An Efficient Modular One-Pot Synthesis of Heparin-Based Anticoagulant Idraparinux

Article abstract of DOI:10.1021/jacs.9b03266

Idraparinux is a fully O-sulfated α-methyl glycoside of heparin pentasaccharide motif known to interact with the antithrombin III domain and act as anticoagulant. The current most effective synthesis of Idraparinux is complicated and nonstereoselective, requiring numerous stepwise procedures with low yields. We report here an efficient modular one-pot synthesis of Idraparinux involving the use of a glycosyl phosphate with 6-O-tert-butyl diphenyl silyl group and a d-glucuronic acid-containing disaccharide thioglycoside with 6-O-acetyl group as donor building blocks for the α-directing one-pot glycosylations with an l-iduronic acid-containing disaccharide acceptor building block. The uronic acid was incorporated in a disaccharide module used in the one-pot synthesis to avoid the complicated late-stage installation of these acidic sugars. The one-pot synthesis of Idraparinux demonstrated here is an effective strategy and should be applicable to the modular assembly of other heparan sulfates with regiodefined sulfation pattern for functional study.

Full text of DOI:10.1021/jacs.9b03266

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Article
An Efficient Modular One-pot Synthesis of
Heparin-Based Anticoag-ulant Idraparinux
Supriya Dey, Hong-Jay Lo, and Chi-Huey Wong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b03266 • Publication Date (Web): 03 Jun 2019
Downloaded from http://pubs.acs.org on June 3, 2019
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Journal of the American Chemical Society
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An Efficient Modular One-pot Synthesis of Heparin-Based
Anticoagulant Idraparinux
Supriya Dey†, Hong-Jay Lo†, Chi-Huey Wong†‡*
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† Department of Chemistry, Scripps Research, 10550 N. Torrey Pines Rd., La Jolla, California, USA, 92037.
‡The Genomics Research Center, Academia Sinica, 128 Academia Rd., Section 2, Taipei, Taiwan 115.
KEYWORDS: Heparin, Idraparinux, Anticoagulant, Modular one-pot Synthesis.
ABSTRACT: Idraparinux is a fully O-sulfated α-methyl glycoside of heparin pentasaccharide motif
known to interact with the antithrombin III domain and act as anti-coagulant. The current most effective
synthesis of Idraparinux is complicated and non-stereoselective, requiring numerous step-wise procedures
with low yields. We report here an efficient modular one-pot synthesis of Idraparinux, involving the use
of a glycosyl phosphate with 6-O-tert-butyl diphenyl silyl group and a D-glucuronic acid-containing
disaccharide thioglycoside with 6-O-acetyl group as donor building blocks for the α-directing one-pot
glycosylations with an L-iduronic acid-containing disaccharide acceptor building block. The uronic acid
was incorporated in a disaccharide module used in the one-pot synthesis to avoid the complicated late-
stage installation of these acidic sugars. The one-pot synthesis of Idraparinux demonstrated here is an
effective strategy and should be applicable to the modular assembly of other heparan sulfates with
regiodefined sulfation pattern for functional study.
INTRODUCTION
Further research in the field has led to the
development of the next generation anticoagulant
Heparin (H) and heparan sulfate (HS) are linear
polyanionic molecules of glycosaminoglycans
(GAGs), known to interact with several
biologically important proteins and play a major
role in various biological processes.1 Heparin-
based drugs have been used in the clinics for the
treatment of thromboembolic diseases2a since
1930 even though the structure and activity
relationship (SAR) was not known at that time.2b
Within its heterogeneous chain, a pentasaccharide
motif binds to the serine protease inhibitor
antithrombin III (AT III) and blocks thrombin and
factor Xa involved in the process of the blood
coagulation cascade.3,4 Since the ground breaking
work of van Boeckel and Petitou3 on the SAR
study of heparin in late 1990s, the development of
heparin-based drugs has been increasingly
important. Remarkably, Fondaparinux (1C) (Fig.
1), the unique AT-binding pentasaccharide motif
was introduced to the market in 2001 due to its
higher anti-Xa activity and longer half-life
compared to the low molecular weight heparin.5
drug
Idraparinux
(1A),
a
synthetic
pentasaccharide analogue of Fondaparinux, which
contains O-sulfation and O-methyl functionalities
instead of N-sulfation and free hydroxyl groups
(Fig 1). Compared to 1C, 1A was known to have
higher anti-Xa activity (Kd = 1.4 ± 0.3 nM) and
longer half-life and was in phase III clinical trial
for the treatment of patients with atrial fibrillation
and venous thromboembolic events.6 The
conformation and sulfation pattern of L-iduronic
acid is important for the anticoagulation properties
of heparin sulfates, including the clinically
important drugs Fondaparinux and Idraparinux.7
Recent study further showed that replacement of
the L-iduronic acid unit by 6-deoxy-L-
talopyranose
completely
diminished
the
anticoagulant activity of 1A.8
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-
OSO3
O
protected
pentasaccharide to 1A was not
1
2
3
4
5
6
7
8
MeO
MeO
-
-
demonstrated in this report. However, most of the
reported synthetic methods still involve long step-
CO2
OSO3
O
-
RO
CO2
O
O
O
MeO
-O3SO
OMe
-O3SO
MeO
-
O
OSO3
O
wise
procedure
and
non-stereoselective
O
O
1A:
1B:
R = Me
NH
-O3SO
glycosylation, with low efficiency and low yield,
making the SAR study and development of new
heparin-based pharmaceuticals difficult to pursue.
In order to overcome this challenge, we have
developed
oligosaccharide
thioglycoside donors with known relative
reactivity values (RRV) to simplify the synthesis
of complex oligosaccharides,18 and have extended
the method to the synthesis of a heparin-like
oligosaccharide19a and related pentasaccharides19b
MeO
-O3SO
S
R =
NH
O
NH
MeO
O
N
O
spacer
biotin
H
-
OSO3
O
9
HO
HO
-
a
programmable
synthesis method,
one-pot
using
-
CO2
OSO3
O
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-O3SHN
O
1C:
O
HO
-
O
CO2
-O3SO
OH
-O3SHN
OH
-
OSO3
O
O
O
O
HO
-O3SHN
-O3SO
OMe
Figure 1: Synthetic pentasaccharide with
anticoagulant activity: Idraparinux (1A),
Idrabiotaparinux (1B) and Fondaparinux (1C)
with
regioselective
O-sulfation
pattern.
Continuing our effort to develop a general and
effective method for the synthesis of heparan
sulfates with regiodefined sulfation pattern, we
direct our effort to explore better building blocks
with appropriate differential protecting groups and
leaving groups (including the thioglycoside and
phosphate20) to be used for the efficient modular
assembly of this class of molecules. We herein
report an efficient modular one-pot method for the
synthesis of the clinically important Idraparinux as
a representative example using designed glycosyl
phosphate and thioglycoside building blocks as
donors for α-selective glycosylation.
However, like Fondaparinux, the long term (more
than 6 months) use of 1A also led to intracranial
bleeding in elderly patients and those with renal
impairment.9 The incidence of major bleeding
complication was later controlled by introducing a
biotin moiety at the C2 position of the non-
reducing end glucose of 1A, to generate the second
generation anticoagulant Idrabiotaparinux 1B,
which can be removed from the patient in case of
overdose or bleeding by injection of avidin.10
In addition, the safety and quality of heparins from
natural sources must be monitored to avoid any
impurity contamination; e.g. the oversulfated
chondroitin sulfate led to more than 200 deaths in
the USA in 2008.11 Thus, the anticoagulants made
by chemical synthesis have attracted more
attention recently12. However, the synthesis of 1A
and related substances is always challenging due
to the possible contamination of heterogeneous
glycosidic linkages and negatively charged
sulfates.13 To date, there are only four different
procedures reported for the synthesis of
Idraparinux. The first synthesis was reported by
Westerduin et al. in 1994.14 Fifteen years later, Yu
and Chen developed an improved synthesis of 1A
in 51 steps with 4 % overall yield.15b More
recently, Borbás and co-workers achieved the
synthesis of 1A in 39 steps from D-glucose.16 In
2017, Mlynarski and co-workers reported the
synthesis of a protected Idraparinux in 32 steps,
including a 23-step linear route from D-cellobiose
and D-glucose in 1.7 % overall yield.17 The
deprotection and chemical sulfation of the
RESULTS AND DISCUSSION
Idraparinux 1A contains fully O-methylated
uronic acids and other sugar units connected to
each other with 1,4-α-β-α-α glycosidic linkages.
We envisioned that the protected Idraparinux 23
could be obtained from one-pot synthesis using the
[1,2,2] approach and the building blocks (5, 13 and
22) shown in the schemes. To generate
stereoselective glycosidic linkages in the one-pot
sequence, we designed the synthetic route with the
following
considerations:
(i)
highly
stereoselective α-glycosylation influenced by the
TBDPS and OAc protecting groups at O-6
position (ii) use of the built-in β-1,4-glycosidic
linkage of D-cellobiose to design a new D-
glucuronic
acid
containing
disaccharide
thioglycoside building block (22) as donor for α-
selective glycosylation, (iii) construction of an L-
iduronic acid-containing disaccharide as acceptor,
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Journal of the American Chemical Society
Scheme 2. Synthesis of D-Glc-β-(1 →4)-D-Glc
disaccharide building block
(iv) masking the hydroxyl groups with TBDPS
group, benzyl ether or acetyl ester for O-sulfation
at the later stage.
1
2
3
4
5
6
7
8
OH
OAc
O
OH
OAc
O
3 steps
(a)
Ph
O
HO
AcO
MeO
Synthesis of monosaccharide and disaccharide
building blocks. The synthesis of monosaccharide
phosphate donor 5 was achieved in two steps from
the glucose thioglycoside 319b (Scheme 1). The
primary hydroxyl group of 3 was initially
protected with TBDPS21 followed by protection of
the rest hydroxyl groups as methyl ether using
MeI/NaH to generate 4. Later, the anomeric
phosphate group20a was installed to yield 5.
O
O
HO
D-(+)Cellobiose
MeO
O
AcO
STol
OMe
OMe
OH
(c)
OH
7
OAc
6
OH
OTBDPS
O
O
O
O
Ph
(b)
O
O
O
O
O
HO
O
MeO
8
MeO
STol
STol
HO
OMe
OMe
OH
OH
9
9
OH
OTBDPS
O
OTBDPS
O
O
O
Ph
(d)
(e)
(g)
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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HO
MeO
O
BnO
O
BnO
STol
MeO
10
STol
OMe
O
OMe
11
OBn
OBn
OTBDPS
O
OAc
O
MeO2C
MeO2C
HO
MeO
O
(f)
HO
MeO
O
O
STol
STol
BnO
BnO
OMe
OMe
OBn
12
13
OBn
Reaction conditions: (a) (i) Ac2O, Py (1:2), 0 oC-
o
Scheme 1. Synthesis of monosaccharide donor
rt, 12 h; (ii) p-CrSH, BF3-Et2O, CH2Cl2, 0 C-rt,
12 h, 68% (two steps); (b) (i) NaOMe, MeOH, rt,
12h; (ii) PhCH(OMe)2, CSA, CH3CN, rt, 12 h, 82
% (two steps); (c) TBDPSCl, Imidazole, CH2Cl2,
3h, 84 %; (d) BnBr, NaH, DMF, 3h, 0 oC-rt, 89 %;
HO
HO
HO
TBDPSO
MeO
MeO
TBDPSO
(b)
(a)
O
O
O
MeO
MeO
STol
STol
OPO(OBu)
OMe
OH
OMe
2
5
3
4
Reaction conditions: (a) (i) TBDPSCl, Imidazole,
CH2Cl2, rt, 3h; then MeI, NaH, DMF, 2h, 0 oC-rt,
85 %; (b) HOPO(OBu)2, NIS,TfOH, CH2Cl2, 4Å
MS, -40 oC, 1 h, 89%.
o
(e) 80 % AcOH-H2O, 70 C, 3h, 89 %; (f) (i)
o
BAIB, TEMPO, CH2Cl2: H2O (2:1), 0 C-rt, 2 h;
(ii) MeI, KHCO3, DMF, rt, 4 h, 0 oC-rt, 77% (two
steps); (g) (i) HF-Py, Py, 0 oC-rt, 12 h; (ii) Ac2O,
Et3N, CH2Cl2, 0 oC-rt, 2 h, 86% (two steps).
The synthesis of the two disaccharide building
blocks Glc-Glc (13) and Ido-Glc (22) were
performed next. The synthesis of 13 was initiated
from commercially available D-cellobiose.
Compound 6 was obtained from D-cellobiose in 3
steps using the literature procedure developed by
Mlynarski and co-workers.17 The hydroxyl groups
in 6 were protected with acetyl (Ac) and readily
converted into 7 using p-toluenethiol (P-
CrSH)/BF3-OEt2. Later, Zémplen de-acetylation
was performed, followed by installation of the
4ʹ,6ʹ-O-benzylidene protection group leading to 8
in excellent yield. In order to protect the 2,3-OH
groups as benzyl ether, the primary hydroxyl
group of the reducing end was protected as
TBDPS ether to generate 9. Next, the NaH/BnBr
mediated O-benzylation led to compound 10 in
excellent yield. Hydrolysis of the 4ʹ,6ʹ-O-
benzylidene acetal using 80 % AcOH led to the
dihydroxy compound 11; upon selective oxidation
For the synthesis of Ido-Glc disaccharide
derivative 22, we used NIS/TMSOTf-mediated
coupling of suitably functionalized idose donor 18
and protected α-methyl glucoside acceptor 19.22
The synthesis of L-Idose donor 18 was
commenced from diacetone glucofuranose 14
which was converted to the L-idose building block
15 using the known procedure.15 It was further
treated with p-toluenethiol in the presence of
BF3∙OEt2 to furnish 16 as a non-separable
anomeric mixture (α:β = 8:1).15b The formation of
the anomeric mixture was not surprising as a
recent study showed that neighboring-group
participation has a minor role for idose donors.23
Removal of the O-acetyl groups under Zémplen
reaction condition followed by 4,6-O-benzylidine
protection led to the chromatographically
separable mixture of 17 in good yield. The α-
anomer 17α was treated with BzCl/Py to furnish
the fully protected glycosyl donor 18 (Scheme 3).
Glycosylation of donor 18 with α-methyl acceptor
19 led to disaccharide 20.15b The O-2-benzoyl
group in disaccharide 20 was removed and further
O-methylated to furnish 21. Hydrolysis of the
4ʹ,6ʹ-O-benzylidene acetal using 80 % AcOH led
to the crude dihydroxy derivative which was
using
TEMPO/BAIB
and
subsequent
esterification with iodomethane in the presence of
KHCO3 furnished the D-glucuronic acid-
containing disaccharide building block 12
(Scheme 2). Finally, the TBDPS ether was readily
deprotected using HF-Py with concurrent
selective O-acetylation to generate disaccharide
13 in excellent yield.
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converted to the L-iduronic acid-containing
protecting groups and promoter. Therefore, we
replaced the anomeric p-toluenethiol group of 4 by
phosphate to generate the corresponding glycosyl
phosphate donor 5 (Scheme 1). Next, one-pot
synthesis was performed using phosphate donor 5
along with the designed disaccharides (13 and 22)
to yield pentasaccharide 23 in 70% yield (Scheme
4). The TBDPS ether group of 23 was removed
selectively using HF-Py for the subsequent
sulfation. This method eliminates the problem
associated with O-sulfation19b to generate 2
(Scheme 5).
1
2
3
4
5
6
7
8
disaccharide building block acceptor 22 using
TEMPO/BAIB mediated selective oxidation of
the primary hydroxyl group to acid and subsequent
esterification using MeI/KHCO3 (Scheme 3).15b
Scheme 3. Synthesis of L-Ido-α-(1 →4)-D-Glc
disaccharide building block
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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7 steps
ref 15
MeO
OH
O
O
O
MeO
OAc
STol
OAc
AcO
(a)
AcO
O
O
O
O
OAc
OAc
OAc
16
15
14
Scheme 4. One-pot synthesis of protected
Idraparinux 23.
MeO
O
MeO
MeO
STol
(c)
STol
STol
O
O
(b)
+
O
O
O
O
OAc
O
O
OH

OH
OBz
MeO2C
HO
MeO
O
17

17
18
O
O
BnO
Ph
Ph
Ph
STol
OMe
(a)
OBn
13
OBn
O
OBn
O
OBn
O
OBn
OTBDPS
O
(b)
HO
BnO
O
O
O
O
MeO
MeO2C
BnO
MeO
MeO
MeO
MeO
BnO
BnO
OPO(OBu)2
19 BnO
(e)
BnO
OMe
O
OMe
BnO
BnO
OMe
OMe
O
OMe
O
5
(d)
O
O
22
OH
OMe
O
O
OBz
OMe
OTBDPS
O
20
21
Ph
Ph
OBn
MeO
MeO
CO2Me
O
OAc
O
MeO
O
O
CO2Me
OMe
MeO
MeO2C
(f)
70%
BnO
O
O
BnO
MeO
BnO
O
OMe
MeO
BnO
O
OBn
23
O
O
22
BnO
OH
OMe
O
MeO
BnO
MeO
Reaction conditions: (a) p-CrSH, BF3-Et2O,
Reaction conditions: (a) TMSOTf (1.0 equiv.),
CH2Cl2, 4Å MS,-45 oC; (b) NIS, -45 oC to -25 oC,
80 min.
o
CH2Cl2, 0 C-rt, 12 h, 88%; (b) (i) NaOMe,
MeOH:CH2Cl2(3:1), rt, 12h; (ii) PhCH(OMe)2,
CSA, CH3CN, rt, 12 h, 17α (82 %); 17β (10 %);
(c) BzCl, Py, 0 oC-rt, 12 h, 84%; (d) NIS, TMSOTf,
CH2Cl2, 4ÅMS , -20 oC to 0 oC, 25 min, 93%; (e)
(i) NaOMe, MeOH:CH2Cl2 (3:1), rt, 1h, (ii) MeI,
NaH, DMF, 0 oC-rt, 3h, 90 % (2 steps); (f) (i) 80
% AcOH-H2O, 70 oC; (ii) BAIB, TEMPO, CH2Cl2:
The O-sulfated pentasaccharide 1A was obtained
from pentasaccharide 2 in a two-step sequences:
(i) saponification of the ester functionalities using
LiOH/H2O2 in THF followed by NaOH in
methanol and unmasking of all OBn groups to OH
under catalytic hydrogenation in the presence
Pd(OH)2/C and (ii) global O-sulfation was
performed using excess SO3-Et3N. Finally, the
crude pentasaccharide was passed through an ion
exchange Dowex 50WX8Na+ and then purified by
Sephadex-G25 gel chromatography using water as
eluent. The pure fractions were concentrated and
lyophilized to furnish compound 1A in 59 % yield
over 2 steps (Scheme 5).
o
H2O (2:1), 0 C-rt, 2 h; (iii) MeI, KHCO3, DMF,
rt, 4 h, 0 oC-rt, 68% (3 steps).
With all the building blocks in hand, we attempted
the one-pot synthesis of protected Idraparinux 23.
The fully protected thioglycoside donor 4 was first
coupled with acceptor 13 in the presence of
NIS/TfOH. After the complete consumption of the
donor, disaccharide 22 was added along with an
additional amount of NIS and TfOH. However, the
formation of desired pentasaccharide 23 was not
observed even though the trisaccharide was
formed initially in ~20%. The exact reason for the
failure was unknown, probably due to the
Scheme 5. Synthesis of Idraparinux
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OTBDPS
O
disaccharide acceptor 22 from glucofuranose for
MeO
MeO
1
2
3
4
5
6
7
8
CO2Me
OAc
O
the one-pot synthesis. While Mlynarski and co-
workers reported the use of cellobiose as starting
material for conversion to an 1,6-anhydride as
acceptor for glycosylation, the glycosylation
reaction was not α-selective17.
MeO
CO2Me
OMe
O
O
O
MeO
23
BnO
MeO
(a)
BnO
O
OBn
O
O
O
BnO
OH
O
MeO
BnO
MeO
MeO
MeO
CO2Me
OAc
O
MeO
CO2Me
OMe
O
O
O
MeO
BnO
2
The synthetic route described here demonstrates
an effective strategy for the modular one-pot
synthesis of the clinically important anti-
coagulant Idraparinux, and we believe this
strategy is also applicable to other related
substances. In 2013, the non-heparin based oral
anticoagulant drugs dabigatran, apixaban,
edoxaban, and rivaroxaban were approved for
clinical use.24 However, the side effects25 of these
drugs clearly indicated that the use of classical
heparin-based anticoagulants is still important for
the antithrombotic therapy.26
MeO
BnO
O
OBn
O
O
O
BnO
-
9
(b)
OSO3
O
MeO
BnO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
33
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35
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeO
MeO
MeO
-
-
CO2
O
OSO3
O
-
MeO
O
CO2
O
MeO
-O3SO
OMe
-O3SO
-
MeO
O
-O3SO
OSO3
O
O
(1A)
Idraparinux
O
MeO
-O3SO
MeO
Reaction conditions: (a) HF-Py, Py, 0 oC-rt, 12 h,
77 %; (b) (i) 1M LiOH, H2O2, THF, -5 oC-rt, 8 h
then 4M NaOH, MeOH, rt, 18 h; then H2, 20 %
Pd(OH)2-C, MeOH : HCOOH (1:0.1), 24 h, rt; (ii)
SO3-Et3N, DMF, 55 oC, 12 h, 59 % (2 steps).
In summary, the modular one-pot synthesis of
Idraparinux described in this work involves the
use of building blocks with differential protecting
groups, and this strategy should be
CONCLUSION
27
complementary to the chemical
and
chemoenzymatic methods 28 developed by many
other groups and applicable to the synthesis of
other heparin-based structures with regiodefined
sulfation pattern for the SAR study and for the
development of new heparin-based medicines.
In conclusion, we have developed an efficient
modular one-pot synthesis of the heparin-based
anticoagulant Idraparinux, using a set of well-
designed glycosyl phosphate and thioglycoside
building blocks in a [1,2,2] approach. The use of
D-cellobiose, containing
a
1,4-β-glycosidic
linkage between the two glucose monomers,
reduced the number of steps and enabled easy
access to the disaccharide building block 13. The
constructions of D-glucuronic acid- and L-
iduronic acid-containing disaccharide building
blocks were performed prior to the modular
assembly of the pentasaccharide backbone, as this
is more effective than the late-stage introduction
of these two acidic sugars.19b The α-selective
glycosylation in the one-pot synthesis is driven by
silyl and acetyl groups at O-6 position in spite of
the presence of non-directing OMe and OBn
protecting groups at C2 of the building blocks. The
main advantages of this synthetic strategy as
compared to the reported methods are: 1) the
stereoselective construction of glycosidic linkages
using glycosyl phosphate and thioglycoside
building blocks (5 and 13) with TBDPS and Ac
protecting groups at O-6 to direct the α-selective
glycosylation; 2) the design of disaccharide
building block 13 from cellobiose and the
Supporting Information: The Supporting
Information is available free of charge on the ACS
publications
website
http://pubs.acs.org.
(Experimental procedures, copies of NMR spectra
for all new compound).
AUTHOR INFORMATION
Corresponding Author
Chi-Huey Wong: wong@scripps.edu or
chwong@gate.sinica.edu.tw
ORCID
Chi-Huey Wong: 0000-0002-9961-7865
Supriya Dey: 0000-0002-8111-9702
Notes
The authors declare no competing financial
interest.
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ACKNOWLEDGMENT
Opin. Investig. Drugs. 2008, 17, 773; (b) Go, A.
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fibrillation: another step sideways. Lancet. 2008,
371, 278. (c) Gandhi, N. S.; Mancera, R. L.
Heparin/heparan sulphate-based drugs. Drug
Discovery Today 2010, 15, 1058. (d) Weitz, J. I.;
Linkins, L.-A. Beyond heparin and warfarin: the
new generation of anticoagulants. Expert Opin.
Invest. Drugs. 2007, 16, 271.
7. Wang, Z.; Hsieh, P.-H.; Xu, Y.; Thieker, D.;
Chai, E. J. E.; Xie, S.; Cooley, B.; Woods, R. J.;
Chi, L.; Liu, J. Synthesis of 3-O-sulfated
Oligosaccharides to understand the Relationship
between Structures and Functions of Heperan
Sulfate. J. Am. Chem. Soc. 2017, 139, 5249.
8. Demeter, F.; Gyöngyösi, T.; Bereczky, Z.;
Kövér, K. E.; Herczeg, M.; Borbás, A.
Replacement of the L-iduronic acid unit of the
anticoagulant pentasaccharide idraparinux by a 6-
This work was supported by the National Institutes
of Health (AI072155), the National Science
Foundation (CHE-1664283), Academia Sinica
and the Kwang Hua Foundation.
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