Deprotection of silyl ethers by using SO3H silica gel: Application to sugar, nucleoside, and alkaloid derivatives

Article abstract of DOI:10.1016/j.tet.2017.07.047

We applied a desilylation procedure using SO₃H silica gel, with the surface modified by alkylsulfonic acid groups, to silylated sugar, nucleoside, and alkaloid derivatives. The treatment with SO₃H silica gel provided desilylated products in good to excellent yield. In the reactions of sugar and nucleoside derivatives, no silyl residue was detected in the crude products, but the crude products of the reaction of alkaloids contained small amounts of silyl residues. Even though the sugar and nucleoside derivatives had a labile glycosyl and C–N bond, respectively, these bonds tolerated the reaction conditions. These outcomes suggested that the desilylation procedure using SO₃H silica gel would be applicable to the deprotection of a variety of types of compounds protected by silyl groups. In a gram scale experiment, the desilylation procedure successfully proceeded without the observation of any silyl residue in the crude product.

Full text of DOI:10.1016/j.tet.2017.07.047

Accepted Manuscript
Deprotection of silyl ethers by using SO H silica gel: Application to sugar, nucleoside,
3
and alkaloid derivatives
Hideaki Fujii, Naoyuki Shimada, Masaki Ohtawa, Fumika Karaki, Masayoshi
Koshizuka, Kohei Hayashida, Mitsuhiro Kamimura, Kazuishi Makino, Tohru
Nagamitsu, Hiroshi Nagase
PII:
S0040-4020(17)30789-5
10.1016/j.tet.2017.07.047
TET 28879
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 May 2017
Revised Date: 20 July 2017
Accepted Date: 26 July 2017
Please cite this article as: Fujii H, Shimada N, Ohtawa M, Karaki F, Koshizuka M, Hayashida K,
Kamimura M, Makino K, Nagamitsu T, Nagase H, Deprotection of silyl ethers by using SO H silica
3
gel: Application to sugar, nucleoside, and alkaloid derivatives, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.07.047.
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ACCEPTED MANUSCRIPT
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Deprotection of silyl ethers by using SO3H
silica gel: Application to sugar, nucleoside,
and alkaloid derivatives
Leave this area blank for abstract info.
Hideaki Fujii, Naoyuki Shimada, Masaki Ohtawa, Fumika Karaki, Masayoshi Koshizuka, Kohei Hayashida, Mitsuhiro
Kamimura, Kazuishi Makino, Tohru Nagamitsu, Hiroshi Nagase
O
NH
CH2OTBS
N
TBSO
OTBS
N
O
O
O
BzO
BzO
Cl
BzO
OTBS
TBSO
Cl
OMe
Excellent yield
Mild conditions
No purification process
Gram scale experiment
✓
✓
✓
✓
Sugar
Nucleoside
Alkaloide
O
SO3H
Si
CH2OH
NH
N
OH
HO
N
O
O
O
BzO
BzO
Cl
BzO
Cl
OMe
OH
OH

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Deprotection of silyl ethers by using SO3H silica gel: Application to sugar, nucleoside,
and alkaloid derivatives
Hideaki Fujii,a,b,* Naoyuki Shimada,b,c Masaki Ohtawa,b,d Fumika Karaki,a,b Masayoshi Koshizuka,c Kohei
Hayashida,a Mitsuhiro Kamimura,e Kazuishi Makino,b,c Tohru Nagamitsu,b,d Hiroshi Nagasea,1
a Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
b Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
c Laboratory of Organic Chemistry for Drug Development, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
d Laboratory of Synthetic Natural Products Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
e FUJI SILYSIA CHEMICAL LTD., 1846, 2-Chome, Kozoji-Cho, Kasugai-Shi, Aichi, 487-0013, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We applied a desilylation procedure using SO3H silica gel, with the surface modified by
alkylsulfonic acid groups, to silylated sugar, nucleoside, and alkaloid derivatives. The treatment
with SO3H silica gel provided desilylated products in good to excellent yield. In the reactions of
sugar and nucleoside derivatives, no silyl residue was detected in the crude products, but the
crude products of the reaction of alkaloids contained small amounts of silyl residues. Even
though the sugar and nucleoside derivatives had a labile glycosyl and C-N bond, respectively,
these bonds tolerated the reaction conditions. These outcomes suggested that the desilylation
procedure using SO3H silica gel would be applicable to the deprotection of a variety of types of
compounds protected by silyl groups. In a gram scale experiment, the desilylation procedure
successfully proceeded without the observation of any silyl residue in the crude product.
Available online
Keywords:
desilylation
SO3H silica gel
solid-supported catalyst
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
The synthetic processes to obtain chemical products,
pharmaceutical products, agrichemicals, etc. have recently been
required to use environmentally benign processes. From such a
viewpoint, solid-supported reagents have been widely used in
organic synthesis.1 We have also already developed and reported
the desilylation process using a silica gel (SO3H silica gel)2
whose surface was modified by alkylsulfonic acid groups.3 The
SO3H silica gel could be repeatedly used for the desilylation
without complicated pretreatment before its reuse. Furthermore,
the desilylation procedure did not require a purification process
because the silyl residues formed during the deprotection were
captured by the silanol groups on the surface of the silica gel
(Scheme 1).2 This feature was observed in the 10th repeated use
of the SO3H silica gel.4 We attempted to apply the desilylation
process to various types of compounds. Herein, we report the
application of a SO3H silica gel to the deprotection of silyl ethers
in sugar, nucleoside, and alkaloid derivatives.
Scheme 1. The deprotection of silyl ethers using SO3H silica
gel.
2. Results and Discussion
2.1. Deprotection of silyl ethers in sugar derivatives
We attempted to apply our desilylation procedure to sugar
derivatives. Glucose, mannose, and galactose derivatives 1a–3a
were selected as silylated sugars. The treatment of 1a–3a with
SO3H silica gel provided the desilylated compounds 1b–3b in
excellent yields (Scheme 2). It was possible to use various
solvents in this procedure, although we have reported that
heptane was optimal.2 Desilylation of 1a using heptane gave the
desilylated product 1b in 98% yield (Scheme 2), whereas the
product 1b was obtained in 92% and 95% yield in the
experiments using toluene and dichloromethane, respectively. It
is noteworthy that neither cleavage of the glycosyl bond nor
epimerization were observed under these reaction conditions,
* Corresponding author. Tel: +81 3 5791 6372; fax: +81 3 3442
5707; E-mail address: fujiih@pharm.kitasato-u.ac.jp
1 Present address: International Institute for Integrative Sleep
Medicine, University of Tsukuba, 1−1−1 Tennodai, Tsukuba,
Ibaraki 305−8577, Japan.

2
Tetrahedron
ACCEPTED MANUSCRIPT
NH2
N
N
N
TBSO
N
O
TBSO
OTBS
8a
Figure 1. Structure of an adenosine derivative 8a.
OH
OH
N
N
SO3H silica gel
50 ºC, 2h
conversion: quant.
yield: 95%
OH
OH
O
O
OTBS
OH
9a
9b
Scheme 4. Desilylation of a morphinane derivative.2
Scheme 2. Desilylation of silylated sugar derivatives.
O
O
N
Me
NH
Me
NH
SO3H silica gel
TBSO
HO
N
O
O
Scheme 5. Desilylation of a silylated proline derivative.
rt, 27h
conversion: quant.
yield: 82%
O
O
OTBS
5a
OH
5b
2.2. Deprotection of silyl ethers in nucleoside derivatives
O
N
O
N
NH
NH
SO3H silica gel
We next attempted desilylation of nucleoside derivatives 5a-8a.
Ethyl acetate was used as a solvent due to the solubility of
nucleoside derivatives 5a and 6a. Even though the C-N bond in
the nucleosides is also labile under strong acid conditions, the
desilylated compounds thymidine (5b) and uridine (6b) were
obtained in excellent yields without the cleavage of the C-N bond
(Scheme 3). No mono- and/or di-silyl derivatives were detected
after the indicated reaction time. The crude products of these
reactions contained no silyl residue. In the case of compound 7a,
chloroform was used as solvent (Scheme 3). The primary siloxy
group was cleaved effectively under our conditions to afford
alcohol 7b in quantitative yield. These results suggested that a
primary siloxy group could be cleaved for short reaction time
whereas the cleavage of a secondary siloxy group required longer
reaction time. Indeed, the progress of the deprotection of the
silylated adenosine derivative 8a5 bearing two secondary siloxy
groups and a primary one (Fig. 1) was slow. The starting material
8a was disappeared after a while, which suggested the
desilylation of a primary siloxy group would be complete, but
mono- and di-silyl derivatives were observed even after 24 hours.
The prolongation of the reaction time (72 hour) furnished the
decomposition of the compounds. It is not clear at present why
silylated adenosine 8a withstood our desilylation conditions, but
the observed decomposition of the compounds was not unnatural
because it is known that purine bases are better leaving groups
than pyrimidine bases.
O
O
TBSO
HO
rt, 15h
conversion: quant.
yield: 88%
O
O
OTBS
OH
OH
TBSO
6a
6b
NBz2
N
NBz2
N
N
N
N
N
SO3H silica gel
TBSO
HO
N
N
rt, 2h
conversion: quant.
yield: quant.
O
O
BzO
BzO
BzO
BzO
7a
7b
Scheme 3. Desilylation of silylated nucleoside derivatives.
even though the glycosyl bond is generally cleavable under the
acidic conditions via the oxocarbenium ion. The fact that no 1-
epimers of 1b–3b were obtained strongly suggested that the
corresponding oxocarbenium ion may not be formed at all during
the desilylation. Galactose derivative 4a, which had the
secondary hydroxy group protected by a TBS group, was
successfully converted into deprotected compound 4b. Although
this conversion required a long reaction time, only the starting
compound 4a was recovered in 8% and no anomerization was
observed. The steric constraint around the secondary siloxy group
would retard the progression of the deprotection. One of the
features of our desilylation method was that no purification
process was required because silyl residues produced during the
reaction were captured by the silanol groups on the surface of the
silica gel. These phenomena were observed by the solid phase
29Si NMR experiments.2 In all cases of silylated sugars, no silyl
residue was detected in the crude products.
2.3. Deprotection of silyl ethers in alkaloid derivatives

We have recently reported that a siloxy group of a morphinan
outcomes suggested that the desilylation procedure using SO3H
silica gel would be applicable to the deprotection of various types
of compounds protected by silyl groups. In a gram scale
experiment, the desilylation procedure successfully proceeded
without the observation of any silyl residue in the crude product.
ACCEPTED MANUSCRIPT
derivative was effectively cleaved under our deprotection method
(Scheme 4).2 As another alkaloid derivative, we chose proline
derivatives. Proline derivatives are useful compounds because
they are used not only as organic catalysts,6 but also as
OTBS
OH
4. Experimental section
O
O
BzO
BzO
BzO
BzO
4.1. General
rt
BzO
BzO
OMe
OMe
All reagents and solvents were obtained from commercial
suppliers and were used without further purification. Infrared
(IR) spectra were recorded on a JASCO FT/IR-460Plus. Nuclear
magnetic resonance (NMR) spectra were recorded on an Agilent
Technologies VXR-400NMR for 1H NMR and 13C NMR.
Chemical shifts were reported as δ values (ppm) reference to
tetramethylsilane. Mass spectra (MS) were obtained on JMS-
AX505HA, JMS-700 MStation, or JMS-100LP instrument by
applying an electrospray ionization (ESI) method. The progress
of the reaction was determined on Merck Silica Gel Art. 5715
(TLC). Silica gel was purchased from Fuji Silysia
(CHROMATOREX® PSQ 60B (60 µm) and SCAVENGER
SO3H SILICA).
3a
3b
1.14 g
SO3H silica gel (935 mg)
SO3H silica gel (500 mg)
835 mg (90%)
48.3 mg (87%)
62.1 mga
Scheme 6. Desilylation of 3a in a gram scale. a This experiment was
shown in scheme 2.
physiologically active compounds. For example, some
derivatives possessing the proline (substituted pyrrolidine) unit
were reported as nicotinic acetylcholine receptor ligands,7
modulators of G-glycoprotein,8 and so on.9 We attempted to
synthesize compound 10b, which was a possible intermediate for
synthesis of a modulator of G-glycoprotein (Scheme 5).8
Compound 10a, which was prepared from TBS ether of prolinol
by benzylation, was treated with SO3H silica gel using methanol
as a solvent to give 10b in 70% yield. As the desilylation of 10a
was not complete at 50 ˚C, higher reaction temperature was
required for reaction completion. One of the features of our
desilylation method was no silyl residue in the crude product.
However, in the desilylation of alkaloids, some amount of silyl
residue remained in the crude product. Since alkaloids are basic
compounds, SO3H groups immobilized on the silica gel surface
might be partly neutralized to retard the trapping of silyl residues
by silanols.
4.2. Preparation of silylated sugar derivatives 1a–4a
4.2.1. General procedure for the preparation of methyl 2,3,4-tri-
O-benzoyl-6-O-(tert-butyl)dimethylsilyl-α-D-pyranosides 1a–3a
Methyl 6-O-(tert-butyl)dimethylsilyl-α-D-glucopyranoside,
methyl 6-O-(tert-butyl)dimethylsilyl-α-D-mannopyranoside and
methyl
6-O-(tert-butyl)dimethylsilyl-α-D-galactopyranoside
were prepared as a starting material according to the literature
procedures.10,11,12 To a solution of the starting material (500 mg,
1.62 mmol) in pyridine (8 mL) was added benzoyl chloride (0.94
mL, 8.10 mmol) at 0 °C. After stirring for 18 h at ambient
temperature, the solution was poured into a mixture of 1 M HCl
and EtOAc, and extracted with EtOAc. The combined organic
layer was washed with successively with brine, saturated aqueous
NaHCO3 solution and brine, and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo followed by column
chromatography (silica gel, hexane/EtOAc = 10/1) provided the
indicated product.
2.4. Gram scale experiments
A large scale reaction sometimes brings troublesome issues
and often requires further optimization of the reaction conditions.
Therefore, we attempted desilylation of a gram scale of 3a
(Scheme 6). To a solution of 3a (1.14 g) in heptane (4.6 mL) was
added SO3H silica gel (935 mg), which was about a tenth of the
amount of SO3H silica gel compared to the amount of SO3H
silica gel using the other reactions shown in this report. After
shaking for 1 min, the resulting powder was left to stand at
ambient temperature for 24 h. The reaction successfully
proceeded to give desilylated product 3b in 90% yield. In a gram
scale experiment, it was possible to monitor the progress of the
reaction by picking up a small amount of the silica gel. No silyl
residue was observed in a crude product.
4.2.1.1. Methyl 2,3,4-tri-O-benzoyl-6-O-(tert-butyl)dimethylsilyl-
α-D-glucopyranoside (1a)
1
A colorless oil. Yield: 75%. H-NMR (400 MHz, CDCl3): δ
0.02 (s, 3H), 0.03 (s, 3H), 0.88 (s, 9H), 3.47 (s, 3H), 3.81 (d, J =
4.4 Hz, 2H), 4.11 (ddd, J = 10.0, 8.4, 4.0 Hz, 1H), 5.22–5.25 (m,
2H), 5.51 (t, J = 10.0 Hz, 1H), 6.13 (m, 1H), 7.26–7.30 (m, 2H),
7.36–7.44 (m, 5H), 7.49–7.53 (m, 2H), 7.85–7.88 (m, 2H), 7.93–
7.99 (m, 4H). 13C-NMR (100 MHz, CDCl3): δ –5.52, –5.45, 18.2,
25.8, 55.2, 62.5, 69.4, 70.4, 70.7, 72.2, 77.2, 96.7, 128.1, 128.28,
128.29, 129.0, 129.1, 129.3, 129.6, 129.7, 129.8, 132.9, 133.15,
133.21, 165.1, 165.8. HR-MS (ESI): Calcd for C34H40O9SiNa
[M+Na]+: 643.2339. Found 643.2343. IR (neat): 2953, 1730,
1280, 1252, 1108, 709 cm-1.
3. Conclusion
The desilylation of sugar, nucleoside, and alkaloid derivatives
using the SO3H silica gel successfully proceeded to provide the
corresponding desilylated compounds. In the reactions of sugar
and nucleoside derivatives, no silyl residue was detected, but the
crude products of the reaction of alkaloids contained small
amounts of silyl residues. Even though sugar and nucleoside
4.2.1.2. Methyl 2,3,4-tri-O-benzoyl-6-O-(tert-butyl)dimethylsilyl-
α-D-mannopyranoside (2a)
1
A colorless oil. Yield: 91%. H-NMR (400 MHz, CDCl3): δ 0.00
(s, 3H), 0.02 (s, 3H), 0.90 (s, 9H), 3.52 (s, 3H), 3.82–3.90 (m,
2H), 4.11 (m, 1H), 4.97 (d, J = 2.0 Hz, 1H), 5.66 (dd, J = 3.2, 1.6
derivatives had
a labile glycosyl bond and C-N bond,
respectively, these bonds tolerated the reaction conditions. These

4
Tetrahedron
ACCEPTED MANUSCRIPT
4.3.1. Methyl 2,3,4-tri-O-benzoyl-α-D-glucopyranoside (1b)
Hz, 1H), 5.70 (dd, J = 10.4, 3.6 Hz, 1H), 5.95 (t, J = 10.4 Hz,
1H), 7.24–7.28 (m, 2H), 7.36–7.42 (m, 3H), 7.45–7.53 (m, 3H),
7.60 (m, 1H), 7.82–7.85 (m, 2H), 7.94–7.97 (m, 2H), 8.09–8.12
(m, 2H). 13C-NMR (100 MHz, CDCl3): δ –5.52, –5.48, 18.2,
25.8, 55.2, 62.3, 66.9, 70.5, 70.6, 71.4, 98.5, 128.2, 128.4, 128.5,
129.2, 129.42, 129.43, 129.66, 129.72, 129.9, 133.0, 133.2,
133.4, 165.3, 165.52, 165.54. HR-MS (ESI): Calcd for
C34H40O9SiNa [M+Na]+: 643.2339. Found: 643.2339. IR (neat):
2953, 1731, 1279, 1261, 1107, 710 cm-1.
1
A colorless oil. Yield: 98%. H-NMR (400 MHz, CDCl3): δ
2.69 (dd, J = 8.4, 6.0 Hz, 1H), 3.47 (s, 3H), 3.74 (m, 1H), 3.83
(m, 1H), 4.04 (m, 1H), 5.26–5.31 (m, 2H), 5.51 (t, J = 10.0 Hz,
1H), 6.23 (t, J = 9.6 Hz, 1H), 7.26–7.31 (m, 2H), 7.36–7.44 (m,
5H), 7.49–7.56 (m, 2H), 7.87–7.89 (m, 2H), 7.96–7.99 (m, 4H).
13C-NMR (100 MHz, CDCl3): δ 55.6, 61.0, 69.5, 69.8, 70.1, 72.0,
97.1, 128.3, 128.4, 128.5, 128.6, 129.0, 129.2, 129.6, 129.9,
123.0, 165.792, 165.799, 166.4. HR-MS (ESI): Calcd for
C28H26O9Na [M+Na]+: 529.1475. Found: 529.1474. IR (neat):
3537, 2933, 1728, 1281, 1107, 710 cm-1.
4.2.1.3. Methyl 2,3,4-tri-O-benzoyl-6-O-(tert-butyl)dimethylsilyl-
α-D
-galactopyranoside (3a)
1
A colorless oil. Yield: 99%. H-NMR (400 MHz, CDCl3): δ –
4.3.2. Methyl 2,3,4-tri-O-benzoyl-α-D-mannopyranoside (2b)
0.04 (s, 3H), 0.01 (s, 3H), 0.85 (s, 9H), 3.48 (s, 3H), 3.73–3.80
(m, 2H), 4.28 (br t, J = 6.8 Hz, 1H), 5.28 (d, J = 3.6 Hz, 1H),
5.61 (dd, J = 10.0, 3.6 Hz, 1H), 5.95–5.99 (m, 2H), 7.22–7.26 (m,
2H), 7.35–7.39 (m, 2H), 7.42 (m, 1H), 7.47–7.53 (m, 3H), 7.61
(m, 1H), 7.78–7.80 (m, 2H), 7.97–7.99 (m, 2H), 8.06–8.08 (m,
2H). 13C-NMR (100 MHz, CDCl3): δ –5.7, –5.6, 18.1, 25.7, 55.5,
61.3, 68.6, 69.1, 69.4, 69.7, 97.5, 128.1, 128.3, 128.5, 129.26,
129.34, 129.6, 129.7, 129.77, 129.81, 132.9, 133.2, 165.4, 165.5,
166.1. HR-MS (ESI): Calcd for C34H40O9SiNa [M+Na]+:
643.2339. Found 643.2347. IR (neat): 2951, 1730, 1282, 1265,
1108, 839, 711 cm-1.
1
A colorless oil. Yield: 95%. H-NMR (400 MHz, CDCl3): δ
2.64 (br, 1H), 3.52 (s, 3H), 3.77–3.84 (m, 2H), 4.06 (m, 1H), 5.01
(d, J = 1.6 Hz, 1H), 5.68 (dd, J = 3.2, 1.6 Hz, 1H), 5.85 (t, J =
10.0 Hz, 1H), 5.98 (dd, J = 10.0, 3.2 Hz, 1H), 7.24–7.27 (m, 2H),
7.37–7.45 (m, 3H), 7.47–7.55 (m, 3H), 7.61 (m, 1H), 7.81–7.84
(m, 2H), 7.97–8.00 (m, 2H), 8.09–8.12 (m, 2H). 13C-NMR (100
MHz, CDCl3): δ 55.5, 61.4, 67.2, 69.6, 70.5, 70.8, 98.7, 128.3,
128.5, 128.6, 128.7, 129.1, 129.3, 129.7, 129.87, 129.89, 133.1,
133.5, 133.6, 165.4, 165.5, 166.5. HR-MS (ESI): Calcd for
C28H26O9Na [M+Na]+: 529.1475. Found: 529.1478. IR (neat)
3533, 2924, 1728, 1283, 1069, 710 cm-1.
4.2.2. Methyl 2,3,6-tri-O-benzoyl-4-O-(tert-butyl)dimethylsilyl-α-
4.3.3. Methyl 2,3,4-tri-O-benzoyl-α-D-galactopyranoside (3b)
D
-galactopyranoside (4a)
1
A colorless oil. Yield: 87%. H-NMR (400 MHz, CDCl3): δ
2.69 (br t, J = 7.2 Hz, 1H), 3.48 (s, 3H), 3.65 (m, 1H), 3.79 (m,
1H), 4.33 (br t, J = 7.2 Hz, 1H), 5.28 (d, J = 3.6 Hz, 1H), 5.72
(dd, J = 10.8, 3.6 Hz, 1H), 5.87 (m, 1H), 5.99 (dd, J = 10.8, 3.2
Hz, 1H), 7.22–7.26 (m, 2H), 7.36–7.45 (m, 3H), 7.48–7.54 (m,
3H), 7.63 (m, 1H), 7.80–7.83 (m, 2H), 7.99–8.01 (m, 2H), 8.10–
8.13 (m, 2H). 13C-NMR (100 MHz, CDCl3): δ 55.7, 60.8, 68.4,
69.1, 69.6, 70.1, 97.5, 128.3, 128.4, 128.7, 128.9, 129.1, 129.2,
129.6, 129.8, 130.0, 133.2, 133.4, 133.7, 165.4, 166.1, 166.8.
HR-MS (ESI): Calcd for C28H26O9Na [M+Na]+: 529.1475.
Found: 529.1476. IR (neat): 3522, 2934, 1726, 1602, 1069, 712
cm-1.
Under an Ar atmosphere, to a solution of methyl 2,3,6-tri-O-
benzoyl-α-D-galactopyranoside (253 mg, 0.5 mmol) and 2,6-
lutidiene (0.12 mL, 1.0 mmol) in CH2Cl2 (1 mL, 0.5 M) was
added tert-butyldimethylsilyl trifluoromethanesulfonate (0.12
mL, 0.5 mmol) at 0 °C. After stirring at ambient temperature for
18 h, the reaction was quenched with saturated aqueous NaHCO3
solution, and extracted with EtOAc. The combined organic layer
was washed with water and brine, and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo followed by column
chromatography (silica gel, hexane/EtOAc = 10/1) provided the
1
title compound (237 mg, 76%) as a colorless oil. H-NMR (400
MHz, CDCl3): δ –0.09 (s, 3H), 0.03 (s, 3H), 0.96 (s, 9H), 3.45 (s,
3H), 4.33–4.43 (m, 2H), 4.54–4.59 (m, 2H), 5.19 (d, J = 4.0 Hz,
1H), 5.65 (dd, J = 10.8, 2.8 Hz, 1H), 5.80 (dd, J = 10.8, 3.6 Hz,
1H), 7.32–7.37 (m, 4H), 7.44–7.51 (m, 4H), 7.60 (m, 1H), 7.95–
7.99 (m, 4H), 8.06–8.08 (m, 2H). 13C-NMR (100 MHz, CDCl3):
δ –4.7, –4.6, 18.2, 25.8, 55.3, 63.7, 68.49, 68.51, 69.4, 71.8, 97.6,
128.30, 128.34, 128.5, 129.48, 128.53, 129.6, 129.7, 129.8,
133.1, 133.16, 133.24, 166.1, 166.2, 166.4. HR-MS (ESI): Calcd
for C34H40O9SiNa [M+Na]+: 643.2339. Found: 643.2346. IR
(neat): 2952, 1723, 1273, 1104, 711 cm-1.
4.3.4. Methyl 2,3,6-tri-O-benzoyl-α-D-galactopyranoside (4b)
A colorless powder. Yield: 80%. 1H-NMR (400 MHz,
CDCl3): δ 3.05 (br, 1H), 3.45 (s, 3H), 4.36 (br t, J = 6.4 Hz, 1H),
4.44 (br, 1H), 4.59 (dd, J = 11.6, 7.2 Hz, 1H), 4.67 (dd, J = 11.6,
5.6 Hz, 1H), 5.23 (d, J = 3.6 Hz, 1H), 5.73 (dd, J = 10.8, 3.2 Hz,
1H), 5.77 (dd, J = 10.8, 2.8 Hz, 1H), 7.31–7.37 (m, 4H), 7.41–
7.51 (m, 4H), 7.56 (m, 1H), 7.67–8.04 (m, 6H). 13C-NMR (100
MHz, CDCl3): δ 55.4, 63.5, 67.7, 68.1, 68.9, 70.8, 97.4, 128.3,
128.36, 128.37, 129.2, 129.3, 129.57, 129.61, 129.7, 129.8,
133.17, 133.18, 133.3, 165.8, 166.1, 166.4. HR-MS (ESI): Calcd
for C28H26O9Na [M+Na]+: 529.1475. Found: 529.1466. IR (neat):
3502, 2020, 1719, 1273, 1105, 706 cm-1.
4.3. General procedure for the desilylation of the sugar
derivatives
To a solution of silylated sugar derivatives (1a–4a) (0.1
mmol) in heptane (0.25 mL, 0.4 M) was added SO3H silica gel
(500 mg). After shaking for 1 min, resulting powder was left to
stand at ambient temperature. After the indicated reaction time,
the powder was put on the glass filter and eluted with MeOH (50
mL). The obtained elute was evaporated in vacuo followed by
column chromatography (silica gel, hexane/EtOAc = 2/1 (1b–3b)
or 4/1 (4b)) provided the desilylated sugar derivatives 1b–4b.
4.4. Desilylation of the sugar derivative 3a (gram scale)
To
a
solution of methyl 2,3,4-tri-O-benzoyl-6-O-(tert-
-glucopyranoside (3a) (1.14 g, 1.84
butyl)dimethylsilyl-α-
D
mmol) in heptane (4.6 mL, 0.4 M) was added SO3H silica gel
(935 mg). After shaking for 1 min, resulting powder was left to
stand at ambient temperature. After 24 h, the powder was put on

the glass filter and eluted with MeOH (500 mL). The obtained
= 3.3, 11.0 Hz, 1H), 4.08 (d, J = 13.7 Hz, 1H), 7.17 (dd, J = 7.7,
7.9 Hz, 1H), 7.31 (dd, J = 1.6, 7.7 Hz, 1H), 7.38 (dd, J = 1.6, 7.9
Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ 23.7, 27.6, 54.7, 56.8,
62.0, 64.9, 127.1, 128.8, 129.2, 132.4, 133.3, 139.3. HR-MS
(ESI): Calcd for C12H16Cl2NO [M+H]+: 260.0609. Found:
260.0602. IR (neat): 3408, 2959, 1449, 1421, 1184, 1079, 1048,
778 cm–1.
ACCEPTED MANUSCRIPT
elute was evaporated in vacuo to yield methyl 2,3,4-tri-O-
benzoyl-α- -glucopyranoside in a satisfactory level of purity
D
(3b) (835 mg, 90%) as a colorless oil.
4.5. General procedure for the desilylation of the nucleoside
derivatives
The silylated nucleosides 5a–7a were prepared according to
the literature procedures.13,14,15 A solution of silylated nucleosides
5a–7a (0.4 mmol) in EtOAc (5a and 6a, 1 mL, 0.4 M) or CHCl3
(7a, 1 mL, 0.4 M) was treated with SO3H silica gel (2 g, 0.2
mmol/g) at ambient temperature. After shaking for 1 min,
resulting powder was left to stand at ambient temperature for the
indicated reaction time. Then, the powder was put on the glass
filter and eluted with MeOH. The obtained elute was evaporated
in vacuo to yield corresponding desilylated Thymidine (5b, 88%
References and notes
1. (a) Ley SV, Baxendale IR, Bream RN, et al. J Chem Soc, Perkin
Trans 1. 2000;3815–4195;
(b) Sartori G, Ballini R, Bigi F, Bosica G, Maggi R, Righi P,
Chem Rev. 2004;104:199–250.
2. Fujii H, Yamada T, Hayashida K, et al. Heterocycles.
2012;85:2685–2691.
1
yield), Uridine (6b, 81% yield) or 7b (quant.). The H NMR
3. The SO3H silica gel has already been commercially developed by
FUJI SILYSIA CHEMICAL LTD.
spectrum of 7b was identical to that reported in the literature.16
Structure of SO3H Silica gel and its specification.
4.6. Preparation and desilylation of the alkaloid derivative
4.6.1. (S)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(2,3-
dichlorobenzyl)pyrrolidine (10a)
Shape: spherical
Pore size: 7 nm
Particle size: 100 mm
SO3H content: 0.5 mmol/g
Containing 5% H2O
Catalog number: CH27
Under an Ar atmosphere, to a suspension of (S)-2-(((tert-
butyldimethylsilyl)oxy)methyl)pyrrolidine (prepared according
to the literature procedure,16 218 mg, 1.01 mmol) and K2CO3
(281 mg, 2.04 mmol) in EtOH (8 mL) was added a solution of
2,3-dichlorobenzyl bromide (281 mg, 1.17 mmol) in EtOH (2
mL) at ambient temperature. The reaction mixture was stirred at
this temperature for 26 h. Then the excess EtOH was removed in
vacuo and the residue was dissolved in EtOAc. The organic layer
was washed with distillated water and brine, dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo followed
by column chromatography (silica gel, hexane/EtOAc = 100/0–
4/1) provided the title compound (340 mg, 90%) as a colorless
oil. Analytically pure sample was obtained by purification with
4. For reuse of the SO3H silica gel, no special pretreatment such as
activation was required. After removing eluent under reduced
pressure, the obtained SO3H silica gel can be used for the next
desilylation reaction.
5. Debarge S, Balzarini J, Maguire AR, J Org Chem. 2011;76:105–
126.
6.
(a) Mukherjee S, Yang JW, Hoffmann S, List B, Chem Rev.
2007;107:5471–5569;
(b) Jensen KL, Dickmeiss G, Jiang H, Albrechtand Ł, Jørgensen
KA, Acc Chem Res. 2012;45:248–264.
7. Recent examples: (a) Scates BA, Lashbrook BL, Chastain BC, et
al. Bioorg Med Chem. 2008;16:10295–10300;
1
preparative TLC (CHCl3). H NMR (CDCl3, 400 MHz): δ 0.02
(s, 3H), 0.04 (s, 3H), 0.87 (s, 9H), 1.55–1.66 (m, 1H), 1.67–1.81
(m, 2H), 1.88–1.98 (m, 1H), 2.27 (dd, J = 7.8, 8.9 Hz, 1H), 2.75–
2.84 (m, 1H), 2.96–3.02 (m, 1H), 3.50 (dd, J = 10.0, 6.2 Hz, 1H),
3.65 (dd, J = 10.0, 5.6 Hz, 1H), 3.67 (d, J = 15.1 Hz, 1H), 4.21
(d, J = 15.1 Hz, 1H), 7.16 (dd, J = 7.6, 7.9 Hz, 1H), 7.33 (d, J =
7.9 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H). 13C NMR (CDCl3, 100
MHz): δ –5.3, –5.2, 18.4, 23.3, 26.1 (3C), 28.5, 55.2, 57.5, 65.6,
67.3, 127.0, 128.6 (2C), 131.8, 132.9, 140.6. HR-MS (ESI):
Calcd for C18H30Cl2NOSi [M+H]+: 374.1474. Found: 374.1470.
IR (neat): 2954, 2856, 1449, 1421, 1361, 1255, 1097, 837, 755
cm–1.
(b) Faundez-Parraguez M, Farias-Rabelo N, Gonzalez-Gutierrez
JP, et al. Bioorg Med Chem. 2013;21:2687–2694;
(c) Onajole OK, Vallerini GP, Eaton JB, et al. ACS Chem
Neurosci. 2016;7:811–822.
8. Carocci A, Catalano A, Turi F, et al. ChemMedChem.
2016;11:93–101.
9. (a) VLA-4 antagonist: Chiba J, Iimura S, Yoneda Y, et al. Chem
Pharm Bull. 2006;54:1515–1529;
(b) FLAP inhibitor: Stock N, Baccei C, Bain G, et al. Bioorg Med
Chem Lett. 2010;20:213–217;
(c) BACE inhibitor: Cumming J, Babu S, Huang Y, et al. Bioorg
Med Chem Lett. 2010;20:2837–2842;
(d) σ1 lignad: Yu L–F, Zhang H–K, Gunosewoyo H, Kozikowski
AP, ACS Med Chem Lett. 2012;3:1054–1058;
(e) falcipain-2 inhibitor: Chakka SK, Kalamuddin M,
Sundararaman S, et al. Bioorg Med Chem. 2015;23:2221–2240;
(f) metallo-β-lactamase inhibitor: Yusof Y, Tan DTC, Arjomandi
OK, Schenk G, McGeary RP, Bioorg Med Chem Lett.
2016;26:1589–1593.
4.6.2. (S)-(1-(2,3-dichlorobenzyl)pyrrolidin-2-yl)methanol (10b)
To a solution of 10a (73.3 mg, 0.196 mmol) in MeOH (5 mL)
was added SO3H silica gel (1.01 g). After shaking for 1 min,
resulting powder was left to stand at 100 ºC. After 4 h, the
reaction mixture was cooled to ambient temperature. The powder
was put on the glass filter and eluted with 2.0 M NH3 in MeOH.
The obtained elute was evaporated in vacuo and the residue was
dissolved in CHCl3. Filtration through a pad of celite and
evaporation in vacuo followed by column chromatography (silica
gel, hexane/EtOAc = 5/1–1/1) provided the title compound (35.5
mg, 70%) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 1.66–
1.76 (m, 2H), 1.82–1.99 (m, 2H), 2.32 (ddd, J = 7.2, 9.4, 9.4 Hz,
1H), 2.60 (br s, 1H), 2.76–2.83 (m, 1H), 2.95–2.99 (m, 1H), 3.45
(dd, J = 2.3, 11.0 Hz, 1H), 3.52 (d, J = 13.7 Hz, 1H), 3.72 (dd, J
10. Lee JC, Francis S, Dutta D, et al. J Org Chem. 2012;77:3082–
3098.
11. Belakhov V, Dovgolevsky E, Rabkin E, Shulami S, Shoham Y,
Baasov T, Carbohydr Res. 2004, 339, 385–392.
12. Chambers DJ, Evans GR, Fairbanks AJ, Tetrahedron.
2005;61:7184–7192.
13. Krim J, Taourirte M, Grünewald C, Krstic I, Engels JW, Synthesis.
2013;45:396–405.
14. Gadakh B, Vondenhoff G, Lescrinier E, Rozenski J, Froeyen M,
Van Aerschot A, Bioorg Med Chem. 2014;22:2875–2886.
15. Debarge S, Balzarini J, Maguire AR, J Org Chem. 2011;76:105–
126.

6
Tetrahedron
ACCEPTED MANUSCRIPT
16. Kim M, Gajulapati K, Kim C, et al. Chem Commun.
2012;48:11443–11445.