Formal Synthesis of Anticoagulant Drug Fondaparinux Sodium

Article abstract of DOI:10.1021/acs.joc.5b02468

The practical formal synthesis of the anticoagulant drug fondaparinux sodium 1 was accomplished using an optimized modular synthetic strategy. The important pentasaccharide 2, a precursor for the synthesis of fondaparinux sodium, was synthesized on a 10 g scale in 14 collective steps with 3.5% overall yield from well-functionalized monosaccharide building blocks. The strategy involved a convergent [3 + 2] coupling approach, with excellent stereoselectivity in every step of glycosylation from the monosaccharide building blocks. Efficient routes to the syntheses of these fully functionalized building blocks were developed, minimizing oligosaccharide stage functional-group modifications. The syntheses of all building blocks avoided rigorous reaction conditions and the use of expensive reagents. In addition, common intermediates and a series of one-pot reactions were employed to enhance synthetic efficiency, improving the yield considerably. In the monosaccharide-to-oligosaccharide assembly reactions, cheaper activators (e.g., NIS/TfOH, TESOTf, and TfOH) were used to facilitate highly efficient glycosylations. Furthermore, crystallization of several monosaccharide and oligosaccharide intermediates significantly simplified purification procedures, which would be greatly beneficial to the scalable synthesis of fondaparinux sodium.

Full text of DOI:10.1021/acs.joc.5b02468

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Article
Formal Synthesis of Anticoagulant Drug Fondaparinux Sodium
Xiang Dai, Wentao Liu, Qilong Zhou, Chunwei Cheng, Chao Yang, Shuqing
Wang, Min Zhang, Pei Tang, Hao Song, Dan Zhang, and Yong Qin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02468 • Publication Date (Web): 09 Dec 2015
Downloaded from http://pubs.acs.org on December 10, 2015
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Formal Synthesis of Anticoagulant Drug Fondaparinux Sodium
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Xiang Dai,†,┴ Wentao Liu,†, ┴ Qilong Zhou,†, ┴ Chunwei Cheng,‡ Chao Yang,†
Shuqing Wang,† Min Zhang,† Pei Tang,*,† Hao Song,‡ Dan Zhang,‡ Yong Qin *,‡
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†Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, China
‡Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education,
West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
Eꢀmail: yongqin@scu.edu.cn
tangpei@cqu.edu.cn
[┴] These authors contributed equally to this work.
Table of contents:
Abstract:
The practical formal synthesis of anticoagulant drug fondaparinux sodium 1 was
accomplished using an optimized modular synthetic strategy. The important
pentasaccharide 2, a precursor for the synthesis of fondaparinux sodium, was
synthesized on 10 g scale in 14 collective steps with 3.5% overall yield from
wellꢀfunctionalized monosaccharide building blocks. The strategy involved a
convergent [3+2] coupling approach, with excellent stereoselectivity in every step of
glycosylation from the monosaccharide building blocks. Efficient routes to the
syntheses of these fully functionalized building blocks were developed, minimizing
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oligosaccharide stage functionalꢀgroup modifications. The syntheses of all building
blocks avoided rigorous reaction conditions and the use of expensive reagents. In
addition, common intermediates and a series of oneꢀpot reactions were employed to
enhance synthetic efficiency, improving the yield considerably. In the
monosaccharide to oligosaccharide assembly reactions, cheaper activators (e.g.,
NIS/TfOH, TESOTf and TfOH) were used to facilitate highly efficient glycosylations.
Furthermore, crystallization of several monosaccharide and oligosaccharide
intermediates significantly simplified purification procedures, which would be greatly
beneficial to the scalable synthesis of fondaparinux sodium.
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Key words:
Heparin, fondaparinux sodium, formal synthesis, glycosylation
1
Introduction
Heparin and its structurally related heparan sulfate are linear polysulfated
polysaccharides with alternating Dꢀglucosamine and either Dꢀglucuronic acid or
Lꢀiduronic acid units.1 They are present on the surface of most animal cells as well as
in the basement membranes and extracellular matrices,2 and play significant roles in
diverse biological processes such as blood coagulation, bacteria and virus infection,
tumor metastasis, cell growth, cell adhesion, wound healing, inflammation, lipid
metabolism, and diseases of the nervous system.1c,3 Heparin, which is isolated from
animal organs, has been widely used clinically as an anticoagulant drug for major
cardiovascular and orthopedic surgeries such as knee surgery and in repairing hip
fractures or hip replacement. Since the 1940s, it has also been used to prevent the
occurrence of venous thrombosis, owing to its high affinity to bind with antithrombin
III.4 Despite its widespread use, current heparin therapies present challenges in
product quality control and material supply safety, due to the many diverse sources
and nonꢀuniformity of the organs used to produce the drug.5 Furthermore, serious
complications such as heparinꢀinduced thrombocytopenia, uncontrolled bleeding, and
osteoporosis may occur during administration of heparin.6 In the early 1980s, a unique
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pentasaccharide domain in heparin chains capable of activating antithrombin III was
discovered. This domain is a serine protease inhibitor that blocks factor Xa in the
coagulation cascade.7 Two pharmaceutical companies, Sanofi and Organon,
synthesized an analogue of this pentasaccharide, which was developed into a novel
antithrombotic drug, fondaparinux sodium, (1, Arixtra®, Figure 1) in 2002.8
Fondaparinux sodium displays superior antithrombotic activity to unfractionated
heparin (molecular weight average 14000) and its lowꢀmolecularꢀweight variants
(molecular weight average 6000),9 and brings about antithrombinꢀmediated activity
exclusively against factor Xa but with no effect on thrombin.10 Moreover, it is much
easier to control product quality during the production process of the artificial
synthetic pentasaccharide agent, which also has several advantages over the
aforementioned naturallyꢀderived heparins in terms of pharmacokinetics.11
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Figure 1. Structure of fondaparinux sodium (Arixtra®)
Although fondaparinux sodium is an outstanding anticoagulant drug compared to
traditional heparins, its high manufacturing cost restricts widespread use as the
synthesis is difficult and tedious.7,8 Indeed, fondaparinux sodium and other heparin
oligosaccharides are generally perceived to be difficult to synthesize.7,8,12d Most of the
time, lengthy chemical processes are required because of the repeated introduction
and removal of protecting groups, and the separation of side products from desired
intermediates is often inefficient, both of which drastically decrease the synthetic
efficiency. Therefore, it is imperative to develop highly efficient strategies for
producing the homogeneous pentasaccharide for clinical applications. Recently, some
progress towards a more efficient synthesis of this pentasaccharide has been made:12
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Hung and coꢀworkers elegantly applied a [4+1] approach to finish the total synthesis
of fondaparinux sodium in 22 linear steps from Dꢀglucosamine•HCl, and the use of
common intermediates and a series of oneꢀpot reactions considerably reduced the
synthetic steps and improved the yield.12a Moreover, Lin12b and Wang12c completed
the synthesis of this pentasaccharide by a convergent [3+2] manner separately. In
contrast to the chemical methods mentioned above, Linhardt and Liu used a
chemoenzymatic synthesis to obtain heparin pentasaccharide in their syntheses of two
structurally homogeneous ultralow molecular weight heparins in 45 and 37% overall
yield over 10 and 12 steps respectively.12d Herein, we describe the formal synthesis of
fondaparinux sodium using a [3+2] optimized modular synthetic strategy from
wellꢀfunctionalized building blocks, which significantly decreases the number of total
synthetic steps and enhances the synthetic efficiency.
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2
Results and Discussion
2.1 Retrosynthetic Analysis for fondaparinux sodium
Our synthetic route to the pentasaccharide required a modular and convergent
strategy using a set of suitablyꢀfunctionalized monosaccharide building blocks. These
were readily accessible and convenient for regioselective placement of multiple
sulfonate groups, allowing the critical stereochemical aspects of glycosylation to be
controlled by the anomeric effect and neighboring group participation. Through
retrosynthetic design (Scheme 1), fondaparinux sodium 1 could be generated from
pentasaccharide 2 via the wellꢀknown Oꢀsulfation/hydrogenation/Nꢀsulfation process,
with free hydroxyl groups and carboxylic groups.13 The latter was accessible from
fully protected pentasaccharides 3 or 4 under hydrolysis conditions. To provide
efficient access to pentasaccharides 3 or 4, we conceived a [3+2] coupling approach
through the disaccharide acceptor 7 (building block AB) and trisaccharide donors 5 or
6 (building block CDE). Compounds 5 and 6 could be prepared from condensation of
the known glucosazide trichloroacetimidate 8 (building block E)14 and disaccharide
acceptors 9 or 10 (building block CD). These latter disaccharides could be constructed
by functionalized monosaccharide donor 14 (building block D)12c and acceptor 13
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(building block C). In contrast, disaccharide 7 may also be assembled through 1ꢀthio
iduronic acid donor 11 (building block B) and glucosamine acceptor 12 (building
block A).15
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The aforementioned five monosaccharide building blocks (8, 11, 12, 13, and 14)
can be prepared from two convenient starting materials with several different methods.
In detail, the glucosazide units 8, 13 and glucosamine unit 12 are all readily attainable
from commercially available Dꢀglucosamine•HCl 17. The iduronic acid unit 11 can
be prepared from the known anhydroꢀLꢀidose 15, which was obtained from diacetone
Dꢀglucose 16 in five steps,16 while 16 could also be converted into glucose derivative
14 in several steps.12c Furthermore, a protection strategy was established for
Oꢀsulfation and selective Nꢀsulfation, as well as for glycosylation stereoselectivity.
Acetyl and benzoyl protecting groups allowed the introduction of the crucial sulfate
groups at the corresponding hydroxy groups. Benzoyl and levulinoyl (Lev) groups
(building blocks 11 and 14a) were selected to facilitate neighboringꢀgroup
participation for the stereoselective introduction of 1,2ꢀtransꢀglycosidic linkages,
while benzyl ethers were used as permanent protecting groups for releasing the
hydroxy groups in a later stage of the synthesis. Azido groups in building blocks 8, 9
and 10 were used as amino functionalities for subsequent Nꢀsulfation, as well as for
utilizing the anomeric effect (bearing a C2ꢀnonparticipating group) to install
1,2ꢀcisꢀglycosidic linkages between the E and CD fragments.12a Furthermore, ester
groups (acetyl or benzoyl) at the O6 position of these intermediates potentially
enhance the stereochemical aspects of the glycosylation by remote participation.
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OSO3Na
O
HO
HO
OSO3Na
O
NaO2C
O
NH
O
OSO3Na
O
NaO3S
E
O
NaO2C
HO
OH
O
6
O
NaO3SO
OH
NH
C
HO
O
D
NaO3S
NH
7
OMe
NaO3SO
B
NaO3S
8
9
1
A
O-sulfation/hydrogenation
/N-sulfation
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ref. 13
OH
O
BnO
BnO
OH
O
HO2C
N3
O
E
O
OH
O
HO2C
OBn
BnO
O
O
HO
OBn
N3
O
BnO
D
C
O
NH
OMe
HO
Cbz
B
2
A
hydrolysis
OBz
O
BnO
BnO
OR
O
R'O2C
N3
O
O
OBz
E
O
MeO2C
BnO
OBn
O
O
O
RO
OBn
N3
BnO
D
C
O
NH
OMe
OBz
BzO
Cbz
B
A
3 R = Bz, R' = Bn
4 R = Ac, R' = Me
OBz
O
[3+2] coupling
approach
BnO
BnO
OR
R'O2C
N3
O
NH
CCl3
O
O
O
O
OBn
O
BnO
BnO
MeO2C
OH
+
O
NH
O
RO
OBn
N3
OMe
OBz
Cbz
OBz
5 R = Bz, R' = Bn
6 R = Ac, R' = Me
CDE
AB
7
3 steps
2 steps
OR
OBz
O
R'O2C
HO
BnO
OBn
O
STol
O
NH
O
O
HO
BnO
BnO
BnO
MeO2C
O
OTBS
+
O
CCl3
RO
OBn
+
N3
NH
N3
OMe
OBz
OTBS
Cbz
E
8
9
R = Bz, R' = Bn
B
11
CD
12
A
10 R = Ac, R' = Me
11 steps
5 steps
7 steps
7 steps
OH
OR
OH
O
O
Ph
O
O
HO
HO
HO
O
O
6 steps
O
O
BnO
HO
RO
HO
HO
OH
BnO
OTBS
C
+
STol
OH
NH2•HCl
BzO
NH2•HCl
17
N3
OR
15
13a R = PMB
13b R = Bz
14a R = Lev
14b R = Bn
17
D
7 steps
5 steps
O
O
OH
O
O
O
16
Scheme 1. A retrosynthetic analysis of fondaparinux sodium 1
2.2 Preparation of Building Block A (Monosaccharide 12)
From the retrosynthetic perspective, we began our synthesis with the preparation of
disaccharide 7 (building block AB), obtained from the coupling of 1ꢀthio iduronic
acid donor 11 and glucosamine acceptor 12. The αꢀmethyl glycoside 12 (building
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block A) was prepared from known 2ꢀazidoglucoside 18 (Scheme 2), the latter was
synthesized from Dꢀglucosamine•HCl 17 in six steps.16c,17 However, at this stage the
anomeric mixture 18 (α/β = 6:1) proved difficult to separate by chromatography:
eluting with 33% ethyl acetate/petroleum ether, the desired αꢀmethyl glycoside
anomer had an Rf value of 0.40, in contrast to the β anomer with an Rf value of 0.35.
We were fortunately able to circumvent this problem using an azide
reductionꢀprotection protocol. Staudinger reaction of the azide anomeric mixture with
PPh3 and silica gel in a THFꢀwater mixture proceeded smoothly and the resulting
crude products were carried forward without further purification. After the protection
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of the amino group with CbzCl and NaHCO3, the desired αꢀmethyl glycoside 12 (J1,2
= 3.6 Hz) could be separated easily in 56% yield via column chromatography, due to
the significantly different Rf values of 12 and 19 (0.40 for 12 and 0.05 for 19, eluting
with 50% ethyl acetate/petroleum ether), while βꢀanomer iminophosphorane 19 (J1,2
=
8.4 Hz) was also obtained in 11% yield. We note that, because the iminophosphorane
group in 19 cannot be further hydrolyzed to the corresponding amine under these mild
conditions, this efficient separation is highly suitable for scalable preparation of
αꢀmethyl glycoside 12 (building block A).
Scheme 2. Synthesis of glucosamine 12 (building block A). Reagents and conditions:
a) 1) PPh3, silical gel, THFꢀH2O (9:1), RT, 3 h; 2) CbzCl, NaHCO3, THFꢀH2O (9:1), 0
oC, 3 h, 56% for 12 and 11% for 19.
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2.3 Preparation of Building Block B (Monosaccharide 11)
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The generation of rare Lꢀidose was one of the most frequently encountered
problems in the synthesis of heparin derivatives.16c,18 To minimize functionalꢀgroup
transformations and circumvent the oxidation steps at subsequent oligosaccharide
stages, we prepared donor 11 (building block B) with suitable protecting groups and a
C5 methyl ester to enhance the efficiency of the entire synthesis. Wang and
coꢀworkers prepared a similar building block B from commercially available
diacetone glucose 16 in 11 steps in their fondaparinux sodium synthesis;12c however,
the repeated introduction and removal of protecting groups decreased the overall
synthetic yield of the building block to 6%. In our initial synthesis of building block B,
we also prepared 1ꢀthio iduronic acid donor 11 from known compound 20 (Scheme 3),
which was synthesized from 16 via seven steps as in reported methods.19 Treatment of
20 with pꢀtoluenethiol in the presence of BF3•Et2O gave thioglycoside 21 in 65%
yield as an anomeric mixture (α/β = 5:2). Removal of the acetyl groups in 21,
followed by the Bu2SnOꢀmediated regioselective protection of the C2 hydroxyl as a
benzoate ester, afforded alcohol 23. The benzoate ester in 23 served as a participating
group to assist the later glycosylation reaction. Finally, blocking the remaining C4
hydroxyl group with tꢀbutyldimethylsilyl ether led to the desired 1ꢀthio iduronic acid
donor 11 in 86% yield. However, this synthesis was inefficient (11 steps and 4%
overall yield), and required expensive reagents and rigorous reaction conditions (low
temperature, anhydrous environments, strong bases, etc.). These issues prompted us to
look for a superior approach more amenable to largeꢀscale preparation.
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Scheme 3. The initial synthesis of monosaccharide 11 (building block B). Reagents
o
and conditions: a) TolSH, BF3•Et2O, DCM, 0 C to RT, 12 h, 65%, α/β = 5:2; b)
MeONa, MeOH, RT, 76%; c) 1) Bu2SnO, MeOH, reflux, 1 h; 2) BzCl, Et3N, dioxane,
0 oC, 1 h, 65%; d) TBSOTf, 2,6ꢀlutidine, DCM, 0 oC to RT, 30 min, 86%.
AnhydroꢀLꢀidopyranoside 15, a crystallizable Lꢀidose intermediate generated from
16 in five steps with 37% overall yield,16c was chosen as a building block for
glycosylation in Hung’s elegant synthesis of fondaparinux sodium.12a We were thus
inspired to employ 15 as an intermediate for our optimized synthesis of building block
B. Unlike Hung’s strategy, we converted 15 into fully functionalized 11 to reduce
oligosaccharideꢀstage modifications (Scheme 4). Acetolysis of the anhydro ring with
an Ac2O/TFA mixture (24)20 followed by preparation of thioglycoside in the presence
of pꢀtoluenethiol and TfOH (25) with subsequent removal of the acetyl groups with
acetyl chloride in methanol was accomplished in a one pot reaction to give known
compound 268e in 60% overall yield as an anomeric mixture (α/β = 5:1). Selective
oxidation of 26 with TEMPOꢀPhI(OAc)2 and subsequent esterification with Me2SO4
provided intermediate 23 in 80% yield. This approach towards 11 (10 steps and 15%
overall yield from 16) was more straightforward and gave better overall yield
compared to the original procedure. Moreover, our oneꢀpot protocol (15 → 26) and
crystallization procedure (16 → 15) considerably simplified the overall synthetic
procedures and minimized wasteful purification steps. Furthermore, mild reaction
conditions and inexpensive reagents were used throughout the process. These
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advantages make this approach more convenient for scalable preparation.
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Scheme 4. The optimized synthesis of monosaccharide 23 (building block B).
o
Reagents and conditions: a) Ac2OꢀTFA (6:1), 60 C, overnight; b) TolSH, TfOH,
DCM, 0 oC; c) AcCl, MeOH, 0 oC to RT, overnight, 60% over 3 steps, α/β = 5:1; d) 1)
PhI(OAc)2, TEMPO, DCMꢀH2O (2:1), RT; 2) Me2SO4, K2CO3, acetone, RT, 80%.
TFA = trifluoroacetic acid, TEMPO = 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxyl free
radical.
2.4 Preparation of Building Block AB (Disaccharide 7)
With suitably functionalized donor 11 and acceptor 12 in hand, we investigated the
synthesis of disaccharide 7. In Wang’s synthesis, the glucosazide uronate disaccharide
(building block AB) was prepared via a BSP/Tf2Oꢀmediated condensation, which
proceeded in 56% yield with excellent αꢀselectivity.12c Lin and coꢀworkers employed
more reactive Lꢀidosyl donors to deliver a series of disaccharides with satisfactory
stereochemical outcome in higher yield,12b but this route required the inevitable
protection and oxidation reactions at the disaccharide stage for the preparation of
suitable uronate acceptors. In our work, we adopted a similar strategy to Wang’s
synthesis for preparing glucosamine uronate disaccharide acceptor 7, without the
additional transformations of functional groups for the designed glycosylation
between building blocks AB and CDE. As shown in Scheme 5, activation of the
anomeric thiophenyl group of idouronate 11 with the NIS/TfOH reagent proceeded
efficiently for condensation with the glucosamine building block 12 to afford desired
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disaccharide 27 with full αꢀselectivity in 67% yield (J1,2 = 5.6 Hz). Subsequently, the
TBS ether group could be readily removed with HF•pyridine to give 7 as an acceptor
for the next glycosylation with trisaccharides 5 and 6 (building block CDE).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Synthesis of disaccharide 7 (building block AB). Reagents and conditions:
a) NIS, TfOH, 4Å molecular sieve, DCM, −40 oC, 1 h, 67%; b) HF•pyridine, RT, 1 h,
90%. NIS = Nꢀiodosuccinimide, TfOH = trifluoromethanesulfonic acid.
2.5 Preparation of Building Blocks C and E (Monosaccharides 13 and 8)
Based on the synthetic plan shown in Scheme 1, an intensive investigation on the
synthesis of crucial trisaccharides 5 and 6 (building block CDE) was carried out.
Target trisaccharides 5 and 6 can be assembled through the glucosazide
trichloroacetimidate acceptor 8 (building block E)14 and disaccharide acceptors 9 or
10 (building block CD). Disaccharides 9 and 10 (building block CD) can be prepared
from the condensation of monosaccharide donor 14 (building block D) with
glucosazide acceptor 13 (building block C). In our synthetic scheme, the glucosazide
monosaccharides 13 (building block C) and 8 (building block E) were readily
prepared using the common intermediate 28 (Scheme 6), which could be easily
synthesized over a 500 g scale from 17 in five steps based on previously reported
methods.19b First, Bu2SnOꢀmediated protection of the C4 and C6 hydroxyl groups in
the presence of excess PMBCl or BzCl generated the desired monosaccharide
acceptors 13a (70%) and 13b (50%), respectively. Then, the known azidoglucose
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trichloroacetimidate acceptor 8 (building block E) was readily synthesized by the
reported procedures14,19b or the alternative method (See Experimental Section). The
synthetic approaches employing a common intermediate significantly reduce the
number of steps and enhance synthetic efficiency.
10
11
12
13
14
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17
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19
20
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23
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26
27
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29
30
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32
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34
35
36
37
38
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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
Scheme 6. Synthesis of building blocks C and E. Reagents and conditions: a) Bu2SnO,
PMBCl (2.5 eq.), TBAI, PhMe, reflux, 11 h, 70%; b) Bu2SnO, BzCl (2.1 eq.), TBAI,
PhMe, reflux, 4 h, then RT overnight, 50%. TBAI = tetrabutylammonium iodide.
2.6 Preparation of Building Block D (Monosaccharides 14, 30 and 35)
To provide the crucial βꢀselectivity in the coupling of building block C with
building block D, four types of monosaccharides (14a, 14b, 30 and 35) were prepared
as donors to probe the critical glycosylations (Scheme 7). Three of the
monosaccharides (14b, 30, and 35) have a Bn group at the O2 and O3 positions,
which serve as permanent protecting groups for this synthesis. The C5 ester group in
35 was installed at the monosaccharide stage to avoid additional oxidation operations
in the subsequent oligosaccharide stage. Moreover, the Lev group in monosaccharide
14a was employed to facilitate neighboringꢀgroup participation in the stereoselective
introduction of the βꢀglycosidic linkage. Two known thioglycoside donors 14a and
14b were readily synthesized without column chromatography purification from 16
using the reported procedures.12c,21 (Scheme 7). The other two donors with different
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anomeric leaving groups, trichloroacetimidates 30 and 35, were also prepared from
the common intermediate 14b. Monosaccharide 30 could be readily prepared from the
corresponding thioglycoside 14b by the TCCAꢀmediated removal of the pꢀtolylthio
group and a trichloroacetimidate formation sequence.22 In contrast, selective removal
of the 4,6ꢀOꢀbenzylidene group in 14b with TFA generated the corresponding diol
31.23 TEMPOꢀPhI(OAc)2 oxidation of the primary hydroxyl group, followed by
esterification delivered 32. After TBS protection, the resulting thioglycoside 33 was
converted into trichloroacetimidate 35 by a similar sequence with pꢀtolylthio group
removal and trichloroacetimidate formation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Synthesis of building block D. Reagents and conditions: a) TCCA,
o
acetoneꢀH2O (3:1), RT, 1 h, 81%; b) Cl3CCN, DBU, DCM, 0 C to RT, 85% for 30
(α/β = 2:1), 64% for 35 (α/β = 7:1); c) TFA, DCMꢀH2O (5:1), 0 oC to RT, 1 h, 85%;
d) 1) PhI(OAc)2, TEMPO, DCMꢀH2O (2:1), RT, 2.5 h; 2) K2CO3, BnBr, Et3N,
acetone, 55 oC, 2 h, 50%; e) TBSOTf, 2,6ꢀlutidine, DCM, 0 oC to RT, 30 min, 82%; f)
NBS, acetoneꢀH2O (9:1), RT, 1 H, 85%, α/β = 5:2. TCCA = trichloroisocyanuric acid,
DBU = 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene, TFA = trifluoroacetic acid, TEMPO =
2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxyl free radical, NBS = Nꢀbromosuccinimide.
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2.7 Preparation of Building Block CD (Disaccharides 9 and 10)
9
With compounds 14, 30, and 35 (building block D) in hand, the glycosylation step
with azidoglucose acceptors 13a and 13b (building block C) was then carefully
investigated. The Ag2CO3ꢀmediated coupling of the glycosyl bromide donor with a
1,6ꢀanhydro glucosazide acceptor was used by Wang and coꢀworkers to form the
desired disaccharide (building block CD) with moderate yield, in a 7:1 β/α ratio.12c
Although this mild glycosylation proceeded slowly (four days), the resulting
disaccharide could be employed in the forthcoming glycosylation reaction without
further modification other than a oneꢀstep deprotection. Unlike Wang’s strategy, the
Lin group straightforwardly synthesized building block CD from cellobiose,12b with a
subsequent selective oxidation that effectively yielded the required uronate
disaccharide. Ideally, we planned to choose uronate donor 35 for the construction of
the βꢀ1,4ꢀlinked disaccharide with azidoglucose acceptors, because the essential
permanent protection of C2, C3 hydroxy groups and an ester group at the C5 position
in this synthesis had been performed at the monosaccharide stage. With respect to
acceptors (building block C), the Bzꢀacceptor 13b was preferable to the
PMBꢀacceptor 13a because no further conversion of the PMB group to a Bz group
was needed after formation of the disaccharide. Unfortunately, the glycosylation of 35
with 13b did not work under various conditions, and we were not able to generate the
desired product (Scheme 8). To our delight, by using PMBꢀacceptor 13a instead of
13b, the glycosylation with 35 in the presence of TESOTf proceeded smoothly to
afford the corresponding glycoside products 36 (J1,2 = 7.2 Hz) and 37 (J1,2 = 3.2 Hz) in
83% combined yield. This reaction had poor stereoselectivity (β/α =1.2:1), but the
anomers could be separated by silica gel column chromatography. In contrast, using
thioglycoside glycosyl donor 14b instead of uronate donor 35, the NIS/TfOHꢀassisted
glycosylation of azidoglucose acceptor 13b led to disaccharide 38 as the sole product
in 80% yield (Scheme 9). However, at this stage, the product stereochemistry in 38
could not be determined on the basis of the coupling constant between the protons at
10
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13
14
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17
18
19
20
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29
30
31
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34
35
36
37
38
39
40
41
42
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47
48
49
50
51
52
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C1 and C2ꢀposition due to the complicated overlapping in the H NMR spectrum of
38. Meanwhile, the trichloroacetimidate 30 (anomeric mixture, α/β = 2:1) was also
used for the critical glycosylation. Subjecting 30 and 13b to the TESOTfꢀpromoted
glycosylation provided the same product 38 in 35% yield, together with a large
amount of starting material, which could be recycled.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8. Glycosylations of donor 35 with glucosazide acceptors 13a and 13b.
Reagents and conditions: a) TESOTf, 4Å molecular sieve, cyclohexane, RT,
overnight, 45% for 36 and 38% for 37.
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Scheme 9. Glycosylations of donors 14b and 30 with glucosazide acceptor 13b.
Reagents and conditions: a) NIS, TfOH, 4Å molecular sieve, DCM, −40 oC, 1 h, 80%;
b) TESOTf, 4Å molecular sieve, DCM, −40 oC, overnight, 35%. NIS =
Nꢀiodosuccinimide, TfOH = trifluoromethanesulfonic acid.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In order to confirm the glycosidic bond configuration of disaccharide 38, we
conducted the following experiments. As shown in Scheme 10, PMB cleavage of
glycoside products 36 and 37 with DDQ, followed by benzoylation with Bz2O and
DMAP in one pot, provided the β disaccharide 39 and
α disaccharide 40 in 56% and
52% yield, respectively. In contrast, the sequential 4,6ꢀOꢀbenzylidene removal of
disaccharide 38 with TFA and PhI(OAc)2ꢀTEMPO mediated oxidation, followed by
esterification, gave compound 41. Blocking the remaining 4ꢀhydroxyl group in 41 by
replacement with the TBS group delivered the corresponding α disaccharide 40 in
80% yield, which unambiguously demonstrated that the glycosylation of donors 14b
or 30 with acceptor 13b exhibited full αꢀselectivity, contrary to our expectations.
Scheme 10. Experimental verification of glycosylation. Reagents and conditions: a) 1)
DDQ, DCMꢀH2O (9:1), RT, 3 h; 2) Bz2O, DMAP, PhMe, reflux, 30 h, 56% (when
o
using 36), 52% (when using 37); b) 1) TFA, DCMꢀH2O (15:1), 0 C to RT; 2).
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PhI(OAc)2, TEMPO, DCMꢀH2O (2:1), RT; 3) K2CO3, BnBr, Et3N, acetone, 50 C,
61%; c) TBSOTf, 2,6ꢀlutidine, DCM, 0 oC to RT, 30 min, 80%. DDQ =
2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀbenzoquinone, TFA = trifluoroacetic acid, TEMPO =
2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxyl free radical.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Using 2ꢀOꢀBn donors (14b, 30, and 35) proved challenging for the stereochemical
aspect of the glycosylations, presumably due to the anomeric effect. To circumvent
this problem, we turned to use a Lev group in place of Bn at the donor O2 position to
achieve a βꢀselectivity resulting from neighboring participation in the glycosylation.
To test this hypothesis, we first carried out the condensation of Levꢀdonor 14a with
Bzꢀacceptor 13b. Unfortunately, the desired product 42 was not formed under various
conditions, and we observed substantial decomposition of the starting materials
(Scheme 11). The inefficient glycosylation likely results from the
electronꢀwithdrawing esters in both the glycosyl donor and azidoglucose acceptor.12a
Pleasingly, use of the PMBꢀacceptor 13a instead of 13b allowed the
NIS/TfOHꢀpromoted glycosylation to proceed well, delivering desired disaccharide
43 with complete β
ꢀselectivity (no α anomer detected) in 80% yield (J1,2 = 7.6 Hz).
OBz
O
HO
OTBS
BzO
Ph
O
Ph
O
OBz
N3
O
13b
O
O
O
O
STol
BnO
O
BnO
OTBS
BzO
OLev
conditions
OLev
14a
N3
42
OPMB
O
HO
PMBO
6
OTBS
Ph
O
4
BnO
OPMB
6'
5
O
O
N3
O
5'
1
13a
4'
O
2
OTBS
PMBO
3
2' N3
OLev
1'
3'
a
43 ( only)
Scheme 11. Glycosylations of donor 14 with glucosazide acceptors 13a and 13b.
Reagents and conditions: a) NIS, TfOH, 4Å molecular sieve, DCM, RT, 1 h, then −40
oC, 1 h, 80%. NIS = Nꢀiodosuccinimide, TfOH = trifluoromethanesulfonic acid.
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9
Following our synthetic plan, functionalꢀgroup transformations were then carried
out to complete the synthesis of suitable acceptors 9 and 10 (Scheme 12).
Hydrazineꢀmediated cleavage of the Lev group in 43, followed by benzylation with
BnBr for permanent protection, furnished disaccharide 45 in 70% yield overall for the
two steps. After removal of the PMB groups in 45 with DDQ in a mixture of DCM
and water, the obtained diol 46 was esterified as benzoate ester or acetate ester to give
47 or 48 respectively. Subsequently, the 4,6ꢀOꢀbenzylidene group in 47 and 48 was
selectively removed using TFA to yield diols 49 and 50 respectively. Selective
oxidation of the primary alcohol, followed by esterification, delivered acceptors 9 and
10 for the later glycosylation in 93% and 65% yield over two steps, respectively. The
preparation of building block CD required 6ꢀstep adjustment of protecting groups.
However, the mild conditions, easy operation, crystallizable intermediates (e.g., 43,
45 and most of intermediates towards 14a) and high synthetic yield (32% overall for 9
and 23% overall for 10 from 14a) demonstrate that this route is scalable. Indeed, in
our laboratory, disaccharides 9 and 10 were successfully prepared on a 100 g scale.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
Ph
Ph
O
4
BnO
OPMB
Ph
O
OPMB
O
6'
5
O
O
O
5'
O
O
a
b
1
4'
O
O
2
BnO
OTBS
OTBS
PMBO
OTBS
3
PMBO
2' N3
OLev
1'
3'
OH
N3
43
44
Ph
O
OH
O
OPMB
O
O
O
O
O
O
d or e
c
O
O
BnO
BnO
OTBS
OTBS
HO
PMBO
OBn
OBn
N3
N3
46
45
Ph
O
OR
O
HO
OR
O
O
O
HO
BnO
O
g or h
f
O
BnO
O
OTBS
RO
RO
OBn
OBn
N3
N3
47 R = Bz
49
R = Bz
50 R = Ac
48
R = Ac
OR
R'O2C
HO
BnO
O
O
N3
building block CD
O
OTBS
RO
OBn
9
R = Bz, R' = Bn
10 R = Ac, R' = Me
Scheme 12. Synthesis of disaccharide acceptors 9 and 10. Reagents and conditions: a)
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N2H4•H2O, pyridineꢀAcOH (3:1), RT, 1 h; b) BnBr, NaH, TBAI, DMF, RT, 50 min,
5
6
7
8
70% over 2 steps; c) DDQ, DCMꢀH2O (10:1), RT, 30 min, 81%; d) preparation of 47,
o
Bz2O, DMAP, PhMe, 60 C, 12 h; e) preparation of 48, Ac2O, DMAP, PhMe, 60 oC,
9
12 h; f) TFA, DCMꢀH2O (10:1), RT, 75% over 2 steps for 49, 78% over 2 steps for 50;
g) preparation of 9, 1) TEMPO, PhI(OAc)2, DCMꢀH2O (2:1), RT; 2) BnBr, K2CO3,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
Et3N, acetone, 60 C, 93%; h) preparation of 10, 1) TEMPO, PhI(OAc)2, DCMꢀH2O
(2:1), RT; 2) Me2SO4, K2CO3, Et3N, acetone, RT, 65%. TBAI = tetrabutylammonium
iodide, DDQ = 2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀbenzoquinone, TFA = trifluoroacetic
acid, TEMPO = 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxyl free radical.
2.8 Preparation of Building Block CDE (Trisaccharides 5 and 6)
With the crucial disaccharide acceptors 9 and 10 in hand, the construction of
trisaccharides 5 and 6 were investigated next (Scheme 13). As anticipated, the highly
stereoselective glycosylations of 9 or 10 with azidoglucose donor 8 worked well. The
combined effects of the anomeric effect and potentially remote participation, as
caused by the orthogonal protecting groups in 8 (N3, O6ꢀBz, and Bn), induced
exclusive αꢀselectivity for this TfOHꢀpromoted glycosylation and delivered the
corresponding trisaccharides 51 (J1,2 = 3.6 Hz) and 52 (J1,2 = 3.2 Hz) in 64% and 85%
yield respectively. Selective removal of the anomeric TBS ether group with
HF•pyridine in MeCN afforded alcohols 53 (85%, α/β = 3:2) and 54 (84%, α/β = 2:1).
These compounds were converted by addition of CCl3CN to trichloroacetimidate
donors 5 (85%, α/β = 4:1) and 6 (77%, α/β = 5:1) for the ultimate glycosylation step.
Due to the functionalization of monosaccharide donor 8 and disaccharide acceptors 9
and 10, the condensation proceeded quickly (within two hours) in high yield and with
excellent αꢀselectivity. The obtained trisaccharides 51 and 52 could be readily
converted to donors 5 and 6 simply by minor modifications at the anomeric position.
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6
7
8
OR
R'O2C
O
OBz
O
HO
NH
CCl3
O
O
BnO
BnO
OTBS
+
BnO
RO
OBn
O
N3
N3
9
R = Bz, R' = Bn
8
10 R = Ac, R' = Me
9
OBz
6
O
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
BnO
4
6'
a
BnO
1
OR
5''
3
2 N3
R'O2C
6''
5'
O
O
O
BnO
4'
O
4''
1'
OTBS
2' OBn
3'' 2'' N3
3'
RO
1''
51 R = Bz, R' = Bn ( only)
52 R = Ac, R' = Me ( only)
OBz
O
BnO
BnO
b
OR
R'O2C
N3
O
O
O
O
OH
BnO
RO
OBn
N3
53 R = Bz, R' = Bn
54
R = Ac, R' = Me
OBz
O
BnO
BnO
c
OR
R'O2C
O
N3
NH
CCl3
O
N3
building block CDE
O
BnO
O
O
RO
OBn
5 R = Bz, R' = Bn
6 R = Ac, R' = Me
Scheme 13. Synthesis of trisaccharides 5 and 6 (building block CDE). Reagents and
conditions: a) TfOH, 4Å molecular sieve, PhMe, −40 oC, 2 h, 64% for 51 and 85% for
52; b) HF•pyridine, MeCN, RT, 1 h, 85% for 53 (α/β = 3:2) and 84% for 54
o
(α/β = 2:1); c) Cl3CCN, DBU, MeCN, 0 C to RT, overnight, 85% for 5 (α/β = 4:1)
and 77% for 6 (α/β = 5:1). TfOH = trifluoromethanesulfonic acid, DBU =
1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene.
2.9 Preparation of Pentasaccharide 2
To complete the synthesis, the convergent [3+2] couplings of trichloroacetimidate
donors 5 and 6 with acceptor 7 in the presence of TfOH effectively achieved both
fullyꢀprotected pentasaccharide targets 3 (J1’’,2’’ = 3.6 Hz) and 4 (J1’’,2’’ = 3.6 Hz), with
complete αꢀselectivity, in 65% and 57% yield respectively (Scheme 14). The
glycosylations were exclusively stereoselective, presumably as a result of the dual
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effects of the ester (R) and N3 groups in building block CDE. Subsequent removal of
5
6
the ester groups from pentasaccharides
3
and
4
under
a
careful
7
8
9
LiOH/H2O2ꢀNaOHꢀmediated hydrolysis condition resulted in reported compound 2 in
acceptable yields after crystallization (60% from 3 and 65% from 4).12b,12c Notably,
pentasaccharide 2 can then be readily converted into the anticoagulant drug
fondaparinux sodium 1 by the wellꢀknown Oꢀsulfation/hydrogenation/Nꢀsulfation
process.13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OBz
OBz
O
BnO
BnO
O
O
OR
R'O2C
OBn
O
N3
NH
CCl3
BnO
O
O
O
MeO2C
OH
NH
+
O
OMe
BnO
O
Cbz
RO
OBn
N3
OBz
5 R = Bz, R' = Bn
6 R = Ac, R' = Me
7
building block AB
building block CDE
a
OBz
4
O
BnO
BnO
1
2 N3
OR
R'O2C
4''
O
O
O
BnO
OBz
O
4'
E
O
4''''
1'
MeO2C
OBn
O
2' OBn
2'' N3
O
RO
1''
BnO
4'''
1''''
O
2''''NH
OMe
Cbz
D
C
1'''
BzO
2'''
3 R = Bz, R' = Bn ( only)
B
A
4
R = Ac, R' = Me ( only)
OH
b
O
BnO
BnO
OH
O
HO2C
N3
O
O
OH
O
O
HO2C
BnO
OBn
O
O
BnO
HO
OBn
N3
O
NH
OMe
Cbz
HO
2
ref.13
OSO3Na
O
HO
HO
OSO3Na
O
NaO2C
O
HO
NH
O
OSO3Na
O
NaO3S
O
NaO3SO
NaO2C
OH
O
O
OH
NH
HO
O
NaO3S
NH
OMe
NaO3SO
NaO3S
1
Scheme 14. Synthesis of pentasaccharide 2. Reagents and conditions: a) TfOH, 4Å
molecular sieve, PhMe, −40 oC, 2 h, 65% for 3 and 57% for 4; b) 1.25M LiOH (aq.),
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H2O2 (30%), THF, −5 oC to RT, 16 h, then 4M NaOH (aq.), MeOH, RT to 35 oC, 26 h,
60% (when using 3), 65% (when using 4). TfOH = trifluoromethanesulfonic acid.
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Conclusion
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Pentasaccharide 2, an important precursor for the synthesis of fondaparinux sodium,
has been synthesized in 14 steps with 3.5% overall yield from wellꢀfunctionalized
monosaccharide building blocks and in 48 collective steps from commercially
available starting materials. We have established a modular and convergent [3+2]
strategy using a series of appropriately orthogonal protecting groups and readily
accessible monosaccharide building blocks. Pentasaccharide 2 could then be easily
converted into fondaparinux sodium in 41% overall yield over 3 steps based on
previously reported methods.13
At the monosaccharide stage, several new and efficient routes to these building
blocks were developed, in particular the use of 1ꢀthio iduronic acid donor 11 (building
block B), glucosamine acceptor 12 (building block A) and azidoglucose acceptor 13
(building block C). All reactions avoided rigorous reaction conditions (avoiding low
temperature, anhydrous environments, strong bases, etc.). The use of common
intermediates and a series of oneꢀpot operations considerably enhanced the synthetic
efficiency and improved the overall yield. Moreover, many intermediates such as
those used to prepare 15, 14 and 30, could be purified by crystallization, simplifying
purification procedures and minimizing waste.
Using these suitablyꢀfunctionalized monosaccharide and oligosaccharide building
blocks, all crucial glycosylations proceeded efficiently in short time with satisfactory
yield (ranging from 57% to 85%) and excellent stereoselectivity, i.e. the desired
coupling product was delivered as a sole anomer in every glycosylation. Cheaper
activators (e.g., NIS/TfOH, TESOTf and TfOH) were employed, and metallic and
expensive reagents were successfully avoided throughout the glycosylation
procedures.
Given such improved purification and efficiency of the glycosylations, our
developed synthetic strategy has great potential for use in the mass production of
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pentasaccharide 2. As a common intermediate for the preparation of fondaparinux
5
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sodium, these results can significantly improve the scalability of this important drug.
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Experimental Section
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General methods
All commercially available reagents were used without further purification. All
solvents were dried and distilled before use; THF and PhMe were distilled from
sodium/benzophenone ketyl; dichloromethane was distilled from calcium hydride;
MeOH was distilled from magnesium methoxide. Chromatography was conducted by
using 200ꢀ300 mesh silica gel. Petroleum ether refers to the 60ꢀ90 °C boiling fraction.
All new compounds gave satisfactory spectroscopic analyses (1H NMR, 13C NMR,
HRMS). IR spectra were recorded on a FT IR spectrometer. NMR spectra were
recorded on 600/400 MHz NMR spectrometers. HRMS spectra were obtained by the
ESIꢀTOF method.
Synthetic procedures and characterization data
Methyl
2ꢀbenzyloxy
carbonylaminoꢀ3ꢀOꢀbenzylꢀ6ꢀOꢀbenzoylꢀ2ꢀdeoxyꢀαꢀDꢀglucopyranoside (12) and
Methyl
2ꢀ(triphenylphosphoranylidene)aminoꢀ3ꢀOꢀbenzylꢀ6ꢀOꢀbenzoylꢀ2ꢀdeoxyꢀβꢀDꢀgluc
opyranoside (19)
The
known
intermediate
methyl
2ꢀ
azidoꢀ3ꢀOꢀbenzylꢀ6ꢀOꢀbenzoylꢀ2ꢀdeoxyꢀDꢀglucopyranoside (18) was prepared from
Dꢀglucosamine hydrochloride 17 by the reported methods.16c,17a,17e To a solution of
α/β anomers 18 (270 g, 654 mmol) in THFꢀwater mixture (9:1, 2.5 L) was added PPh3
(257 g, 981 mmol) and silica gel (28 g) at room temperature. After stirring at room
temperature for 3 h, the reaction was cooled to 0 °C and sequentially added NaHCO3
(110 g, 1310 mmol) and CbzCl (138 ml, 1012 mmol), the resulting solution was kept
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for 3 h at 0 °C and then added water (1 L) and EtOAc (1 L). After separation, the
aqueous phase was extracted with EtOAc (3 × 1 L). The combined organic phases
were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude
product was purified by column chromatography (petroleum ether/ethyl acetate = 5:1
to dichloromethane/methanol = 50:1) to yield 12 (190 g, 56%)15 and 19 (46 g, 11%).
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o
Compound 12: Rf = 0.4 (petroleum ether/ethyl acetate, 2/1, v/v); mp 152ꢀ154 C;
23
α
+63.2 (c 0.3, CH2Cl2)
;
IR (KBr) 3496, 3316, 2909, 1706, 1689, 1541, 1320,
[ ]
D
1
1298, 1267, 1118, 1053, 1028, 711, 695; NMR data in CDCl3: H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 7.6 Hz, 2H), 7. 50 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H),
7.28ꢀ7.19 (m, 10H), 5.08 (d, J = 12.0 Hz, 1H), 5.01 (d, J = 12.4 Hz, 1H), 4.94 (d, J =
10.0 Hz, 1H, NH), 4.67 (s, 2H), 4.65ꢀ4.59 (m, 2H), 4.44 (dd, J = 12.4, 2.0 Hz, 1H),
3.96ꢀ3.90 (m, 1H), 3.80ꢀ3.76 (m, 1H), 3.60 (t, J = 9.2 Hz, 1H), 3.50 (t, J = 9.2 Hz,
1H), 3.30 (s, 3H), 2.95 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 166.9, 155.9,
138.2, 136.2, 133.2, 129.7, 129.5, 128.5, 128.4, 128.2, 128.1, 127.9, 127.8, 99.0, 80.4,
74.7, 70.3, 70.0, 67.0, 63.5, 55.1, 54.3. The spectral data was in agreement with the
reported data.15 NMR data in Acetoneꢀd6: 1H NMR (600 MHz, Acetoneꢀd6) δ 8.07 (d,
J = 7.8 Hz, 2H), 7. 64 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.37ꢀ7.23 (m, 10H),
6.30 (d, J = 9.6 Hz, 1H), 5.13 (d, J = 12.6 Hz, 1H), 5.04 (d, J = 12.6 Hz, 1H),
4.93ꢀ4.90 (m, 2H), 4.79 (d, J = 10.8 Hz, 1H), 4.72 (d, J = 3.6 Hz, 1H), 4.66 (dd, J =
12.0, 2.4 Hz, 1H), 4.52 (dd, J = 12.0, 6.0 Hz, 1H), 3.95ꢀ3.88 (m, 2H), 3.78ꢀ3.70 (m,
2H), 3.40 (s, 3H); 13C NMR (150 MHz, Acetoneꢀd6) δ 166.7, 157.0, 140.3, 138.3,
133.9, 131.2, 130.2, 129.4, 129.1, 128.8, 128.6 128.5, 128.4, 127.9, 100.0, 81.4, 75.3,
71.0, 66.6, 64.8, 55.9, 55.3;HRMS [M + Na]+ calcd for C29H31NO8Na 544.1947,
found 544.1958;
Compound 19: Rf = 0.05 (petroleum ether/ethyl acetate, 2/1, v/v), Rf = 0.25
23
(dichloromethane/methanol, 50/1, v/v)
;
α
−7.1 (c 0.2, CH2Cl2); IR (KBr) 3476,
[ ]
D
2924, 2107, 1720, 1453, 1276, 1116, 1056, 740, 713; 1H NMR (600 MHz, CDCl3) δ
8.01ꢀ7.99 (d, J = 11.4 Hz, 2H), 7.81ꢀ7.76 (m, 6H), 7.69ꢀ7.65 (t, J = 7.8 Hz, 3H),
7.55ꢀ7.51 (m, 7H), 7.42ꢀ7.38 (m, 2H), 7.26ꢀ7.23 (m, 5H), 5.15 (d, J = 11.4 Hz, 1H),
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4.99 (d, J = 8.4 Hz, 1H), 4.95 (d, J = 11.4 Hz, 1H), 4.59 (dd, J = 12.0, 5.4 Hz, 1H),
4.55ꢀ4.49 (m, 2H), 3.83ꢀ3.79 (m, 1H), 3.35 (t, J = 9.0 Hz, 1H), 3.10 (s, 3H), 2.63 (dd,
J = 18.0, 9.0 Hz, 1H); 13C NMR (150MHz, CDCl3): δ 166.8, 138.9, 134.2, 134.1,
134.0, 133.9, 133.0, 129.8, 129.5, 129.4, 128.3, 128.2, 127.5, 127.4, 122.9, 122.2,
102.9, 82.4, 75.2, 73.7, 72.0, 64.0, 59.5, 56.3; HRMS [M + H]+ calcd for C39H39NO6P
648.2510, found 648.2504.
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Methyl
(4ꢀmethylphenyl
2,4ꢀdiꢀOꢀacetylꢀ3ꢀOꢀbenzylꢀ1ꢀthioꢀLꢀidopyranoside)uronate (21)
The known intermediate methyl 1,2,4ꢀtriꢀOꢀacetylꢀ3ꢀOꢀbenzylꢀLꢀidopyranoate (20)
was prepared from diacetone glucose 16 by the reported methods.19 Under nitrogen, to
a solution of 20 (50 g, 118 mmol) in CH2Cl2 (1 L) was successively added BF3•OEt2
(75 mL, 594 mmol) and pꢀtoluenethiol (TolSH, 16 g, 155 mmol) at 0 oC. The reaction
mixture was allowed to warm to room temperature and stirred for 12 h. Et3N (72 mL)
was added to quench the reaction, and water (100 mL) was subsequently added into
the reaction flask. After separation, the aqueous phase was extracted with CH2Cl2 (3 ×
100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered
and evaporated in vacuo. The residue was purified by column chromatography
(petroleum ether/ethyl acetate = 6:1) to afford compound 21 (37 g, 65%, α/β = 5:2). Rf
1
= 0.4 (petroleum ether/ethyl acetate, 3/1, v/v); H NMR (400 MHz, CDCl3) δ
7.48ꢀ7.23 (m, 9.8H), 7.13ꢀ7.07 (m, 2.8H), 5.64 (br s, 0.4H), 5.56 (s, 1H), 5.39 (br s,
1H), 5.19 (br s, 1H), 5.16 (br s, 0.4 H), 5.13 (br s, 1H), 5.09 (s, 0.8H), 4.82 (d, J =
11.6 Hz, 1H), 4.74ꢀ4.70 (m, 1.8H), 3.91ꢀ3.89 (m, 0.4H), 3.85ꢀ3.83 (m, 1H), 3.77 (s,
4.2H), 2.32 (s, 1.2H), 2.30 (s, 3H), 2.11 (s, 1.2H), 2.04 (s, 1.2H), 2.03 (s, 6H); 13C
NMR (100MHz, CDCl3) δ 169.8, 169.5, 168.7, 137.5, 136.9, 136.8, 133.2, 132.5,
131.8, 131.3, 130.2, 129.7, 128.5, 128.4, 128.3, 128.3, 128.2, 128.0, 127.8, 127.7,
86.4, 85.1, 74.3, 72.9, 72.7, 72.2, 71.4, 69.0, 68.6, 67.9, 66.9, 66.8, 52.5, 21.0, 21.0,
20.9, 20.7; HRMS [M + Na]+ calcd for C25H28O8SNa 511.1403, found 511.1405.
Methyl (4ꢀmethylphenyl 3ꢀOꢀbenzylꢀ1ꢀthioꢀLꢀidopyranoside)uronate (22)
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To a solution of 21 (42 g, 86 mmol) in MeOH (550 mL) was added MeONa (3.7 g,
68 mmol) at room temperature and the reaction was stirred at the same temperature.
Once the reaction was complete, the reaction mixture was neutralized with 2M HCl
o
(aq.) at 0 C, and then extracted with CH2Cl2 (3 × 500 mL). The combined organic
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phases were dried over anhydrous Na2SO4, filtered and evaporated under reduced
pressure. The crude product was purified by column chromatography (petroleum
ether/ethyl acetate = 2:1) to afford compound 22 (26 g, 76%, α/β = 5:2). Rf = 0.3
(petroleum ether/ethyl acetate, 1/1, v/v);1H NMR (400 MHz, CDCl3) δ 7.47ꢀ7.25 (m,
9.8H), 7.14ꢀ7.09 (m, 2.8H), 5.49 (s, 1H), 5.24 (br s, 1H), 5.12 (s, 0.4 H), 4.78 (d, J =
11.6 Hz, 1H), 4.62 (d, J = 12.0 Hz, 1.4H), 4.49 (s, 0.4 H), 4.18ꢀ4.10 (m, 2H),
3.95ꢀ3.90 (m, 0.8H), 3.82 (s, 4.2H), 3.60 (d, J = 7.6 Hz, 1.4H), 3.45 (d, J = 6.8 Hz,
1H), 3.39 (d, J = 6.4 Hz, 0.4H), 2.34 (s, 1.2H), 2.32 (s, 3H); 13C NMR (100MHz,
CDCl3) δ 170.6, 137.5, 137.3, 132.4, 132.3, 131.6, 129.8, 129.7, 128.6, 128.5, 128.2,
128.0, 127.7, 90.0, 87.1, 75.2, 74.5, 72.5, 72.4, 69.0, 68.6, 68.5, 67.4, 52.6, 21.1;
HRMS [M + Na]+ calcd for C21H24O6SNa 427.1191, found 427.1193.
Methyl (4ꢀmethylphenyl 2ꢀOꢀbenzoylꢀ3ꢀOꢀbenzylꢀ1ꢀthioꢀLꢀidopyranoside)uronate
(23)
To a solution of diol 22 (45 g, 111 mmol) in anhydrous MeOH (800 mL) was added
dibutyltin oxide (Bu2SnO, 30 g, 120 mmol). The resulting reaction mixture was
refluxed under nitrogen for 1 h and then concentrated and dried under vacuum. Next,
the residue was dissolved in 1,4ꢀdioxane (1.5 L), benzoyl chloride (120 mL, 1042
mmol) and Et3N (150 mL, 1082 mmol) was added sequentially into the reaction
o
vessel at 0 C. The reaction was stirred at same temperature for 1 h and neutralized
with 2M HCl (aq.). After concentration, water (200 mL) was added and then extracted
with CH2Cl2 (3 × 150 mL). The combined organic phases were dried over anhydrous
Na2SO4, filtered and evaporated under reduced pressure. The crude product was
purified by column chromatography (petroleum ether/ethyl acetate = 4:1) to afford
compound 23 (37 g, 65%, α/β = 5:2). Rf = 0.4 (petroleum ether/ethyl acetate, 2/1, v/v);
1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 0.8H), 7.99 (d, J = 8.0 Hz, 2H),
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7.60ꢀ7.30 (m, 14H), 7.11 (d, J = 8.0 Hz, 2.8H), 5.67 (s, 1H), 5.50 (br s, 1H), 5.42 (br s,
1.4H), 5.25 (s, 0.4H), 4.92 (d, J = 12.0 Hz, 1H), 4.80 (d, J = 12.0 Hz, 0.4H), 4.72 (d, J
= 11.6 Hz, 0.4H), 4.70 (d, J = 12.0 Hz, 1H), 4.60 (br s, 0.4H), 4.17ꢀ4.11 (m, 1.4H),
4.04ꢀ4.02 (m, 0.4H), 3.95ꢀ3.92 (m, 1H), 3.84 (s, 4.2H), 2.84 (d, J = 11.6 Hz, 1.4H,
OH), 2.33 (s, 4.2H); 13C NMR (100MHz, CDCl3) δ 169.5, 168.6, 165.2, 164.7, 137.9,
137.7, 136.9, 133.6, 132.4, 132.0, 131.7, 131.6, 129.8, 129.7, 129.6, 128.7, 128.5,
128.4, 128.0, 127.9, 127.6, 87.0, 85.4, 76.2, 74.4, 73.5, 72.5, 72.2, 70.2, 69.5, 68.8,
68.1, 67.3, 52.4, 20.9; HRMS [M + Na]+ calcd for C28H28O7SNa 531.1453, found
531.1458.
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Methyl
(4ꢀmethylphenyl
2ꢀOꢀbenzoylꢀ3ꢀOꢀbenzylꢀ4ꢀOꢀtertꢀbutyldimethylsilylꢀ1ꢀthioꢀLꢀidopyranoside)uron
ate (11)
Under nitrogen atmosphere, a solution of 23 (10 g, 20 mmol) in CH2Cl2 (500 mL)
was added 2,6ꢀlutidine (7 mL, 60 mmol), the reaction was cooled to 0 oC and TBSOTf
(5.5 mL, 24 mmol) was added slowly. The resulting reaction mixture was allowed to
warm to room temperature and stirred for 30 min, then water (100 mL) was added to
quench the reaction. After separation, the aqueous phase was extracted with CH2Cl2
(3 × 100 mL). The combined organic phases were dried over anhydrous Na2SO4,
filtered and evaporated in vacuo. The residue was purified by column chromatography
(petroleum ether/ethyl acetate = 20:1) to afford compound 11 (10.7 g, 86%, α/β = 9:1).
1
Rf = 0.6 (petroleum ether/ethyl acetate, 5/1, v/v); H NMR (400 MHz, CDCl3) δ 8.18
(d, J = 8.0 Hz, 0.2H),8.07 (d, J = 7.6 Hz, 1.8H), 7.56ꢀ7.27 (m, 10H), 7.10 (d, J = 7.6
Hz, 2H), 5.76 (br s, 0.9H), 5.37 (br s, 0.9H), 5.30 (s, 0.1H), 5.26 (d, J = 2.4 Hz, 1H),
4.95 (d, J = 12.0, 0.9H), 4.85 (d, J = 11.6, 0.1H), 4.71 (d, J = 12.0 Hz, 1H), 4.12ꢀ4.10
(m, 0.9H), 4.01 (br s, 0.1H), 3.92 (br s, 0.1H), 3.84ꢀ3.82 (m, 0.9H), 3.80 (s, 1H), 2.30
(s, 3H), 0.68 (s, 9H), ꢀ0.10 (s, 3H), ꢀ0.33 (s, 3H); 13C NMR (100MHz, CDCl3) δ 169.7,
165.6, 137.3, 137.2, 133.2, 131.6, 131.5, 130.0, 129.6, 129.4, 128.4, 128.2, 128.1,
128.0, 86.4, 73.6, 72.3, 70.0, 69.3, 68.9, 52.0, 25.4, 21.0, 17.6, ꢀ4.4, ꢀ6.0; HRMS [M +
Na]+ calcd for C34H42O7SSiNa 645.2318, found 645.2325.
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1,4,6ꢀTriꢀOꢀacetylꢀ2ꢀOꢀbenzoylꢀ3ꢀOꢀbenzylꢀLꢀidopyranose (24)17b
7
8
9
1,6ꢀAnhydride 15 (230 g, 646 mmol), prepared from diacetone glucose 16 by the
reported methods,16c was dissolved in the mixed solvent Ac2OꢀTFA (6:1, 480 mL),
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o
and the reaction was stirred at 60 C overnight. When TLC showed that the reaction
was complete, the mixture was neutralized with saturated NaHCO3 (aq.) (600 mL)
and then water (500 mL) was added as well. The resulting reaction mixture was
extracted with CH2Cl2 (5 × 800 mL). The combined organic layers were sequentially
washed with brine and saturated NaHCO3 (aq.), dried over Na2SO4, filtered, and
concentrated in vacuo to afford crude compound 2417b as α/β mixture (5:4), which was
directly used without further purification for the ensuing reaction. Analytic sample
1
was obtained by column chromatography. H NMR (400 MHz, CDCl3) δ 8.06 (d, J =
8.0 Hz, 1.6H), 8.01 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.4 Hz, 2H), 7.53ꢀ7.20 (m, 14.4H),
6.19 (br s, 1H), 6.16 (br s, 0.8H), 5.28 (br s, 0.8H), 5.18 (br s, 1H), 4.97 (br s, 1H),
4.91 (br s, 0.8H), 4.78ꢀ4.67 (m, 3.6H), 4.58 (t, J = 6.4 Hz, 1H), 4.42 (t, J = 6.4 Hz,
0.8H), 4.28ꢀ4.16 (m, 3.6H), 3.97 (br s, 0.8H), 3.88 (br s, 1H), 2.01 (s, 3H), 1.96 (br s,
3 × OAc, 7.8H), 1.87 (s, 3H), 1.85 (s, 2.4H); 13C NMR (100MHz, CDCl3) δ 170.1,
170.0, 169.6, 168.4, 168.2, 164.9, 164.5, 137.1, 136.6, 133.3, 133.1, 129.6, 129.5,
129.4, 129.0, 128.8, 128.2, 128.2, 128.1, 128.0, 128.0, 127.8, 127.5, 127.4, 127.1,
90.9, 90.1, 73.2, 72.6, 71.9, 71.6, 71.4, 66.4, 66.0, 65.8, 65.6, 65.2, 61.9, 20.5, 20.4,
20.3, 20.2, 20.1. The spectral data was in agreement with the reported data.17b
4ꢀMethylphenyl 2ꢀOꢀbenzoylꢀ3ꢀOꢀbenzylꢀ4,6ꢀdiꢀOꢀacetylꢀ1ꢀthioꢀLꢀidopyranoside
(25)
Under nitrogen, to a solution of crude 24 in CH2Cl2 (1.7 L) was successively added
pꢀtoluenethiol (TolSH, 75 g, 681 mmol) and triflic acid (TfOH, 5.9 mL, 67 mmol) at 0
oC. The reaction mixture was stirred at the same temperature. Once the reaction was
complete, Et3N (15 mL) was added to quench the reaction and evaporated in vacuo.
The resulting oil 25 was directly used without further purification for the ensuing
1
reaction. Analytic sample was obtained by column chromatography (α/β = 5:1). H
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The Journal of Organic Chemistry
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NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.0 Hz, 0.4H), 8.06 (d, J = 7.6 Hz, 2H),
7.59ꢀ7.29 (m, 12H), 7.23 (d, J = 7.6 Hz, 0.4H), 7.11 (d, J = 7.6 Hz, 2H), 5.56 (br s,
1H), 5.46 (br s, 1H), 5.34 (br s, 0.2H), 5.29 (br s, 0.2H), 5.13ꢀ5.10 (m, 1.2H), 4.99 (br
s, 1H), 4.92 (d, J = 12.0 Hz, 1.2H), 4.81 (d, J = 11.6 Hz, 0.2H), 4.76 (d, J = 11.6 Hz,
1H), 4.33ꢀ4.22 (m, 2.4H), 4.02 (br s, 0.2H), 3.91 (br s, 1H), 2.32 (s, 3.6H), 2.07 (s,
3.6H), 1.95 (s, 3.6H); 13C NMR (100MHz, CDCl3) δ 170.5, 169.9, 164.9, 137.7, 137.0,
133.4, 132.3, 131.9, 131.3, 129.9, 129.7, 129.6, 129.3, 128.4, 128.3, 127.9, 127.7,
127.6, 86.4, 84.5, 72.9, 72.6, 71.6, 69.6, 68.7, 67.0, 65.8, 64.4, 62.9, 21.0, 20.7, 20.6,
20.4; HRMS [M + Na]+ calcd for C31H32O8SNa 587.1716, found 587.1721.
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4ꢀMethylphenyl 2ꢀOꢀbenzoylꢀ3ꢀOꢀbenzylꢀ1ꢀthioꢀLꢀidopyranoside (26)8e
To a solution of crude 25 in MeOH (2.3 L) was added AcCl (80 mL, 1131 mmol)
at 0 oC. After stirring at room temperature overnight, the reaction was cooled to 0 °C
and neutralized with saturated NaHCO3 (aq.). The resulting mixture was extracted
with CH2Cl2 (3 × 800 mL). The combined organic phases were dried over anhydrous
Na2SO4, filtered and evaporated in vacuo. The residue was purified by column
chromatography (petroleum ether/ethyl acetate = 4:1) to afford compound 268e (186 g,
α/β = 5:1, 60% from compound 15) as light yellow syrup. Rf = 0.4 (petroleum
ether/ethyl acetate, 2/1, v/v); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.0 Hz, 0.4H),
8.05 (d, J = 7.6 Hz, 2H), 7.60ꢀ7.29 (m, 12H), 7.12 (d, J = 7.6 Hz, 2.4H), 5.57 (br s,
1H), 5.53 (br s, 1H), 5.44 (br s, 0.2H), 5.33 (br s, 0.2H), 4.91 (d, J = 12.0 Hz, 1H),
4.81ꢀ4.79 (m, 1.2H), 4.67 (d, J = 12.0 Hz, 1.2H), 4.15ꢀ4.03 (m, 0.4H), 3.96ꢀ3.88 (m,
4H), 3.72 (br s, 0.2H), 2.98 (br s, OH), 2.32 (s, 3.6H); 13C NMR (100MHz, CDCl3) δ
165.3, 164.9, 137.8, 137.2, 133.5, 132.4, 131.8, 131.2, 129.7, 129.6, 129.0, 128.5,
128.4, 127.9, 127.7, 87.0, 85.1, 74.9, 74.1, 72.5, 72.2, 70.8, 69.8, 68.2, 68.0, 66.7,
63.0, 62.6, 21.0. The spectral data was in agreement with the reported data.8e
Methyl (4ꢀmethylphenyl 2ꢀOꢀbenzoylꢀ3ꢀOꢀbenzylꢀ1ꢀthioꢀLꢀidopyranoside)uronate
(23)
To a solution of diol 26 (281g, 585 mmol) in the mixed solvent CH2Cl2ꢀwater (2:1,
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