Efficient one-pot syntheses of α-d-arabinofuranosyl tri- and tetrasaccharides present in cell wall polysaccharide of Mycobacterium tuberculosis

Article abstract of DOI:10.1016/j.tet.2009.11.038

Two α-d-arabinofuranosyl oligosaccharides (2 and 3) found as constituent parts of the polysaccharide portion from the cell wall of Mycobacterium tuberculosis have been efficiently synthesized via a one-pot glycosylation procedure in which a key step is th

Full text of DOI:10.1016/j.tet.2009.11.038

Tetrahedron 66 (2010) 87–93
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient one-pot syntheses of
a- -arabinofuranosyl tri- and tetrasaccharides
D
present in cell wall polysaccharide of Mycobacterium tuberculosis
*
Xing-Yong Liang, Li-Min Deng, Xia Liu, Jin-Song Yang
Key Laboratory of Drug Targeting and Delivery Systems, Ministry of Education, Department of Chemistry of Medicinal Natural Products, School of Pharmacy, Sichuan University,
Chengdu 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two
portion from the cell wall of Mycobacterium tuberculosis have been efficiently synthesized via a one-pot
glycosylation procedure in which a key step is the chemoselective activation between -arabinofuranosyl
trichloroacetimidate donor 4 and partially protected aryl thioglycosides 5 or 7, respectively.
Ó 2009 Elsevier Ltd. All rights reserved.
a-D-arabinofuranosyl oligosaccharides (2 and 3) found as constituent parts of the polysaccharide
Received 4 September 2009
Received in revised form
29 October 2009
Accepted 6 November 2009
Available online 10 November 2009
D
Keywords:
Mycobacterium tuberculosis
One-pot glycosylation
Chemoselective glycosylation
Arabinofuranose
1. Introduction
multiple byproducts as a result of migration of acyl functions during
some deprotection reactions in furanose.13a The other method is
a one-pot strategy, which was demonstrated by Lowary13a and
Ning13b recently to be highly concise and rapid for producing fur-
Mycobacteria including the pathogens Mycobacterium tubercu-
losis and Mycobacterium leprae are the causative agents of tubercu-
losis (TB), the world’s most lethal bacterial disease.1–3 The cell wall of
mycobacteria is comprised of two major polysaccharides, arabino-
galactan (AG) and lipoarabinomannan (LAM), in which all of the
arabinose and galactose residues exist in furanose form.4,5 The
organism’s ability to make these polysaccharides is crucial to its
survival and pathogenicity, and therefore, the enzymes, such as
arabinosyltransferases (AraTs), involved in the biosynthesis of the
mycobacterial biopolymers have attracted wide attention as targets
of new drugs for the treatment of TB and other mycobacterial dis-
eases.6–9
Since the structural motifs of mycobacterial AG and LAM, such as
hexasaccharide 1 (Fig. 1), a key scaffold found at the non-reducing
termini of these polysaccharides, can be employed as useful tools in
clarifying the biosynthetic pathway by which the biopolymers are
assembled10 and in further exploring potential anti-TB agents that
target the enzymes involved in mycobacteria glycan biosynthesis,11
thechemicalsynthesisofthesemotifsandstructurallyrelatedanalogs
is an area of current interest. In this context, two synthetic methods
are applied. The one used often is a stepwise condensation ap-
proach,12 but its obviousdisadvantages includethetediouslyselective
protection and deprotection manipulations and the formation of
anosyl oligomers containing D-arabinofuranosyl or L-galactofuranosyl
moieties. Besides, there have been considerable studies on the one-
pot synthesis of pyranosidic oligosaccharides,14 but so far similar
studies on that of furanosidic oligosaccharides were still little ex-
plored. Therefore, we decided to develop new one-pot glycosylation
methodologies to synthesize the oligofuranose fragments of myco-
bacterial cell wall polysaccharides. Reported here is an efficient
OH
HO
OH
O
O
O
OH
OH
HO
HO
OH
O
O
O
O
OH
OH
O
O
OH
O
OH
2
O
OMe
OH
HO
OH
OH
OH
O
O
O
O
O
OH
OH
OH
OR
O
HO
HO
OH
O
OH
O
O
OH
O
O
O
OH
1, R = AG or LAM
HO
OMe
OH
OH
3
* Corresponding author. Tel./fax: þ86 28 85503723.
E-mail address: yjs@scu.edu.cn (J.-S. Yang).
Figure 1. Hexasaccharide motif (1) and synthetic targets (2 and 3).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.038

88
X.-Y. Liang et al. / Tetrahedron 66 (2010) 87–93
synthesis of trisaccharide 212a and tetrasaccharide 312a (Fig.1), two
-arabinofuranosyl portions of 1, by a one-pot approach based on the
chemoselectiveglycosylationbetweenatrichloroacetimidatedonor4
and a partially protected aryl thioglycosides acceptor 5 or 7,
respectively.
a-
presence of catalytic boron trifluoride etherate (BF3$Et2O) in
dichloromethane proceeded smoothly to give -phenyl thioglyco-
side 12 or its analogy p-methylphenyl
-thioglycoside 13,17 re-
D
a
a
spectively. Both products were then debenzoylated upon reaction
with sodium methoxide in methanol to furnish the corresponding
triols 14 and 1512a in 79% and 84% isolated yields, respectively.
Conversion of the resulting alcohol 14 to the thioglycoside alcohol
512f involved (i) regioselective protection with an excess of t-
BuPh2SiCl to 5-O-t-butyldiphenylsilyl ether 16, (ii) benzoylation of
the remaining 2,3-di-OHs to 17, and (iii) removal of 6-O-silyl group
with tetrabutylammonia fluoride (TBAF) in THF to the desired
product. In addition, access to phenyl thioglycoside 7 with 3,5-OHs
free required first the synthesis of 3,5-O-di-tert-butylsilylene acetal
18,18 which could be prepared by reaction of triol 14 with di-(tert-
butyl)silyl bis(trifluoromethanesulfonate) ((t-Bu)2Si(OTf)2) in DMF
(86% yield). Then, followed by 2-O-benzoylation to 20 (93% yield)
and liberation of 3,5-di-OHs with fluoride ion (72% yield), compound
18 was converted to 7. Meanwhile, through the similar three-step
procedure as described for the preparation of 7, triol 15 was readily
converted, via intermediates 1919 and 21, to the corresponding p-
methylphenyl thioglycoside 8.
2. Results and discussion
For one-pot synthesis of the target oligosaccharides, we envi-
sioned that they could be assembled by a key chemoselective gly-
cosylation in two steps from monomeric building blocks 4–9
(Fig. 2): (i) trichloroacetimidate 4 was to be selectively activated to
couple with thioglycoside acceptors 5 (6) or 7 (8), respectively, and
(ii) the obtained di- or trisaccharide thioglycosides would be used
as glycosyl donors to glycosylate with methyl glycoside 9 to give the
corresponding protected targets. In addition, benzoyl (Bz) group
would be utilized as the sole temporary hydroxyl-protecting group
to eliminate the need for selective deprotection reactions and as the
neighboring participating group at C-2 of the donors to ensure the
desired
a
-stereoselectivity of each glycosylation.
HO
NH
HO
BzO
OBz
SR
OBz
SR
The synthetic route of the 2,3-O-benzoyl protected glycosyl
OBz
O
O
O
acceptor 912a was slightly modified compared to the literature
O
CCl3
method (Scheme 2). The pure
anomeric mixture by recrystallization in ethanol and subsequent
a
-1116 was separated from the
OH
OBz
OBz
4
5 R = Ph
6 R = Tol
7 R = Ph
8 R = Tol
treatment with NaOCH3 afforded a
-methyl glycoside triol 2216 in
RO
OH
BzO
OBz
HO
OBz
O
a, b
O
O
OMe
CH3
Tol =
OMe
OH
Me
O
OBz
OBz
9
22 R = H
11
c
t
23 R = OSi BuPh2
Figure 2. Monosaccharide building blocks required for the assembly of 2 and 3.
t-BuPh2SiO
OBz
The arabinose derivatives 413b and 615 were prepared according to
the literature procedures. The preparation of building blocks 5, 7, and
O
e
d
9
OMe
OBz
8 was carried out as illustrated in Scheme 1. Treatment of
with methanol under Fisher glycosylation conditions furnished
methyl
-arabinofuranosides (10)16 as a mixture of anomers (
¼3:1), which was directly esterified under standard conditions to
afford tribenzoate 1116 in 72% yield from
-arabinose. Subsequent
D-arabinose
24
D
a/
Scheme 2. Reagents and conditions: (a) recrystallization separation of anomers; (b)
NaOCH3 (cat.), CH3OH, rt, 2 h, two steps 68%; (c) t-BuPh2SiCl (1.1 equiv), imidazole,
DMF, 0 ꢀC/rt, overnight, 86%; (d) BzCl (7.0 equiv), pyridine, 0 ꢀC/rt, overnight, 87%;
(e) TBAF (0.6 equiv), THF, 0 ꢀC/rt, 3 h, 75%.
b
D
condensation of 11 with thiophenol or p-methylphenylthiol in the
RO
BzO
OBz
OH
O
OR
O
a
c
O
HO
OMe
OH
SR
OH
D-arabinose
OBz
OR
10 R = H
11 R = Bz
12 R = Ph
13 R = Tol
b
t-BuPh2SiO
t-BuPh2SiO
OH
OBz
O
O
g
f
5
SPh
SPh
e
OH
16
OBz
HO
OH
O
d
17
SR
OH
h
14 R = Ph
15 R = Tol
O
O
OH
OBz
SR
j
i
O
O
7
or
8
Si
Si
t-Bu
t-Bu
t-Bu
t-Bu
SR
O
O
18 R = Ph
19 R = Tol
20 R = Ph
21 R = Tol
Scheme 1. Reagents and conditions: (a) MeOH, AcCl (1.0 equiv), rt, 4 h; (b) BzCl (4.0 equiv), pyridine, 55 ꢀC, 30 min, two steps 72%; (c) PhSH or p-MePhSH (1.4 equiv), BF3$Et2O
(cat.), CH2Cl2, 0 ꢀC/rt, 8 h, for 12: 80%, for 13: 78%; (d) NaOCH3 (cat.), CH3OH, rt, 2 h, for 14: 79%, for 15: 84%; (e) t-BuPh2SiCl (1.5 equiv), imidazole, DMF, 0 ꢀC/rt, overnight, 79%;
(f) BzCl (7.0 equiv), pyridine, 0 ꢀC/rt, 5 h, 91%; (g) TBAF (0.6 equiv), THF, 0 ꢀC/15 ꢀC, 3.5 h, 78%; (h) (t-Bu)2Si(OTf)2 (1.1 equiv), 2,6-lutidine, DMF, 2 h, for 18: 0 ꢀC, 86%, for 19:
ꢁ20 ꢀC/rt, 89%; (i) BzCl (3.5 equiv), pyridine, 0 ꢀC/rt, overnight, for 20: 93%; (j) TBAF (0.4 equiv), THF, 0 ꢀC/rt, 3 h, for 7: 72%, for 8: 70% (two steps from 19).

X.-Y. Liang et al. / Tetrahedron 66 (2010) 87–93
89
68% yield over these two steps. Initial attempts to prepare 5-O-silyl
ether 23 by reaction of 22 with t-BuPh2SiCl in pyridine at 0 ꢀC12a
failed and only the starting 22 was recovered after workup. Alter-
natively, exposure of 22 to t-BuPh2SiCl and imidazole in DMF
proved viable and thus led to our expected 2312a in a respectable
yield of 86%. Then, the target 9 was synthesized via a similar series
of transformations: benzoylation of 23 gave 24 in 87% yield, which
was then desilylated affording 9 (75%).
With all necessary monosaccharide units in hand, we then ex-
amined two sets of coupling reactions to assess the possibility of
chemoselective activation between the trichloroacetimidate 4 and
the partially benzoylated aryl thioglycosides 5–8, respectively
(Scheme 3). As the first set of the test reactions, the glycosylation of 4
with either 5 or 6 in the presence of a catalytic amount of trime-
thylsilyl triflate (TMSOTf) in CH2Cl2 at ꢁ20 ꢀC afforded stereospecif-
ically 1,2-trans glycosidic linkage of disaccharide thioglycosides 25 or
26, accordingly, in equally high yields. Neither self-condensed
conditions, the imidate 4 was activated exclusively to be a glycosyl
donor to undergo the coupling with the thioglycoside 5 or 6, which
was unreactive as an acceptor. This Lewis acid-promoted preferential
activation of trichloroacetimidate donor over thioglycoside donor
observed in arabinofuranose12h was in full agreement with the one
observed formerly in either galactofuranose13a or pyranose species.20
In the second set of reactions, the imidate 4 was used to couple with
thioglycosides 7 and 8, respectively, under the same activation con-
ditions. As expected, 7, as a diol acceptor, was readily coupled with
the relatively reactive 4, giving an 81% yield of 3,5-branched
D-ara-
binofuranosyl trisaccharide thioglycoside 27 with complete -selec-
a
tivity. However, the coupling of 4 with 8 using TMSOTf or BF3$Et2O as
promoter failed to provide the desired trisaccharide. Instead, an un-
usual intermolecular p-methylphenylthio (STol) transfer from the
acceptor 8 to the donor 4 took place,20b,21 and thus monosaccharide
sulfide 13 was formed as a major product together with chromato-
graphically inseparable degradation products derived from the gly-
cosyl substrates. Apparently, compared with the anomeric
phenylthio (SPh) in 7, the STol group at the anomeric center in 8 is
more nucleophilic because it contains an electron-donating methyl
group on the para position of the phenyl ring. So, the STol moiety of 8
rather than its 3,5-hydroxyl groups reacted with the oxacarbenium
ion formed after activation of the imidate donor 4, and this led to the
formation of the undesirable aglycon transfer product 13.
Having established the chemoselective activation methodology,
we next attempted to assemble the suitable building blocks into the
target sugars 2 and 3 bya one-pot method as illustrated in Scheme 4.
First, the imidate 4 was coupled with the glycosyl alcohol 5 by
activation with catalytic TMSOTf in CH2Cl2 at ꢁ20 ꢀC. On gradual
warming to approximately 0 ꢀC, a new spot, disaccharide 2513a was
visible on TLC. Then, the reaction was re-cooled to 0 ꢀC and sub-
sequent addition of the alcohol 9 and promoter N-iodosuccinimide
(NIS) in conjunction with silver triflate (AgOTf) drove the second
glycosylation to proceed, giving rise to trisaccharide methyl gly-
coside 28 after 30 min. Upon purification by silica gel column
chromatography, 28 was obtained in a 64% overall yield. The
structure of 28 was readily determined through the use of NMR
spectroscopy and ESI-MS spectrometry. In its 1H NMR spectrum,
product of the thioglycoside nor
b-stereoisomer was detected in both
glycosylations. These results indicated that, under the glycosylation
BzO
OBz
O
O
HO
NH
OBz
SR
BzO
OBz
a
O
O
OBz
SR
O
CCl3
+
OBz
O
OBz
OBz
4
OBz
5 R = Ph
6 R = Tol
25 R = Ph
26 R = Tol
BzO
OBz
O
O
OBz
HO
HO
OBz
OBz
O
O
b
b
4
+
+
OBz
SPh
27
SPh
O
OH
O
7
BzO
OBz
OBz
BzO
OBz
O
O
4
STol
STol
OH
OBz
the characteristic resonances due to the three H-1 signals of a-D-Ara
appeared as singlets at dH 5.51, 5.64, and 5.66 ppm and the 13C NMR
spectrum revealed that the chemical shifts of the anomeric carbons
were at dC 105.8,105.9, and 106.8 ppm, respectively. Therefore, both
13
8
Scheme 3. Reagents and conditions: (a) 4 (1.2 equiv), 5 or 6 (1.0 equiv), TMSOTf
(0.2 equiv), 4 Å molecular sieves, CH2Cl2, ꢁ20 ꢀC/0 ꢀC, 0.5 h, for 25: 94%, for 26: 85%;
(b) 4 (2.3 equiv), 7 or 8 (1.0 equiv), TMSOTf (0.4 equiv), for 27: 81%, for 13: 91%.
1H and 13C NMR data are consistent with the
a-arabinofuranoside
BzO
OBz
O
O
BzO
OBz
OBz
O
OBz
O
a
9
b
2
4
5
+
+
O
OBz
OBz
O
OBz
O
OBz
O
SPh
25
28
OMe
OBz
OBz
BzO
OBz
BzO
OBz
O
O
O
O
OBz
O
OBz
OBz
OBz
a
9
b
OBz
O
3
4
7
O
O
OBz
OBz
SPh
O
O
O
O
OBz
27
BzO
OBz
29
OMe
BzO
OBz
Scheme 4. Reagents and conditions: (a) 4, 5 or 7 (1.0 equiv), TMSOTf (cat.), 4 Å molecular sieves, CH2Cl2, ꢁ20 ꢀC/0 ꢀC, 1 h; then 9 (0.6 equiv), NIS (0.9 equiv), AgOTf (0.3 equiv),
CH2Cl2, 0 ꢀC, 30 min, for 28: 4 (1.2 equiv), 64%, for 29: 4 (2.3 equiv), 66%; (b) NaOCH3 (cat.), CH3OH, rt, 2 h, for 2: 80%, for 3: 85%.

90
X.-Y. Liang et al. / Tetrahedron 66 (2010) 87–93
anomeric stereochemistry.18 Further support for the structure of 28
came from HR ESI-MS data, which gave an (MþNa)þ signal at m/z
1179.3244 (calcd 1179.3257).
warmed gradually to room temperature. The reaction was stirred for
8 h at the same temperature, at the end of which time TLC indicated
that it was finished. The reaction was quenched with triethylamine
and the mixture was concentrated. The resulting residue was purified
bycolumn chromatography (6:1, petroleum–EtOAc) to give 12 (1.82 g,
80%) as a colorless syrup. To a solution of 12 (1.91 g, 3.45 mmol) in
MeOH and CH2Cl2 (7:1, 40 mL) was added NaOCH3 (32 mg) at room
temperature.Themixturewasstirredatthesametemperaturefor2 h,
at the endof which time TLC indicated the reactionwas complete. The
solution was concentrated to dryness, and the resulting residue was
purified by column chromatography (15:1, CH2Cl2–MeOH) to afford
Second, the branched tetrasaccharide benzoate 29, protected
precursor of sugar 3, was also synthesized through the similar one-
pot glycosylation procedures (Scheme 4). Thus, coupling of the
donor 4 with the acceptor 7 mediated by TMSOTf afforded the in-
termediate trisaccharide 27, which was then glycosylated in situ
with 9 activated again with NIS–AgOTf reagent system to yield 29 in
66% overall yield. As was done for 28, a combination of NMR and MS
data could be used to establish the structure of 29. In its 1H NMR
spectrum, the four anomeric hydrogens appeared as three singlets
14 (762 mg, 79%) as a colorless syrup. Rf 0.35 (8:1, CH2Cl2–MeOH);
20
and one doublet (J1,2 0–1.2 Hz), indicative of the
a
-arabinofuranosyl
[a]
þ67.4 (c 0.6, CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.47 (d, 1H, J
D
linkages. Additionally, the 13C NMR spectrum showed four
anomeric carbons at dC 105.7, 105.8, 106.0, and 106.7 ppm. The
structure of 29 was further confirmed by its HR ESI-MS at m/z
1519.4192 (MþNa)þ, which was identical with the calculated exact
mass of the molecule.
1.6 Hz, Ph), 7.45 (s,1H, Ph), 7.20–7.28 (m, 3H, Ph), 5.40 (d,1H, J 2.0 Hz,
H-1), 4.14 (s, 2H, H-2, H-3), 4.09 (s, 1H, H-4), 3.81 (d, 1H, J 12.0 Hz, H-
5a), 3.72 (d, 1H, J 12.0 Hz, H-5b); 13C NMR (100 MHz, CDCl3):
d 133.7,
131.9, 129.1, 127.7, 91.9, 83.4, 81.9, 76.9, 61.1; HR ESI-MS: calcd for
C11H14O4S [MþNa]þ, 265.0511, found m/z 265.0507.
Finally, removal of the benzoate esters of both 28 and 29
obtained from the one-pot procedures under standard saponifica-
tion conditions yielded the fully deprotected products that were
spectroscopically consistent with the target molecules 2 and 3 in
80% and 85% yields, respectively. Additional confirmation of the
structures was provided by comparison of their analytical data (1H
and 13C NMR, MS) with those previously reported.12a
4.3. p-Methylphenyl 1-thio-a-D
-arabinofuranoside (15)12a
Using the same procedures as described for the preparation of 14,
methyl glycoside 11 (1.75 g, 3.68 mmol) was coupled first with p-
methylphenylthiol (0.65 g, 5.2 mmol) catalyzed by BF3$Et2O (3.1 mL,
24.5 mmol) to afford 13 (1.62 g, 78%) as a colorless syrup. Subsequent
debenzoylation of the obtained 13 (1.7 g, 3.0 mmol) with NaOCH3
(29 mg) afforded 15 (645 mg, 84%) as a colorless syrup. The data for
this compound matched those previously reported.12a
3. Conclusion
In summary, we described a very efficient one-pot synthesis of
two
a-D-arabinofuranosyl oligosaccharides 2 and 3. The chemo-
4.4. Phenyl 5-O-tert-butyldiphenylsilyl-1-thio-a-D-
selective glycosylations of the
D-arabinofuranosyl trichloro-
arabinofuranoside (16)
acetimidate donor 4 with the partially protected thioglycoside
acceptors (5 or 7, respectively) were the common strategy-level steps
in the synthesis. The synthetic processes, in which the glycosyl
building blocks are assembled sequentially in a one-pot manner,
display obvious advantages over the reported stepwise protocols.12a
Not only can the target linear and branched oligosaccharide struc-
tures be produced simply and rapidly, but also the unexpected acyl
migration side reaction occurring in furanose rings is avoided. Fur-
ther application of the present method to the synthesis of other oli-
gosaccharide fragments of mycobacterial arabinan is ongoing.
To a solution of 14 (123 mg, 0.51 mmol) in dry DMF (1.5 mL) was
added imidazole (118 mg) followed by t-BuPh2SiCl (0.2 mL) at 0 ꢀC
and the resulting mixture was warmed gradually to room tem-
perature. The mixture was stirred overnight at the same tempera-
ture, at the end of which time TLC indicated the reaction was
complete. The mixture was diluted with EtOAc (15 mL), and then
the reaction mixture was washed with water and brine. The organic
layer was separated and dried over anhydrous Na2SO4, filtered, and
concentrated. The resulting residue was purified by column chro-
matography (3:1, petroleum–EtOAc) to afford 16 (194 mg, 79%) as
20
4. Experimental
a pale syrup. Rf 0.3 (2:1, petroleum–EtOAc); [
a
]
D
þ132.7 (c 1.25,
CHCl3); 1H NMR (400 MHz, CDCl3):
d
7.65–7.69 (m, 4H, Ph), 7.50–
4.1. General methods
7.52 (m, 2H, Ph), 7.35–7.46 (m, 6H, Ph), 7.26–7.34 (m, 3H, Ph), 5.60
(s, 1H, H-1), 4.31 (d, 1H, J 7.2 Hz, H-3), 4.21–4.25 (m, 2H, H-2, H-4),
3.87 (dd, 1H, J 2.8, 11.2 Hz, H-5a), 3.79 (dd, 1H, J 1.2, 11.2 Hz, H-5b),
All reactions were performed under a nitrogen atmosphere and
monitored by thin layer chromatography (TLC) using Silica Gel
GF254 plates with detection by charring with 10% (v/v) H2SO4 in
EtOH or by UV detection. Solvents used in the reactions were dis-
tilled from appropriate drying agents prior to use. Silica gel (200–
300 mesh) was used for column chromatography. Optical rotations
were measured with a PE-314 automatic polarimeter at 20ꢂ1 ꢀC for
solutions in a 1.0 dm cell. HR ESI-MS spectra were acquired on
Agilent 6210 TOF LC/MS instrument. 1H and 13C NMR spectra were
obtained on Bruker AC-E 200 or Varian INOVA-400/54 spectrom-
eters in CDCl3 with tetramethylsilane (TMS) as internal reference.
1.05 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3):
d 135.7, 135.6,
132.0, 131.8, 130.1, 130.1, 129.1, 128.0, 127.9, 127.5, 92.8, 86.0, 81.2,
78.7, 64.0, 26.7, 19.1; HR ESI-MS: calcd for C27H32O4SSi [MþNa]þ,
503.1682, found m/z 503.1678.
4.5. Phenyl 2,3-di-O-benzoyl-5-O-tert-butyldiphenylsilyl-1-
thio-a-D-arabinofuranoside (17)
To a stirred solution of 16 (113 mg, 0.24 mmol) in pyridine
(2.3 mL) was added slowly BzCl (0.2 mL) at 0 ꢀC and the resulting
mixture was warmed gradually to room temperature. The reaction
was stirred for 5 h at the same temperature, at the end of which
time TLC indicated it was finished. The reaction was quenched with
methanol (0.05 mL), diluted with CH2Cl2 (20 mL), and then the
mixture was washed with water and brine. The organic layer was
separated and dried over anhydrous Na2SO4, filtered, and concen-
trated. The resulting residue was purified by column chromatog-
Chemical shifts (d) are expressed in parts per million downfield
from the internal TMS absorption.
4.2. Phenyl 1-thio-a-D-arabinofuranoside (14)
To a solution of 1116 (1.95 g, 4.1 mmol) in dichloromethane
(28.5 mL) at 0 ꢀC was added thiophenol (0.6 mL, 5.8 mmol) dropwise.
The reaction mixture was stirred at 0 ꢀC for 15 min, then BF3$Et2O
(3.4 mL, 26.8 mmol) was added and the resulting mixture was
raphy (80:1, petroleum–EtOAc) to afford 17 (147 mg, 91%) as a pale
20
yellow syrup. Rf 0.45 (40:1, petroleum–EtOAc); [
a
]
þ45.1 (c 2.0,
D

X.-Y. Liang et al. / Tetrahedron 66 (2010) 87–93
91
CHCl3); 1H NMR (400 MHz, CDCl3):
d
8.13 (s, 1H, Ph), 8.11 (d, 1H, J
and the resulting mixture was warmed gradually to 15 ꢀC. The
reaction was stirred for 3 h at the same temperature, at the end of
which time TLC indicated it was finished. The reaction was diluted
with CH2Cl2 (20 mL), and then the mixture was washed with
saturated aqueous (NH4)2SO4 and brine. The organic layer was
separated and dried over anhydrous Na2SO4, filtered, and con-
centrated. The resulting residue was purified by column chroma-
1.2 Hz, Ph), 7.99 (s, 1H, Ph), 7.97 (d, 1H, J 1.6 Hz, Ph), 7.71–7.72 (m,
4H, Ph), 7.58–7.64 (m, 4H, Ph), 7.48–7.53 (m, 2H, Ph), 7.37–7.42 (m,
4H, Ph), 7.29–7.35 (m, 6H, Ph), 5.78 (d, 1H, J 2.0 Hz, H-1), 5.73 (dd,
1H, J 2.0, 4.8 Hz, H-3), 5.68 (t, 1H, J 2.0 Hz, H-2), 4.64 (dd, 1H, J 4.4,
9.2 Hz, H-5a), 4.06 (d, 2H, J 4.4 Hz, H-4, H-5b), 1.06 (s, 9H, C(CH3)3);
13C NMR (100 MHz, CDCl3):
d 165.5, 165.3, 135.6, 135.6, 133.4, 132.1,
130.0, 129.9, 129.7, 129.7, 129.0, 128.5, 128.4, 127.7, 127.6, 91.0, 83.2,
82.4, 77.5, 63.5, 26.7, 19.3; HR ESI-MS: calcd for [MþNa]þ
C41H40O6SSi [MþNa]þ, 711.2207, found m/z 711.2205.
tography (2:1, petroleum–EtOAc) to afford 8 (293 mg, 70% for two
steps) as a colorless syrup. Rf 0.35 (1:1, petroleum–EtOAc); [a]
D
20
þ182.5 (c 1.25, CHCl3); 1H NMR (400 MHz, CDCl3):
d 8.01–8.03 (m,
2H, Ph), 7.58–7.56 (m, 1H, Ph), 7.44–7.58 (m, 4H, Ph), 7.15 (d, 2H, J
8.0 Hz, Ph), 5.68 (d, 1H, J 3.2 Hz, H-1), 5.14 (t, 1H, J 3.2 Hz, H-2),
4.27–4.36 (m, 2H, H-5a, H-5b), 3.94–3.99 (m, 1H, H-3), 3.78–3.84
4.6. Phenyl 2-O-benzoyl-3,5-O-(di-tert-butylsilylene)-1-thio-
a
-D
-arabinofuranoside (20)
(m, 1H, H-4), 2.34 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d 167.2,
Prepared from 1818 (416 mg, 1.09 mmol) and BzCl (0.46 mL) as
described for the synthesis of 17. The crude product was purified by
column chromatography (100:1, petroleum–EtOAc) to afford 20
138.2, 133.8, 132.8, 129.8, 129.5, 128.7, 128.5, 89.6, 87.1, 82.7, 76.2,
61.2, 21.1; HR ESI-MS: calcd for C19H20O5S [MþNa]þ, 383.0924,
found m/z 383.0921.
(498 mg, 93%) as a pale yellow oil. Rf 0.5 (30:1, petroleum–EtOAc);
20
[
a]
þ79.9 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3):
d
8.02 (d, 1H, J
4.9. General procedure for the chemoselective glycosylations
between trichloroacetimidate 4 and aryl thioglycosides 5–8
D
7.2 Hz, Ph), 8.09 (d, 1H, J 1.2 Hz, Ph), 7.46–7.62 (m, 5H, Ph), 7.26–7.33
(m, 3H, Ph), 5.53 (dd, 1H, J 4.8, 6.8 Hz, H-2), 5.47 (d, 1H, J 4.8 Hz, H-
1), 4.43 (dd, 1H, J 4.8, 9.6 Hz, H-5a), 4.36 (dd, 1H, J 6.8, 9.6 Hz, H-3),
4.11–4.17 (m, 1H, H-4), 4.06 (t, 1H, J 9.6 Hz, H-5b), 1.06 (s, 9H,
A mixture of the trichloroacetimidate 4 (1.2 or 2.3 mmol), the
thioglycoside acceptor (0.10 mmol), and freshly activated 4 Å mo-
lecular sieves (120 mg) in dry CH2Cl2 (3.5 mL) was cooled to ꢁ20 ꢀC.
The suspension was stirred for 15 min, then a solution of TMSOTf
(0.02 or 0.04 mmol) in CH2Cl2 (0.50 mL) was added dropwise and
the resulting mixture was warmed slowly to 0 ꢀC. The reaction was
stirred for 0.5 h at the same temperature, at the end of which time
TLC indicated it was finished. The reaction was quenched with
a drop of Et3N, diluted with CH2Cl2 (10 mL), filtered, and concen-
trated. The resulting residue was purified by column chromatog-
raphy eluted with petroleum–EtOAc to afford the corresponding
di- or trisaccharide thioglycosides.
C(CH3)3), 1.01 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3):
d 165.6,
133.9, 133.4, 131.7, 129.9, 128.9, 128.5, 127.6, 89.5, 81.4, 79.7, 73.5,
67.2, 27.4, 27.0, 22.6, 20.1; HR ESI-MS: calcd for C26H34O5SSi
[MþNa]þ, 509.1788, found m/z 509.1785.
4.7. Phenyl 2-O-benzoyl-1-thio-a-D-arabinofuranoside (7)
To a solution of 20 (577 mg, 1.15 mmol) in THF (3.1 mL) was
added TBAF (4.6 mL, 1.0 M in THF) at 0 ꢀC and the resulting mixture
was warmed gradually to room temperature. The reaction was
stirred for 3 h at the same temperature, at the end of which time
TLC indicated it was finished. The reaction was diluted with CH2Cl2
(20 mL), and then the reaction mixture was washed with saturated
aqueous (NH4)2SO4 and brine. The organic layer was separated and
dried over anhydrous Na2SO4, filtered, and concentrated. The
resulting residue was purified by column chromatography (2:1,
petroleum–EtOAc) to afford 7 (295 mg, 72%) as a colorless syrup. Rf
0.35 (1:1, petroleum–EtOAc); [
(400 MHz, CDCl3):
7.44–7.50 (m, 2H, Ph), 7.29–7.37 (m, 3H, Ph), 5.76 (d, 1H, J 3.2 Hz, H-
1), 5.16 (t, 1H, J 3.2 Hz, H-2), 4.29–4.38 (m, 2H, H-3, H-4), 3.98 (dd,
1H, J 3.2, 12.4 Hz, H-5a), 3.83 (dd, 1H, J 3.6, 12.4 Hz, H-5b); 13C NMR
4.9.1. Phenyl 5-O-(2,3,5-tri-O-benzoyl-
a-D-arabinofuranosyl)-2,3-di-
O-benzoyl-1-thio- -arabinofuranoside (25). Prepared from
a-D
4
(74 mg, 0.12 mmol) and thioglycoside acceptor 5 (45 mg, 0.10 mmol).
The crude product was purified by column chromatography (6:1,
petroleum–EtOAc) to afford 25 as a colorless syrup (84 mg, 94%). Rf
20
0.4 (3:1, petroleum–EtOAc); [
a
]
þ36.0 (c 0.7, CHCl3); 1H NMR
D
20
a
]
þ173.5 (c 1.42, CHCl3); 1H NMR
(400 MHz, CDCl3): d 8.09 (d, 2H, J 8.0 Hz, Ph), 7.98–8.04 (m, 6H, Ph),
D
d
8.02–8.04 (m, 2H, Ph), 7.53–7.56 (m, 3H, Ph),
7.94 (d, 2H, J 8.0 Hz, Ph), 7.54–7.62 (m, 4H, Ph), 7.43–7.52 (m, 5H, Ph),
7.36–7.41 (m, 4H, Ph), 7.22–7.29 (m, 7H, Ph), 5.81 (d, 1H, J 0.8 Hz, H-
10), 5.75 (d, 1H, J 5.2 Hz, H-20), 5.73 (s, 1H, H-2), 5.62 (s,1H, H-1), 5.58
(d, 1H, J 4.8 Hz, H-3), 5.44 (s, 1H, H-30), 4.82 (dd, 1H, J 3.2, 12.0 Hz, H-
5a0), 4.71–4.73 (m, 2H, H-4, H-40), 4.65 (dd, 1H, J 4.8, 12.0 Hz, H-5b0),
4.28 (dd,1H, J 4.4,11.2 Hz, H-5a), 4.00 (dd,1H, J 3.2,11.2 Hz, H-5b); 13C
(100 MHz, CDCl3):
d 167.2, 133.8, 132.1, 129.9, 129.1, 128.6, 127.8,
89.4, 87.2, 82.8, 76.2, 61.2; HR ESI-MS: calcd for C18H18O5S
[MþNa]þ, 369.0767, found m/z 369.0768.
NMR (100 MHz, CDCl3): d 166.2,165.7,165.5,165.3,165.2,133.7,133.6,
133.5,133.3,133.0,131.9,130.0,129.9,129.8,129.8,129.7,129.0,128.9,
128.8,128.5,128.5,128.3,128.3,127.6,105.9, 91.3, 82.1, 82.0, 81.9, 81.2,
77.7, 77.3, 65.9, 63.6; HR ESI-MS: calcd for C51H42SO13S [MþNa]þ,
917.2238, found m/z 917.2243.
4.8. p-Methylphenyl 2-O-benzoyl-1-thio-a-D-
arabinofuranoside (8)
To a stirred solution of 1919 (473 mg, 1.19 mmol) in dry pyridine
(5.5 mL) was added BzCl (0.5 mL) at 0 ꢀC and the resulting mixture
was warmed gradually to room temperature. The reaction was
stirred for 3 h at the same temperature, at the end of which time
TLC indicated it was finished. The reaction was quenched with
methanol (0.1 mL), diluted with CH2Cl2 (25 mL), and then the
mixture was washed with water and brine. The organic layer was
separated and dried over anhydrous Na2SO4, filtered, and con-
centrated. The resulting residue was purified quickly by a short
column chromatography (100:1, petroleum–EtOAc) to afford 2-O-
benzoylated product 21 (520 mg) as a pale yellow oil, which was
contaminated with a trace of inseparable impurity. The obtained
oil (520 mg) was dissolved in THF (3.1 mL), the resulting solution
was cooled to 0 ꢀC and then TBAF (4.6 mL, 1 M in THF) was added
4.9.2. p-Methylphenyl 5-O-(2,3,5-tri-O-benzoyl-
a-D-arabinofurano-
syl)-2,3-di-O-benzoyl-1-thio- -arabinofuranoside (26). Prepared
a-D
from 4 (70 mg, 0.115 mmol) and thioglycoside acceptor 6 (45 mg,
0.097 mmol). The crude product was purified by column chroma-
tography (6:1, petroleum–EtOAc) to afford 26 as a colorless syrup
20
(75 mg, 85%). Rf 0.4 (3:1, petroleum–EtOAc); [
a
]
þ37.4 (c 0.9,
D
CHCl3); 1H NMR (400 MHz, CDCl3):
d
8.10 (dd, 2H, J 0.9 8.0 Hz, Ph),
7.98–8.04 (m, 6H, Ph), 7.95 (dd, 2H, J 0.9, 8.0 Hz, Ph), 7.55–7.61 (m,
2H, Ph), 7.43–7.51 (m, 7H, Ph), 7.35–7.41 (m, 4H, Ph), 7.24–7.29 (m,
4H, Ph), 5.74 (d, 1H, J 1.6 Hz, H-10), 5.73 (d, 1H, J 2.4 Hz, H-20), 5.72
(d, 1H, J 1.6 Hz, H-2), 5.62 (d, 1H, J 0.9 Hz, H-1), 5.58 (d, 1H, J 4.8 Hz,
H-3), 5.44 (s, 1H, H-30), 4.83 (dd, 1H, J 3.2, 11.6 Hz, H-5a0), 4.71–4.73
(m, 2H, H-4, H-40), 4.65 (dd, 1H, J 4.8, 11.6 Hz, H-5b0), 4.28 (dd, 1H, J

92
X.-Y. Liang et al. / Tetrahedron 66 (2010) 87–93
4.4, 11.2 Hz, H-5a), 4.00 (dd, 1H, J 2.8, 11.2 Hz, H-5b), 2.29 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3):
166.1, 165.7, 165.5, 165.2, 165.2,
77.3, 66.0, 65.9, 63.6, 54.9; HR ESI-MS: calcd for C65H56O20 [MþNa]þ,
1179.3257, found m/z 1179.3244.
d
133.6, 133.5, 133.3, 132.6, 130.0, 129.8, 129.8, 129.8, 129.1, 128.5,
128.3, 106.0, 91.6, 82.1, 81.9, 81.4, 81.2, 77.6, 77.3, 66.0, 63.6, 21.1; HR
ESI-MS: calcd for C52H44O13S [MþNa]þ, 931.2401, found m/z
931.2399.
4.10.2. Methyl
anosyl)-2-O-benzoyl-
arabinofuranoside (29). Using the same procedures as described for
the one-pot preparation of 28, trichloroacetimidate donor 4
(120 mg, 0.198 mmol), and thioglycoside 7 (30 mg, 0.087 mmol)
5-O-[3,5-di-O-(2,3,5-tri-O-benzoyl-
a-D-arabinofur-
a
-
D
-arabinofuranosyl]-2,3-di-O-benzoyl-a-D-
4.9.3. Phenyl 3,5-di-O-(2,3,5-tri-O-benzoyl-
O-benzoyl-1-thio- -arabinofuranoside (27). Prepared from
(121 mg, 0.2 mmol) and thioglycoside acceptor
a-D-arabinofuranosyl)-2-
a-D
4
were coupled first by activation with TMSOTf (5.5 mL, 0.03 mmol),
7
(30 mg,
then the resulting trisaccharide thioglycoside 27 was glycosylated
with the acceptor 9 (22 mg, 0.059 mmol) promoted by NIS (25 mg,
0.112 mmol) and AgOTf (9 mg, 0.036 mmol) to give a crude product,
which was purified by column chromatograph (4:1, petroleum–
0.087 mmol). The crude product was purified by column chroma-
tography (6:1, petroleum–EtOAc) to afford 27 as a colorless syrup
20
(86.7 mg, 81%). Rf 0.5 (2:1, petroleum–EtOAc); [
a
]
þ34.5 (c 0.8,
D
CHCl3); 1H NMR (400 MHz, CDCl3):
d
8.12 (d, 2H, J 7.2 Hz), 8.00–8.04
EtOAc) to afford 29 (57 mg, 66%) as a colorless syrup. Rf 0.4 (2:1,
20
(m,10H), 7.92 (d, 2H, J 7.2 Hz), 7.50–7.60 (m, 5H), 7.41–7.48 (m, 5H),
7.28–7.40 (m, 7H), 7.21–7.27 (m, 9H), 5.78 (s, 1H), 5.63 (d, 1H, J
0.8 Hz), 5.61 (t, 1H, J 1.6 Hz), 5.61 (d, 1H, J 3.6 Hz), 5.54 (d, 2H, J
1.6 Hz), 5.52 (d, 1H, J 4.4 Hz), 5.38 (s, 1H), 4.71–4.77 (m, 2H), 4.62–
4.69 (m, 4H), 4.55–4.60 (m, 2H), 4.15 (dd,1H, J 4.4,11.6 Hz), 3.94 (dd,
petroleum–EtOAc); [
CDCl3):
a]
þ10.6 (c 0.85, CHCl3); 1H NMR (400 MHz,
D
d
8.05–8.07 (m, 2H), 7.89–8.03 (m, 15H), 7.47–7.60 (m, 7H),
7.17–7.45 (m, 21H), 5.64 (d, 1H, J 5.6 Hz), 5.55 (s, 2H), 5.53 (s, 1H),
5.50 (d, 2H, J 1.2 Hz), 5.47 (d, 1H, J 4.8 Hz), 5.44 (d, 1H, J 1.2 Hz), 5.41
(d, 2H, J 4.0 Hz), 5.11 (s, 1H), 4.77 (dd, 1H, J 3.2, 11.6 Hz), 4.73 (dd, 1H,
J 5.6, 9.6 Hz), 4.53–4.64 (m, 7H), 4.37–4.39 (m, 1H), 4.18 (dd, 1H, J
4.4, 11.2 Hz), 4.09–4.13 (m, 1H), 3.93 (dt, 1H, J 2.4, 11.2 Hz), 3.44 (s,
1H, J 2.4, 11.6 Hz); 13C NMR (100 MHz, CDCl3):
d 166.1, 166.0, 165.7,
165.6, 165.5, 165.2, 165.2, 134.1, 133.6, 133.5, 133.5, 133.5, 133.4,
133.0, 133.0, 131.6, 130.0, 130.0, 129.9, 129.8, 129.7, 129.7, 129.7,
129.0, 128.5, 128.5, 128.4, 128.3, 127.4, 106.0, 105.8, 90.9, 83.1, 82.0,
81.8, 81.7, 81.7, 81.6, 81.1, 77.7, 77.5, 65.5, 63.6, 63.6; HR ESI-MS:
calcd for C70H58O19S [MþNa]þ, 1257.3185, found m/z 1257.3183.
3H, OCH3); 13C NMR (100 MHz, CDCl3):
d 166.2, 166.0, 165.7, 165.6,
165.5, 165.5, 165.4, 165.1, 164.9, 133.4, 133.4, 133.3, 132.9, 132.9,
129.9, 129.9, 129.8, 129.8, 129.7, 129.7, 129.2, 129.1, 129.0, 128.5,
128.5, 128.4, 128.4, 128.3, 128.2, 128.2, 106.7, 106.0, 105.8, 105.7,
82.9, 82.1, 82.0, 81.8, 81.7, 81.6, 81.4, 81.3, 77.9, 77.7, 77.2, 77.2, 65.7,
65.5, 63.7, 63.6, 54.9; HR ESI-MS: calcd for C84H72O26 [MþNa]þ,
1519.4204, found m/z 1519.4192.
4.9.4. p-Methylphenyl
2,3,5-tri-O-benzoyl-1-thio-a-D-arabinofur-
anoside (13). Prepared from 4 (120 mg, 0.198 mmol) and thio-
glycoside acceptor 8 (30 mg, 0.083 mmol). The crude product was
purified by column chromatography (10:1, petroleum–EtOAc) to
afford 13 as a colorless syrup (43 mg, 91%). The data for this com-
pound matched those previously reported.17
4.11. Methyl 5-O-[5-O-(
furanosyl]- -arabinofuranoside (2) and methyl 5-O-[3,5-di-
O-( -arabinofuranosyl)- -arabinofuranosyl]-
arabinofuranoside (3)
a-D-arabinofuranosyl)-a-D-arabino-
a-D
a
-D
a
-D
a-D-
4.10. The one-pot synthesis of the protected oligosaccharides
28 and 29
To a solution of 28/29 (0.04 mmol) in MeOH and CH2Cl2 (7:1,
1.03 mL) was added NaOCH3 (2 mg). After the reaction was stirred
for 2 h at room temperature, TLC analysis indicated completion. The
solution was concentrated to dryness. The resulting residue was
purified by column chromatography (3:1, CH2Cl2–MeOH) to afford
2/3 as a colorless syrup in a yield of 80% for 2 and 85% for 3, re-
spectively. Their analytical data (1H and 13C NMR, MS) were iden-
tical with those previously reported.12a
4.10.1. Methyl 5-O-[5-O-(2,3,5-tri-O-benzoyl-
a-
D-arabinofuranosyl)-
2,3-di-O-benzoyl- -arabinofuranosyl]-2,3-di-O-benzoyl-a-D
a
-
D
-arabino-
furanoside (28). A mixture of trichloroacetimidate donor 4 (70 mg,
0.115 mmol), thioglycoside acceptor 5 (44 mg, 0.098 mmol), and
freshly activated 4 Å molecular sieves (115 mg) in dry CH2Cl2
(3.5 mL) was cooled to ꢁ20 ꢀC. The suspension was stirred for
15 min and then a solution of TMSOTf (3 mL, 0.02 mmol) in CH2Cl2
(0.50 mL) was added dropwise and the resulting mixture was
warmed slowly to 0 ꢀC. The reaction was stirred for 1 h at the same
temperature, at the end of which time TLC indicated the complete
consumption of the starting materials. A solution of methyl glyco-
side 9 (22 mg, 0.059 mmol) in CH2Cl2 (1 mL) was added to the re-
action mixture at 0 ꢀC. After being stirred for 15 min at 0 ꢀC, the
resulting mixture were added NIS (25 mg, 0.112 mmol) and AgOTf
(9 mg, 0.036 mmol). The reaction was stirred for 30 min at the same
temperature, then quenched with Et3N, diluted with CH2Cl2
(10 mL), filtered, and concentrated. The resulting residue was pu-
rified by column chromatography (4:1, petroleum–EtOAc) to afford
Acknowledgements
This work was financially supported by NSFC (Grant Nos.
30300434 and 20672074), Ministry of Education (No. NCET-08-
0377), and Sichuan Province (No. 08ZQ026-029) of China.
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20
(2:1, petroleum–EtOAc); [
a
]
þ1.25 (c 0.4, CHCl3); 1H NMR
D
(400 MHz, CDCl3):
d
7.98–8.05 (m,10H), 7.90–7.93 (m, 4H), 7.36–7.59
(m, 15H), 7.22–7.29 (m, 6H), 5.66 (s, 1H), 5.64 (s, 1H), 5.64 (s, 1H),
5.63 (s, 1H), 5.57 (d, 1H, J 4.8 Hz), 5.51 (d, 1H, J 1.2 Hz), 5.47 (s, 1H),
5.41 (s, 1H), 5.12 (s, 1H), 4.83 (dd, 1H, J 3.2, 12.0 Hz), 4.71–4.74 (m,
1H), 4.63–4.67 (m, 2H), 4.41–4.44 (m, 1H), 4.24 (dd, 1H, J 4.4,
11.2 Hz), 4.20 (dd, 1H, J 4.4, 11.2 Hz), 3.98 (dd, 1H, J 2.8, 11.2 Hz), 3.94
(dd,1H, J 2.8,11.2 Hz), 3.44 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3):
d
166.2, 165.7, 165.7, 165.6, 165.5, 165.2, 165.2, 133.4, 133.4, 133.2,
133.2, 133.0, 129.9, 129.9, 129.8, 129.8, 129.7, 128.5, 128.4, 128.3,
128.3, 106.8, 105.9, 105.8, 82.0, 81.9, 81.9, 81.7, 81.6, 81.6, 81.2, 77.8,

X.-Y. Liang et al. / Tetrahedron 66 (2010) 87–93
93
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