Development of a Novel Method for Trimethylsilylation of Saccharides?

Article abstract of DOI:10.1055/s-0040-1705990

The trimethylsilyl (TMS) group is widely used in carbo?hydrate synthesis, although this protecting group is unstable and its post-synthetic purification challenging. The successful trimethylsilyl?ation of carbohydrates mediated by recyclable and efficient

Full text of DOI:10.1055/s-0040-1705990

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–G
paper
A
en
J.-S. Chen et al.
Paper
Synthesis
Development of a Novel Method for Trimethylsilylation of
Saccharides
Jyun-Siao Chen◊a
Yi-Fan Ke◊a
Heng-Yan Lin◊a
Wesley Linb
Wei-Chung Yenc
Hsin-Ru Wud
Shun-Yuan Luo*a
a Department of Chemistry, National Chung Hsing University,
Taichung 402, Taiwan
syluo@dragon.nchu.edu.tw
b Morrison Academy, Taichung 406, Taiwan
c Taipei Municipal Neihu High School, Taipei 114, Taiwan
d Instrumentation Center, MOST, National Tsing Hua University,
Hsinchu 300, Taiwan
◊ These authors contributed equally
Corresponding Author
Received: 18.10.2020
Accepted after revision: 10.11.2020
Published online: 19.01.2021
groups by using chlorosilanes,8 hexamethyldisilazane
(HMDS),4c,9 or hydrosilanes10 as silylating reagents in the
past several decades.11
DOI: 10.1055/s-0040-1705990; Art ID: ss-2020-g0542-op
Among silyl ethers the most typically known one is the
trimethylsilyl group (TMS), which is commonly used for the
protection of functional groups in carbohydrates because
its C–O–Si bonds can be easily cleaved at the O–Si bond. In
particular, TMS groups also play a pivotal role in one-pot
reactions.12 While many TMS protecting reagents are
known, HMDS is the most popular silylating agent because
it is stable, commercially available, and inexpensive. More-
over, silylation with HMDS proceeds under almost nearly
neutral conditions, requires no special precautions, and
produces only ammonia (NH3) as a reaction by-product.13
However, in spite of all of its advantages, one prominent
disadvantage of HMDS is its low silylating power in the ab-
sence of a suitable catalyst. Consequently, in order to in-
crease the silylating efficiency of HMDS, a variety of cata-
lysts have been reported.14 Following the method of
Firouzabadi et al., we applied a method on carbohydrate
chemistry with phosphotungstic acid (PTA) as a catalyst,
which yielded good results.14c
Recently, we reported on the phosphotungstic acid
(PTA)-catalyzed protections along with the glycosylation of
carbohydrates.15 PTA is a heteropolyacid, which is a mem-
ber of an increasingly important class of environmentally
friendly catalysts for a variety of organic reactions.16 PTA is
frequently regarded as a green catalyst on account of its
commercial availability, stability, non-toxicity, eco-friendli-
ness, separability from liquid products, and most impor-
tantly, its recyclability.14c,17
Abstract The trimethylsilyl (TMS) group is widely used in carbo-
hydrate synthesis, although this protecting group is unstable and its
post-synthetic purification challenging. The successful trimethylsilyl-
ation of carbohydrates mediated by recyclable and efficient acidic cata-
lyst PTA/HMDS and the novel reagent, TMSOAc (TEA/TMSOAc), under
alkaline condition is reported. The advantages of these methods are
that the reactions proceed in good to excellent yields without applying
column chromatography for purification.
Key words phosphotungstic acid, trimethylsilyl acetate, trimethyl-
silylation, recover, reused, catalysis
Carbohydrates play diverse and essential roles in bio-
molecules,1 including protein folding, viral and bacterial in-
fections, masking immuno-responses, fertilization, em-
bryogenesis, neural development, cell proliferation, cell
growth, cell-cell communication, and the formation of spe-
cific tissues.2 Because of its importance in biology, carbo-
hydrate chemistry is a very active field of research.3 As it is
known, saccharides are soluble in water and poorly soluble
in almost any other organic solvent except for a few excep-
tions. However, silyl protecting groups improve the solubil-
ity to solve this problem.4
The development of efficient methods for the silylation
of carbohydrate is an important area of research in carbo-
hydrate chemistry as the thermal stability and polarity can
be significantly changed by silyl groups.5,6 Silyl ethers and
derivatives are widely applied as protecting groups in car-
bohydrate syntheses owing to their relative stability toward
alkaline and acidic hydrolysis as well as high specificity for
fluoride-mediated cleavage.7 As of now, considerable prog-
ress has been made regarding the silylation of hydroxyl
In this paper, trimethylsilyl acetate, more often known
as TMSOAc, was used as a TMS donor as well as acidic
reagent in the trimethylsilylation of the starting material
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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J.-S. Chen et al.
Paper
Synthesis
-methyl-D-glucopyranoside (1a). Though TMSOAc is typi-
cally found as the by-product of reactions it serves as an
even better carbohydrate silylation reagent. Among its
many advantages, TMSOAc reduces the necessary purifica-
tion process, while still providing a stable product in good
yield.18 Owing to the relatively polar nature of the acidic re-
agents, TMSOAc is easily separated from the other major
product.19 This property allows the pure product to be ob-
tained without further purification.
In light of the advantages of both the acidic catalyst PTA
and the novel reagent TMSOAc, our team used the new cat-
alyst and reagent to explore their application in the tradi-
tionally reported trimethylsilylation procedures (Scheme
1). In this study, experiments are performed with different
catalysts, reagents, and conditions to find the best reagent
for TMS protecting of various carbohydrates while provid-
ing the highest yield in the shortest time. Additionally, the
recycling potential of PTA is examined, and its repeated use
is tested, providing favorable yields.
Table 1 Optimized Conditions for Trimethylsilylation with HMDS and
Various Acids
OH
O
OTMS
O
acid, HMDS
HO
HO
TMSO
TMSO
DCM, 60 °C, 2 h
HO
TMSO
OMe
OMe
1a
2a
Entry
Acid (equiv)
HMDS (equiv)
Yield (%)
1
TfOH (0.2)
TMSOTf (0.2)
H2SO4 (0.2)
PTSA (0.2)
BF3·OEt2 (0.2)
AgOTf (0.2)
Cu(OTf)2 (0.2)
CSA (0.2)
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.1
2.5
3.0
2.5
2.5
94
98
43
2
2
3a
4a
5
1
6a
7a
8a
9
14
4
45
95
98
95
96
99
98
94
96
PTA (0.2)
10
11
12
13
14
15b
16c
PTA (0.25)
PTA (0.30)
PTA (0.25)
PTA (0.25)
PTA (0.25)
PTA (0.25)
PTA (0.25)
PTA, HMDS
acidic
conditions
O
O
X
X
(HO)n
(TMSO)n
TMSOAc, TEA
basic
conditions
Scheme 1 Conception of trimethylsilylation under acidic and basic
conditions
a Isolated yield.
b The reaction was performed at r.t.
c Starting material used: 1.0 g.
Various limitations exist with the traditionally reported
reagents, such as their more expensive cost, strong corro-
siveness, toxicity, and their ability to be easily destroyed
under atmosphere. Following the method of Firouzabadi
and co-workers,14c using PTA in the application of trimeth-
ylsilylation in carbohydrate synthesis, the catalytic activity
of PTA was compared with the other acidic catalysts (Table
1).
First, trimethylsilylation of -methyl-D-glucopyranoside
(1a) was activated by HMDS (2.2 equiv) and the acid cata-
lyst (0.20 equiv) to afford the product 2a as shown in Table
1. The homogeneous acid catalysts TfOH and TMSOTf pro-
duced 94% and 98% of yield, respectively (Table 1, entries 1,
2). However, H2SO4 and p-toluenesulfonic acid (PTSA) af-
forded only 43% and 2% yield of the trimethylsilylated prod-
uct due to the generation of massive tri-TMS side-products
without regioselective protection (entries 3, 4). It should be
noted that the BF3·OEt2 afforded a very-low yield because
the presence of F atoms is unfavorable with trimethylsilyla-
tion (entry 5). The reaction in heterogeneous acid catalysts
such as silver trifluoromethanesulfonate (AgOTf), copper(II)
trifluoromethanesulfonate [Cu(OTf)2], camphorsulfonic
acid (CSA), and PTA was also tested for the activation of
HMDS. The lower yields from using AgOTf, Cu(OTf)2, and
CSA result from their poor heterogeneous catalytic efficien-
cy (entries 6–8). Gratifyingly, PTA furnished a yield of up to
95% as the heterogeneous catalyst (entry 9). In addition,
PTA also has many advantageous properties, many of which
include its reusability, weak corrosiveness, and thermal sta-
bility. These results indicated that PTA is the favorable cata-
lyst for this reaction. We further examined the effect of the
best condition for protecting carbohydrates with trimethyl-
silyl groups catalyzed by PTA. The finding showed that rais-
ing the PTA to 0.25 equivalent would increase the yield to
98% (entry 10). Meanwhile when PTA was raised to 0.3
equivalent or when HMDS was lowered to 2.1 equivalents,
the yields of product 2a were lowered (entries 11, 12). De-
lightfully, the increase in the amount of HMDS to 2.5 equiv-
alents, allowed the desired product 2a to be obtained in a
slightly higher yield of 99% (entry 13). However, the in-
crease of HMDS to 3.0 equivalents, led to a decreased yield
of 98% (entry 14). Decreasing the temperature gave lower
yields, likely due to the fact that PTA was not thermally ac-
tivated. This occurs since the reaction is heterogeneous (en-
try 15). Finally, a control experiment on an amplified scale
to repeat the conditions of entry 15 resulted in the same
yield of 96% (entry 16).
Under the optimal conditions, we studied the reaction
ranging from pyranose to furanose (Scheme 2). The product
2b was obtained in good yield (90%), when phenyl-1-thio-
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J.-S. Chen et al.
Paper
Synthesis
-D-glucoside (1b) was used as the starting material. The
use of free-OH glucose 1c afforded the desired product 2c in
92% yield when HMDS was increased to 3.1 equivalents. On
the other hand, 1-thiolcresol galactose reacted well to give
the target product 2d (99%), while free-OH galactose inhib-
ited the formation of compound 2e due to the increased
steric hindrance at C4 position (81%). The use of mannose
(1f) as starting material afforded the desired product 2f in
99% yield. Furthermore, the reaction could be extended to
N3-protected glucosamine (2g). In addition, the product 2h
was formed from the glucosamine with N-phthalimide
(NPhth) protecting group 1h, thus demonstrating that
NPhth protection was tolerated under the PTA. After the
successful trimethylsilylation of pyranose substrates, our
attention was then directed to furanose, which could also
serve as important precursors in biochemistry and the syn-
thesis such as ribose. At first, the substrate 1i was subjected
to the per-O-trimethylsilylation, which resulted in the de-
sired product 2i in 99% yield. Similarly, substrates 1j, 1k,
and 1l provided the desired trimethylsilyl protection prod-
ucts 2j–1, 2k, and 2l in good yields (99%, 96%, and 91%). No-
tably, the benzylidene protecting group can also exist sta-
bly under this reaction environment, and the product 2m
with a yield of 94% was obtained. A plausible mechanism
for the PTA trimethylsilylation of carbohydrates is present-
ed in the Supporting Information.
acidification. Hence, the recycled PTA was again added to
the same starting material 1a. The reaction conducted un-
der the same method of Table 1 gave the desired product 2a
in 97% to 99% yield and the recovered yield of PTA was over
80% (Figure 1). Furthermore, the catalyst could be recycled
at least 6 times, while still maintaining the excellent yield.
To our knowledge, this is the first time that catalytic
trimethylation has been performed repeatedly with PTA.
Figure 1 Reusing PTA for trimethylsilylation
Having established the trimethylsilyation with acid con-
ditions by PTA and HMDS, we explored the same reaction
under other conditions. To our excitement, the silyl ester
TMSOAc could be a novel reagent for the trimethylsilylation.
To demonstrate the application of TMSOAc, per-O-TMS pro-
tecting conditions were tested using -methyl-D-glucopy-
ranoside (1a) as the starting material (see Table 2). Initially,
when the trimethylsilylation of 1a was executed with only
TMSOAc, the expected product was not found (Table 2, en-
try 1). Since the alkaline condition enhanced the reactivity,
a series of organic bases were used. Solid bases such as 4-
dimethylaminopyridine (DMAP) and imidazole were used
to generate product 2a in 33% and 50% yield, respectively
(entries 2, 3). Then, the base was altered to pyridine, which
is frequently used in the literature, but the result was the
same as without base (entry 4). We also tested the base
such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and
piperidine, and the change in base allowed the trimethylsi-
lylated products to be isolated in better yields (83% and 88%,
entries 5, 6). Altering the base to triethylamine (TEA) also
considerably increased the yield (91%, entry 7). The optimal
conditions had to be modulated to maximize the yield, so
different equivalents of TEA were tested in the following
entries. However, the yield of 2a decreased while the
amount of TEA was changed (76% and 82%, entries 8, 9). To
sum up, entry 7 corresponded to a slightly better yield than
all other entries, so TEA was chosen as the base reagent. We
also examined different times and temperatures in the re-
action but found that no changes benefited this reaction
PTA (0.25 equiv)
HMDS (0.625 equiv/OH)
O
O
X
X
(HO)n
1b–m
(TMSO)n
2b–m
DCM, 60 °C, 2 h
TMSO
TMSO
OTMS
O
TMSO
TMSO
O
O
TMSO
TMSO
TMSO
STol
OTMS
STol
TMSO
TMSO
OTMS
OTMS
2c, 92%,b α only
2b, 90%,a β only
2d, 99%,a β only
TMSO
TMSO
OTMS
O
OTMS
TMSO
TMSO
TMSO
TMSO
O
O
TMSO
TMSO
OTBS
OTMS
N3
OTMS
OTMS
2g, 98%,c β only
2e, 81%,b α/β = 32:5
2f, 99%,b α only
O
TMSO
O
OTMS
O
TMSO
TMSO
STol
TMSO
TMSO
TMSO
NPhth
TMSO
OTMS
2j–1, 99%,a α only
TMSO
OTMS
2h, 92%,d β only
2i, 99%,a α only
O
OTMS
O
Ph
O
OTMS
TMSO
TMSO
O
O
TMSO
TMSO
2l, 91%,a α only
TMSO
OTMS
TMSO
OMe
OTMS
2k, 96%,a α/β = 1:2
2m, 94%,e α only
Scheme 2 Trimethylsilylation of variety of saccharides by HMDS with
PTA catalyst. a HMDS (2.5 equiv) was used; b HMDS (3.1 equiv) was
used; c HMDS (1.9 equiv) was used; d HMDS (2.2 equiv) was used and
stirred for 6 h; e HMDS (1.3 equiv) was used.
After the reactions were completed, the PTA was recy-
cled via filtration. Several reagents were tested, and Amber-
lite® IR 120 H was found to be the best reagent in terms of
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G

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J.-S. Chen et al.
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Synthesis
(entries 10–13). Under the standard conditions, when the
amount of TMSOAc was increased the reaction was less ef-
fective (entry 14).
TMSOAc (2.0 equiv/OH )
TEA
O
O
X
X
(HO)n
1b–m
(TMSO)n
neat
2b–m
TMSO
TMSO
OTMS
O
TMSO
TMSO
TMSO
TMSO
O
TMSO
Table 2 Different Conditions of Trimethylsilylation of 1a with TMSOAc
O
TMSO
STol
OTMS
2b, 86%,a β only
OTMS
OTMS
STol
OTMS
OH
O
OTMS
O
2c, 98%,b α/β = 2:1
base
2d, 85%,c β only
TMSOAc (8.0 equiv)
TMSO
TMSO
HO
HO
TMSO
OTMS
O
TMSO
OMe
OTMS
O
HO
25 °C, 8 h
TMSO
TMSO
TMSO
TMSO
OMe
O
TMSO
TMSO
2a
1a
OTBS
OTMS
TMSO
N3
OTMS
OTMS
2g, 98%,d β only
2e, 92%,b α/β = 2:1
2f, 93%,b α only
Entry
Base (equiv)
Yield (%)
O
O
OTMS
TMSO
OTMS
TMSO
O
1
–
NR
33
50
NR
83
88
91
76
82
68
35
55
85
80
TMSO
TMSO
TMSO
STol
NPhth
2
DMAP (4.0)
imidazole (4.0)
pyridine (4.0)
DBU (4.0)
piperidine (4.0)
TEA (4.0)
TEA (2.0)
TEA (6.0)
TEA (4.0)
TEA (4.0)
TEA (4.0)
TEA (4.0)
TEA (4.0)
TMSO
OTMS
TMSO
OTMS
2i, 99%,e α/β = 1:1
2h, trace
2j-2, 99%,e α only
3
O
OTMS
OTMS
Ph
O
O
O
O
OTMS
4
TMSO
TMSO
TMSO
TMSO
TMSO
TMSO
OMe
5
OTMS
2l, 95%,e α/β = 2:3
2m, 97%,f α only
2k, 99%,e α/β = 1:1
6
7
Scheme 3 Trimethylsilylation of a variety of saccharides with TEA and
TMSOAc. a TMSOAc (10.0 equiv) and TEA (6.0 equiv) were used at 40 °C
for 4 h; b TMSOAc (10.0 equiv) and TEA (5.0 equiv) were used at 25 °C
for 8 h. c TMSOAc (8.0 equiv) and TEA (4.0 equiv) were used at 25 °C for
24 h; d TMSOAc (6.0 equiv) and TEA (3.0 equiv) were used at 25 °C for 8
h; e TMSOAc (8.0 equiv) and TEA (4.0 equiv) were used at 25 °C for 8 h;
f TMSOAc (4.0 equiv) and TEA (2.0 equiv) were used at 25 °C for 8 h.
8
9
10a
11b
12c
13d
14e
by the reaction of PTA and HMDS, or the protection by
TMSOAc with base, only side-products of NH3 or AcOH are
formed, and these by-products can be removed easily by
extraction or vacuum to acquire the desired product.
a Reaction time: 4 h.
b Reaction time: 12 h.
c Reaction temperature: 0 °C.
d Reaction temperature: 40 °C.
e TMSOAc (10.0 equiv) was used.
In conclusion, this study demonstrated the exceptional-
ly well catalysis for the trimethylsilylation of a variety of
pyranoses and furanoses by PTA with major advantages in
the catalyst’s mild reaction conditions and thermal stabili-
ty. In addition, the PTA can also be recovered by simple fil-
tration and reused in a high yield. We also found a novel re-
agent, TMSOAc, for the trimethylsilylation of carbohydrates
under base conditions with the advantages of being com-
mercially available and cheap. Most importantly, the acetic
acid by-product can be removed by rotary evaporation. In
summary, we believe that the two synthetic conditions for
silyl ether formation of carbohydrates reported here would
be friendly for the generation of their silylated products.
After optimizing the conditions of our proposed meth-
od, we next turned to screen the same compounds used in
Scheme 2 (Scheme 3), which can also be easily trimethylsi-
lylated with TMSOAc. Gratifyingly, TMS-protected general
pyranoses could successfully afford the product in good to
excellent yields (85–99%, 2b–g). Unexpectedly, when the
starting material was 1h, the yield was not well. It is specu-
lated that the oxygen anion activity is lower under alkaline
conditions, which results in its poor activity, because NPhth
is an electron-withdrawing group. To further demonstrate
the efficiency of this new method for carbohydrates, we
performed the reaction with several furanoses. Excellent
yields were obtained for all of the examples (2i–l). Since
TMSOAc will produce AcOH as a by-product, in order to test
the tolerance of benzylidene to this reagent, we also tried
1m for the reaction. To our delight, the reaction could
smoothly produce a high yield of product 2m (97%).
The reactions with TMSOAc were conducted in a flame-dried glass-
ware under N2 atmosphere. DCM, THF, toluene, MeOH, and DMF were
purified and dried from a safe purification system containing activat-
ed Al2O3. All reagents were purchased from commercial sources and
used without purification, unless otherwise mentioned. Flash column
chromatography was carried out on Silica Gel 60. TLC was performed
on pre-coated glass plates of Silica Gel 60 F254; detection was executed
by spraying with a solution of Ce(NH4)2(NO3)6 (0.5 g), (NH4)6Mo7O24
(24.0 g), and H2SO4 (28.0 mL) in H2O (500.0 mL) and heating on a hot
plate. Optical rotations were measured at 589 nm (Na). 1H and 13C
NMR spectra were recorded with 400 MHz instruments. Chemical
Finally, the saccharides with free OH and their different
acid-base conditions can be adjusted according to experi-
mental needs, the OH on the saccharides are protected by
TMS to obtain the carbohydrate derivatives. Following an
already described methodology that the product obtained
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G

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J.-S. Chen et al.
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Synthesis
shifts are in ppm from Me4Si generated from the CDCl3 lock signal at
 = 7.26. Mass spectra were analyzed on orbitrap instrument with an
ESI source.
1,2,3,4,6-Penta-O-trimethylsilyl--D-glucopyranoside (2c)
Prepared according to the general procedure 1; colorless oil; yield:
553.6 mg (92%),  only; Rf = 0.50 (EtOAc/hexane 1:18); []D29 +76.00 (c
1.2, DCM).
Trimethylsilylation of Sugars by PTA-Catalyzed HMDS; General
Procedure 1
1H NMR (CDCl3, 400 MHz):  = 5.00 (d, J = 3.2 Hz, 1 H), 3.77 (t, J = 8.8
Hz, 1 H), 3.74–3.63 (m, 3 H), 3.40 (t, J = 8.8 Hz, 1 H), 3.33 (dd, J = 9.0,
3.0 Hz, 1 H), 0.17 (s, 9 H), 0.15 (s, 18 H), 0.13 (s, 9 H), 0.11 (s, 9 H).
13C NMR (CDCl3, 100 MHz):  = 93.9, 74.2, 74.0, 72.5, 72.2, 62.3, 1.3,
0.9, 0.4, 0.2, –0.3.
To a solution of 1a–m (200 mg, 1.0 equiv) and PTA (0.25 equiv) in
DCM (10 mL) were added HMDS (0.625 equiv/OH) and stirred at 60 °C
for 2 h. After removal of the solvent by rotorary evaporation, PTA was
filtered and recovered. The residue was diluted with hexane and the
hexane layer was washed with sat. NaHCO3 (3 ×). The hexane layer
was dried (anhyd MgSO4) and filtered. Evaporating the organic layer
in vacuum furnished the desired product 2a–m (Scheme 2).
HRMS (ESI): m/z [M + Na]+ calcd for C21H52O6Si5Na: 563.2508; found:
563.2542.
4-Methylphenyl-2,3,4,6-tetra-O-trimethylsilyl-1-thio--D-galacto-
pyranoside (2d)
Trimethylsilylation of Sugars with TEA and TMSOAc; General Pro-
cedure 2
Prepared according to the general procedure 1; colorless oil; yield:
401.5 mg (99%); Rf = 0.65 (EtOAc/hexane 1:11); []D –31.8 (c 1.0,
DCM).
1H NMR (CDCl3, 400 MHz):  = 7.41 (d, J = 8.2 Hz, 1 H), 7.07 (d, J = 8.0
Hz, 1 H), 4.51 (d, J = 9.2 Hz, 1 H), 3.94–3.89 (m, 1 H), 3.65 (d, J = 3.2 Hz,
1 H), 3.64 (d, J = 1.2 Hz, 1 H), 3.47–3.41 (m, 1 H), 2.31 (s, 3 H), 0.17 (s,
9 H), 0.16 (s, 9 H), 0.14 (s, 9 H), 0.10 (s, 9 H).
29
To a solution of 1a–m (200 mg, 1.0 equiv) and TEA (1.0 equiv/OH)
were added TMSOAc (2.0 equiv/OH) and the mixture was stirred for 8
h under N2 atmosphere. The mixture was diluted with hexane and the
hexane layer was washed with sat. NaHCO3 (3 ×) and brine (3 ×). The
hexane layer was dried (anhyd MgSO4) and filtered. Evaporating the
organic layer in vacuum furnished the desired product 2a–m (Scheme
3).
13C NMR (CDCl3, 100 MHz):  = 136.4, 131.7, 130.8, 129.3, 89.9, 79.0,
77.1, 71.5, 70.6, 61.1, 21.0, 1.2, 0.7, 0.5, –0.5.
HRMS (ESI): m/z [M + Na]+ calcd for C25H50O5SSi4Na: 597.2354; found:
Reusable Procedure of PTA Catalyst
To further develop a reusability method of PTA catalyst, PTA was re-
covered from the reaction system by simple filtration after the com-
pletion of each run, and washed with EtOAc. Then PTA was dissolved
in H2O (10 mL, per gram of PTA) and stirred with Amberlite® IR 120 H
(3.0 g, per gram of PTA) overnight, filtered, and dried under vacuum
prior to its reuse for the next reaction cycle under the identical reac-
tion conditions.
597.2380.
1,2,3,4,6-Penta-O-trimethylsilyl-D-galactopyranoside (2e)
Prepared according to the general procedure 1; colorless oil; yield:
484.5 mg (81%); / = 32:5; Rf = 0.49 (EtOAc/hexane 1:30); []D
+76.9 (c 1.0, DCM).
1H NMR (CDCl3, 400 MHz):  = 5.04 (d, J = 2.0 Hz, 1 H), 4.40 (d, J = 7.2
Hz, 0.16 H), 3.90 (m 2 H), 3.81 (s, 2 H), 3.62 (t, J = 8.8 Hz, 1 H), 3.53
(dd, J = 9.6, 5.6 Hz, 1 H), 0.14 (s, 18 H), 0.13 (s, 9 H), 0.11 (s, 9 H), 0.10
(s, 9 H).
13C NMR (CDCl3, 100 MHz):  = 94.5, 72.2, 71.1, 70.5, 69.9, 61.1, 0.5,
0.4, 0.2, 0.0, –0.6.
29
Methyl-2,3,4,6-tetra-O-trimethylsilyl--D-glucopyranoside (2a)
Prepared according to the general procedure 1; colorless oil; yield:
29
496.5 mg (99%); Rf = 0.52 (EtOAc/hexane 1:9); []D +97.09 (c 1.1,
DCM)
1H NMR (CDCl3, 400 MHz):  = 4.61 (d, J = 3.6 Hz, 1 H), 3.75 (t, J = 8.6
Hz, 2 H), 3.67 (dd, J = 11.6, 5.2 Hz, 1 H), 3.53–3.40 (m, 3 H), 3.34 (s, 3
H), 0.16 (s, 9 H), 0.15 (s, 9 H), 0.15 (s, 9 H), 0.12 (s, 9 H).
HRMS (ESI): m/z [M + Na]+ calcd for C21H52O6Si5Na: 563.2508; found:
563.2610.
13C NMR (CDCl3, 100 MHz):  = 99.5, 75.1, 73.8, 71.8, 71.6, 61.9, 54.3,
1.2, 0.7, 0.4, –0.4.
1,2,3,4,6-Penta-O-trimethylsilyl--D-mannopyranoside (2f)
Prepared according to the general procedure 1; colorless oil; yield:
597.7 mg (99%);  only; Rf = 0.57 (EtOAc/hexane 1:22).
1H NMR (CDCl3, 400 MHz):  = 4.85 (d, J = 1.6 Hz, 1 H), 3.84–3.76 (m, 2
H), 3.68 (d, J = 3.2 Hz, 2 H), 3.60 (t, J = 2.0 Hz, 1 H), 3.54–3.49 (m, 1 H),
0.10 (s, 9 H), 0.09 (s, 9 H), 0.06 (s, 9 H), 0.05 (s, 9 H).
13C NMR (CDCl3, 100 MHz):  = 95.5, 75.2, 74.6, 72.1, 68.1, 62.3, 0.6,
0.5, 0.2, –0.3.
HRMS (ESI): m/z [M + Na]+ calcd for C21H52O6Si5Na: 563.2508; found:
HRMS (ESI): m/z [M + Na]+ calcd for C19H46O6Si4Na: 505.2269; found:
505.2268.
p-Tolyl-2,3,4,6-tetra-O-trimethylsilyl-1-thio--D-glucopyranoside
(2b)
Prepared according to the general procedure 1; white solid; yield:
28
359.1 mg (90%); mp 66–68 °C; Rf = 0.53 (EtOAc/hexane 1:22); []D
–44.50 (c 1.2, DCM).
1H NMR (CDCl3, 400 MHz):  = 7.43 (d, J = 8.0 Hz, 2 H), 7.07 (d, J = 8.0
Hz, 2 H), 4.58–4.53 (m, 1 H), 3.79 (dd, J = 11.0, 2.2 Hz, 1 H), 3.63 (dd,
J = 11.2 , 6.4 Hz, 1 H), 3.44 (t, J = 5.4 Hz, 3 H), 3.28–3.23 (m, 1 H), 2.32
(s, 3 H), 0.24 (s, 9 H), 0.17 (s, 9 H), 0.16 (s, 9 H), 0.11 (s, 9 H).
563.2542.
tert-Butyldimethylsilyl-2-azido-2-deoxy-3,4,6-tri-O-trimethyl-
silyl--D-glucopyranoside (2g)
13C NMR (CDCl3, 100 MHz):  = 136.7, 131.9, 131.1, 129.4, 89.7, 81.1,
79.9, 75.2, 71.6, 62.6, 21.1, 1.7, 1.4, 0.9, –0.3.
Prepared according to the general procedure 1; white solid; yield:
329.6 mg (98%); mp 37–39 °C; Rf = 0.67 (EtOAc/hexane 1:22); []D
28
+8.545 (c 1.1, DCM)
HRMS (ESI): m/z [M + Na]+ calcd for C25H50O5SSi4Na: 597.2354; found:
597.2351.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G

F
J.-S. Chen et al.
Paper
Synthesis
1H NMR (CDCl3, 400 MHz):  = 4.48 (d, J = 7.6 Hz, 1 H), 3.72 (m, 2 H),
3.58 (dd, J = 9.4, 8.6 Hz, 1 H), 3.24 (dd, J = 9.8, 8.6 Hz, 1 H), 3.14–3.06
(m, 2 H), 0.93 (s, 9 H), 0.19 (s, 9 H), 0.15 (s, 6 H), 0.14 (s, 9 H), 0.10 (s, 9
H).
1H NMR (CDCl3, 400 MHz):  = 4.82 (d, J = 3.2 Hz, 1 H), 3.79 (m, 1 H),
3.74 (dd, J = 7.8, 2.6 Hz, 1 H), 3.61 (t, J = 2.8 Hz, 1 H), 3.60–3.56 (m, 1
H), 3.50 (dd, J = 11.2, 8.4 Hz, 1 H), 0.13 (s, 9 H), 0.12 (s, 18 H), 0.10 (s, 9
H).
13C NMR (CDCl3, 100 MHz):  = 97.3, 76.7, 76.5, 71.4, 69.9, 61.6, 25.6,
13C NMR (CDCl3, 100 MHz):  = 95.6, 74.3, 72.6, 68.5, 64.0, 0.4, 0.3,
17.9, 0.9, 0.7, –0.4, –4.3, –5.3.
0.02, –0.2.
HRMS (ESI): m/z [M + Na]+ calcd for C21H49N3O5Si4Na: 558.2647;
HRMS (ESI): m/z [M + Na]+ calcd for C17H43O5Si4Na: 461.2007; found:
found: 558.2648.
461.2011.
2-Deoxyl-4-methylphenyl-2-phthalimido-1-thio-3,4,6-tri-O-
trimethylsilyl--D-glucopyranoside (2h)
1,2,3,5-Tetra-O-trimethylsilyl-D-ribofuranoside (2k)
Prepared according to the general procedure 1; colorless oil; yield:
582.5 mg (96%); / = 1:2; Rf = 0.65 (EtOAc/ hexane 1:22); []D
–16.833 (c 1.2, DCM).
29
Prepared according to the general procedure 1; white solid; yield:
279.3 mg (92%); mp 123–125 °C; Rf = 0.35 (EtOAc/hexane 1:9); []D
29
+46.7 (c 1.0, DCM).
1H NMR (CDCl3, 400 MHz):  = 4.85 (d, J = 3.6 Hz, 0.52 H), 4.75 (d, J =
7.2 Hz, 1 H), 3.99 (t, J = 10.4 Hz, 0.74 H), 3.87 (s, 0.54 H), 3.87 (s, 1 H),
3.68 (s, 0.68 H), 3.67 (d, J = 2.8 Hz, 1 H), 3.65–3.59 (m, 1 H), 3.52–3.44
(m, 1 H), 3.42–3.40 (t, J = 3.4 Hz, 0.55 H), 3.22 (dd, J = 7.2, 3.2 Hz, 1 H),
3.20–3.16 (m, 0.66 H), 0.14 (s, 9 H), 0.12 (s, 6 H), 0.12 (s, 9 H), 0.11 (s,
9 H), 0.10 (s, 9 H), 0.10 (s, 8 H), 0.09 (s, 4 H).
1H NMR (CDCl3, 400 MHz):  = 7.99 (d, J = 22.4 Hz, 2 H), 7.88 (s, 2 H),
7.42–7.37 (m, 2 H), 7.14 (d, J = 8 Hz, 2 H), 5.58 (d, J = 10 Hz, 1 H), 4.54
(t, J = 9.2 Hz, 1 H), 4.31 (t, J = 10.2 Hz, 1 H), 3.94 (dt, J = 11.6, 7.2 Hz, 3
H), 3.83 (t, J = 9.0 Hz, 1 H), 3.52 (d, J = 7.8 Hz, 1 H), 2.42 (s, 3 H), 0.32 (s,
9 H), 0.29 (s, 9 H), 0.01 (s, 9 H).
13C NMR (CDCl3, 100 MHz):  = 137.7, 134.1, 132.8, 131.9, 129.4,
13C NMR (CDCl3, 100 MHz):  = 94.7, 92.6, 74.9, 73.8, 73.6, 70.6, 63.8,
123.6, 123.12, 83.7, 80.7, 74.7, 72.5, 61.8, 56.8, 21.1, 0.84, 0.76, –0.2.
58.1, 0.5, 0.4, 0.3, –0.02, –0.06, –0.18.
HRMS (ESI): m/z [M + Na]+ calcd for C30H45NO6SSi3Na: 654.2173;
HRMS (ESI): m/z [M]+ calcd for C17H43O5Si4: 439.2188; found:
found: 654.2177.
439.2187.
1,2,3,5-Tetra-O-trimethylsilyl--D-xylofuranoside (2i)
1,2,3,5-Tetra-O-trimethylsilyl--D-arabinofuranoside (2l)
Prepared according to the general procedure 1; white solid; yield:
581.3 mg (99%); mp 36–38 °C;  only; Rf = 0.49 (EtOAc/hexane 1:22);
[]D30 +69.8 (c 1.0, DCM).
Prepared according to the general procedure 1; colorless oil; yield:
531.2 mg (91%);  only; Rf = 0.45 (EtOAc/hexane 1:22); []D29 –54.33
(c 1.0, DCM).
1H NMR (CDCl3, 400 MHz):  = 4.93 (d, J = 3.2 Hz, 1 H), 3.69 (t, J = 8.4
Hz, 1 H), 3.64 (t, J = 10.0 Hz, 1 H), 3.53–3.46 (m, 1 H), 3.43 (dd, J = 10.2,
5.4 Hz, 1 H), 3.34 (dd, J = 9.0, 3.0 Hz, 1 H), 0.15 (s, 9 H), 0.13 (s, 9 H),
0.12 (s, 18 H).
13C NMR (CDCl3, 100 MHz):  = 94.2, 74.12, 74.07, 71.9, 62.3, 0.9, 0.4,
0.3, 0.2.
1H NMR (CDCl3, 400 MHz):  = 4.95 (d, J = 2.4 Hz, 1 H), 3.86–3.82 (m, 1
H), 3.73–3.63 (m, 3 H), 3.43 (dd, J = 11.2, 5.6 Hz, 1 H), 0.07 (s, 9 H),
0.06 (s, 9 H), 0.05 (s, 9 H), 0.05 (s, 9 H).
13C NMR (CDCl3, 100 MHz):  = 94.0, 71.3, 70.0, 64.1, 0.2, 0.1, –0.1.
HRMS (ESI): m/z [M]+ calcd for C17H43O5Si4: 439.2188; found:
439.2186.
HRMS (ESI): m/z [M]+ calcd for C17H43O5Si4: 439.2188; found:
439.2183.
Methyl-4,6-O-benzylidene-2,3-di-O-trimethylsilyl--D-glucopyra-
noside (2m)
1,2,3,5-Tetra-O-trimethylsilyl--D-lyxopyranoside (2j-1)
Prepared according to the general procedure 1; colorless oil; yield:
Prepared according to the general procedure 1; colorless oil; yield:
577.5 mg (99%);  only; Rf = 0.44 (EtOAc/hexane 1:22); []D29 +20.636
(c 1.1, DCM).
1H NMR (CDCl3, 400 MHz):  = 4.61 (s, 1 H), 3.91–3.84 (m, 1 H), 3.81
(dd, J = 11.2, 5.2 Hz, 1 H), 3.69–3.66 (m, 1 H), 3.36 (dd, J = 8.4, 2.8 Hz, 1
H), 3.06 (dd, J = 11.2, 9.6 Hz, 1 H), 0.14 (s, 9 H), 0.13 (s, 18 H), 0.10 (s, 9
H).
285 mg (94%); Rf = 0.37 (EtOAc/hexane 1:9); []D29 +44.5 (c 1.2, DCM).
1H NMR (CDCl3, 400 MHz):  = 7.51–7.47 (m, 2 H), 7.38–7.32 (m, 3 H),
5.51 (s, 1 H), 4.62 (d, J = 3.6 Hz, 1 H), 4.27 (dd, J = 10, 4.6 Hz, 1 H), 3.96
(t, J = 9.0 Hz, 1 H), 3.80 (dd, J = 10, 4.8 Hz, 1 H), 3.71 (t, J = 10.2 Hz, 1
H), 3.62 (dd, J = 8.8, 4.0 Hz, 1 H), 3.42 (s, 3 H), 0.18 (s, 9 H), 0.10 (s, 9
H).
13C NMR (CDCl3, 100 MHz):  = 128.8, 128.1, 126.1, 101.7, 101.0, 82.1,
74.1, 71.7, 69.1, 62.3, 55.4, 0.7, 0.3.
13C NMR (CDCl3, 100 MHz):  = 95.7, 75.0, 74.6, 67.6, 66.1, 0.5, 0.3,
0.08, 0.02.
HRMS (ESI): m/z [M + Na]+ calcd for C20H34O6Si2Na: 449.1792; found:
449.1779.
HRMS (ESI): m/z [M + Na]+ calcd for C17H43O5Si4Na: 461.2007; found:
461.2011.
1,2,3,5-Tetra-O-trimethylsilyl--D-lyxofuranoside (2j-2)
Funding Information
Prepared according to the general procedure 2; colorless oil; yield:
577.7 mg (99%);  only; Rf = 0.81 (EtOAc/hexane 1:18); []D29 +183.0
(c 1.0, DCM).
The authors thank the Ministry of Science and Technology (MOST) in
Taiwan (MOST 107-2113-M-005-021) and National Chung Hsing Uni-
versity for financial support.
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G

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J.-S. Chen et al.
Paper
Synthesis
Acknowledgment
(11) Fukumoto, Y.; Hirano, M.; Chatani, N. ACS Catal. 2017, 7, 3152.
(12) (a) Yoshikawa, M.; Tamura, Y.; Wakabayashi, R.; Tamai, M.;
Shimojima, A.; Kuroda, K. Angew. Chem. Int. Ed. 2017, 56, 13990.
(b) Wang, C. C.; Lee, J. C.; Luo, S. Y.; Kulkarni, S. S.; Huang, Y. W.;
Lee, C. C.; Chang, K. L.; Hung, S. C. Nature 2007, 446, 896.
(c) Chang, K.-L.; Zulueta, M. M. L.; Lu, X.-A.; Zhong, Y.-Q.; Hung,
S.-C. J. Org. Chem. 2010, 75, 7424. (d) Huang, T.-Y.; Zulueta, M.
M. L.; Hung, S.-C. Org. Lett. 2011, 13, 1506. (e) Patil, P. S.; Lee, C.-
C.; Huang, Y.-W.; Zulueta, M. M. L.; Hung, S.-C. Org. Biomol.
Chem. 2013, 11, 2605. (f) Huang, Y.-W.; Zulueta, M. M. L.; Hung,
S.-C. Org. Biomol. Chem. 2014, 12, 376. (g) Chen, C. W.; Wang, C.
C.; Li, X. R.; Witek, H.; Mong, K.-K. T. Org. Biomol. Chem. 2020,
18, 3135.
J.-S.C. and S.-Y.L. designed the research. J.-S.C. and Y.-F.K. optimized
conditions for the reactions listed in Table 1. Y.-F.K. and W.L. prepared
compounds 2a–m of Scheme 2. Y.-F.K. prepared the recovery and re-
use of PTA for Figure 1. H.-Y.L. and Y.-F.K. optimized conditions for the
reactions shown in Table 2. H.-Y.L. and W.-C.Y. prepared compounds
2a–m of Scheme 3. H.R.W. analyzed the mass data. J.-S.C. wrote the
manuscript with the help of S.-Y.L.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1705990.
(13) (a) Seddighi, M.; Shirini, F.; Goli-Jolodar, O. RSC Adv. 2016, 6,
23564. (b) Nikbakht, F.; Ghonchepour, E.; Ziyadi, H.; Heydari, A.
RSC Adv. 2014, 4, 34428. (c) Moghadam, M.; Tangestaninejad, S.;
Mirkhani, V.; Mohammadpoor Baltork, I.; Gharaati, S. Appl.
Organomet. Chem. 2009, 23, 446.
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G