Efficient synthesis of Idraparinux, the anticoagulant pentasaccharide

Article abstract of DOI:10.1016/j.bmcl.2009.03.155

An efficient [DEF+GH] route was developed to the synthesis of Idraparinux, which is a fully O-sulfated, O-methylated mimic of the unique Antithrombin III binding domain of heparin.

Full text of DOI:10.1016/j.bmcl.2009.03.155

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3875–3879
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Efficient synthesis of Idraparinux, the anticoagulant pentasaccharide
*
Chen Chen, Biao Yu
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient [DEF+GH] route was developed to the synthesis of Idraparinux, which is a fully O-sulfated, O-
methylated mimic of the unique Antithrombin III binding domain of heparin.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 4 February 2009
Revised 25 March 2009
Accepted 30 March 2009
Available online 5 April 2009
Keywords:
Idraparinux
Heparin
Anticoagulant
Pentasaccharide
Synthesis
Heparin, a sulfated polysaccharide belonging to the family of
glycosaminoglycans, has been shown to interact with a number
of biologically important proteins, thereby playing an essential role
in the regulation of various physiological processes.1 Nevertheless,
the most well known is its anticoagulant activity; heparin has been
used clinically as an anticoagulant since 1935.2 Heparin binds with
high affinity to the protease inhibitor antithrombin III (AT III),
thereby increasing the inhibitory potency of AT III relative to the
coagulation factors Xa and thrombin (IIa). However, due to its mul-
tiple biological functions, clinical use of heparin also leads to unde-
sirable side effects, such as bleeding complications or heparin-
induced thrombocytopenia (HIT). In addition, because of its short
half-life of approximately one hour in human body, heparin must
be given frequently or as a continuous infusion. Thanks to the leg-
endary works, especially those relatively recently from van Boeckel
and Petitou3 the SAR of the anticoagulant activity of heparin has
been clearly deciphered. Remarkably, Fondaparinux (B in Fig. 1),
a structural analog of the unique antithrombin-binding pentasac-
charide domain of heparin (A in Fig. 1),4 was developed as a new
antithrombotic drug under the name ‘Arixtra’ in the USA and Eur-
ope in 2001. Compared to unfractionated heparin and low molec-
ular-weight heparin, Fondaparinux has higher anti-Xa activity
and longer half-life. Continuous research leads to more potent
derivatives; Idraparinux (1 in Fig. 1), a fully O-sulfated, O-methyl-
ated analog, is not only much easier to synthesize than Fondapar-
inux5 but also displays higher anti-Xa activity and a longer
duration of action.6 Thus, Idraparinux had been developed into
phase III clinical trial for the prevention of thromboembolic events
in patients with atrial fibrillation and for the prevention and treat-
ment of venous thromboembolic events (VTE).7 Herein we report
an efficient synthetic route to Idraparinux (1).
The retrosynthetic analysis was shown in Figure 2. The glyco-
sidic bond disconnection between the F and G ring was made in
the target molecule to provide the trisaccharide donor 3 and disac-
charide 4, of which are close in terms of synthetic complexity. The
carboxylic acid function was planned to be elaborated at the disac-
charide level to bypass the glycosidic coupling with the usually
inactive uronate derivatives.
The preparation of the monosaccharide building blocks 6, 8 and
10 employed routine transformations starting from
D-glucose or
the ready available methyl
Scheme 1.
a-D-glucopyranoside as outlined in
The
the epimerization of the 5-OH of a
intramolecular epoxide formation (Scheme 2).13 Thus, methylation
of 1,2:5,6-di-O-isopropylidene- -glucofuranose (14) followed by
L
-idopyranose building block 7 was synthesized through
D
-glucofuranose derivative via
a-D
selective removal of the 5,6-O-isopropylidene group gave vicinal
diol 15. Selective protection of the primary hydroxyl group with
the bulky pivaloyl group, followed by mesylation of the remaining
secondary hydroxyl group and treatment with t-BuOK in t-BuOH,
furnished the epoxide 1714 in high yield (86% for 5 steps). Acidic
treatment of epoxide 17 with 0.1 M H2SO4 at 60 °C resulted in
hydrolysis of the 1,2-O-isopropylidene group and opening of the
5,6-epoxide, giving 3-O-methyl-
acetylated to provide a mixture of the anomeric acetates 18. Treat-
ment of 18 with 4-methoxyphenol and TMSOTf afforded the -gly-
L-idopyranose, which was directly
a
coside 19, which was subjected to removal of the acetyl groups;
the resulting 2,4,6-triol was then treated with benzaldehyde and
trifluoroacetic acid to provide the 4,6-O-benzylidene derivative
* Corresponding author.
E-mail address: byu@mail.sioc.ac.cn (B. Yu).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.155

3876
C. Chen, B. Yu / Bioorg. Med. Chem. Lett. 19 (2009) 3875–3879
D
E
F
G
H
-
-
-
-
OSO3
O
CO2
OSO3
OSO3
O
-O
O
O
Pentasaccharide (A)
CO2
OH
-
O
O
OSO3
OH
OH
OH
O
O
O
-
O
X=Ac or SO3
-
-
-
NHSO3
OSO3
NHX
OH
NHSO3
-
-
-
-
OSO3
CO2
OSO3
OSO3
-O
O
O
O
O
CO2
OH
-
O
O
Fondaparinux (B)
Idraparinux (1)
OSO3
OH
OH
OH
O
O
OMe
NHSO3
HO
-
-
-
-
NHSO3
OSO3
NHSO3
OH
O
-
-
-
-
OSO3
O
OSO3
O
CO2
OSO3
-O
O
CO2
-
O
-
O
OSO3
OMe
OMe
OSO3
O
OMe
O
MeO
OMe
OSO3
-
-
OSO3
OMe
OMe
OMe
Fig. 1. The anticoagulant pentasaccharides Fondaparinux and Idraparinux (1).
OBn
O
OBn
O
OBn
O
CO2Bn
O
O
CO2Bn
OMe
Idraparinux
O
O
OBn
OBn
OMe
OMe
O
O
(1)
OMe
OBn
MeO
OBn
OMe
OMe
OMe
2
CO2Bn
O
OBn
O
OBn
OBn
O
NH
O
O
CO2Bn
+
CCl3
O
O
O
OBn
OMe
MeO
OMe
OBn
O
OMe
HO
OMe
OBn
OMe
OMe
OMe
OBn
4
3
OBn
O
OBn
O
OBn
O
OBn
O
OMe
O
NH
O
CCl3
O
HO
HO
MeO
MeO
O
OMP
O
CCl3
+
+
BnO
NH
MeO
BnO
O
BnO
OBz
OMe
OMe
OMe
6
OBn
O
8
5
7
Ph
OBn
O
OAc
O
NH
CCl3
+
HO
BnO
AcO
AcO
OMP
O
OBn
OAc
10
9
Fig. 2. The retrosynthetic analysis of Idraparinux (1).
OBn
O
6 steps, 42%
Ref. 8
20. The remaining 2-hydroxyl group was benzoylated to give 21,
which was subjected to the oxidative removal of the 4-methoxy-
phenyl group; the resulting lactol was treated with CCl3CN and
a
MeO
MeO
D
-Glcα-OMe
OH
6
OMe
11
DBU to provide the desired L-idopyranosyl donor 7.
O
Glycosylation of the 4-OH-glucopyranoside derivative 10 with
glucopyranosyl trichloroacetimidate 915 in the presence of
trimethylsilyl trifluoromethylsulfonate and 4 Å molecular sieves
in dichloromethane at ꢀ20 °C gave the desired b-(1?4)-disaccha-
ride 22 in 92% yield (Scheme 3). Saponification of 22 followed by
40,60-O-benzylidene formation afforded disaccharide 23. Methyla-
tion of the remaining 2- and 3-hydroxyl groups on 23 afforded
compound 24. The 4,6-O-benzylidene group was hydrolyzed with
75% AcOH at 75 °C, the resulting diol was subjected to TEMPO
mediated selective oxidation of the primary alcohol to the
Ph
O
3 steps, 67%
Ref. 9
80%
O
D-Glcα-OMe
8
BnO
Ref. 10
BnO
12
OMe
O
5 steps, 66%
Ref. 11
82%
Ph
O
D-Glc
O
10
OMP
BnO
Ref. 10
OBn
13
Scheme 1. Preparation of the monosaccharide building blocks 6, 8, and 10.
Reagents and conditions: (a) CCl3CN, DBU, CH2Cl2, 0 °C to rt, 88%.8–11

C. Chen, B. Yu / Bioorg. Med. Chem. Lett. 19 (2009) 3875–3879
3877
O
O
HO
HO
PivO
MsO
O
O
O
O
O
a, b
c, d
e
f, g
OMe
OH
OMe
OMe
O
O
O
O
Ref. 12
O
O
O
O
14
15
16
17
OMP
OMP
OMP
OMe
O
OMe
O
OMe
O
OMe
O
i, j
k
l, m
h
OAc
7
O
O
O
AcO
AcO
OH
O
OBz
OAc OAc
OAc OAc
Ph
Ph
19
20
21
18
Scheme 2. Preparation of the L-idopyranose building block 7. Reagents and conditions: (a) Me2SO4, KOH, DMSO, rt; (b) 60% aq AcOH, rt; (c) PivCl, pyridine, 0 °C; (d) MsCl,
pyridine, 0 °C to rt; (e) t-BuOK, t-BuOH, CH2Cl2, 0 °C to rt, 86% (5 steps); (f) 0.1 M aq H2SO4, 60 °C; (g) Ac2O, DMAP, pyridine, 0 °C to rt, 76% (2 steps); (h) p-MeOPhOH, TMSOTf,
MS 4 Å, CH2Cl2, 0 °C to rt, 89%; (i) NaOMe, MeOH, rt; (j) PhCHO, TFA, rt, 76% (2 steps); (k) BzCl, Et3N, DMAP, CH2Cl2, 0 °C to rt, 100%; (l) CAN, CH3CN, toluene, H2O, rt, 91%; (m)
CCl3CN, DBU, CH2Cl2, 0 °C to rt, 100%.12
BnO
OAc
O
BnO
9
O
BnO
O
a
BnO
O
b, c
e-g
Ph
O
O
OMP
AcO
AcO
OMP
OMP
+
O
HO
O
10
OH
OAc
OBn
OBn
23
22
BnO
O
d
BnO
O
Ph
O
O
5
O
MeO
OMe
OBn
24
Scheme 3. Preparation of the disaccharide 5. Reagents and conditions: (a) TMSOTf, 4 Å MS, CH2Cl2, ꢀ20 °C to rt, 92%; (b) NaOMe, MeOH, rt; (c) PhCH(OMe)2, p-TsOH.H2O,
DMF, 50 °C, 95% (2 steps); (d) Me2SO4, NaH, DMF, 0 °C to rt, 100%; (e) 75% aq. AcOH, 75 °C; (f) TEMPO, KBr, NaHCO3, TBAB, Aliquate 336, Ca(ClO)2, CH2Cl2, 0 °C; (g) BnBr,
KHCO3, DMF, rt, 75% (3 steps).
OBn
O
OBn
O
OMe
OMe
O
O
O
O
7
+
8
O
O
a
b
O
O
Ph
Ph
BnO
BnO
BzO
HO
BnO
BnO
OMe
OMe
26
25
OBn
O
O
OMe
c
d-g
O
O
O
Ph
4
BnO
MeO
BnO
27
OMe
Scheme 4. Preparation of the disaccharide 4. Reagents and conditions: (a) TMSOTf, 4 Å MS, CH2Cl2, ꢀ20 °C to rt, 99%; (b) NaOMe, MeOH, THF, rt, 94%; (c) NaH, Me2SO4, THF,
0 °C to rt, 97%; (d) p-TsOH.H2O, MeOH, CH2Cl2, rt; (e) TEMPO, KBr, NaHCO3, TBAB, Aliquate 336, Ca(ClO)2, CH2Cl2, 0 °C; (f) NaClO2, NaH2PO4, t-BuOH, rt; (g) BnBr, KHCO3, DMF,
rt, 66% (4 steps).
carboxylic acid,16 which was then benzylated to yield the benzyl
ester 5 in good yield (75% for 3 steps). During these transforma-
tions, the sugar moiety ring F could be regarded as a stable
anomeric protecting group of ring E.
mary 60-hydroxyl group was selectively oxidized first to the alde-
hyde then to the carboxylic acid, which was then esterified to
afford the disaccharide benzyl ester 4.17b
The final elaboration of the pentasaccharide 1 was illustrated in
Scheme 5. Coupling of the glucopyranosyl trichloroacetimidate 6
with disaccharide acceptor 5 in the presence of trimethylsilyl
trifluoromethylsulfonate and powdered 4 Å molecular sieves at
The synthesis of the G-H unit was started with the glycosylation
of the 4-OH-glucopyranoside derivative 8 with the
L-idopyranosyl
trichloroacetimidate 7 (Scheme 4). The -(1?4)-linked disaccha-
a
ride 25 was yielded in nearly quantitative yield and anomeric
selectivity. In this case, both the neighboring participation of the
2-O-benzoyl group and the anomeric effect of the 1C4 conformation
room temperature in diethyl ether afforded the desired
trisaccharide 28 in a yield of 66%, together with 15% of the sepa-
rable b-coupled product 28b. The anomeric 4-methoxyphenyl
group in trisaccharide 28 was removed with CAN, and the result-
ing lactol was readily converted into the trisaccharide trichloroace-
timidate 3. Coupling of donor 3 with the disaccharide acceptor 4 in
the presence of trimethylsilyl trifluoromethylsulfonate and
powdered 4 Å molecular sieves at room temperature in
a-coupled
a
which is locked by the 4,6-O-benzylidene group in the
L
-idopyran-
a
osyl donor 7 contributed to the high
a
-selectivity.17 The 20-O-ben-
zoyl group in disaccharide 25 was removed and the resulting
hydroxyl group was methylated to afford compound 27. After
removal of the 40,60-O-benzylidene group in 27, the resulting pri-

3878
C. Chen, B. Yu / Bioorg. Med. Chem. Lett. 19 (2009) 3875–3879
OBn
O
OBn
O
MeO
MeO
BnO
CO2Bn
O
BnO
O
CO2Bn
MeO
MeO
BnO
O
MeO
6
OMP
BnO
O
O
a
O
MeO
O
OMP
e, f
MeO
+
+
MeO
O
OBn
OMe
28β
OBn
OMe
28α
5
b, c
d
3
1
2
4
Scheme 5. Final elaboration of the pentasaccharide 1. Reagents and conditions: (a) TMSOTf, Et2O, 4 Å MS, rt, 66% (28a), 15% (28b); (b) CAN, CH3CN, toluene, H2O, rt, 72%; (c)
CCl3CN, DBU, CH2Cl2, rt, 98%; (d) TMSOTf, 4 Å MS, CH2Cl2, rt, 51% (73% based on recovery of 4); (e) Pd/C (10%), H2, t-BuOH, H2O, rt; (f) SO3ꢂEt3N, DMF, 50 °C, 93% (2 steps).
17. For other examples of 4,6-locked idose glycosyl donors, see: (a) Bourhis, P.;
dichloromethane afforded the fully protected pentasaccharide 2 in
51% yield (73% based on recovery of 4). Finally, pentasaccharide 2
Machetto, F.; Duchaussoy, P.; Herault, J.-P.; Mallet, J.-M.; Herbert, J.-M.;
Petitou, M.; Sinay, P. Bioorg. Med. Chem. Lett. 1997, 7, 2843; (b) Barroca, N.;
was subject to hydrogenolysis of the benzyl protecting groups. The
highly polar product without purification was O-sulfated directly
with triethylamine-sulfur trioxide complex to afford the sulfated
pentasaccharide 16a in an excellent yield of 93% (for two steps).
Summarizing, the potent anti-thromboembolic pentasaccharide
Idraparinux (1) was synthesized in total 51 steps and in 4% overall
Jacquinet, J.-C. Carbohydr. Res. 2002, 337, 673; (c) Kuszmann, J.; Medgyes, G.;
Boros, S. Carbohydr. Res. 2004, 339, 1569; (d) Tatai, J.; Fugedi, P. Org. Lett. 2007,
9, 4647.
18. Selected data for the key compounds. Compound 21: ½a D23
ꢀ54.7 (c 0.9, CHCl3);
ꢁ
1H NMR (300 MHz, CDCl3) d 3.65 (s, 3H), 3.74 (br s, 1H), 3.77 (s, 3H), 4.08–4.17
(m, 3H), 4.34 (d, J = 12.6 Hz, 1H), 5.40 (br s, 1H), 5.63 (s, 1H), 5.71 (s, 1H), 6.82
(d, J = 9.0 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 7.22–7.39 (m, 6H), 7.48–7.58 (m, 3H),
8.01 (d, J = 6.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 55.6, 58.2, 60.3, 65.4, 69.7,
72.8, 76.5, 97.2, 100.9, 114.5, 117.7, 126.3, 128.1, 128.2, 128.9, 129.4, 130.1,
133.1, 137.8, 150.5, 154.9, 165.6; MALDI–MS m/z 515.7 [M+Na]+; MALDI-HRMS
yield from D-glucose and methyl a-D
-glucopyranoside.18 The syn-
thetic route is convergent with a linear sequence of 27 steps, and
the transformations are scalable. The 4-methoxyphenol glycoside
intermediates are easy to be purified by crystallization.
calcd for C28H28O8Na [M+Na]+ 515.1676, found 515.1668. Compound 22: ½a 2D3
ꢁ
ꢀ16.2 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) d 1.95 (s, 3H), 1.97 (s, 3H), 1.99
(s, 3H), 2.00 (s, 3H), 3.29–3.38 (m, 1H), 3.43–3.48 (m, 1H), 3.60–3.72 (m, 2H),
3.73–3.82 (m, 2H), 3.77 (s, 3H), 3.88 (d, J = 12.9 Hz, 1H), 3.95–4.05 (m, 1H), 4.14
(dd, J = 12.9, 3.9 Hz, 1H), 4.50 (d, J = 12.3 Hz, 1H), 4.65–4.76 (m, 4H), 4.85 (d,
J = 7.2 Hz, 1H), 4.90–5.08 (m, 5H), 6.81 (d, J = 9.0 Hz, 1H), 7.01 (d, J = 9.0 Hz,
1H), 7.20–7.43 (m, 15H); 13C NMR (100 MHz, CDCl3) d 20.46, 20.50, 20.52, 20.6,
55.5, 61.5, 67.7, 67.9, 71.6, 71.9, 73.0, 73.6, 74.7, 74.9, 75.0, 81.4, 82.5, 100.0,
102.7, 114.4, 118.4, 127.2, 127.6, 127.9, 128.0, 128.2, 128.5, 137.8, 138.1, 138.9,
151.4, 155.3, 169.0, 169.3, 170.1, 170.5; MALDI-MS m/z 909.5 [M+Na]+;
MALDI–HRMS calcd for C48H54O16Na, [M+Na]+ 909.3304, found 909.3298.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (20572122 and 20621062) and the Committee of Science
and Technology of Shanghai (06XD14026 and 04DZ19213) is grate-
fully acknowledged.
Compound 5: ½a 2D3
ꢁ
ꢀ16.4 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3) d 2.81 (d,
J = 2.4 Hz, 1H), 2.96 (t, J = 9.0 Hz, 1H), 3.02 (d, J = 8.7 Hz, 1H), 3.49 (s, 3H), 3.53–
3.61 (m, 2H), 3.62 (s, 3H), 3.65–3.76 (m, 3H), 3.78 (s, 3H), 3.83–3.90 (m, 2H),
3.97–4.06 (m, 1H), 4.50 (d, J = 7.2 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.66 (d,
J = 12.0 Hz, 1H), 4.76 (d, J = 11.4 Hz, 1H), 4.77 (d, J = 10.5 Hz, 1H), 4.87 (d,
J = 7.5 Hz, 1H), 4.98 (d, J = 10.5 Hz, 1H), 5.09 (d, J = 11.4 Hz, 1H), 6.80 (d,
J = 9.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 7.20–7.35 (m, 20H); 13C NMR (100 MHz,
CDCl3) d 55.6, 60.5, 60.9, 67.0, 68.2, 71.5, 73.3, 74.1, 74.9, 75.0, 75.0, 77.2, 81.5,
82.6, 83.4, 85.1, 102.7, 102.7, 114.5, 118.4, 127.1, 127.6, 127.8, 128.0, 128.1,
128.2, 128.3, 128.4, 135.0, 138.1, 138.3, 139.0, 151.5, 155.2, 168.8; ESI-MS m/z
873.3 [M+Na]+; MALDI-HRMS calcd for C49H54O13Na, [M+Na]+ 873.3457, found
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ꢁ
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14. van den Broek, L. A. G. M.; Vermaas, D. J.; Heskamp, B. M.; van Boeckel, C. A. A.
Recl. Trav. Chim. Pays-Bas. 1993, 112, 82.
3.08 (d, J = 12.9 Hz, 1H), 3.37 (s, 3H), 3.54 (s, 3H), 3.55–3.95 (m, 9H), 4.02 (br s,
1H), 4.49 (ABq, 2H), 4.60–4.82 (m, 4H), 5.08–5.15 (m, 3H), 5.35 (s, 1H), 7.10–
7.55 (m, 23H), 7.93 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 55.1, 58.1,
59.2, 66.4, 66.4, 68.2, 69.3, 70.1, 72.2, 73.2, 73.3, 73.3, 75.2, 76.7, 80.0, 80.1,
97.1, 97.9, 100.7, 126.3, 127.27, 127.32, 127.4, 127.80, 127.84, 128.0, 128.08,
128.12, 128.14, 128.2, 128.4, 128.7, 129.5, 129.96, 133.00, 137.7, 138.0, 138.2,
139.1, 165.6; ESI-MS m/z 855.4 [M+Na]+; MALDI-HRMS calcd for C49H52O12Na,
[M+Na]+ 855.3351, found 855.3345. Compound 27: ½a 2D3
ꢁ
ꢀ6.5 (c 0.9, CHCl3); 1
H
NMR (300 MHz, CDCl3) d 3.09 (d, J = 13.2 Hz, 1H), 3.17–3.22 (m, 1H), 3.38 (s,
3H), 3.38–3.43 (m, 1H), 3.43 (s, 3H), 3.50 (s, 3H), 3.59 (dd, J = 9.3, 3.3 Hz, 1H),
3.68 (br s, 2H), 3.60–3.73 (m, 2H), 3.82–3.87 (m, 2H), 3.93 (t, J = 9.3 Hz, 1H),
4.50–4.65 (m, 4H), 4.67 (br s, 1H), 4.78 (d, J = 11.7 Hz, 1H), 4.81 (d, J = 5.4 Hz,
1H), 5.05 (d, J = 8.1 Hz, 1H), 5.28 (s, 1H), 7.22–7.48 (m, 20H); 13C NMR
(100 MHz, CDCl3) d 55.0, 58.3, 59.6, 61.8, 68.2, 68.4, 70.3, 72.7, 73.1, 73.2, 75.4,
77.8, 80.0, 80.3, 82.1, 97.8, 99.6, 100.1, 126.0, 127.3, 127.3, 127.4, 127.7, 127.8,
128.0, 128.11, 128.13, 128.2, 128.5, 137.6, 137.86, 137.91, 138.9; ESI-MS m/z
765.3 [M+Na]+; MALDI-HRMS calcd for C43H50O11Na, [M+Na]+ 765.3245, found
765.3257. Compound 28
a
: ½a 2D3
ꢁ
41.4 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) d
2.82 (t, J = 8.1 Hz, 1H), 2.96–3.04 (m, 2H), 3.13–3.20 (m, 1H), 3.25–3.40 (m, 4H),
3.45 (s, 3H), 3.49 (s, 3H), 3.52 (s, 3H), 3.55 (s, 3H), 3.58 (s, 3H), 3.61 (s, 3H),
3.60–3.74 (m, 6H), 3.77 (s, 3H), 3.75–3.90 (m, 4H), 3.95–4.08 (m, 2H), 4.44–
5.03 (m, 12H), 5.53 (d, J = 3.6 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 7.01 (d, J = 9.0 Hz,
2H), 7.20–7.40 (m, 20H); 13C NMR (100 MHz, CDCl3) d 55.6, 59.3, 60.0, 60.3,
60.5, 60.6, 67.4, 67.85, 67.89, 70.7, 73.3, 73.4, 74.0, 74.3, 75.1, 75.2, 75.4, 77.5,
78.9, 81.5, 81.6, 82.7, 83.2, 83.9, 85.8, 96.3, 102.7, 102.8, 114.5, 118.5, 127.2,
127.5, 127.6, 127.8, 128.07, 128.11, 128.2, 128.3, 128.4, 128.5, 134.9, 138.1,
138.2, 138.3, 138.8, 151.5, 155.2, 168.2; MALDI-MS m/z 1167.1 [M+Na]+;
MALDI–HRMS calcd for C65H76O18Na, [M+Na]+ 1167.4924, found 1167.4955.
15. Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980, 19, 731.
16. (a) Lin, F.; Peng, W.; Xu, W.; Han, X.; Yu, B. Carbohydr. Res. 2004, 339, 1219; (b)
Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559; (c)
Anelli, P. L.; Banfi, S.; Montanari, F.; Quici, S. J. Org. Chem. 1989, 54, 2970.
Compound 28b: ½a D23
ꢁ
ꢀ6.0 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) d 2.82 (t,

C. Chen, B. Yu / Bioorg. Med. Chem. Lett. 19 (2009) 3875–3879
3879
J = 8.4 Hz, 1H), 2.99 (t, J = 8.4 Hz, 1H), 3.02 (t, J = 8.4 Hz, 1H), 3.06–3.22 (m, 3H),
3.35 (s, 3H), 3.47 (s, 3H), 3.50 (s, 3H), 3.53 (s, 3H), 3.59 (s, 3H), 3.61–3.74 (m,
4H), 3.75 (s, 3H), 3.85–4.05 (m, 3H), 4.22 (d, J = 7.8 Hz, 1H), 4.47–5.15 (m, 10H),
4.87(d, J = 7.2 Hz, 1H), 6.79 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.15–7.40
(m, 20H); 13C NMR (100 MHz, CDCl3) d 55.5, 60.2, 60.5, 60.56, 60.59, 67.2, 68.0,
68.7, 73.1, 73.3, 74.55, 74.57, 75.0, 75.05, 75.12, 77.4, 78.4, 79.1, 81.4, 82.7,
83.0, 83.9, 84.0, 86.3, 102.6, 102.77, 102.83, 114.4, 118.3, 127.1, 127.3, 127.4,
127.5, 127.9, 128.0, 128.15, 128.24, 128.4, 128.5, 134.9, 138.1, 138.3, 138.4,
138.9, 151.4, 155.1, 167.7; ESI-MS m/z [M+Na]+; MALDI-HRMS calcd for
5.17 (d, J = 3.3 Hz, 1H), 5.24 (d, J = 6.9 Hz, 1H), 5.52 (d, J = 3.3 Hz, 1H), 7.20–7.37
(m, 45H); 13C NMR (100 MHz, CDCl3) d 55.3, 59.2, 60.0, 60.2, 60.3, 60.6, 66.6,
67.3, 67.5, 67.9, 68.1, 70.3, 70.8, 71.0, 72.9, 73.3, 73.4, 73.6, 74.1, 74.2, 75.2,
75.4, 77.2, 77.5, 78.8, 78.9, 79.3, 79.5, 80.1, 80.7, 81.6, 83.2, 83.5, 83.8, 85.7,
96.3, 98.3, 98.7, 100.2, 103.0, 127.1, 127.2, 127.4, 127.5, 127.7, 127.8, 128.0,
128.2, 128.4, 128.5, 135.0, 135.3, 137.8, 138.3, 138.5, 139.2, 168.3, 169.1;
MALDI–MS m/z 1801.8 [M+Na]+; MALDI-HRMS calcd for C101H118O28Na,
[M+Na]+ 1801.7702, found 1801.7688. Compound 1: ½a 2D3
ꢁ
54.2 (c 1.0, H2O);
1H NMR (400 MHz, D2O) d 3.27 (t, J = 8.4 Hz, 1H), 3.30–3.38 (m, 2H), 3.47 (s,
3H), 3.53 (s, 3H), 3.56 (s, 6H), 3.58 (s, 3H), 3.62 (s, 3H), 3.63 (s, 3H), 3.64 (s, 6H),
3.75 (d, J = 10.0 Hz, 1H), 3.83–3.97 (m, 4H), 3.98 (t, J = 8.8 Hz, 1H), 4.06–4.18
(m, 3H), 4.19–4.45 (m, 8H), 4.56 (br t, J = 9.6 Hz, 1H), 4.65 (t, J = 9.2 Hz, 1H),
4.66 (d, J = 7.6 Hz, 1H), 5.00 (br s, 1H), 5.11 (br s, 1H), 5.17 (d, J = 3.6 Hz, 1H),
5.43 (d, J = 3.2 Hz, 1H), 5.47 (d, J = 4.0 Hz, 1H); ESI-MS m/z 774.1
C65H76O18Na, [M+Na]+ 1167.4924, found 1167.4881. Compound 2: ½a 2D3
ꢁ
47.4 (c
1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d 2.88 (t, J = 8.4 Hz, 1H), 2.96 (t,
J = 7.5 Hz, 1H), 3.17 (t, J = 9.7 Hz, 1H), 3.12–3.21 (m, 1H), 3.27 (s, 3H), 3.35–3.52
(m, 6H), 3.37 (s, 3H), 3.44 (s, 6H), 3.47 (s, 3H), 3.52 (s, 3H), 3.55 (s, 6H), 3.69–
3.75 (m, 9H), 3.75–3.90 (m, 6H), 3.98 (t, J = 9.3 Hz, 1H), 4.30 (d, J = 7.5 Hz, 1H),
4.43–4.62 (m, 7H), 4.62–4.69 (m, 5H), 4.73–4.83 (m, 3H), 4.83–5.04 (m, 5H),
[Mꢀ8Na+6H]2ꢀ, 763.0; [Mꢀ9Na+7H]2ꢀ, 508.5 [Mꢀ9Na+6H]3ꢀ
.