC-6) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ
1035.31. Found: 1035.30. Anal. Calcd for C38H62Na2O28 (1012.86): C,
63.57; H, 6.38. Found: C, 64.03; H, 6.59.
1604, 1496, 1453, 1367, 1316, 1239, 1217, 1155, 1101, 1042, 903, 856,
819, 739, 698, 605, 540, 477 cmꢁ1 1H NMR (CDCl3, 360 MHz):
;
d
¼7.79e7.11 (m, 42H, arom), 5.15 (d, 1H, J 2.5 Hz), 5.08e5.05 (m,
3H), 4.88e4.25 (m, 18H), 3.95e3.83 (m, 5H), 3.74e3.62 (m, 10H),
3.55e3.51 (m, 3H), 3.40e3.32 (m, 6H), 3.58, 3.41, 3.40, 3.34, 3.33,
3.31 (6ꢂs, 18H, 6ꢂOCH3), 3.29e3.05 (m, 3H), 2.01, 1.90, 1.88 (3ꢂs,
4.13. Nona-sodium [methyl(2,3,4-tri-O-methyl-6-O-sulfo-
9H, 3ꢂCH3) ppm; 13C NMR (CDCl3, 90 MHz):
¼169.9, 169.7, 169.4
d
nato-
pyranosyluronate)-(1/4)-(2,3,6-tri-O-sulfonato-
pyranosyl)-(1/4)-(2,3-di-O-methyl- -idopyr-
a
-
D
-glucopyranosyl)-(1/4)-(2,3-di-O-methyl-
b
-
D
-gluco-
(4ꢂCO), 139.2, 128.9, 138.1, 138.0, 137.9, 137.8, 137.4, 135.9, 133.1,
132.7 (9ꢂCq arom), 128.6e125.4 (42C, arom), 99.5, 99.4, 97.8, 97.6,
97.7 (5ꢂC-1), 83.0, 81.7, 79.8, 79.6, 79.5, 79.1, 79.0, 76.4, 76.2, 74.9,
74.8, 72.4, 71.1, 70.8, 70.0, 68.9, 68.2 (20C, skeleton carbons), 73.6,
73.5, 73.3, 73.2, 73.1 (6ꢂCH2Ph, CH2NAP), 68.7, 68.3, 68.1, 67.1 (4ꢂC-
6), 60.5, 60.2, 59.0, 58.5, 55.0, 51.5 (6ꢂOCH3), 20.9, 20.8, 20.5
(3ꢂCH3) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ
1845.76. Found: 1846.07. Anal. Calcd for C102H118O30 (1822.77): C,
67.16; H, 6.52. Found: C, 67.98; H, 6.88.
a-D-gluco-
a-L
anosyluronate)-(1/4)-2,3,6-tri-O-sulfonato-a-D-glucopyr-
anoside] (Idraparinux) (2)
Compound 17 (49 mg, 0.048 mmol) was treated with SO3$Et3N
complex (305 mg, 1.68 mmol) in DMF (2.5 mL). After 24 h stirring at
50 ꢀC, the reaction mixture was neutralized with satd aq NaHCO3
(705 mg, 8.40 mmol) and the resulting mixture was concentrated in
vacuo. The crude product was treated with Dowex ion-exchange
resin (Naþ form), and then purified by Sephadex G-25 column
4.15. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(6-O-(2-naphthyl)methyl- -glucopyranosyl)-
(1/4)-(2,3,6-tri-O-benzyl- -glucopyranosyl)-(1/4)-
(methyl 3-O-methyl- -idopyranosyluronate)-(1/4)-2,3,6-
tri-O-benzyl- -glucopyranoside (20)
a-D-glucopyr-
b-D
chromatography eluting with H2O to give 2 as a white powder
a-D
25
(61 mg, 73%); 210e215 ꢀC (decomp.); [
a
]
þ5.0 (c 0.11, MeOH);
a-L
D
(lit.6
(KBr): 3462, 2948, 2844, 1740, 1630, 1254, 1146, 1038, 1002, 941,
810, 738, 583 cmꢁ1 1H NMR (D2O, 500 MHz):
¼5.49 (d, 1H, J1,2
[
a
]
D
þ55 (H2O)); Rf 0.37 (6:7:1 CH2Cl2/MeOH/H2O); IR nmax
a-D
;
d
Compound 19 (460 mg, 0.252 mmol) was deacetylated as de-
scribed for the synthesis of 14. The crude product was purified by
3.5 Hz, H-1-D), 5.47 (d, 1H, J1,2 3.4 Hz, H-1-F), 5.23 (d, 1H, J1,2 3.3 Hz,
H-5-G), 5.18 (d, 1H, J1,2 3.3 Hz, H-1-H), 5.06 (s, 1H, H-1-G), 4.69 (d,
1H, J1,2 6.8 Hz, H-1-E), 4.64e4.56 (m, 2H, H-3-H, H-3-F), 4.40e4.36
(m, 3H, H-2-H, H-6a-H, H-6a-F), 4.32e4.26 (m, 5H, H-2-F, H-4-G, H-
6a-D, H-6b-H, H-6b-F), 4.16e4.13 (m, 1H, H-6b-D), 4.10e4.08 (m,
2H, H-5-F, H-5-H), 3.97e3.85 (m, 5H, H-4-F, H-4-H, H-4-E, H-5-E,
H-3-G), 3.79e3.77 (m, 1H, H-5-D), 3.65, 3.60, 3.58, 3.57, 3.55, 3.48
(6ꢂs, 24H, 8ꢂOCH3), 3.54e3.52 (m, 2H, H-3-D, H-3-E), 3.48e3.46
silica gel chromatography (9:1 CH2Cl2/acetone) to give 20 (423 mg,
25
99%) as a colourless syrup; [
a]
þ4.7 (c 0.17, CHCl3); Rf 0.52 (9:1
D
CH2Cl2/acetone); IR nmax (KBr): 3437, 3060, 3028, 2930, 1764, 1735,
1603, 1496, 1453, 1364, 1309, 1256, 1207, 1152, 1099, 1042, 911, 855,
819, 738, 698, 543, 477 cmꢁ1
;
1H NMR (CDCl3, 360 MHz):
d
¼7.79e7.15 (m, 42H, arom), 5.16 (s, 1H), 5.04e4.93 (m, 4H),
4.81e4.33 (m, 17H), 3.99e3.75 (m, 12H), 3.69e3.65 (m, 4H),

M. Herczeg et al. / Tetrahedron 69 (2013) 3149e3158
3157
3.63e3.37 (m, 11H), 3.60, 3.53, 3.42, 3.35, 3.32, 3.28 (6ꢂs, 18H,
6ꢂOCH3), 3.20e3.15 (m, 3H) ppm; 13C NMR (CDCl3, 90 MHz):
73.1, 72.7 (7ꢂCH2Ph), 68.3, 67.9, 67.2, 61.7 (4ꢂC-6), 60.6, 60.4, 60.2,
60.0, 59.8, 59.4, 55.1, 51.3 (9ꢂOCH3) ppm; MALDI-TOF (positive
ion): m/z calcd for [MþNa]þ 1622.79. Found: 1622.11. Anal. Calcd for
C88H110O27 (1598.72): C, 66.07; H, 6.93. Found: C, 66.21; H, 7.03.
d
¼169.5 (CO), 138.9, 138.7, 137.7, 137.6, 137.5, 137.4, 137.3, 135.9
(10ꢂCq arom), 128.3e125.4 (42C, arom), 102.2, 100.6, 100.0, 97.6,
95.5 (5ꢂC-1), 83.6, 82.4, 81.5, 80.2, 79.9, 79.4, 79.1, 77.6, 76.0, 75.8,
74.4, 74.2, 73.4, 71.2, 70.9, 70.3, 69.9, 66.7, 65.7 (20C, skeleton car-
bons), 74.8, 74.3, 73.8, 73.2, 73.1, 72.9 (7ꢂCH2Ph, CH2NAP), 68.6,
68.5, 68.1, 67.6 (4ꢂC-6), 64.0, 60.1, 59.8, 57.4, 54.8, 51.6
(6ꢂOCH3) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ
1719.73. Found: 1719.99. Anal. Calcd for C96H112O27 (1696.74): C,
67.91; H, 6.65. Found: C, 68.11; H, 6.82.
4.18. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(sodium 2,3-di-O-methyl- -glucopyr-
anosyluronate)-(1/4)-(2,3,6-tri-O-benzyl- -glucopyr-
anosyl)-(1/4)-(methyl 2,3-di-O-methyl-
a-D-glucopyr-
b-D
a-D
a-L-
idopyranosyluronate)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyr-
anoside (23)
4.16. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(2,3-di-O-methyl-6-O-(2-naphthyl)methyl-
glucopyranosyl)-(1/4)-(2,3,6-tri-O-benzyl- -glucopyr-
anosyl)-(1/4)-(methyl 2,3-di-O-methyl- -idopyr-
-glucopyrano-
a-D-glucopyr-
Pentasaccharide 22 (130 mg, 0.081 mmol) was dissolved in
CH2Cl2 (2 mL) and H2O (1 mL), and TEMPO (3 mg, 0.019 mmol) and
BAIB (177 mg, 0.549 mmol) were added. The solution was stirred
vigorously for 5 h at room temperature. The reaction mixture was
quenched by the addition of 10% aq Na2S2O3 solution (8 mL) and
extracted with CH2Cl2 (2ꢂ10 mL), and the combined organic layers
were dried, and concentrated. The crude product was purified by
b-D-
a-D
a-L
anosyluronate)-(1/4)-2,3,6-tri-O-benzyl-a-D
side (21)
Compound 20 (410 mg, 0.241 mmol) was methylated as de-
scribed for the synthesis of 15. The crude product was purified by
silica gel chromatography (1:1 n-hexane/EtOAc) to give 21 (212 mg,
silica gel chromatography (85:15 CH2Cl2/acetone) to give 23 (90 mg,
25
68%) as a colourless oil; [
a
]
þ6.7 (c 0.05, CHCl3); Rf 0.47 (85:15
D
CH2Cl2/acetone); IR nmax (KBr): 3436, 3028, 2926, 1743, 1495, 1453,
1364, 1216, 1101, 1075, 1039, 912, 749, 697, 562 cmꢁ1 1H NMR
(CDCl3, 360 MHz):
51%) as a colourless syrup; [
a]
25 þ5.7 (c 0.11, CHCl3); Rf 0.47 (1:1 n-
D
;
hexane/EtOAc); IR nmax (KBr): 3443, 3061, 3028, 2931, 2359, 1952,
1742, 1634, 1603, 1496, 1453, 1364, 1320, 1269, 1209, 1148, 1102,
1046, 966, 913, 818, 738, 698, 602, 559, 477 cmꢁ1; 1H NMR (CDCl3,
d
¼7.36e7.17 (m, 35H, arom), 5.38 (d, 1H, J 3.6 Hz),
5.27 (d, 1H, J 6.8 Hz), 5.11 (d, 1H, J 3.3 Hz), 4.87e4.41 (m, 18H), 4.32
(d,1H, J 7.7 Hz), 3.87e3.79 (m, 9H), 3.71e3.67 (m, 6H), 3.65e3.35 (m,
2H), 3.19e3.12 (m, 4H), 2.98e2.90 (m, 2H), 3.63, 3.61, 3.57, 3.53, 3.47,
3.45, 3.44, 3.40, 3.36 (9ꢂs, 27H, 9ꢂOCH3) ppm; 13C NMR (CDCl3,
360 MHz):
d
¼7.77e7.12 (m, 42H, arom), 5.60 (d, 1H, J 3.5 Hz), 5.29
(d, 1H, J 6.7 Hz), 5.12 (d, 1H, J 3.2 Hz), 5.04 (d, 1H, J 11.7 Hz),
4.89e4.32 (m, 18H), 4.14e4.10 (m, 1H), 3.99e3.72 (m, 15H),
3.64e3.35 (m, 5H), 3.60, 3.59, 3.54, 3.50, 3.47, 3.45, 3.39, 3.36 (8ꢂs,
27H, 9ꢂOCH3), 3.27e3.15 (m, 4H), 3.02e2.97 (m, 2H) ppm; 13C NMR
90 MHz):
d
¼169.6, 169.0 (2ꢂCO), 139.0, 138.6, 138.2, 138.1, 137.6
(7ꢂCq arom), 128.5e127.1 (35C, arom), 102.3, 99.8, 98.6, 98.1, 97.2
(5ꢂC-1), 85.0, 84.0, 83.2, 82.8, 81.6, 80.4, 80.0, 79.5, 79.3, 78.9, 78.6,
76.4, 76.0, 75.5, 73.8, 72.3, 70.8, 70.4, 70.1 (20C, skeleton carbons),
75.4, 75.0, 73.4, 73.3, 73.2, 72.7 (7ꢂCH2Ph), 69.0, 67.9, 67.2 (3ꢂC-6),
60.6, 60.4, 60.1, 59.3, 55.2, 51.3 (9ꢂOCH3) ppm; MALDI-TOF (positive
ion): m/z calcd for [MþNa]þ 1657.67. Found: 1657.99. Anal. Calcd for
C88H107NaO28 (1634.68): C, 64.61; H, 6.59. Found: C, 64.95; H, 6.91.
(CDCl3, 90 MHz):
d¼169.5 (CO), 139.2, 138.9, 138.1, 138.0, 137.8,
137.6, 136.1, 133.0, 132.6 (10ꢂCq arom), 128.3e125.3 (42C, arom),
102.4, 99.8, 98.6, 98.0, 96.0 (5ꢂC-1), 86.3, 84.6, 83.2, 81.6, 80.4, 79.9,
79.2, 79.0, 78.5, 76.4, 76.3, 74.4, 72.3, 72.2, 70.9, 70.5, 70.1 (20C,
skeleton carbons), 75.3, 74.5, 73.4, 73.2, 73.1, 73.0, 72.6 (7ꢂCH2Ph,
CH2NAP), 69.1, 67.8, 67.3 (4ꢂC-6), 60.5, 60.4, 60.1, 60.0, 59.9, 59.5,
59.2, 55.0, 51.2 (9ꢂOCH3) ppm; MALDI-TOF (positive ion): m/z calcd
for [MþNa]þ 1762.97. Found: 1762.06. Anal. Calcd for C99H118O27
(1738.79): C, 68.34; H, 6.84. Found: C, 67.81; H, 6.97.
Acknowledgements
ꢀ
The work is supported by the TAMOP 4.2.1/B-09/1/KONV-2010-
0007 project. The project is co-financed by the European Union and
the European Social Fund. Financial support of the Hungarian Re-
search Fund (K 105459 and PD 73064) is also acknowledged.
4.17. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(2,3-di-O-methyl- -glucopyranosyl)-(1/4)-
(2,3,6-tri-O-benzyl- -glucopyranosyl)-(1/4)-(methyl 2,3-
di-O-methyl- -idopyranosyluronate)-(1/4)-2,3,6-tri-O-
benzyl- -glucopyranoside (22)
a-D-glucopyr-
b-D
a-D
a-L
Supplementary data
a-D
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.02.076.
To a vigorously stirred solution of 21 (200 mg, 0.115 mmol) in
CH2Cl2 (1.8 mL) and H2O (0.2 mL) DDQ (39 mg, 0.172 mmol) was
added. After 30 min the mixture was diluted with CH2Cl2 (50 mL)
and extracted with aq NaHCO3 (2ꢂ10 mL), and H2O (10 mL), dried
and concentrated. The crude product was purified by silica gel
References and notes
1. Eikelboom, J. W.; Witz, J. I. Circulation 2010, 121, 1523e1532.
chromatography (9:1 CH2Cl2/acetone) to give 22 (134 mg, 73%) as
2. (a) Rosenberg, R. D.; Damus, P. S. J. Biol. Chem. 1973, 248, 6490e6505; (b) Choay,
25
€
J.; Lormeau, J.-C.; Petitou, M.; Sinay, P.; Fareed, J. Ann. N.Y. Acad. Sci. 1981, 370,
a colourless oil; [
a
]
þ7.1 (c 0.09, CHCl3); Rf 0.54 (9:1 CH2Cl2/ace-
D
€
644e649; (c) Thunberg, L.; Backstrom, G.; Lindahl, U. Carbohydr. Res. 1982, 100,
tone); IR nmax (KBr): 2931, 2359, 2341, 1743, 1455, 1362, 1218, 1147,
393e410; (d) Kim, Y. S.; Lee, K. B.; Linhardt, R. J. Thromb. Res. 1988, 51, 97e104.
3. Petitou, M.; Nancy-Portebois, V.; Dubreucq, G.; Motte, V.; Meuleman, D.; de
Kort, M.; van Boeckel, C. A. A.; Vogel, G. M. T.; Wisse, J. A. J. Thromb. Haemostasis
2009, 102, 808e810.
1101, 1037, 771, 697, 668, 457 cmꢁ1 1H NMR (CDCl3, 360 MHz):
;
d
¼7.38e7.16 (m, 35H, arom), 5.51 (d, 1H, J 3.8 Hz), 5.27 (d, 1H, J
6.7 Hz), 5.12 (d, 1H, J 3.4 Hz), 4.90e4.51 (m, 15H), 4.44 (d, 1H, J
6.0 Hz), 4.25 (d, 1H, J 7.9 Hz), 3.89e3.78 (m, 8H), 3.74e3.67 (m, 5H),
3.65e3.35 (m, 8H), 3.62, 3.58, 3.55, 3.49, 3.48, 3.46, 3.44, 3.43, 3.36
(9ꢂs, 27H, 9ꢂOCH3), 3.25e3.15 (m, 4H), 2.97e2.93 (m, 2H), 2.15 (br
4. (a) van Boeckel, C. A. A.; Petitou, M. Angew. Chem., Int. Ed. Engl. 1993, 32,
1671e1690; (b) van Boeckel, C. A. A.; Petitou, M. Angew. Chem., Int. Ed. 2004, 43,
3118e3133.
€
5. (a) Sinay, P.; Jacquinet, J.-C.; Petitou, M.; Duchaussoy, P.; Lederman, I.; Choay, J.;
Torri, G. Carbohydr. Res. 1984, 132, C5eC9; (b) van Boeckel, C. A. A.; Beetz, T.;
Vos, J. N.; de Jong, A. J. M.; van Aelst, S. F.; van den Bosch, R. H.; Mertens, J. M. R.;
van der Vlugt, F. A. J. Carbohydr. Chem. 1985, 4, 293e321.
6. Westerduin, P.; van Boeckel, C. A. A.; Basten, J. E. M.; Broekhoven, M. A.; Lucas,
H.; Rood, A.; van der Heiden, H.; van Amsterdam, R. G. M.; van Dinther, T. G.;
Meuleman, D. G.; Visser, A.; Vogel, G. M. T.; Damm, J. B. L.; Overklift, G. T. Bioorg.
Med. Chem. 1994, 2, 1267e1280.
s, 1H, OH) ppm; 13C NMR (CDCl3, 90 MHz):
d
¼169.5 (CO), 138.9,
138.8, 138.2, 138.0, 137.8, 137.6 (7ꢂCq arom), 128.3e127.0 (35C,
arom), 102.5, 99.8, 98.6, 98.1, 96.5 (5ꢂC-1), 86.2, 84.7, 83.3, 83.2,
81.6, 80.4, 80.0, 79.3, 79.2, 78.6, 77.0, 76.4, 75.6, 74.0, 73.0, 72.3,
70.9, 70.8, 70.1 (20C, skeleton carbons), 75.3, 75.0, 73.4, 73.3, 73.2,

3158
M. Herczeg et al. / Tetrahedron 69 (2013) 3149e3158
ꢀ
7. Harenberg, J. Thromb. Haemostasis 2009, 102, 811e815.
17. (a) Codee, J. D. C.; van der Marel, G. A.; van Boeckel, C. A. A.; van Boom, J. H. Eur.
ꢀ ꢀ
ꢀ
ꢀ
8. Herczeg, M.; Lazar, L.; Borbas, A.;Liptak, A.;Antus, S. Org. Lett. 2009,11, 2619e2622.
J. Org. Chem. 2002, 3954e3965; (b) Orgueira, H. A.; Bartolozzi, A.; Schell, P.;
Litjens, R. E. J. N.; Palmacci, E. R.; Seeberger, P. H. Chem.dEur. J. 2003, 9,
140e169.
ꢀ ꢀ
ꢀ
ꢀ
9. Lazar, L.; Herczeg, M.; Fekete, A.; Borbas, A.; Liptak, A.; Antus, S. Tetrahedron
Lett. 2010, 51, 6711e6714.
10. Herczeg, M.; Lazar, L.; Mandi, A.; Borbas, A.; Komaromi, I.; Liptak, A.; Antus, S.
ꢀ ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
18. Codee, J. D. C.; van den den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft, H. S.; van
Carbohydr. Res. 2011, 346, 1827e1836.
Boom, J. H.; van der Marel, G. A. Org. Lett. 2003, 5, 1947e1950.
19. Lohman, G. J. S.; Hunt, D. K.; Hogermeier, J. A.; Seeberger, P. H. J. Org. Chem.
2003, 68, 7559e7561.
20. Ek, M.; Garegg, P. J.; Hultberg, H.; Oscarson, S. J. Carbohydr. Chem. 1983, 2,
305e311.
21. Das, T.; Shashidhar, M. S. Carbohydr. Res. 1997, 297, 243e249.
22. (a) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; Alderfer, J. L.; Matta, K. L.
Tetrahedron Lett. 2000, 41, 169e173; (b) Wright, J. A.; Yu, J.; Spencer, J. B. Tet-
rahedron Lett. 2001, 42, 4033e4036.
23. (a) De Mico, A.; Margarita, R.; Parlanti, R.; Vescovi, A.; Piancatelli, G. J. J. Org.
Chem. 1997, 62, 6974e6977; (b) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64,
293e295.
ꢀ ꢀ
}
ꢀ
ꢀ
€
11. Lazar, L.; Mezo, E.; Herczeg, M.; Liptak, A.; Antus, S.; Borbas, A. Tetrahedron
2012, 68, 7386e7399.
ꢀ ꢀ
€
ꢀ
ꢀ
12. Herczeg, M.; Lazar, L.; Bereczky, Zs.; Kover, K. E.; Timari, I.; Kappelmayer, J.;
ꢀ
ꢀ
Liptak, A.; Antus, S.; Borbas, A. Chem.dEur. J. 2012, 18, 10643e10652.
13. Chen, Ch.; Yu, B. Bioorg. Med. Chem. Lett. 2009, 19, 3875e3879.
14. (a) Boulineau, F. P.; Wei, A. J. Org. Chem. 2006, 69, 3391e3399; (b) Hernandez-
Torres, J. M.; Achkar, J.; Wei, A. J. Org. Chem. 2004, 69, 7206e7211.
ꢀ
ꢀ
ꢀ ꢀ
15. Liptak, A.; Jodal, I.; Nanasi, P. Carbohydr. Res. 1975, 44, 1e11.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
16. (a) Borbas, A.; Szabo, Z. B.; Szilagyi, L.; Benyei, A.; Liptak, A. Tetrahedron 2002,
ꢀ
ꢀ
ꢀ
58, 5723e5732; (b) Jakab, Zs.; Mandi, A.; Borbas, A.; Benyei, A.; Komaromi, I.;
ꢀ ꢀ
ꢀ
Lazar, L.; Antus, S.; Liptak. Carbohydr. Res. 2009, 344, 2444e2453.