Highly efficient synthesis of 1-thioglycosides in solution and solid phase using iminophosphorane bases

Article abstract of DOI:10.1016/S0008-6215(99)00327-4

Disaccharides of 1-thioglycosides, an important class of glycomimics, can be synthesized by direct S-alkylation in exceptionally high yields when iminophosphorane bases are employed. The reaction conditions employed appear to be general and stereospecific

Full text of DOI:10.1016/S0008-6215(99)00327-4

www.elsevier.nl/locate/carres
Carbohydrate Research 325 (2000) 169–176
Highly efficient synthesis of 1-thioglycosides in solution
and solid phase using iminophosphorane bases
Weizheng Xu, Shawn A. Springfield, John T. Koh *
The Department of Chemistry and Biochemistry, Uni6ersity of Delaware, Newark, DE 19716, USA
Received 29 October 1999; accepted 7 December 1999
Abstract
Disaccharides of 1-thioglycosides, an important class of glycomimics, can be synthesized by direct S-alkylation in
exceptionally high yields when iminophosphorane bases are employed. The reaction conditions employed appear to
be general and stereospecific. Axial and equatorial 4-triflates and primary tosylates of alkyl pyranosides provided
excellent yields of thio-disaccharides without substantial elimination products. The iminophosphorane bases also
proved to be useful in solid support-bound couplings of thioglycosides though with lower efficiency. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: Glycomimics; Solid-phase synthesis; Thioglycosides
1. Introduction
The attributes of the direct alkylation ap-
proach to thioglycoside synthesis are greatly
overshadowed by the poor yields often associ-
ated with the reaction with secondary pyran-
oside electrophiles in solution. Relatively high
yields (75%) have been obtained for the thiol-
alkylation coupling of pyranosides in solution
[6]. However, yields in the range of 30–60%
are more common and have been shown to
result from competing elimination reactions
and the transesterification of O-acyl or O-ben-
zoyl protecting groups to the anomeric thio-
late [2,7–10]. One strategy has been to couple
the furanose form of an electrophile, which is
less likely to eliminate, and subsequently to
convert it to the desired pyranoside [11]. More
recently, it has been demonstrated that high
yields of thio-oligosaccharides can be obtained
using support-bound glycosyl thiolates where
elimination products are not incorporated into
the growing thio-oligosaccharide [12]. How-
ever, to obtain consistent high yields of solu-
tion-phase coupling of thioglycosides still
Several recent reports have highlighted a
renewed interest in the synthesis of 1-thiogly-
cosides as glycomimics that have favorable
chemical and biological stability [1–4]. The
direct alkylation of glycosyl thiolates is a par-
ticularly attractive route to thio-oligosaccha-
ride construction because it generally occurs
with retention of anomeric configuration re-
sulting from the observation that glycosyl
thiolates do not mutarotate under basic condi-
tions [2,5,6]. The straightforward, stereospe-
cific construction of 1-thioglycosides from
configurationally pure glycosyl thiolates,
which is essentially independent of neighbor-
ing group effects, makes direct alkylation
of glycosyl thiolates an attractive approach
to the construction of libraries of glycomim-
ics.
* Corresponding author. Tel.: +1-302-8311947.
E-mail address: johnkoh@udel.edu (J.T. Koh)
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00327-4

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W. Xu et al. / Carbohydrate Research 325 (2000) 169–176
Scheme 1. (a) TBDPSCl, TEA, DMAP; (b) i. (PPh3)3RhCl, ii. I2/pyridine; (c) CCl3CN, DBU; (d) HSAc.
remains a significant challenge. This report
illustrates the use of iminophosphorane bases
to obtain thioglycosides by direct alkylation
couplings in solution in unprecedented yields.
In addition to demonstrating the efficiency of
these reactions in solution, we have also
demonstrated their utility in the synthesis of
support-bound thioglycosides.
4)-linked thiopyranoside by direct alkylation
of glycosyl thiolates in solution. Importantly,
none of the a-linked thiodisaccharide was ob-
served in these reactions, demonstrating that
these reactions are indeed stereospecific. The
more basic (but less hindered) iminophospho-
rane bases 9 and 10 afforded only moderate to
poor yields of 7 with significant elimination
side products.
2. Results and discussion
Generic benzyl-protected model compounds
5 and 6 were synthesized (Scheme 1) and were
used to survey a variety of commonly em-
ployed coupling conditions. Reaction of the
thiolate generated from in situ deprotection of
5 with piperidine in the presence of potassium
tert-butoxide or DBU in DMSO or HMPA
afforded only low yields of the desired S-
linked disaccharide 7 (Table 1, entries 1–3).
In these reactions elimination is the major
competing reaction; however, the amount of
elimination side products is notably less when
DBU is employed as a base compared with
tert-butoxide. These observations led us to
consider the highly hindered iminophospho-
rane bases (Schwesinger bases) as suitable
non-nucleophilic bases for this reaction [13].
The reaction yields are significantly in-
creased when 8 is employed as a base instead
of DBU or tert-butoxide. Our yields obtained
for small-scale model reactions show excellent
yields of compound 7 with almost no elimina-
tion side products, as demonstrated by high-
performance liquid chromatography (HPLC)
(Table 1, entry 5). This is perhaps the highest
yield yet reported for the synthesis of a (1“
Table 1
Direct alkylation-coupling yields in solution using various
bases a
Entry
Bases
Solvent
Yield 7 (isolated) (%)
1
2
3
4
5
6
7
KOtBu
Me2SO
HMPA
HMPA
Me2SO
CH3CN
CH3CN
CH3CN
(33)
(29)
(44)
(86)
92 (85)
66
KOtBu
DBU
8
8
9
10
44
a Yields determined by HPLC or reported as isolated yields,
(), from 20-mg scale reactions.

W. Xu et al. / Carbohydrate Research 325 (2000) 169–176
171
Scheme 2.
Scheme 3. (a) NaH, tert-butyl-4-bromomethylbenzoate; (b) i. (PPh3)3RhCl, ii. I2/pyridine; (c) CCl3CN, DBU; (d) HSAc.
drin assay, to be greater than 97%. The
support-bound thioacetate was deprotected by
treatment with piperidine, washed and treated
with a solution of compound 6 and 8. The
resulting product was cleaved from solid sup-
port with TFA to afford the thiodisaccharide
19 in an overall yield of 48% for the deprotec-
tion, alkylation and cleavage (Scheme 4).
The stability of 19 to the cleavage condi-
tions of 10% TFA testifies to the unique sta-
bility of the thioglycosidic linkage. Although
the overall yields are only modest, yields may
be improved with the use of alternative sup-
ports. The use of iminophosphorane bases
should be a notable improvement over exist-
ing methods for solution-phase couplings.
In addition to the equatorial triflate 6, the
axial triflate 11 and the primary tosylates 13
could also be coupled in high yield to the
corresponding to (1“4)- and (1“6)-linked
thiodisaccharides 12 and 14 (Scheme 2). These
results illustrate that efficient thioglycoside
coupling using 8 is indeed general and can
potentially be used to assemble a range of
thiodisaccharide structures.
The efficiency of the iminophosphorane
base-promoted alkylation in solution has led
us to investigate glycosyl couplings of sup-
port-bound thiolates. The support-bound cou-
pling of thiopyranosides by direct alkylation
has recently been reported [12,14]. Compound
18 was synthesized as a model that would
allow attachment of a range of standard
amine-functionalized supports (Scheme 3).
Compound 18 was attached to RINK-func-
tionalized PEG-polystyrene resin (Novasyn
TGR) using standard DCC coupling. The per-
centage loading was determined, using ninhy-
3. Experimental
General methods.—All synthetic com-
pounds were purchased from Aldrich Chemi-

172
W. Xu et al. / Carbohydrate Research 325 (2000) 169–176
Scheme 4.
cal Company, unless otherwise noted. NMR
spectra were recorded on Bruker DXR 400
and AM 250 spectrometers. Chromatography
was performed using ICN SiliTech (60A) flash
silica gel. HPLC analysis was performed on a
Shimadsu LC-10AT with an SPD-10A UV–
Vis detector using an Econosil C18/5 m 250×
4.6 mm column (Alltech). Mass spectra were
obtained by the University of Delaware Mass-
Spect. Lab using a Micromass AutospecQ or
Bruker BiflexIII MALDI-TOF spectrometer.
for C46H52O6Si+Na: 751.3431. Found:
751.3467.
2,3,4-Tri-O-benzyl-6-O-tert-butyldiphenylsi-
lyl-h-
D-glucopyranosyl
trichloroacetimidate
(4).—To a degassed solution of 2 (1.75 g, 2.40
mmol), DABCO (80 mg, 0.71 mmol) in 40 mL
of 95% EtOH, was added RhCl(Ph3P)3 (0.18
g, 0.19 mmol). The solution was heated to
reflux for 6 h. After cooling, the solution was
concentrated in vacuo and redissolved CH2Cl2
(50 mL). This solution was washed with water
(50 mL), brine (50 mL) and then dried over
MgSO4 and concentrated in vacuo to afford a
crude enol ether. To a solution of the crude
enol ether in THF (23 mL), water (7 mL) and
pyridine (0.79 mL) was added I2 (1.22 g, 4.81
mmol). The solution was stirred for 10 min at
ambient temperature, then cooled to 0 °C and
treated with 10% aq Na2SO3 (50 mL). After 15
min at 0 °C, the solution was extracted with
EtOAc (3×50 mL). The combined aqueous
extracts were washed with 10% aq Na2SO3
(2×50 mL) and water (50 mL), dried over
MgSO4 and concentrated in vacuo. Flash
chromatography (1:9 EtOAc–toluene) af-
forded 1.40 g (1.96 mmol, 85%) of allyl 2,3,4-
Allyl
2,3,4-tri-O-benzyl-6-O-tert-butyldi-
-glucopyranoside (2).—To a so-
phenylsilyl-h-
D
lution of 1 (0.12 g, 0.24 mmol), triethylamine
(30 mg, 0.30 mmol) and 4-dimethylaminopyr-
idine (12 mg, 0.1 mmol) in 30 mL of dry
CH2Cl2, was added tert-butylchlorodiphenyl-
silylane (74 mg, 0.27 mmol). After 3 h at room
temperature, the solution was diluted with 60
mL of CH2Cl2 and washed with water (60
mL), satd aq NH4Cl (60 mL) and brine (60
mL). The organic fraction was dried over
MgSO4 and evaporated in vacuo. Flash chro-
matography (1:3 EtOAc–hexanes) afforded
1
0.17 g (0.23 mmol, 94%) of 2. H NMR (250
MHz, CDCl3): l 7.70–7.10 (m, 25 H), 5.93
(m, 1 H), 5.28 (dd, J 17.0, 1.6 Hz, 1 H), 5.18
(dd, J 10.0, 1.6 Hz, 1 H), 4.99 (d, J 10.7 Hz,
1 H), 4.83 (d, J 10.7 Hz, 1 H), 4.88 (d, J 10.7
Hz, 1 H), 4.85 (d, J 4.2 Hz, 1 H, H-1), 4.83 (d,
J 12.0 Hz, 1 H), 4.79 (d, J 12.0 Hz, 1 H), 4.60
(d, J 10.7 Hz, 1 H), 4.15 (dd, J 13.2, 6.5 Hz,
1 H), 4.04 (dd, J 9.1, 9.2 Hz, 1 H), 3.96 (d, J
3.0 Hz, 1 H), 3.86 (m, 2 H), 3.74 (m, 1 H),
3.61 (dd, J 10.0, 10.0 Hz, 1 H), 3.57 (dd, J 9.5,
3.7 Hz, 1 H), 1.06 (s, 9 H). 13C NMR (63
MHz, CDCl3): l 138.8, 138.3, 138.2, 135.8,
135.6, 133.8, 133.6, 133.3, 129.6, 129.0, 125.3,
118.2, 95.2, 82.2, 80.3, 75.2, 75.1, 73.1, 71.7,
67.8, 62.9, 26.8, 19.3. HRFABMS: m/z Calcd
tri-O-benzyl-6-O-tert-butyldiphenylsilyl- -gluc
D
opyranoside (3) as a mixture of anomers.
FABMS: m/z Calcd for C43H48O6Si+Na:
711.3. Found: 711.3. The mixture of anomers
was used in subsequent reactions without fur-
ther purification.
To a solution of 3 (0.40 g, 0.58 mmol) and
DBU (0.097 mL, 0.70 mmol) in 5 mL of
CH2Cl2 was added Cl3CCN (0.58 mL, 5.8
mmol). After 4 h, the reaction mixture was
directly applied to a column of silica and
eluted with toluene to afford 0.39 g (0.46
mmol, 81%) of 4. 1H NMR (250 MHz,
CDCl3): l 8.56 (s, 1 H), 7.68–7.18 (m, 25 H),

W. Xu et al. / Carbohydrate Research 325 (2000) 169–176
173
afford 0.50 g (0.84 mmol, 96%) of compound
6. H NMR (250 MHz, CDCl3): l 7.40–7.25
6.59 (d, J 3.5 Hz, 1 H, H-1), 4.95 (d, J 10.8
Hz, 1 H), 4.92 (d, J 10.6 Hz, 1 H), 4.83 (d, J
10.8 Hz, 1 H), 4.80 (d, J 11.6 Hz, 1 H), 4.70
(d, J 11.6 Hz, 1 H), 4.67 (d, J 10.6 Hz, 1 H),
4.08 (t, J 9.1 Hz, 1 H), 3.96–3.91 (m, 3 H),
3.87–3.73 (m, 2 H), 1.04 (s, 9 H). 13C NMR
(63 MHz, CDCl3): l 161.3, 138.6, 138.1,
138.0, 135.8, 135.6, 133.6, 133.1, 129.6, 129.0,
128.4, 128.3, 128.2, 128.0, 127.8, 127.7, 127.6,
127.5, 125.3, 94.3, 91.4, 81.5, 79.9, 76.9, 75.8,
75.4, 74.3, 72.9, 62.4, 26.8, 19.3.
1
(m, 15 H), 5.02 (t, J 9.7 Hz, 1 H), 4.94 (d, J
10.3 Hz, 1 H), 4.83 (d, J 10.2 Hz, 1 H), 4.75
(d, J 10.3 Hz, 1 H), 4.60–4.45 (m, 4 H), 4.06
(t, J 9.4 Hz, 1 H), 3.98–3.96 (m, 1 H), 3.69–
3.58 (m, 3 H), 3.38 (s, 3 H). 13C NMR (63
MHz, CDCl3): l 149.8, 137.7, 137.5, 137.4,
135.0, 128.6, 128.3, 128.2, 128.1, 128.0, 127.8,
127.7, 127.6, 133.4, 97.9, 81.4, 80.1, 77.9, 75.5,
73.7, 73.6, 67.7, 67.5, 55.7.
1 - S -Acetyl - 2,3,4 - tri - O -benzyl - 6 - O - tert-
Methyl 2,3,6-tri-O-benzyl-4-S-(2,3,4-tri-O-
butyldiphenylsilyl - 1 - thio - i -
D-glucopyranose
benzyl-6-O-tert-butyldiphenylsilyl-i-
D
-gluco-
(5).—To a solution of 4 (0.62 g, 0.74 mmol)
in 10 mL of CH2Cl2 was added thiolacetic
acid (0.80 mL, 11.2 mmol) under N2. After 12
h at ambient temperature, the solution was
diluted with 50 mL of CH2Cl2 and washed
with satd aq NaHCO3 (2×50 mL), water (50
mL), and then brine (50 mL). The organic
layer was dried over MgSO4 and concentrated
in vacuo. Flash chromatography with 3:97
EtOAc–toluene afforded 0.46 g (0.60 mmol,
pyranosyl)-4-thio-h-
D
-glucopyranoside (7).—
To a solution of 5 (17.8 mg, 2.33×10−2
mmol) in 0.8 mL of CH3CN was added pipe-
ridine (5 mL, 5×10−2 mmol) under N2. After
15 min, BEMP 8 (10 mL, 3.4×10−2 mmol)
was added. Then a solution of 6 (17.0 mg,
2.85×10−2 mmol) in 0.5 mL CH3CN was
added to the above reaction mixture. After
stirring overnight at ambient temperature, the
solution was diluted with 5 mL of EtOAc and
washed with water (2×5 mL), and then brine
(5 mL). The organic layer was dried over
MgSO4 and concentrated in vacuo. Flash
chromatography with 3:7 EtOAc–hexanes af-
forded 23.3 mg (20.3×10−2 mmol, 85%) of
1
82%) of compound 5. H NMR (400 MHz,
CDCl3): l 7.75–7.66 (m, 4 H), 7.43–7.21 (m,
21 H), 5.19 (d, J 10.0 Hz, 1 H, H-1), 4.93–
4.89 (m, 3 H), 4.82 (d, J 10.8 Hz, 1 H), 4.78
(d, J 10.7 Hz, 1 H), 4.77 (d, J 10.8 Hz, 1 H),
3.93 (m, 2 H), 3.86 (dd, J 9.4, 9.4 Hz, 1 H),
3.77 (dd, J 8.8, 9.1 Hz, 1 H), 3.55 (dd, J 8.8,
8.8 Hz, 1 H), 3.46 (dt, J 9.5, 2.2 Hz, 1 H), 2.57
(s, 3 H), 1.06 (s, 9 H). 13C NMR (100 MHz,
CDCl3): l 192.7, 138.3, 138.2, 137.9, 135.9,
135.6, 133.5, 133.0, 129.6, 129.5, 128.5, 128.4,
128.3, 128.0, 127.8, 127.7, 127.6, 127.4, 86.7,
81.5, 80.7, 80.0, 77.4, 75.9, 75.4, 75.1, 62.5, 30.
8, 26.8, 19.3. HRFABMS: m/z Calcd for
C45H50O6SSi+Na:769.2995.Found:769.3033.
1
compound 7. H NMR (400 MHz, CDCl3): l
7.69 (dd, J 7.9, 1.4 Hz, 2 H), 7.63 (dd, J 8.0,
1.3 Hz, 2 H), 7.46–7.08 (m, 36 H), 4.95 (d, J
10.7 Hz, 1 H), 4.93 (d, J 9.7 Hz, 1 H), 4.86 (d,
J 10.9 Hz, 1 H), 4.82 (d, J 12.1 Hz, 1 H), 4.81
(d, J 10.8 Hz, 1 H), 4.77 (d, J 11.0 Hz, 1 H),
4.73 (d, J 10.7 Hz, 1 H), 4.65 (d, J 12.8 Hz, 1
H), 4.63 (obsc, 1 H), 4.61 (d, J 12.2 Hz, 1 H),
4.57 (d, J 10.9 Hz, 1 H), 4.44 (d, J 12.1 Hz, 1
H), 4.34 (d, J 12.1 Hz, 1 H), 4.24 (dm, J 7.6
Hz, 1 H), 4.06–4.09 (m, 2 H), 3.88 (dd, J 11.0,
1.7 Hz, 1 H), 3.85–3.71 (m, 3 H), 3.66–3.58
(m, 2 H), 3.54 (dd, J 8.8, 8.8 Hz, 1 H), 3.39 (s,
3 H), 3.38 (d, obsc, 1 H), 3.37 (dd, J 8.8 Hz,
1 H), 3.19–3.12 (m, 1 H), 1.05 (s, 9 H). 13C
NMR (100 MHz, CDCl3): l 138.6, 138.5,
138.1, 135.7, 135.5, 133.46, 133.15, 129.8,
129.7, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7,
127.6, 127.5, 127.4, 127.3, 127.2, 98.8, 86.3,
83.8, 82.9, 79.8, 79.2, 77.7, 77.3, 75.7, 74.8,
74.7, 73.8, 73.1, 72.9, 72.8, 70.1, 63.2, 55.2,
46.9, 26.8, 19.4. HRFABMS: m/z Calcd for C71-
H78O10SiS+Na: 1173.4981. Found: 1173.4981.
Methyl
methylsulfonyl-h-
a solution of methyl 2,3,6-tri-O-benzyl-a-
2,3,6-tri-O-benzyl-4-O-trifiuoro-
D
-glucopyranoside (6).—To
D-
glucopyranoside (0.41 g, 0.88 mmol) and 1.8
mL of pyridine in 15 mL of CH2Cl2 was
added Tf2O (1.5 mL, 8.8 mmol) at 0 °C under
N2. After 0.5 h at 0 °C and 1 h at ambient
temperature, the solution was concentrated in
vacuo, redissolved in 20 mL of CH2Cl2 and
washed with ice-cold 10% aq KHSO4 (15 mL),
satd aq NaHCO3 (15 mL), water (15 mL) and
brine (15 mL). The organic layer was then
dried over MgSO4, concentrated in vacuo to

174
W. Xu et al. / Carbohydrate Research 325 (2000) 169–176
127.2, 127.0, 95.7, 87.0, 83.4, 82.0, 81.1, 79.7,
Allyl
benzyl-6-O-tert-butyldiphenylsilyl-i-
pyranosyl)-4-thio-h- -galactopyranoside (12).
—To a solution of allyl 2,3,6-tri-O-benzyl-a-
-galactopyranoside (0.26 g, 0.53 mmol) and
2,3,6-tri-O-benzyl-4-S-(2,3,4-tri-O-
77.4, 77.1, 75.9, 75.5, 75.3, 74.8, 73.3, 73.2,
70.9, 68.0, 63.1, 47.0, 26.9, 19.3. HRFABMS:
m/z Calcd for C73H80O10SSi+Na: 1199.5139.
Found: 1199.5186.
D
-gluco-
D
D
Methyl 2,3,4-tri-O-benzyl-6-O-(4-methyl-
1.1 mL of pyridine in 10 mL of CH2Cl2 was
added Tf2O (0.89 mL, 5.3 mmol) at 0 °C
under N2. After 0.5 h at 0 °C and 1 h at
ambient temperature, the solution was con-
centrated in vacuo, then redissolved in 15 mL
of CH2Cl2 and washed with ice-cold 10% aq
KHSO4 (10 mL), satd aq NaHCO3 (10 mL),
water (10 mL) and brine (10 mL). The organic
layer was then dried over MgSO4 and concen-
trated in vacuo to afford 0.32 g (0.51 mmol,
97%) of compound 11. The product was im-
mediately used without further purification.
To a solution of 5 (14.0 mg, 1.88×10−2
mmol) in 0.8 mL of CH3CN was added pipe-
ridine (4 mL, 4×10−2 mmol) under N2. After
15 min, BEMP 8 (8 mL, 2.8×10−2 mmol) was
added. Then a solution of 11 (13.2 mg, 2.12×
10−2 mmol) in 0.5 mL CH3CN was added to
the above reaction mixture. After stirring
overnight at ambient temperature, the solu-
tion was diluted with 5 mL of EtOAc and
washed with water (2×5 mL), and then brine
(5 mL). The organic layer was dried over
MgSO4 and concentrated in vacuo. Flash
chromatography with 3:7 EtOAc–hexanes af-
forded 17.9 mg (1.52×10−2 mmol, 81%) of
compound 12. 1H NMR (400 MHz, CDCl3): l
7.68 (d, J 8.3 Hz, 2 H), 7.62 (d, J 8.2 Hz, 2 H),
7.40–7.10 (m, 36 H), 5.80 (m, 1 H), 5.18 (dd,
J 17.2, 1.4 Hz, 1 H), 5.10 (dd, J 10.3, 1.0 Hz,
1 H), 4.97 (d, J 11.2 Hz, 1 H, H-1), 4.90 (d, J
10.8 Hz, 1 H), 4.86 (d, J 10.6 Hz, 1 H), 4.85
(d, J 10.9 Hz, 1 H), 4.83 (d, J 10.9 Hz, 1 H),
4.82 (d, J 4.0 Hz, 1 H, H-1), 4.79 (d, J 12.0
Hz, 1 H), 4.70 (d, J 11.8 Hz, 1 H), 4.69 (d, J
10.1 Hz, 1 H), 4.64 (d, J 10.0 Hz, 1 H), 4.56
(d, J 10.2 Hz, 1 H), 4.39 (m, 1 H), 4.02 (dd, J
10.6, 4.6 Hz, 1 H), 3.97–3.92 (m, 3 H), 3.87–
3.73 (m, 4 H), 3.67 (t, J 8.9 Hz, 1 H), 3.57–
3.54 (m, 2 H), 3.43 (t, J 9.4 Hz, 1 H), 3.26 (t,
J 10.8 Hz, 1 H), 3.22 (d, J 9.5, 2.1 Hz, 1 H),
benzenesulfonyl)-h- -glucopyranoside (13).—
D
To a solution of methyl 2,3,4-tri-O-benzyl-a-
D-glucopyranoside (0.35 g, 0.75 mmol) and
pyridine (0.12 mL, 1.50 mmol) in 3 mL of
CHCl3, was added a solution of TsCl (0.22 g,
1.16 mmol) in 5 mL of CHCl3 at 0 °C under
N2. After 6 h the solution was diluted to 25
mL with CHCl3 and washed with water (2×
15 mL) and brine (20 mL). The organic layer
was dried over MgSO4 and concentrated in
vacuo. Flash chromatography with 1:9
EtOAc–toluene afforded 0.40 g (0.38 mmol,
1
86%) of compound 13. H NMR (250 MHz,
CDCl3): l 7.75 (d, J 8.3 Hz, 2 H), 7.34–7.12
(m, 17 H), 4.97 (d, J 10.9 Hz, 1 H), 4.82 (d, J
10.7 Hz, 1 H), 4.77 (d, J 10.9 Hz, 1 H), 4.76
(d, J 12.1 Hz, 1 H), 4.56 (d, J 12.1 Hz, 1 H),
4.52 (d, J 3.5 Hz, 1 H, H-1), 4.42 (d, J 10.7
Hz, 1 H), 4.18 (m, 2 H), 3.95 (dd, J 9.2, 9.3
Hz, 1 H), 3.76 (m, 1 H), 3.46 (dd, J 9.6, 3.6
Hz, 1 H), 3.43 (dd, J 9.1, 9.3 Hz, 1 H), 3.31 (s,
3 H), 2.39 (s, 3 H). 13C NMR (63 MHz,
CDCl3): l 144.8, 138.5, 137.9, 137.7, 132.8,
129.8, 128.5, 128.4, 128.1, 127.9, 127.8, 127.6,
98.0, 81.8, 79.7, 76.9, 75.7, 74.9, 73.4, 68.6,
68.5, 55.3, 21.6. HRFABMS: m/z Calcd for
C35H38O8S+Na: 641.2185. Found: 641.2174.
Methyl 2,3,4-tri-O-benzyl-6-S-(2,3,4-tri-O-
benzyl-6-O-tert-butyldiphenylsilyl-i-
pyranosyl)-6-thio-h- -glucopyranoside
D
-gluco-
(14).
D
—To a solution of 5 (25.1 mg, 3.36×10−2
mmol) in 0.8 mL of CH3CN was added pipe-
ridine (7 mL, 7×10−2 mmol) under N2. After
15 min, BEMP 8 (15 mL, 5.2×10−2 mmol)
was added. Then a solution of 13 (24.9 mg,
4.03×10−2 mmol) in 0.5 mL of CH3CN was
added to the above reaction mixture. After
stirring overnight at ambient temperature, the
solution was diluted with 5 mL of EtOAc and
washed with water (2×5 mL), and then brine
(5 mL). The organic layer was dried over
MgSO4 and concentrated in vacuo. Flash
chromatography with 1:3 EtOAc–hexanes af-
forded 32.0 mg (2.78×10−2 mmol, 83%) of
compound 14. 1H NMR (400 MHz, CDCl3): l
13
1.03 (s, 9 H). C NMR (100 MHz, CDCl3): l
139.0, 138.4, 138.3, 138.2, 138.1, 135.8, 135.6,
133.7, 133.3, 133.1, 129.7, 128.4, 128.3, 128.2,
128.1, 128.0, 127.7, 127.6, 127.5, 127.4, 127.3,

W. Xu et al. / Carbohydrate Research 325 (2000) 169–176
175
142.6, 138.8, 138.2, 133.7, 131.3, 129.5, 128.4,
128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.2,
118.2, 95.7, 82.1, 80.9, 79.9, 77.7, 75.7, 75.1,
73.2, 72.8, 70.2, 68.8, 68.2, 28.2. HRFABMS:
m/z Calcd for C42H48O8+Na: 703.3247.
Found: 703.3231.
7.75 (dd, J 5.9, 2.3 Hz, 2 H), 7.69 (dd, J 7.9,
1.4 Hz, 2 H), 7.46–7.14 (m, 36 H), 4.98, (d, J
10.8 Hz, 1 H), 4.90 (d, J 10.8 Hz, 1 H), 4.90
(d, J 8.9 Hz, 1 H), 4.88 (d, J 10.5 Hz, 1 H),
4.85 (d, J 10.7 Hz, 1 H), 4.80 (d, J 10.9 Hz, 1
H), 4.76 (d, J 12.2 Hz, 1 H), 4.75 (d, J 10.4
Hz, 1 H), 4.69 (d, J 10.7 Hz, 1 H), 4.66 (d, J
13.7 Hz, 1 H), 4.63 (d, J 12.2 Hz, 1 H), 4.58
(d, J 11.1 Hz, 1 H), 4.56 (d, J 10.4 Hz, 1 H),
4.55 (d, J 1.7 Hz, 1 H), 3.97 (t, J 9.3 Hz, 1 H),
3.93–3.85 (m, 3 H), 3.77 (t, J 9.3 Hz, 1 H),
3.65 (t, J 8.9 Hz, 1 H), 3.48 (dd, J 9.6, 3.9, Hz,
1 H), 3.42 (t, J 9.6 Hz, 1 H), 3.32 (s, 3 H), 3.33
(t, obsc, 1 H), 3.27 (d, J 9.6, 2.5 Hz, 1 H), 3.11
(dd, 13.6, 8.0 Hz, 1 H), 2.89 (dd, J 13.6, 8.0
2,3,4,-Tri-O-benzyl-6-O-[4-(tert-butoxycar-
bonyl)benzyl]-h- -glucopyranosyl trichloroace-
D
timidate (17).—To a degassed solution of 15
(0.50 g, 0.74 mmol) and DABCO (0.021 g,
0.019 mmol) in 15 mL of 95% EtOH was
added RhCl(Ph3P)3 (0.068 g, 0.073 mmol).
The solution was heated to reflux for 6 h.
After cooling, the solution was concentrated
in vacuo and the residue was redissolved in
CH2Cl2 (40 mL). This solution was washed
with water (40 mL) followed by 40 mL of
brine and then dried over MgSO4 and concen-
trated in vacuo, to afford a crude enol ether.
To a solution of the crude enol ether in THF
(23 mL), water (7 mL) and pyridine (0.26 mL)
was added I2 (1.22 g, 4.81 mmol). The solu-
tion was stirred for 10 min at ambient temper-
ature, then cooled to 0 °C and treated with
10% aq Na2SO3 (20 mL). After 15 min at
0 °C, the solution was extracted with ether
(3×30 mL). The combined organic extracts
were washed with 10% aq Na2SO3 (2×50
mL) and water (50 mL), dried over MgSO4
and concentrated in vacuo. The residue was
chromatographed (1:4 EtoAc–toluene) to af-
ford 0.38 g of 16 (0.34 mmol, 81%) as a
mixture of anomers. HRFABMS: m/z Calcd
for C39H44Cl3O8N+Na: 663.2934. Found:
663.2966. The refined anomeric mixture was
used in subsequent reactions without further
purification.
13
Hz, 1 H), 1.03 (s, 9 H). C NMR (100 MHz,
CDCl3): l 138.7, 138.5, 138.2, 138.1, 135.9,
135.5, 133.7, 133.0, 129.6, 128.5, 128.4, 128.3,
128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 97.8,
86.7, 85.0, 82.3, 81.9, 81.0, 79.9, 79.7, 77.6,
75.9, 75.7, 75.4, 75.2, 75.1, 73.3, 71.5, 62.7,
55.2, 31.2, 26.8, 19.3. HRFABMS: m/z Calcd
for C71H78O10SSi+Na: 1173.498104. Found:
1173.498104.
Allyl 2,3,4-tri-O-benzyl-6-O-[4-(tert-buto-
xycarbonyl)benzyl]-h- -glucopyranoside (15).
D
—To a solution of 1 (0.67 g, 1.37 mmol) in 20
mL of dry DMF was added NaH (66 mg, 1.65
mmol) under N2. After 20 min, a solution of
tert-butyl 4-bromomethylbenzoate (0.37 g,
1.37 mmol) in 5 mL of anhyd DMF was
added dropwise. The solution was heated to
85 °C for 12 h. After cooling, the solution was
poured into 70 mL of water and extracted
with EtOAc (3×50 mL). The combined or-
ganic extracts were washed with water (50
mL) and brine (50 mL) and dried over
MgSO4. The solution was evaporated in
vacuo, and the residue was chromatographed
1:19 EtOAc–toluene) to afford 0.80 g (1.14
To a solution of 16 (0.28 g, 0.44 mmol) and
DBU (0.079 mL, 0.53 mmol) in 6 mL CH2Cl2
was added Cl3CCN (0.44 mL, 4.4 mmol) un-
der N2. After 4 h, the reaction mixture was
directly applied to a silica gel column and
eluted with toluene to afford 0.28 g (0.35
1
mmol, 86%) of 15. H NMR (250 MHz,
CDCl3): l 7.93 (d, J 8.2 Hz, 2 H), 7.37–7. 14
(m, 17 H), 5.93 (m, 1 H), 5.30 (dd, J 17.2, 1.3,
1 H), 5.21 (dd, J 17.2, 1.3 Hz, 1 H), 5.00 (d, J
12.8 Hz, 1 H), 4.85 (d, J 10.6 Hz, 1 H), 4.82
(d, J 3.8 Hz, 1 H, H-1), 4.81 (d, J 12.8 Hz, 1
H), 4.77 (d, J 12.0 Hz, 1 H), 4.65 (d, J 12.1
Hz, 1 H), 4.62 (d, J 12.8 Hz, 1 H), 4.48 (d, J
12.8 Hz, 1 H), 4.47 (d, J 10.9 Hz, 1 H),
4.19–3.96 (m, 3 H), 3.83–3.54 (m, 5 H), 1.58
(s, 9 H). 13C NMR (63 MHz, CDCl3): l 165.5,
1
mmol, 82%) of the imidate 17. H NMR (250
MHz, CDCl3): l 8.58 (s, 1 H), 7.92 (d, J 8.3
Hz, 2 H), 7.35–7.12 (m, 17 H), 6.51 (d, J 3.5
Hz, 1 H, H-1), 4.99–4.46 (m, 8 H), 4.09–3.97
(m, 2 H), 3.79–3.67 (m, 4 H), 1.58 (s, 9 H).
HRFABMS: m/z Calcd for C41H44Cl3O8N+
Na: 806.2030. Found: 806.2041.

176
W. Xu et al. / Carbohydrate Research 325 (2000) 169–176
2,3,4-Tri-O-benzyl-6-O-[4-(tert-butoxycar-
bonyl)benzyl]-1-S-acetyl-1-thio-i- -gluco-
TFA–CH2Cl2. After 10 min, the resin was
D
washed with CH2Cl2 (3×3 mL). The collected
washings were concentrated in vacuo to afford
4.2 mg (3.9 mmol, 50%) of compound 19. The
yield was confirmed by HPLC analysis to be
pyranose (18).—To a solution of 17 (0.28 g,
0.36 mmol) and HSAc (0.5 mL, 7.0 mmol) in
10 mL of CH2Cl2 was added BF3·Et2O (0.030
mL, 0.24 mmol) under N2. After 12 h at
ambient temperature, the reaction was diluted
with 50 mL of CH2Cl2 and washed with 50
mL of satd aq NaHCO3, 50 mL of water and
50 mL of brine. The organic layer was dried
over MgSO4, concentrated in vacuo and chro-
matographed (1:3 EtOAc–toluene) to afford
0.19 g (0.30 mmol, 83%) of the thioacetate 18.
1H NMR (250 MHz, CDCl3): l 8.05 (d, J 8.1
Hz, 2 H), 7.43–7.14 (m, 17 H), 5.17 (d, J 10.1
Hz, 1 H, H-1), 4.88–4.50 (m, 8 H), 3.76–3.58
(m, 6 H), 2.37 (s, 3 H). 13C NMR (63 MHz,
CDCl3): l 192.8, 170.9, 144.4, 138.3, 138.0,
137.8, 130.3, 129.0, 128.4, 128.2, 128.0, 127.8,
127.7, 127.3, 86.8, 81.7, 80.3, 79.3,77.0, 75.8,
75.4, 75.0, 72.7, 68.9, 30.9. HRMS (MALDI):
m/z Calcd for C37H38O8S+Na: 665.218.
Found: 665.220.
1
48%. H NMR (250 MHz, CDCl3): 7.70 (d, J
8.2 Hz, 2 H), 7.41–7.20 (m, 32 H), 4.88–4.47
(m, 14 H), 4.30–4.10 (m, 4 H), 3.76–3.50 (m,
9 H), 3.39 (s, 3 H), 3.34 (m, 1 H). HR-
FABMS: m/z Calcd for C63H67N1O11S+Na:
1068.4333. Found: 1068.4358.
Acknowledgements
We thank the American Chemical Society
Petroleum Research Fund (ACS PRF
c32608-G1) and the University of Delaware
Research Foundation for financial support.
S.A.S. was supported by an undergraduate
summer fellowship from Zeneca pharmaceuti-
cals.
Methyl 2,3,6-tri-O-benzyl-4-S-(2,3,4-tri-O-
benzyl-6-O-(4-carboxamidobenzyl)-i-
D
-gluco-
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To a mixture of NovaSyn TGR Resin (112
mg, 0.022 mmol) and 0.5 mL of CH2Cl2 was
added a premixed solution of compound 18
(60 mg, 0.093 mmol), DCC (18 mg, 0.087
mmol) and DMAP (1.5 mg, 0.012 mmol) in
1.5 mL of CH2Cl2 under N2. The reaction
mixture was mixed for 36 h. After filtration,
the resin was washed with CH2Cl2 (5 mL),
MeOH (5 mL) and CH2Cl2 (5 mL). The resin
was dried under vacuum. The amount of unre-
acted amine was quantified using standard
ninhydrin
assay
(Perkin–Elmer/Applied
Biosystems) to obtain a percentage loading of
98%. To 36 mg of the loaded resin (0.0072
mmol) was added 1 mL of 1:4 piperidine–
CH3CN. After 2 h, the resin was washed with
CH3CN (2×5 mL). To the support-bound
thiol was added a solution of compound 6 (26
mg, 0.044 mmol) and BEMP 8 (13 mL, 0.045
mmol) in CH3CN (0.6 mL). After shaking for
48 h, the resin was filtered and washed with
CH2Cl2 (2×5 mL), MeOH (2×5 mL) and
CH3CN (2×5 mL) and dried under vacuum.
To the dried resin was added 1 mL of 1:9