Syntheses of novel acarviosin analogs with anhydro or unsaturated sugar moieties

Article abstract of DOI:10.1016/j.tet.2012.09.037

A new class of pseudoacarviosins with 2,3-anhydro or unsaturated sugar moieties were synthesized efficiently. The designed target disaccharides were constructed by the glycosylation reactions using 2,3-anhydromonosaccharides as glycosyl donors. The glycosylation reactions were carried out in a highly stereoselective manner in most cases, especially when the preactivation protocol was used. The anhydrosugar units of disaccharides were kept intact during the deprotection operations of protective groups. Furthermore, the disaccharides containing anhydrosugar moieties were smoothly converted to the unsaturated disaccharides via the base-promoted rearrangement of sugar epoxides.

Full text of DOI:10.1016/j.tet.2012.09.037

Tetrahedron 68 (2012) 9355e9363
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Syntheses of novel acarviosin analogs with anhydro or unsaturated sugar moieties
*
Yuan-Yuan Wang, De-Cai Xiong, Qin Li, Yuan Wang, Xin-Shan Ye
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd No. 38, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2012
Received in revised form 2 September 2012
Accepted 7 September 2012
Available online 14 September 2012
A new class of pseudoacarviosins with 2,3-anhydro or unsaturated sugar moieties were synthesized
efficiently. The designed target disaccharides were constructed by the glycosylation reactions using 2,3-
anhydromonosaccharides as glycosyl donors. The glycosylation reactions were carried out in a highly
stereoselective manner in most cases, especially when the preactivation protocol was used. The anhy-
drosugar units of disaccharides were kept intact during the deprotection operations of protective groups.
Furthermore, the disaccharides containing anhydrosugar moieties were smoothly converted to the un-
saturated disaccharides via the base-promoted rearrangement of sugar epoxides.
Keywords:
2,3-Anhydrosugar
Pseudoacarviosins
Glycosylation
Preactivation
Ó 2012 Elsevier Ltd. All rights reserved.
Rearrangement
1. Introduction
Carbohydrate mimetics as inhibitors of carbohydrate-processing
enzymes have been attractive target compounds for synthetic
chemists and biochemists, not only because they can serve as useful
biological tools for studying the biological functions of glycans1 but
also because they may have great potential as drugs to treat a va-
riety of carbohydrate-mediated diseases2, such as diabetes, obesity,
lysosomal storage disorders, cancer, and viral infections.3 For in-
stance, acarbose 1 (Fig. 1), a potent
a-glucosidase inhibitor, is
a natural product, which is an orally active agent sold for the
treatment of type II diabetes either on its own or in combination
with other medications.4 Inspired by the success of acarbose 1, in
order to obtain improved and more potent compounds, quite a few
acarbose 1 analogs that exhibit very pronounced inhibitory effects
on intestinal a-glucosidase have been reported and some of them
have aroused medical interest in the treatment of diabetes and
related disorders.5,6 Namiki and co-workers reported the synthesis
of a series of valienamine 2 analogs and some of them exhibited
comparative inhibitory activities with acarbose 1.7 The Shing group
reported an enantiospecific synthesis of
a pseudoacarviosin
showing to be a potent inhibitor of
a
-glucosidases.8 Sabrina et al.
prepared a series of 4-substituted 1,2,3-triazoles conjugated with
sugars, some of which displayed up to 25-fold higher inhibitory
potency than the complex oligosaccharide acarbose 1.9
* Corresponding author. Fax: þ86 10 82802724; e-mail address: xinshan@
Fig. 1. Structures of acarbose, valienamine, acarviosin, methyl acarviosin, 2,3-
anhydrosugar moiety.
bjmu.edu.cn (X.-S. Ye).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.037

9356
Y.-Y. Wang et al. / Tetrahedron 68 (2012) 9355e9363
The strong inhibition of human amylases by acarbose 1 (mi-
cromolar Ki) is attributed to the valienamine ring.10 However,
valienamine 2 itself is only a weak
-glucosidase inhibitor.11 The
glucosidase inhibitory activity increases when it is linked to
a mono- or tri-saccharide moiety as in acarviosin 3 and acarbose 1,
respectively.12 Acarviosin 3 contains the valienamine unit con-
2. Results and discussion
a
a
-
The synthesis of target compounds 6 and 7 was described in
Scheme 1, starting from p-tolyl 2,3-anhydro-4,6-O-benzylidene-1-
thio-
b
-D-allopyranoside (15) and methyl 2,3-di-O-benzyl-6-
deoxy-a-D-glucopyranoside (16), which were prepared according
nected to a 6-deoxy-
methyl acarviosin 4, obtained from the methanolysis of acarbose 1,
has been shown to exhibit stronger -amylase inhibitory activity
D
-glucose residue by 1,4-N-linkage. Moreover,
to the previous reports.15,16 The acceptor 16 was glycosylated with
donor 15 in dichloromethane at ꢀ40 ꢁC by the standard protocol,17
using N-iodosuccinimide (NIS)-silver triflate (AgOTf)18 as promoter.
The coupling product 6a and its anomeric isomer 7a were obtained
in 35% and 42% isolated yields, respectively. Compounds 6a and 7a
underwent hydrogenolysis over Pearlman’s catalyst yielding the
target compounds 6 and 7 smoothly. It is noteworthy that during
the hydrogenolysis process, the anhydrosugar moiety in 6 and 7
was kept intact very well.
a
than acarbose 1.13 To search for new acarviosin analogs, we pos-
tulated that 2,3-anhydrosugar moiety 5 could mimic the structure
of valienamine 2 due to some conformational similarity of the
hexene ring to the anhydro pyranose ring, so disaccharides 6e8
(Fig. 2) were designed. On the other hand, it has been illustrated
that S-linked glycosides, in which the interglycosidic oxygen atom
is replaced by a sulfur atom, can be of enhanced utility and more
stable to hydrolytic enzymes.14 Thus, S-linked disaccharides 9 and
10 were designed. Compounds 11 and 12 were also designed to
compare the effect of the substitution of 6-deoxy-a-D-glucoside
with a 6-deoxy- -galactoside on glucosidase inhibition. In addi-
a-D
tion, to mimic the planar structure in 4, we designed unsaturated
sugars 13 and 14. So some new pseudoacarviosins 6e14, which are
novel molecules that have not been explored as glucosidase in-
hibitors, were designed. We describe herein the syntheses of these
pseudoacarviosins.
Scheme 1. Reagents and conditions: (a) NIS, AgOTf, ꢀ40 ꢁC, 35% for 6a, 42% for 7a; (b)
H2, Pd(OH)2, THF/EtOH, 85% for 6, 87% for 7.
The synthesis of compound 8 was described in Scheme 2. Thi-
oglycoside 1715 was treated with p-toluenesulfonic acid in metha-
nol followed by acetylation to provide 18 in 81% yield. Glucoside
1919 was selectively deoxygenated at the C-6 position by successive
tosylation and LiAlH4 reduction to give glycosyl acceptor 20. The
glycosylation of 18 and 20 afforded disaccharide 8a in 67% yield in
the form of pure a-anomer. It is noteworthy that no b-anomer was
isolated in the glycosylation reaction. Comparing with the
benzylidene-protected donor 15, the glycosylation of di-acetyl-
protected donor 18 showed excellent stereoselectivity, yielding
the product with glycosidic bond trans to the epoxide ring. Treat-
ment of 8a with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ)
followed by deacetylation with potassium carbonate provided the
target disaccharide 8 in 85% yield. Again, the anhydrosugar unit in
compound 8 was kept intact.
The synthesis of S-linked disaccharides 9 and 10 was shown in
Scheme 3. Compound 20 was treated with triphenylphosphine and
iodine in the presence of imidazole providing iodide 21 in 86%
yield, which, on exposure to potassium thioacetate in DMF, affor-
ded 22 in 67% yield. Treatment of 22 with potassium carbonate led
to thioglycoside 23 in 75% yield. On the other hand, compound 15
was transformed to glycosyl donor 24 in the same manner as de-
scribed in the preparation of 18. With two building blocks 23 and
24 in hand, the glycosylation reaction was performed. Based on the
glycosyl donor-preactivation protocol,20 following the procedure
Fig. 2. Structures of the designed new acarviosin analogs.

Y.-Y. Wang et al. / Tetrahedron 68 (2012) 9355e9363
9357
Scheme 2. Reagents and conditions: (a) TsOH, MeOH; then Ac2O, Py, 81%; (b) TsCl, Py; then LiAlH4, 67%; (c) NIS, AgOTf, ꢀ40 ꢁC, 67%; (d) DDQ, CH2Cl2/H2O; then K2CO3, MeOH, 85%.
developed by the Crich group21 and modified by the Lowary
group,17 donor 24 was preactivated with diphenyl sulfoxide and
triflic anhydride (Ph2SO/Tf2O)22 in the presence of 2,4,6-tri-tert-
butylpyrimidine (TTBP), which was followed by the addition of
thiol 23, affording disaccharide 9a in the form of
a-anomer in 81%
isolated yield. Again, the anomeric isomer ( -anomer) was not
b
obtained. Treatment of 9a with DDQ followed by the addition of
potassium carbonate provided the target product 9 successfully. In
the same manner, compound 23 was glycosylated with 18 to pro-
vide disaccharide 10a as the sole
b-coupling product with high
stereoselectivity. The deprotection of compound 10a afforded 10.
The synthesis of compounds 11 and 12 was shown in Scheme 4.
Compound 20 was successively treated with triflic anhydride and
potassium thioacetate to give 25 in 63% yield. Compound 25 was
further treated with potassium carbonate in methanol to provide
the galactose-type thiol 26 in 80% yield. The coupling reaction of 24
and 26 by the same protocol as described in the preparation of 9a
stereoselectively afforded S-linked disaccharide 11a in 75% isolated
Scheme 3. Reagents and conditions: (a) I2, PPh3, Im, THF, 86%; (b) KSAc, DMF, 67%; (c)
K2CO3, CH3OH, 75%; (d) TsOH, MeOH; then Ac2O, Py, 70%; (e) Ph2SO/Tf2O, TTBP, CH2Cl2,
ꢀ78 ꢁC, 81% for 9a, 77% for 10a; (f) DDQ, CH2Cl2/water; then K2CO3, MeOH, 81% for 9,
72% for 10.
Scheme 4. Reagents and conditions: (a) Tf2O, Py, CH2Cl2; then KSAc, DMF, 63%; (b)
K2CO3, CH3OH, 80%; (c) Ph2SO/Tf2O, TTBP, CH2Cl2, ꢀ78 ꢁC, 75% for 11a, 79% for 12a; (d)
DDQ, CH2Cl2/water; then K2CO3, MeOH, 75%.

9358
Y.-Y. Wang et al. / Tetrahedron 68 (2012) 9355e9363
yield. Finally, the para-methoxybenzyl (PMB) and acetyl groups in
11a were removed to result in disaccharide 11 in 75% yield. On the
Distinguishing
anomeric
stereochemistry
in
2,3-
anhydroglycosides is essential to the structure assignments. In
other hand, the coupling reaction of 18 and 26 yielded the
b
-linked
the case of O-linked glycosides, for 2,3-anhydrofuranosides, Lowary
disaccharide 12a as the sole coupling product, which underwent
deprotection to provide 12 smoothly. Interestingly, it was found
that in the preparation of S-linked disaccharides, when the 2,3-
anhydro donor is allose-type, the exclusive coupling product is
et al. have demonstrated that the magnitude of 1JC-1 ,H-1 is the only
reliable method for establishing anomeric stereochemistry in the
2,3-anhydrosugar derivatives.23a For 2,3-anhydropyranosides, re-
ferring to the previous report,23b it was found that in the case of
0
0
manno-type, the 1JC-1 ,H-1 of
a-glycosides is about 170 Hz, whereas
0 0
the
a
-glycoside; when the 2,3-anhydro donor is mannose-type, the
-glycoside. This might be explained as the
the 1JC-1 ,H-1 of
b
-glycosides is 160e165 Hz; in the case of allo-type,
0
0
exclusive product is the
b
the 1JC-1 ,H-1 of
of
(about 100 ppm), and the JH-1 ,H-2 of
larger than that of -glycosides (0.5 or 0 Hz). Based on these ob-
a
-glycosides is larger than that of
b-glycosides, dC1
0
0
0
following: in the preactivation conditions, mannose-type donor 18
was preactivated to favorably produce the triflate intermediate 18i,
in which the glycosidic bond is trans to the epoxide ring, which was
a
-glycosides (<95 ppm) is smaller than that of
b
-glycosides
3
0
0
a
-glycosides (>2.5 Hz) is
followed by an S
the -glycoside; whereas allose-type donor 24 was preactivated to
dominantly form the glycosyl triflate 24i, which was attacked by
a glycosyl acceptor in the S 2-like manner, yielding the -glycoside
N2-like attack from a glycosyl acceptor, affording
b
b
servations, the anomeric stereochemistry in these 2,3-
anhydrosugar residues was determined. These NMR data for com-
pounds 6a, 7a, and 8a are presented in Table 1.
N
a
(Scheme 5). The excellent stereoselectivity highlights the impor-
tance of preactivation protocol to the stereochemistry outcomes
toward glycosylations.
The assignments of anomeric stereochemistry in the S-linked
2,3-anhydroglycosides can be problematic due to the difference
1
0
0
between the JC-1 ,H-1 values in the O- and S-series. Evidently, for
Scheme 5. Proposed mechanism for the stereoselective formation of S-linked disaccharides.
The synthesis of disaccharides 13 and 14 was displayed in Scheme
6. Previously, method for rearranging 2,3-anhydromono-
Table 1
The NMR parameters in compounds 6a, 7a, and 8aa
a
3
1
0 b
saccharides to unsaturated monosaccharides was developed by
us.15 The preparation of more complex unsaturated disaccharides by
this protocol was attempted. Thus, when the anhydro disaccharide
11 was treated with t-BuOK in DMF at 50 ꢁC, the rearranged product
13 was obtained smoothly in 75% isolated yield. In the same way, the
base-promoted rearrangement of disaccharide 12 provided the tar-
get unsaturated sugar 14.
0
0
0
Entry Compound Epoxide JH1 ,H2 JC1 ,H1 Chemical shift Anomeric
(Hz)
(Hz)
of C-10 (ppm) stereochemistry
1
2
3
6a
7a
8a
allo-
allo-
manno-
3.0
0
0
170.24 94.73
168.19 97.70
176.81 96.19
a
b
a
a
Spectra measured in CDCl3.
Measured using HMBC experiments.
b
the
b-anomer, the stereochemistry may be established un-
ambiguously by the observation of nuclear Overhauser interactions
between H-10, H-4, and H-50. Indeed, NOESY spectrum was used to
confirm the configurations of 9ae12a. For example, for 9a, a strong
NOE signal was observed between H-10 and H-4, while no NOE
signal was seen between H-10 and the H-50. These data are con-
sistent with the a-stereochemistry in 9a.
3. Conclusions
In summary, starting from readily available monosaccharides,
nine new pseudoacarviosin analogs with 2,3-anhydro or un-
saturated sugar moieties were designed and synthesized. The
syntheses involved the glycosylation reactions by using 2,3-
anhydromonosaccharides as glycosyl donors, and in most cases,
the coupling reactions proceeded in a highly stereoselective man-
ner, especially when the preactivation protocol was applied.
Scheme 6. Reagents and conditions: (a) t-BuOK, DMF, 50 ꢁC, 75% for 13, 30% for 14.

Y.-Y. Wang et al. / Tetrahedron 68 (2012) 9355e9363
9359
Furthermore, some 2,3-anhydrodisaccharides were able to undergo
the base-promoted rearrangement to form unsaturated di-
saccharides. Due to the potential applications of these pseudoa-
carviosin analogs in drug discovery, the disclosed design strategy
and synthetic approach may facilitate the construction of this type
of pseudoacarviosins with biological importance.
5H), 3.56 (t, 1H, J¼4.0 Hz), 3.37e3.39 (m, 4H), 3.31e3.33 (m, 2H),
1.24 (d, 3H, J¼6.0 Hz); 13C NMR (125 MHz, CD3OD)
d 101.14, 95.18,
81.35, 75.73, 73.94, 71.24, 67.23, 66.25, 62.27, 56.17, 55.50, 55.35,
18.58; HRMS (ESI) Anal. Calcd for C13H22O9Na [MþNa]þ 345.1156.
Found 345.1160.
4.3. Methyl 4-O-(2,3-anhydro-b-D-allopyranosyl)-6-deoxy-a-
4. Experimental section
D-glucopyranoside (7)
4.1. Methyl 4-O-(2,3-anhydro-4,6-O-benzylidene-
anosyl)-2,3-di-O-benzyl-6-deoxy- -glucopyranoside (6a)
and methyl 4-O-(2,3-anhydro-4,6-di-O-benzylidene- -allo-
pyranosyl)-2,3-di-O-benzyl-6-deoxy- -glucopyranoside (7a)
a
-
D
-allopyr-
Compound 7a (100 mg, 0.169 mmol) was dissolved in a mixture
a-
D
of THF and EtOH (25 mL, THF/EtOH¼4:1), palladium hydroxide
(10 mg) was added, and the mixture was stirred under H2 atmo-
sphere for 2 days. Filtration and concentration gave disaccharide 7
b-D
a-D
(47 mg, 87% yield) as a colorless oil: ½a D25
ꢂ
þ90.2 (c 1.4, water); 1H
Compounds 1515 (25.0 mg, 0.069 mmol), 1616 (17.2 mg,
NMR (500 MHz, CD3OD)
d
4.93 (s,1H, H-10), 4.59 (d,1H, J¼4.0 Hz, H-
ꢀ
0.046 mmol), and 4 A molecular sieves (400 mg) were dried
1), 3.94 (dd, 1H, J¼1.5, 9.5 Hz), 3.77 (dd, 1H, J¼2.5, 12.0 Hz),
3.59e3.72 (m, 3H), 3.42e3.45 (m, 1H), 3.36e3.41 (m, 6H), 3.20 (dd,
1H, J¼8.5, 9.5 Hz), 1.28 (d, 3H, J¼6.0 Hz); 13C NMR (125 MHz,
overnight under vacuum in the presence of P2O5. To this mixture
was added CH2Cl2 (5 mL); the mixture was cooled to ꢀ40 ꢁC, and
then NIS (16.6 mg, 0.074 mmol) and AgOTf (3.6 mg, 0.014 mmol)
were successively added. After stirring for 20 min at ꢀ40 ꢁC, the
reaction mixture was warmed to ꢀ25 ꢁC. Once the color of the
reaction was changed to pink, it was cooled again to ꢀ40 ꢁC. After
another 30 min, the reaction mixture turned dark red and was
neutralized by the addition of triethylamine. The mixture was di-
luted with CH2Cl2, filtered through Celite and concentrated. The
residue was purified by flash column chromatography on silica gel
(petroleum ether/EtOAc 20:1) to give 6a (9.5 mg, 35% yield) as
a colorless syrup and 7a (11.1 mg, 42% yield) as a colorless syrup. For
CD3OD)
d 102.99, 101.58, 80.20, 72.57, 72.21, 71.57, 70.80, 70.55,
67.73, 66.21, 62.89, 55.71, 17.18; HRMS (ESI) Anal. Calcd for
C13H22O9Na [MþNa]þ 345.1156. Found 345.1162.
4.4. p-Tolyl 2,3-anhydro-4,6-di-O-acetyl-1-thio-b-D-man-
nopyranoside (18)
Compound 1715 (2.08 g, 5.60 mmol) was dissolved in MeOH
(60 mL) at 0 ꢁC, and TsOH (0.29 g,1.68 mmol) was added slowly. The
mixture was stirred. After consumption of the starting material
(3 h), triethylamine was added to neutralize the solution to pH 7,
the mixture was then filtered and concentrated. The crude product
was dissolved in pyridine (30 mL), and acetic anhydride (1.61 mL,
12.80 mmol) was added. The reaction mixture was stirred over-
night. After consumption of the starting material, the mixture was
concentrated. The residue was purified by flash column chroma-
tography on silica gel (petroleum ether/EtOAc 5:1) to give 18
compound 6a: ½a 2D5
ꢂ
þ70.8 (c 1.4, CHCl3); 1H NMR (500 MHz, CDCl3)
d
7.49e7.60 (m, 2H), 7.26e7.48 (m, 13H), 5.54 (s, 1H, benzylidene),
5.35 (d, 1H, J¼3.0 Hz, H-10), 5.07 (d, 1H, J¼11.5 Hz, eCH2e), 4.74 (d,
1H, J¼12.0 Hz, eCH2e), 4.72 (d, 1H, J¼11.5 Hz, eCH2e), 4.65 (d, 1H,
J¼12.0 Hz, eCH2e), 4.55 (d, 1H, J¼3.5 Hz, H-1), 4.14 (dd, 1H, J¼5.0,
10.3 Hz), 4.00e4.08 (m, 2H), 3.88 (dd, 1H, J¼1.0, 9.0 Hz), 3.78e3.84
(m, 1H), 3.63 (t, 1H, J¼10.0 Hz), 3.51 (dd, 1H, J¼3.5, 9.5 Hz), 3.42 (d,
1H, J¼4.0 Hz), 3.38 (s, 3H), 3.35 (t, 1H, J¼9.5 Hz), 3.08 (dd, 1H, J¼3.0,
(1.60 g, 81% yield) as white solids: ½a D25
ꢂ
ꢀ45.3 (c 1.4, CHCl3); 1H
4.0 Hz), 1.24 (d, 3H, J¼6.5 Hz); 13C NMR (125 MHz, CDCl3)
d
138.85,
NMR (400 MHz, CDCl3)
d
7.48 (d, 2H, J¼8.0 Hz), 7.13 (d, 2H,
137.94, 137.04, 129.22, 128.49, 128.46, 128.31, 128.14, 127.96, 127.60,
127.50,126.22,102.62 (benzylidene), 97.71 (C-1), 94.73 (C-10), 81.84,
80.44, 79.89, 77.71, 75.57, 73.11, 68.64, 65.75, 60.25, 55.04, 53.07,
50.69, 17.60; HRMS (ESI) Anal. Calcd for C34H38O9Na [MþNa]þ
J¼8.0 Hz), 5.17 (d,1H, J¼0.8 Hz), 4.93 (d,1H, J¼9.2 Hz), 4.17e4.19 (m,
2H), 3.57e3.60 (m, 1H), 3.41 (d, 1H, J¼3.6 Hz), 3.27 (d, 1H, J¼3.6 Hz),
2.35 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
170.59, 169.48, 138.12, 132.47, 129.79, 129.64, 82.97, 74.99, 63.33,
613.2408, found 613.2417; 1JC1,H1¼174.17 Hz; 1JC1 ,H1 ¼170.24 Hz. For
63.23, 54.11, 51.32, 21.11, 20.76, 20.72; HRMS (ESI) Anal. Calcd for
0
0
compound 7a: ½a 2D5
ꢂ
þ65.4 (c 1.4, CHCl3); 1H NMR (500 MHz, CDCl3)
C17H24NO6S [MþNH4]þ 370.1319. Found 370.1319.
d
7.26e7.48 (m, 15H), 5.42 (s, 1H, benzylidene), 5.21 (s, 1H, H-10),
4.93 (d, 1H, J¼11.0 Hz, eCH2e), 4.88 (d, 1H, J¼11.0 Hz, eCH2e), 4.77
(d, 1H, J¼12.5 Hz, eCH2e), 4.64 (d, 1H, J¼12.0 Hz, eCH2e), 4.52 (d,
1H, J¼3.5 Hz, H-1), 3.95e3.98 (m, 2H), 3.86 (t, 1H, J¼9.0 Hz),
3.73e3.79 (m, 1H), 3.59e3.64 (m, 1H), 3.50e3.52 (m, 2H),
3.36e3.41 (m, 6H), 1.30 (d, 3H, J¼6.5 Hz); 13C NMR (125 MHz,
4.5. Methyl 2,3-di-O-p-methoxybenzyl-6-deoxy-a-D-glucopyr-
anoside (20)
Compound 1919 (14.05 g, 32.33 mmol) and p-toluenesulfonyl
chloride (12.30 g, 64.99 mmol) were added into pyridine (200 mL)
at 0 ꢁC. The mixture was stirred overnight allowing the reaction to
be warmed up to room temperature. The reaction mixture was
diluted with EtOAc. The organic phase was successively washed
with 1 N HCl aqueous solution (three times), saturated NaHCO3
aqueous solution, and brine, dried over Na2SO4. After removal of
the solvent, the tosylated crude product was dissolved in THF
(200 mL) and LiAlH4 (3.60 g, 129.32 mmol) was added. The mixture
was stirred at room temperature overnight, then heated under
reflux for 2 h. After completion of the reaction, the mixture was
quenched by the slow addition of ice, then filtered through Celite.
The filtered cake was washed with EtOAc, and the resulting cloudy
yellowish solution was filtered again through Celite. The combined
organic solutions were successively washed with 1 N HCl aqueous
solution, water, saturated NaHCO3 aqueous solution, and brine,
dried (MgSO4), filtered, and concentrated. The residue was purified
by flash column chromatography on silica gel (petroleum ether/
CDCl3) d 139.24,138.10,137.03,129.21,128.42,128.31,128.26,128.10,
127.88, 127.38, 127.16, 126.21, 102.54 (benzylidene), 97.90 (C-1),
97.70 (C-10), 83.74, 80.10, 79.69, 77.34, 75.24, 73.43, 68.65, 66.03,
60.47, 55.48, 55.21, 51.30, 18.11; HRMS (ESI) Anal. Calcd for
C34H38O9Na
JC1,H1¼168.81 Hz; JC1 ,H1 ¼168.19 Hz.
[MþNa]þ
613.2408,
found
613.2422;
1
1
0
0
4.2. Methyl 4-O-(2,3-anhydro-
-glucopyranoside (6)
a-D-allopyranosyl)-6-deoxy-a-
D
Compound 6a (63 mg, 0.107 mmol) was dissolved in a mixture
of THF and EtOH (20 mL, THF/EtOH¼4:1), palladium hydroxide
(10 mg) was added, and the mixture was stirred under H2 atmo-
sphere for 2 days. The mixture was filtered and concentrated to give
disaccharide 6 (29 mg, 85% yield) as a colorless oil: ½a D25
þ110.6 (c
ꢂ
1.4, water); 1H NMR (500 MHz, CD3OD)
d
5.56 (d, 1H, J¼3.5 Hz, H-
10), 4.59 (d, 1H, J¼4.0 Hz, H-1), 3.84e3.86 (m, 1H), 3.64e3.77 (m,
EtOAc 5:1) to give 20 (9.01 g, 67% yield) as white solids: ½a D25
þ30.2
ꢂ

9360
Y.-Y. Wang et al. / Tetrahedron 68 (2012) 9355e9363
(c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.26e7.31 (m, 4H),
4.8. Methyl 2,3-di-O-p-methoxybenzyl-6-deoxy-4-iodo-
a-D-
6.86e6.90 (m, 4H), 4.94 (d, 1H, J¼11.2 Hz), 4.71 (d, 1H, J¼11.6 Hz),
4.59e4.62 (m, 2H), 4.50 (d, 1H, J¼3.6 Hz), 3.80 (s, 6H), 3.70e3.60
(m, 2H), 3.48 (dd, 1H, J¼3.6, 9.6 Hz), 3.36 (s, 3H), 3.11 (t, 1H,
J¼9.2 Hz), 2.09 (s, 1H), 1.22 (d, 3H, J¼6.0 Hz); 13C NMR (100 MHz,
galactopyranoside (21)
Compound 20 (4.07 g, 9.54 mmol), I2 (4.85 g, 19.08 mmol), PPh3
(7.50 g, 29.16 mmol), and imidazole (1.95 g, 29.16 mmol) were
added into THF (100 mL) at room temperature, and the ensuing
mixture was stirred at 80 ꢁC overnight. When the starting material
disappeared, the reaction mixture was cooled to room temperature,
diluted with toluene, and washed successively with saturated
NaHCO3, 5% sodium thiosulfate, and water. The aqueous phase was
extracted with ethyl acetate, and the combined organic layers were
washed with water and brine, dried (MgSO4), filtered, and con-
centrated. The residue was purified by flash column chromatogra-
phy on silica gel (petroleum ether/EtOAc 15:1) to give 21 (4.30 g,
CDCl3)
d 159.42, 159.37, 130.88, 130.15, 129.70, 129.64, 114.06,
113.86, 98.07, 80.84, 79.68, 75.27, 74.87, 72.64, 66.77, 55.25 (2C),
55.09, 17.63; HRMS (ESI) Anal. Calcd for C23H34NO7 [MþNH4]þ
436.2330. Found 436.2340.
4.6. Methyl 4-O-(2,3-anhydro-4,6-di-O-acetyl-
a
-D
-mannopyr-
anosyl)-2,3-di-O-p-methoxybenzyl-6-deoxy-a-D-glucopyrano-
side (8a)
86% yield) as a colorless oil: ½a D25
ꢂ
þ24.0 (c 1.4, CHCl3); 1H NMR
Compounds 18 (30.0 mg, 0.085 mmol), 20 (23.8 mg,
(400 MHz, CDCl3)
d 7.26e7.34 (m, 4H), 6.83e6.89 (m, 4H), 4.76 (d,
ꢀ
0.057 mmol), and 4 A molecular sieves (400 mg) were dried over-
1H, J¼12.0 Hz), 4.66 (d, 1H, J¼11.2 Hz), 4.58 (d, 1H, J¼12.0 Hz), 4.54
(d, 1H, J¼12.0 Hz), 4.48 (d, 1H, J¼4.0 Hz), 4.44 (d, 1H, J¼2.8 Hz),
3.77e3.82 (m, 7H), 3.34 (s, 3H), 3.13e3.19 (m, 2H), 1.20 (d, 3H,
night under vacuum in the presence of P2O5. To this mixture was
added CH2Cl2 (5 mL); the mixture was cooled to ꢀ40 ꢁC, NIS
(20.5 mg, 0.091 mmol) and AgOTf (6.9 mg, 0.027 mmol) were
successively added. After stirring for 20 min at ꢀ40 ꢁC, the mixture
was warmed to ꢀ25 ꢁC. Once the color of the reaction was changed
to pink, it was cooled again to ꢀ40 ꢁC. After another 30 min, the
reaction mixture turned dark red and was then neutralized by the
addition of triethylamine. The mixture was diluted with CH2Cl2,
filtered through Celite, and concentrated. The residue was purified
by flash column chromatography on silica gel (petroleum ether/
J¼6.0 Hz); 13C NMR (100 MHz, CDCl3)
d 159.11, 159.04, 130.88,
130.33, 129.96, 129.62, 129.17, 113.63, 113.57, 98.92, 76.68, 75.39,
73.29, 70.74, 63.87, 55.14, 55.08, 55.07, 47.29, 22.90; HRMS (ESI)
Anal. Calcd for C23H33NO6I [MþNH4]þ 546.1347. Found 546.1333.
4.9. Methyl 2,3-di-O-p-methoxybenzyl-4-acetylthio-6-deoxy-
a-
D-glucopyranoside (22)
EtOAc 8:1) to give 8a (24.6 mg, 67% yield) as a colorless syrup: ½a D25
ꢂ
Compound 21 (5.70 g, 10.80 mmol) and potassium thioacetate
þ10.0 (c 1.4, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.26e7.29 (m, 2H),
(4.90 g, 43.20 mmol) were dissolved in DMF (80 mL) at room
temperature, and the mixture was stirred at 90 ꢁC for 2 h. After the
starting material was consumed, the reaction mixture was cooled
to room temperature, diluted with ethyl acetate, and washed with
water. The water phase was extracted with ethyl acetate, and the
combined organic phase was washed with water and brine, dried
(MgSO4), filtered, and concentrated. The residue was purified by
flash column chromatography on silica gel (petroleum ether/EtOAc
7.22e7.24 (m, 2H), 6.85e6.88 (m, 4H), 5.52 (s, 1H, H-10), 4.95 (d, 1H,
J¼11.0 Hz), 4.76 (d, 1H, J¼10.0 Hz), 4.70 (d, 1H, J¼11.5 Hz), 4.62 (d,
1H, J¼11.0 Hz), 4.57 (d, 1H, J¼11.5 Hz), 4.47 (d, 1H, J¼3.5 Hz, H-1),
4.07 (d, 2H, J¼4.0 Hz), 3.84e3.91 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H),
3.69 (dd, 1H, J¼6.5, 9.5 Hz), 3.49 (dd, 1H, J¼3.5, 9.5 Hz), 3.36e3.40
(m, 4H), 3.16 (d, 1H, J¼4.0 Hz), 2.81 (d, 1H, J¼3.5 Hz), 2.04 (s, 3H),
2.11 (s, 3H), 1.26 (d, 3H, J¼6.0 Hz); 13C NMR (125 MHz, CDCl3)
d
170.73, 169.48, 159.48, 159.30, 130.44, 129.99, 129.77, 129.53,
20:1) to give 22 (3.41 g, 67% yield) as a yellowish syrup: ½a D25
þ60.1
ꢂ
114.00, 113.89, 97.83 (C-1), 96.19 (C-10), 81.31, 81.19, 80.19, 75.13,
72.86, 65.62, 65.02, 63.04, 55.29, 55.26, 55.20, 53.24, 49.15, 20.79,
20.72, 18.17. HRMS (ESI) Anal. Calcd for C33H42O13K [MþK]þ
(c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.21e7.28 (m, 4H),
6.83e6.86 (m, 4H), 4.81 (d, 1H, J¼10.8 Hz), 4.73 (d, 1H, J¼11.6 Hz),
4.61 (d, 1H, J¼10.4 Hz), 4.57 (d, 1H, J¼12.0 Hz), 4.50 (d, 1H,
J¼3.2 Hz), 3.68e3.80 (m, 8H), 3.54 (dd,1H, J¼3.6, 9.2 Hz), 3.36e3.45
(m, 4H), 2.32 (s, 3H), 1.21 (d, 3H, J¼6.4 Hz); 13C NMR (100 MHz,
1
1
0
0
685.5117. Found 685.5117; JC1,H1¼167.09 Hz; JC1 ,H1 ¼176.81 Hz.
4.7. Methyl 4-O-(2,3-anhydro-
a-
D-mannopyranosyl)-6-deoxy-
CDCl3) d 193.56, 159.31, 158.99, 130.83, 130.18, 129.76, 129.64,
a
-
D
-glucopyranoside (8)
129.20, 128.82, 127.78, 113.75, 113.51, 113.31, 98.34, 80.63, 77.60,
75.39, 72.87, 66.69, 55.23, 55.17, 55.15, 50.89, 30.56, 18.28; HRMS
(ESI) Anal. Calcd for C25H36NO7S [MþNH4]þ 494.2207. Found
494.2213.
To a solution of compound 8a (50 mg, 0.077 mmol) in CH2C12
(1 mL) and water (9 mL) at room temperature was added 2,3-
dichloro-5,6-dicyano-l,4-benzoquinone (34 mg, 0.15 mmol), and
the mixture was stirred at room temperature for 1 h. The mixture
was diluted with saturated aqueous NaHCO3 solution, and extrac-
ted with EtOAc. The combined organic layers were washed with
saturated aqueous NaHCO3 solution (four times), and then dried
(Na2SO4), concentrated. The crude product was dissolved in MeOH
(20 mL), and K2CO3 (12.7 mg, 0.092 mmol) was added slowly. The
mixture was stirred. After consumption of the starting material
(5 h), to the reaction mixture was added acidic resin to neutralize
the solution to pH 7. The mixture was filtered and concentrated. The
residue was purified by flash column chromatography on silica gel
(MeOH/EtOAc 1:10) to give 8 (21.0 mg, 85% yield) as a colorless oil:
4.10. Methyl 2,3-di-O-p-methoxybenzyl-6-deoxy-4-thio-a-D-
glucopyranoside (23)
Compound 22 (1.60 g, 3.40 mmol) was dissolved in MeOH
(35 mL) at room temperature, and potassium carbonate (0.56 g,
4.10 mmol) was added slowly. After consumption of the starting
material (12 h), the reaction mixture was treated with acidic resin
to neutralize the solution to pH 7. The mixture was filtered and
concentrated. The residue was purified by flash column chroma-
tography on silica gel (petroleum ether/EtOAc 10:1) to give 23
(1.10 g, 75% yield) as a yellowish syrup: ½a D25
ꢂ
ꢀ26.7 (c 1.4, CHCl3); 1H
½
a 2D5
ꢂ
þ109.3 (c 1.4, CHCl3); 1H NMR (400 MHz, D2O)
d
4.83 (s, 1H, H-
NMR (400 MHz, CDCl3) d 7.26e7.34 (m, 4H), 6.85e6.89 (m, 4H), 4.89
10), 4.65 (d,1H, J¼4.0 Hz, H-1), 4.17e4.19 (m,1H), 3.94 (dd,1H, J¼6.8,
9.5 Hz), 3.89e3.92 (m, 2H), 3.78e3.83 (m, 3H), 3.76 (d, 1H,
J¼3.2 Hz), 3.66e3.73 (m, 2H), 3.34 (s, 3H), 1.27 (d, 3H, J¼6.8 Hz); 13C
(d, 1H, J¼10.4 Hz), 4.73 (d, 1H, J¼11.8 Hz), 4.72 (d, 1H, J¼10.2 Hz),
4.60 (d, 1H, J¼11.8 Hz), 4.53 (d, 1H, J¼3.2 Hz), 3.81 (s, 3H), 3.80 (s,
3H), 3.60e3.71 (m, 2H), 3.44 (dd, 1H, J¼3.5, 9.4 Hz), 3.38 (s, 3H),
2.57e2.60 (m, 1H), 1.72 (d, 1H, J¼6.0 Hz), 1.30 (d, 3H, J¼6.2 Hz); 13C
NMR (125 MHz, CD3OD) d: 100.92, 99.32, 87.28, 73.64, 73.48, 73.28,
67.22, 65.78, 62.35, 57.80, 55.59, 55.44, 18.01; HRMS (ESI) Anal.
NMR (100 MHz, CDCl3) d 159.41, 159.31, 130.68, 130.20, 129.83,
Calcd for C13H22O9Na [MþNa]þ 345.1156. Found 345.1159.
129.68, 113.85, 113.82, 98.39, 81.40, 80.54, 75.81, 72.73, 68.59, 55.27,

Y.-Y. Wang et al. / Tetrahedron 68 (2012) 9355e9363
9361
55.24, 48.16, 19.19; HRMS (ESI) Anal. Calcd for C23H34NO6S
J¼9.2 Hz), 3.80 (dd, 1H, J¼6.0, 10.8 Hz), 3.69e3.75 (m, 4H),
3.54e3.61 (m, 2H), 3.46 (dd, 1H, J¼4.0, 9.6 Hz), 3.29 (s, 3H), 2.48 (t,
1H, J¼10.8 Hz), 1.28 (d, 3H, J¼6.4 Hz); 13C NMR (125 MHz, D2O)
[MþNH4]þ 452.2101. Found 452.2112.
4.11. p-Tolyl 2,3-anhydro-4,6-di-O-acetyl-1-thio-
b-D
-allopyr-
d 100.02, 78.93, 73.24, 73.01, 70.06, 67.82, 65.07, 61.08, 58.94, 56.76,
anoside (24)
55.80, 53.47, 19.24; HRMS (ESI) Anal. Calcd for C13H22O8SK [MþK]þ
377.0662. Found 377.0671.
Compound 15 (1.02 g, 2.80 mmol) was dissolved in MeOH
(60 mL) at 0 ꢁC, and TsOH (0.14 g, 0.84 mmol) was added slowly.
After consumption of the starting material (3 h), triethylamine was
added to neutralize the solution to pH 7, and then the reaction
mixture was filtered and concentrated. The crude product was
dissolved in pyridine (30 mL), and acetic anhydride (0.79 mL,
8.40 mmol) was added. The mixture was stirred overnight. After
consumption of the starting material, the reaction mixture was
concentrated. The residue was purified by flash column chroma-
tography on silica gel (petroleum ether/EtOAc 5:1) to give 24
4.14. Methyl 4-S-(2,3-anhydro-4,6-di-O-acetyl-
anosyl)-2,3-di-O-p-methoxybenzyl-6-deoxy-a-D-glucopyrano-
side (10a)
b
-
D
-mannopyr-
Compound 10a was prepared by the coupling reaction of 18
(26.0 mg, 0.076 mmol) and 23 (65.0 mg, 0.152 mmol) in the same
manner as described in the synthesis of 9a, the product was puri-
fied by flash column chromatography on silica gel (petroleum
ether/EtOAc 3:1) to give 10a (39.0 mg, 77% yield) as a colorless
(0.69 g, 70% yield) as white solids: ½a D25
ꢂ
þ23.5 (c 1.4, CHCl3); 1H
syrup: ½a 2D5
ꢂ
þ17.9 (c 1.4, CHCl3); 1H NMR (500 MHz, CDCl3)
NMR (400 MHz, CDCl3)
d
7.47 (d, 2H, J¼7.6 Hz), 7.14 (d, 2H,
d 7.33e7.35 (m, 2H), 7.26e7.29 (m, 2H), 6.85e6.87 (m, 4H), 5.00 (s,
J¼7.6 Hz), 5.14 (s, 1H), 4.93 (d, 1H, J¼9.6 Hz), 4.15 (d, 2H, J¼2.4 Hz),
3.81e3.83 (m, 1H), 3.64 (d, 1H, J¼3.6 Hz), 3.97 (s, 1H), 2.36 (s, 3H),
1H, H-10), 4.85e4.89 (m, 2H, H-40, eCH2e), 4.78 (d, 1H, J¼10.5 Hz,
eCH2e), 4.73 (d, 1H, J¼12.0 Hz, eCH2e), 4.59 (d, 1H, J¼10.5 Hz,
eCH2e), 4.53 (d, 1H, J¼3.5 Hz, H-1), 4.15 (dd, 1H, J¼3.0, 12.3 Hz, H-
6a0), 4.02 (dd,1H, J¼6.0,12.0 Hz, H-6b0), 3.75e3.84 (m, 8H, H-3, H-5,
eOCH3, eOCH3), 3.52 (dd, 1H, J¼3.5, 9.0 Hz, H-2), 3.44e3.47 (m, 1H,
H-50), 3.37 (s, 3H, eOCH3), 3.13e3.16 (m, 2H, H-20, H-30), 2.74 (t, 1H,
J¼10.5 Hz), 2.11 (s, 3H, eCH3), 2.04 (s, 3H, eCH3), 1.36 (d, 3H,
2.09 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 170.54, 170.05, 138.83,
133.77, 129.65, 127.33, 79.77, 69.89, 66.58, 62.79, 58.46, 52.14, 21.10,
20.74, 20.69; HRMS (ESI) Anal. Calcd for C17H20O6SNa [MþNa]þ
375.0873. Found 375.0871.
4.12. Methyl 4-S-(2,3-anhydro-4,6-di-O-acetyl-
a
-D
-allopyr-
J¼6.5 Hz, eCH3); 13C NMR (125 MHz, CDCl3)
d 170.57,169.46,159.39,
159.18, 130.89, 130.23, 129.66, 113.83, 113.66, 98.15, 81.07, 77.82,
77.60, 75.51, 75.12, 72.83, 67.51, 63.26, 62.94, 55.23, 53.93, 52.48,
anosyl)-2,3-di-O-p-methoxybenzyl-6-deoxy-
a
-D
-glucopyrano-
side (9a)
51.82, 20.77, 20.67, 19.04; HRMS (ESI) Anal. Calcd for C33H43O12
S
Compound 24 (25.0 mg, 0.071 mmol), TTBP (28.7 mg,
[MþH]þ 663.2470. Found 663.2478.
ꢀ
0.142 mmol), Ph2SO (11.5 mg, 0.057 mmol), and 4 A molecular
sieves (400 mg) were dried for 3 h under vacuum in the presence of
P2O5. To this mixture was added CH2Cl2 (5 mL), and the mixture
4.15. Methyl 4-S-(2,3-anhydro-
b-D-mannopyranosyl)-6-
deoxy- -glucopyranoside (10)
a-D
was cooled to ꢀ78 ꢁC. Tf2O (10.8
mL, 0.064 mmol) was added, and
the mixture was allowed to stir for 10 min. The mixture was then
stirred for 20 min followed by the addition of 23 (49.0 mg,
0.142 mmol). After 2 h, the reaction was warmed to room tem-
perature and triethylamine was then added. The reaction mixture
was filtered through Celite and the filtrate was concentrated. The
residue was purified by flash column chromatography on silica gel
(petroleum ether/EtOAc 3:1) to give 9a (37.0 mg, 81% yield) as
Compound 10 was prepared from 10a (80.0 mg, 0.121 mmol) in
the same manner as described in the synthesis of compound 8 from
8a, the product was purified by flash column chromatography on
silica gel (MeOH/EtOAc 1:10) to give 10 (29.0 mg, 72% yield) as
white solids: ½a D25
ꢂ
þ80.2 (c 1.4, water); 1H NMR (400 MHz, D2O)
d
5.18 (s, 1H, H-10), 4.67 (s, 1H, H-1), 3.88 (dd, 1H, J¼6.2, 10.9 Hz),
3.65e3.72 (m, 3H), 3.43e3.51 (m, 2H), 3.40 (d, 1H, J¼3.9 Hz), 3.33
(d, 1H, J¼3.9 Hz), 3.26 (s, 3H), 3.18e3.22 (m, 1H), 2.55 (t, 1H,
a colorless syrup: ½a D25
ꢂ
þ11.8 (c 1.4, CHCl3); 1H NMR (500 MHz,
CDCl3)
d
7.25e7.30 (m, 4H), 6.85e6.88 (m, 4H), 5.66 (d,1H, J¼3.5 Hz,
J¼10.6 Hz), 1.30 (d, 3H, J¼6.2 Hz); 13C NMR (125 MHz, D2O)
d 99.91,
H-10), 5.08 (dd, 1H, J¼1.5, 9.8 Hz, H-40), 5.02 (d, 1H, J¼10.5 Hz,
eCH2e), 4.72 (d, 1H, J¼12.0 Hz, eCH2e), 4.68 (d, 1H, J¼10.5 Hz,
eCH2e), 4.60 (d, 1H, J¼12.0 Hz, eCH2e), 4.53 (d, 1H, J¼3.0 Hz, H-1),
4.14e4.19 (m, 2H, H-50, H-6a0), 4.00e4.03 (m, 1H, H-6b0), 3.89 (t, 1H,
J¼10.0 Hz, H-3), 3.80 (s, 6H, eOCH3, eOCH3), 3.63e3.69 (m, 1H, H-
5), 3.50 (dd,1H, J¼2.0, 4.0 Hz, H-30), 3.46 (dd,1H, J¼3.5, 9.5 Hz, H-2),
3.37 (s, 3H, eOCH3), 3.24 (t, 1H, J¼4.0 Hz, H-20), 2.60 (t, 1H,
J¼11.0 Hz, H-4), 2.10 (s, 3H, eCH3), 2.04 (s, 3H, eCH3), 1.34 (d, 3H,
80.75, 78.69, 73.28, 70.03, 69.00, 62.19, 61.37, 57.99, 55.79, 54.45,
53.48, 18.90; HRMS (ESI) Anal. Calcd for C13H22O8SK [MþK]þ
377.0662. Found 377.0661.
4.16. Methyl 2,3-di-O-p-methoxybenzyl-4-acetylthio-6-deoxy-
a-
D-galactopyranoside (25)
Compound 20 (2.32 g, 5.54 mmol), Tf2O (1.81 mL, 11.08 mmol),
J¼6.0 Hz); 13C NMR (125 MHz, CDCl3)
d
170.56, 170.16, 159.37,
and pyridine (1.8 mL, 22.16 mmol) were dissolved in CH2Cl2 (15 mL)
at ꢀ30 ꢁC, and the mixture was stirred at room temperature for 2 h.
After the starting material was consumed, the reaction mixture was
diluted with ethyl acetate, and washed with NaHCO3. The aqueous
phase was extracted with ethyl acetate, and the combined organic
phase was washed with brine, dried (MgSO4), filtered, and con-
centrated. The crude product and potassium thioacetate (2.53 g,
22.16 mmol) were dissolved in DMF (80 mL) at room temperature,
and the mixture was stirred at 90 ꢁC for 2 h. After the starting
material was consumed, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and washed with water.
The aqueous phase was extracted with ethyl acetate, and the
combined organic phase was washed with brine, dried (MgSO4),
filtered, and concentrated. The residue was purified by flash col-
umn chromatography on silica gel (petroleum ether/EtOAc 20:1) to
159.08, 131.04, 130.07, 129.67, 129.21, 113.81, 113.67, 98.21, 82.63,
80.64, 80.29, 75.94, 72.59, 66.99, 66.25, 64.82, 62.56, 56.64, 55.26,
55.21, 55.18, 52.46, 51.80, 20.75, 20.64, 19.26; HRMS (ESI) Anal.
Calcd for C33H43O12S [MþH]þ 663.2470. Found 663.2491.
4.13. Methyl 4-S-(2,3-anhydro-
-glucopyranoside (9)
a-D-allopyranosyl)-6-deoxy-a-
D
Compound 9 was prepared from 9a (40.0 mg, 0.060 mmol) in
the same manner as described in the synthesis of compound 8 from
8a, the product was purified by flash column chromatography on
silica gel (MeOH/EtOAc 1:10) to give 9 (16.0 mg, 81% yield) as white
solids: ½a 2D5
ꢂ
þ89.8 (c 1.4, water); 1H NMR (400 MHz, D2O)
d 5.64 (d,
1H, J¼3.2 Hz, H-10), 4.68 (d, 1H, J¼3.6 Hz, H-1), 3.93 (d, 1H,

9362
Y.-Y. Wang et al. / Tetrahedron 68 (2012) 9355e9363
give 25 (1.66 g, 63% yield) as a yellowish syrup: ½a D25
ꢂ
þ27.6 (c 1.4,
J¼11.7 Hz), 4.49 (d,1H, J¼3.7 Hz, H-1), 4.02e4.03 (m,1H), 4.00e4.01
(m, 1H), 3.99e4.00 (m, 2H), 3.80 (s, 6H), 3.73 (d, 1H, J¼2.0 Hz), 3.65
(t, 1H, J¼4.0 Hz), 3.61 (d, 1H, J¼3.9 Hz), 3.58 (d, 1H, J¼3.7 Hz),
3.34e3.35 (m, 4H), 2.10 (s, 3H), 2.03 (s, 3H), 1.35 (d, 3H, J¼6.4 Hz);
CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.25e7.27 (m, 4H), 6.84e6.86
(m, 4H), 4.79 (d,1H, J¼11.7 Hz), 4.57 (ABq, 2H, J¼11.2 Hz), 4.48e4.50
(m, 2H), 4.26 (d, 1H, J¼3.4 Hz), 4.20 (d, 1H, J¼6.4 Hz), 4.13 (dd, 1H,
J¼4.5, 10.0 Hz), 3.80 (s, 6H), 3.38 (dd, 1H, J¼3.8, 10.0 Hz), 3.34 (s,
3H), 2.42 (s, 3H), 1.16 (d, 3H, J¼6.3 Hz); 13C NMR (100 MHz, CDCl3)
13C NMR (125 MHz, CDCl3)
d 170.64, 169.48, 159.30, 159.21, 130.92,
130.59, 129.65, 129.17, 113.82, 113.76, 98.75, 79.11, 78.77, 74.92,
73.11, 73.02, 65.47, 63.20, 55.26, 54.06, 51.49, 51.44, 20.80, 20.75,
18.44; HRMS (ESI) Anal. Calcd for C33H43O12S [MþH]þ 663.2470.
Found 663.2478.
d
195.23, 159.26, 159.15, 130.59, 130.27, 129.59, 129.39, 113.74, 99.05,
75.95, 73.33, 71.51, 64.45, 55.37, 55.25, 51.02, 30.93, 17.70; HRMS
(ESI) Anal. Calcd for C25H36NO7S [MþNH4]þ 494.2207. Found
494.2208.
4.20. Methyl 4-S-(2,3-anhydro-a-D-allopyranosyl)-6-deoxy-a-
4.17. Methyl 2,3-di-O-p-methoxybenzyl-6-deoxy-4-thio-
a-
D-
D-galactopyranoside (11)
galactopyranoside (26)
Compound 11 was prepared from 11a (55.0 mg, 0.083 mmol) in
Compound 25 (0.50 g, 1.05 mmol) was dissolved in MeOH
(35 mL) at room temperature, and potassium carbonate (0.17 g,
1.26 mmol) was added slowly. After consumption of the starting
material (12 h), the reaction mixture was treated with acidic resin
to neutralize the solution to pH 7. The mixture was filtered and the
filtrate was concentrated. The residue was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc 8:1) to give
the same manner as described in the synthesis of compound 8 from
8a, the product was purified by flash column chromatography on
silica gel (MeOH/EtOAc 1:10) to give 11 (21.0 mg, 75% yield) as
white solids: ½a D25
ꢂ
þ99.0 (c 1.4, water); 1H NMR (500 MHz, D2O)
d
5.43 (d, 1H, J¼3.5 Hz, H-10), 4.75 (d, 1H, J¼4.0 Hz, H-1), 4.33 (dd,
1H, J¼6.5, 5.1 Hz), 4.05e4.08 (m, 2H), 3.88e3.92 (m, 2H), 3.79 (dd,
1H, J¼4.0, 12.5 Hz), 3.79 (dd, 1H, J¼4.0, 12.5 Hz), 3.67 (dd, 1H, J¼1.5,
4.3 Hz), 3.56 (dd, 1H, J¼4.0, 10.5 Hz), 3.42e3.39 (m, 4H), 1.42 (d, 3H,
a 25
26 (0.36 g, 80% yield) as a yellowish syrup: ½ ꢂD þ4.1 (c 1.4, CHCl3);
1H NMR (400 MHz, CDCl3)
d
7.27e7.32 (m, 4H), 6.84e6.89 (m, 4H),
J¼6.5 Hz); 13C NMR (125 MHz, D2O)
d 100.15, 80.85, 70.27, 69.97,
4.77 (d, 1H, J¼11.6 Hz), 4.57e4.62 (m, 3H), 4.52 (d, 1H, J¼3.6 Hz),
4.13 (ddd, 1H, J¼12.8, 6.4, 4.4 Hz), 3.96 (dd, 1H, J¼4.4, 9.8 Hz), 3.90
(dd, 1H, J¼3.6, 7.6 Hz), 3.80 (s, 3H), 3.79 (s, 3H), 3.41 (td, 1H, J¼4.8,
1.6 Hz), 3.34 (s, 3H), 1.69 (d, 1H, J¼4.8 Hz), 1.25 (d, 3H, J¼6.2 Hz); 13C
69.77, 67.00, 65.06, 61.02, 58.60, 56.79, 56.25, 55.84, 17.74; HRMS
(ESI) Anal. Calcd for C13H22O8SK [MþK]þ 377.0662. Found 377.0662.
4.21. Methyl 4-S-(2,3-anhydro-b-D-mannopyranosyl)-6-
NMR (100 MHz, CDCl3)
d
159.19, 159.13, 130.59, 130.40, 129.61,
deoxy- -galactopyranoside (12)
a-D
129.20, 113.74, 113.68, 98.95, 76.68, 74.59, 73.21, 71.54, 64.21, 55.19,
46.90, 18.43; HRMS (ESI) Anal. Calcd for C23H34NO6S [MþNH4]þ
452.2101. Found 452.2116.
Compound 12 was prepared from 12a (98.0 mg, 0.148 mmol) in
the same manner as described in the synthesis of compound 8 from
8a, the product was purified by flash column chromatography on
silica gel (MeOH/EtOAc 1:10) to give 12 (37.0 mg, 75% yield) as
4.18. Methyl 4-S-(2,3-anhydro-4,6-di-O-acetyl-
a-
D-allopyr-
anosyl)-2,3-di-O-p-methoxybenzyl-6-deoxy-
a
-D
-galactopyr-
white solids: ½a D25
ꢂ
þ77.0 (c 1.4, water); 1H NMR (500 MHz, D2O)
anoside (11a)
d
5.26 (s, 1H, H-10), 4.74 (d, 1H, J¼3.5 Hz, H-1), 4.34 (dd, 1H, J¼5.5,
12.5 Hz), 4.12 (dd, 1H, J¼4.0, 10.3 Hz), 3.81 (dd, 1H, J¼2.5, 14.8 Hz),
3.76 (dd, 1H, J¼4.0, 10.0 Hz), 3.69e3.71 (m, 1H), 3.59e3.62 (m, 3H),
3.45 (d, 1H, J¼4.0 Hz), 3.58 (s, 3H), 3.28e3.32 (m, 1H), 1.35 (d, 3H,
Compound 11a was prepared by the coupling reaction of 24
(24.0 mg, 0.069 mmol) and 26 (60.0 mg, 0.139 mmol) in the same
manner as described in the synthesis of 9a, the product was puri-
fied by flash column chromatography on silica gel (petroleum
ether/EtOAc 5:1) to give 11a (34.0 mg, 75% yield) as a colorless
J¼6.0 Hz); 13C NMR (125 MHz, D2O)
d 100.18, 80.91, 80.79, 70.56,
69.78, 66.96, 62.35, 61.42, 57.79, 55.84, 55.62, 53.60, 18.31; HRMS
(ESI) Anal. Calcd for C13H22O8SK [MþK]þ 377.0662. Found 377.0670.
syrup: ½a 2D5
ꢂ
þ56.6 (c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.26e7.31 (m, 4H), 6.85e6.89 (m, 4H), 5.29 (s, 1H, H-10), 4.93 (d,
4.22. Methyl 4-S-(1,2-dideoxy-D-ribo-hex-1-enopyranosyl)-6-
1H, J¼9.3 Hz), 4.79 (d, 1H, J¼1.7 Hz), 4.76 (d, 1H, J¼1.8 Hz), 4.61
(ABq, 2H, J¼11.5 Hz), 4.52 (d, 1H, J¼3.8 Hz, H-1), 4.13e4.19 (m, 2H),
4.04e4.11 (m, 2H), 3.91 (dd, 1H, J¼3.8, 9.8 Hz), 3.81 (s, 3H), 3.80 (s,
3H), 3.49e3.50 (m, 1H), 3.33e3.38 (m, 4H), 3.28 (d, 1H, J¼3.6 Hz),
2.20 (d,1H, J¼3.6 Hz), 2.13 (s, 3H), 2.03 (s, 3H),1.34 (d, 3H, J¼7.4 Hz);
deoxy- -galactopyranoside (13)
a-D
To an ice-cooled solution of 11 (71.0 mg, 0.21 mmol) in DMF
(5 mL) was added t-BuOK (40.0 mg, 0.63 mmol). The mixture was
stirred at 50 ꢁC for 5 h and then diluted with ethyl acetate. The
solution was washed with brine. The organic layer was dried
(Na2SO4), filtered, and concentrated. The residue was purified by
column chromatography (methanol/ethyl acetate, 1:8, 1% TEA) to
13C NMR (125 MHz, CDCl3)
d 170.40, 170.33, 159.31, 158.99, 130.78,
130.45, 129.72, 128.67, 113.79, 113.73, 98.77, 80.27, 77.16, 76.28,
73.19, 71.92, 66.49, 65.44, 64.91, 61.93, 56.84, 55.36, 55.24, 52.80,
52.73, 20.82, 20.71, 18.10; HRMS (ESI) Anal. Calcd for C33H43O12
S
provide compound 13 (59.0 mg, 75% yield) as a colorless oil: ½a D25
ꢂ
[MþH]þ 663.2470. Found 663.2480.
þ19.3 (c 1.4, water); 1H NMR (500 MHz, D2O)
d 5.32 (d, 1H,
J¼6.0 Hz), 4.63 (d, 1H, J¼4.0 Hz, H-1), 4.20e4.23 (m, 1H), 3.92e3.96
(m, 3H), 3.75e3.80 (m, 2H), 3.66 (dd, 1H, J¼2.4, 12.2 Hz), 3.58 (dd,
1H, J¼5.2, 12.4 Hz), 3.43 (dd, 1H, J¼4.0, 10.4 Hz), 3.28 (s, 3H), 1.29 (d,
4.19. Methyl 4-S-(2,3-anhydro-4,6-di-O-acetyl-
b-
D-mannopyr-
anosyl)-2,3-di-O-p-methoxybenzyl-6-deoxy-a-D-galactopyr-
anoside (12a)
3H, J¼6.4 Hz); 13C NMR (100 MHz, D2O)
d 155.26, 102.99, 101.58,
70.27, 69.97, 69.77, 67.00, 65.06, 61.02, 58.60, 56.79, 56.25, 17.74;
HRMS (ESI) Anal. Calcd for C13H22O8SK [MþK]þ 377.0662. Found
377.0660.
Compound 12a was prepared by the coupling reaction of 18
(27.0 mg, 0.078 mmol) and 26 (67.0 mg, 0.155 mmol) in the same
manner as described in the synthesis of 9a, the product was puri-
fied by flash column chromatography on silica gel (petroleum
ether/EtOAc 5:1) to give 12a (41.0 mg, 79% yield) as a colorless
4.23. Methyl 4-S-(1,2-dideoxy-D-arabino-hex-1-enopyranosyl)-
6-deoxy- -galactopyranoside (14)
a-D
syrup: ½a 2D5
ꢂ
þ24.5 (c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3)
d:
7.26e7.31 (m, 4H), 6.84e6.87 (m, 4H), 5.34 (d, 1H, J¼3.4 Hz, H-10),
5.19 (dd, 1H, J¼1.6, 9.9 Hz), 4.69e4.76 (m, 3H), 4.57 (d, 1H,
Compound 14 was prepared from 12 (71.0 mg, 0.21 mmol) in the
same manner as described in the synthesis of compound 13 from

Y.-Y. Wang et al. / Tetrahedron 68 (2012) 9355e9363
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nol/ethyl acetate, 1:9, 1% TEA) to provide compound 14 (21.3 mg,
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30% yield) as a colorless oil: ½a D25
ꢂ
ꢀ25.7 (c 1.4, water); 1H NMR
(500 MHz, D2O)
d
5.13 (d, 1H, J¼2.0 Hz), 4.61 (d, 1H, J¼4.1 Hz, H-1),
7. Namiki, S.; Kangouri, K.; Nagate, T.; Hara, H.; Sugita, K.; Omura, S. J. Antibiot.
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9. Ferreira, S. B.; Sodero, A. C. R.; Cardoso, M. F. C.; Lima, E. S.; Kaiser, C. R.; Silva, F.
4.53 (d,1H, J¼4.7 Hz), 4.21 (dd,1H, J¼1.4, 6.4 Hz), 3.97e4.01 (m,1H),
3.67 (dd,1H, J¼2.3,12.4 Hz), 3.62 (dd,1H, J¼4.1,10.2 Hz), 3.58 (d,1H,
J¼9.6 Hz), 3.45e3.49 (m, 2H), 3.25 (s, 3H), 3.14e3.19 (m,1H),1.22 (d,
3H, J¼6.4 Hz); 13C NMR (100 MHz, D2O)
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78.93, 70.56, 69.78, 66.96, 62.35, 61.42, 57.79, 55.84, 55.62, 18.31;
HRMS (ESI) Anal. Calcd for C13H22O8SK [MþK]þ 377.0662. Found
377.0660.
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This work was financially supported by the National Natural
Science Foundation of China (21072014) and ‘973’ grant from the
Ministry of Science and Technology of China (2012CB822100).
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Supplementary data
Supplementary data related to this article can be found at http://
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