A convenient preparation of glycosyl sulfoxides and its application to the synthesis of Salidroside epimer

Article abstract of DOI:10.1016/j.tetlet.2016.04.045

A facile and green approach for the preparation of glycosyl sulfoxides utilizing 30% aqueous H₂O₂ in phenol or acetic acid is described. Advantages include relatively mild conditions, high chemoselectivity, and good tolerance to a wide range of protective groups. Furthermore, the epimer of Salidroside containing one 1,2-cis glycosidic bond was synthesized in three steps in 90.1% overall yield using glucopyranosyl sulfoxide as the glycosyl donor.

Full text of DOI:10.1016/j.tetlet.2016.04.045

Tetrahedron Letters 57 (2016) 2277–2279
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convenient preparation of glycosyl sulfoxides and its
application to the synthesis of Salidroside epimer
⇑
Qing Wang, Xiong Wei, Kaijun Liao, Hui Li, Xiangbao Meng, Zhongjun Li
The State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and green approach for the preparation of glycosyl sulfoxides utilizing 30% aqueous H2O2 in
phenol or acetic acid is described. Advantages include relatively mild conditions, high chemoselectivity,
and good tolerance to a wide range of protective groups. Furthermore, the epimer of Salidroside contain-
ing one 1,2-cis glycosidic bond was synthesized in three steps in 90.1% overall yield using glucopyranosyl
sulfoxide as the glycosyl donor.
Received 26 January 2016
Revised 31 March 2016
Accepted 13 April 2016
Available online 15 April 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Glycosyl sulfoxides
Aqueous H2O2
Oxidation
1,2-cis glycosidic bond
Salidroside epimer
Glycosyl sulfoxides, first introduced by Kahne and co-workers,1
have been widely used as highly reactive glycosyl donors in carbo-
hydrate chemistry.2 Owing to its noticeable advantages including
the corresponding mild activated conditions,3 excellent anomeric
stereocontrol,4 and suitability in both solution5 and solid-phase6
synthesis, glycosylation using glycosyl sulfoxides is one of the most
powerful tools for preparing oligosaccharides and glycoconju-
gates.7 For instance, glycosyl sulfoxides with 4,6-benzylidene was
applied in the construction of b-mannoside by Crich and coworkers
in 1996.8 And in recent years, another type of glycosyl sulfoxides
containing 2-auxiliary group was successfully used to form
1,2-cis-glucoside by Boons.9 The construction of both the two types
of glycosidic bonds is a challenge in carbohydrate chemistry.
Although glycosyl sulfoxides have been shown to be useful
agents in carbohydrate chemistry, their preparations, especially
the conversion from glycosyl sulfides to glycosyl sulfoxides, still
need improvement. One of the most popular oxidants is
m-chloroperoxybenzoic acid (m-CPBA) in the preparation of glyco-
syl sulfoxides from thioglycosides.10 However, this method suffers
from a number of shortcomings, such as the requirement of low
temperature to avoid over-oxidation to the sulfone, the insolubility
of m-CPBA in the reaction solvent, and the difficulty to separate
m-chlorobenzoic acid byproduct from the sulfoxides. In recent
years, other oxidants including 1-fluoropyridinium triflates and
magnesium monoperoxyphthalate have been used.11 However,
they either need complex procedures or produce undesired
OPG
O
OPG
O
OPG
O
30%H2O2
O
S
O
S
O
R
PGO
PGO
SR
PGO
PGO
PGO
Phenol
or
Acetic acid
+
PGO
R
OPG
OPG
OPG
undetected
PG = Acyl, Ether, Silicon Eher, Acetal, Ketal
R = P-tolyl, Et, Nitrophenyl
Scheme 1. Preparation of glycosyl sulfoxides using 30% aqueous H2O2.
by-products. Therefore, the green oxidant, hydrogen peroxide,
has come to the chemist’s mind because of its low cost for
production and transportation, effective-oxygen content, and the
formation of water as a by-product.12 The oxidation of sulfides to
sulfoxides by hydrogen peroxide has been shown to be one of
the most attractive methods.13 Herein, a convenient, green, and
chemoselective procedure for the preparation of glycosyl sulfox-
ides using 30% aqueous H2O2 in phenol or acetic acid was
developed (Scheme 1). Compared with the previous Letters,14 this
method is more chemoselective, without using any special solvent
and low-temperature reactor.
Initially, thioglycoside 1a was chosen as the model substrate to
study the oxidation conditions to glycosyl sulfoxide 1b (Table 1).
We primarily used the hydrogen peroxide/phenol system.15 As
shown in Table 1, when dichloromethane was used as the solvent,
the reaction failed to produce the desired product, possibly
because of the poor solubility of hydrogen peroxide in DCM
(Table 1, entry 1). When thioglycoside 1a was dissolved in phenol
in the presence of 30% aqueous H2O2 as a syrup, no reaction
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2016.04.045
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

2278
Q. Wang et al. / Tetrahedron Letters 57 (2016) 2277–2279
Table 1
Table 2
Oxidation of glycosyl sulfide 1 to sulfoxide 1b
Preparation of glycosyl sulfoxides via H2O2 mediated oxidationa
Entry
1
Thioglycoside
Glycosyl Sulfoxide
Yieldb,e (%)
OAc
OAc
O
30%H O
2
2
O
S
O
OAc
OAc
O
Phenol
Solvent
AcO
AcO
AcO
AcO
STol
Tol
90.2c
92.2d
O
O
OAc
1a
OAc
1b
AcO
AcO
STol
STol
STol
AcO
AcO
OAc
OAc
1a
1b
OAc
OAc
OAc
Entry H2O2
(equiv)
Phenol
(equiv)
Solvent Temp
Time
(h)
Yielda
(%)
OAc
O
O
O
86.5
85.9
(°C)
2
3
4
5
STol
AcO
AcO
OAc
OAc
2a
2b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2
12
12
12
12
12
12
12
10
8
2
2
2
2
DCM
rt
rt
3
3
3
3
3
3
3
3
3
3
3
3
3
N.R.
N.R.
78.5
86.0
2
2
2
2
2
2
2
2
2
2
2
2
2
None
None
None
None
None
None
None
None
DCM
MeCN
MEOH
AcOH
AcOH
OAc
O
OAc
O
AcO
AcO
AcO
AcO
40
50
60
70
80
60
60
60
60
60
60
rt
86.4
86.4
AcO
AcO
3b
3a
STol
87.1
STol
O
Complex
Complex
90.2
Complex
N.R.
N.R.
N.R.
76.1
92.2
OBz
O
OBz
O
O
STol
94.7
73.4
BzO
BzO
BzO
BzO
STol
4a
4b OBz
OBz
OBn
OBn
O
STol
87.0
57.0
O
O
BnO
BnO
BnO
Ph
STol
BnO
OBn
5b
OBn
5a
O
2
24
O
Ph
Ph
O
O
O
O
O
63.4
61.8
a
STol
STol
STol
Isolated yield.
6
7
AcO
AcO
OAc
OAc
6b
7b
6a
Ph
O
O
O
STol
O
O
O
O
77.0
81.8
occurred even after 3 h at room temperature (Table 1, entry 2).
Interestingly, when the reaction mixture was warmed to 40 °C,
desired sulfoxide 1b was produced in the yield of 78.5% (Table 1,
entry 3). And when the temperature was raised to 50 °C and
60 °C, the yields were increased to 86% and 87.1%, respectively
(Table 1, entries 4 and 5). However, a further increase of tempera-
ture led to complex products, and no product was formed (Table 1,
entries 6 and 7). As phenol is hard to remove, we also tried to
reduce its equivalent used. When the equivalent of phenol was
reduced to 10, the yield was increased to 90.2% (Table 1, entry
8). But when the equivalent of phenol was reduced further, the
reaction became complex (Table 1, entry 9). Because the reaction
mixture was still too sticky to stir, additional solvent was again
added to the reaction. When DCM, MeCN, and MeOH were used
for the reaction, no product was obtained (Table 1, entries
10–12). To our delight, when AcOH was used as the solvent, 1b
was obtained in the yield of 76.1% (Table 1, entry 13). And the yield
was increased to 92.2% when the reaction was stirred at rt,
although it needed 24 h to complete. In the end, we obtained
two optimized reaction conditions: (a) 2 equiv H2O2 in 10 equiv
phenol at 60 °C for 3 h; (b) 2 equiv H2O2 and 2 equiv phenol in
AcOH at room temperature for 24 h.
BnO
BnO
OBn
OBn
7a
AcO
AcO
MeO
MeO
OAc
OAc
O
O
49.9
85.3
O
O
O
O
8
8a
8b
OMe
O
STol
OMe
STol
O
OAc
O
OAc
O
O
O
STol
Complex
75
O
O
STol
STol
9
10
11
OAc
9b
OAc
9a
OTrt
OTrt
O
O
STol
16.8
57.7
O
AcO
AcO
AcO
AcO
OAc
OAc
10a
10b
OTBDPS
O
OTBDPS
O
Complex
75.6
O
BzO
BzO
BzO
BzO
STol
STol
OBz
OBz
11b
11a
Ph
O
O
Ph
O
O
O
O
O
Complex
72.8
STol
STol
12
13
TBDMSO
12a
OAc
TBDMSO
12b
OAc
OAc
OAc
O
S
O
O
AcO
AcO
AcO
AcO
18.5
29.4
S
OAc
OAc
NO2
NO2
13a
13b
The scope of the oxidation reaction was subsequently investi-
gated under the optimized conditions (Table 2). Galactose and
mannose substrates (2a and 3a, Table 2, entries 2 and 3) under-
went the oxidation reaction to form the corresponding product
in excellent yields, suggesting that the carbohydrate type had no
effect on the reaction. Both substrate 4a with electron-withdraw-
ing group (Bz) and 5a with electron-donating group (Bn) could
be converted smoothly to the sulfoxides under condition a, in
yields of 94.7% and 87.0%, respectively. However, when using con-
dition b, the yield decreased to 73.4% and 57.0%, respectively, likely
owing to the low reactivity at rt caused by steric hindrance (Table 2,
entries 4 and 5). The substrate 6a with benzylidene and acetyl
groups produced the corresponding product in moderate yield
under both conditions while the more active substrate 7a with
benzylidene and benzyl groups produced the corresponding pro-
duct in relative higher yield (Table 2, entries 6 and 7). The other
substrates 8a and 9a with the acetal group afforded products in
good yields under the condition b but in poor yields under the con-
dition a, likely because of the acid labile protecting groups (Table 2,
entries 8 and 9). Other acid-sensitive protecting groups such as
OAc
O
OAc
O
SEt
89.4
80.8
O
AcO
AcO
AcO
AcO
14
15
SEt
OAc
OAc
14b
14a
OAc
OAc
O
S
O
O
O
92.4
82.2
AcO
AcO
AcO
AcO
S
O
15a
15b
Ph
Ph
a
b
c
Reactions were conducted at 0.40 mmol scale.
Isolated yield.
Reaction condition: 2 equiv H2O2 in 10 equiv phenol at 60 °C.
Reaction condition: 2 equiv H2O2 and 2 equiv phenol in AcOH.
The products were R and S isomer mixture and cannot be separated by column
d
e
chromatography.
TBDMS, TBDPS, and trityl were also investigated and the
compounds containing these protecting groups behaved similarly
as 8a and 9a (10a, 11a, and 12a, Table 2, entries 10–12). Substrate
13a, a sulfide with the electron-withdrawing group on the sulfur
atom, underwent the reaction in a very poor yield (Table 2,

Q. Wang et al. / Tetrahedron Letters 57 (2016) 2277–2279
2279
OH
National Natural Science Foundation of China (NSFC No.
21072017, 21072016, 20972012).
OAc
O
AcO
AcO
OAc
O
BzO
OBz
O
O
O
OMe
AcO
AcO
Ph
Supplementary data
S
98.5%
O
Ph
S
16
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.04.
045.
15b
MeO
OMe
MeO
OMe
Tf2O, DTBMP, 4A MS,
-10 °C ~ -40 °C ~RT
OMe
OH
References and notes
1. TFA, DCM
2. NH3, MeOH
O
HO
HO
1. Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111,
6881.
2. Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2002, 124, 2263; Nicolaou, K. C.; Mitchell,
H. J.; Rodríguez, R. M.; Fylaktakidou, K. C.; Suzuki, H.; Conley, S. R. Chem. Eur. J.
2000, 6, 3149; Nicolaou, K. C.; Li, Y.; Sugita, K.; Monenschein, H.; Guntupalli, P.;
Mitchell, H. J. J. Am. Chem. Soc. 2003, 125, 15443.
OH
HO
O
17
, 99%
Scheme 2. Synthesis of 2-(4-hydroxyphenyl)ethyl-a-D-glucopyranoside with
glycosyl sulfoxide.
3. Carpintero, M.; Nieto, I.; Fernandez-Mayoralas, A. J. Org. Chem. 2001, 66, 1768;
Thompson, C.; Ge, M.; Kahne, D. J. Am. Chem. Soc. 1999, 121, 1237; Wipf, P.;
Reeves, J. T. J. Org. Chem. 2001, 66, 7910; Kartha, K. P. R.; Kaerkkeainen, T. S.;
Marsh, S. J.; Field, R. A. Synth. Lett. 2001, 260; Nagai, H.; Kawahara, K.;
Matsumura, S.; Toshima, K. Tetrahedron Lett. 2001, 42, 4159.
4. Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198; Crich, D.; Sun, S. Tetrahedron
1998, 54, 8321.
entry 13). But substrates 14a and 15a with electron-donating alkyl
substitutions provided the corresponding product in over 80%
yields (Table 2, entries 14 and 15).
Having compound 15b in hand, we attempted to synthesize the
epimer of natural product Salidroside, 2-(4-hydroxyphenyl)ethyl-
5. (b) Silva, D. J.; Kahne, D.; Kraml, M. C. J. Am. Chem. Soc. 1994, 116, 2641; (b) Lin,
Y.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239.
6. Yan, L.; Taylor, C. M.; Goodnow, R.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953;
Liang, R.; Yan, L.; Loebach, J.; Ge, M.; Uozumi, Y.; Sekanina, K.; Horan, N.;
Gildersleeve, J.; Thompson, C.; Smith, A.; Biswas, K.; Still, W. C.; Kahne, D.
Science 1996, 274, 1520; Silva, D. J.; Wang, H.; Allanson, N. M.; Jain, R. K.; Sofia,
M. J. J. Org. Chem. 1999, 64, 5926.
7. Taylor, J. G.; Li, X.; Oberthur, M.; Zhu, W.; Kahne, D. E. J. Am. Chem. Soc. 2006,
128, 15084; Crich, D.; Wu, B.; Jayalath, P. J. Org. Chem. 2007, 72, 6806; Bai, Y.;
Lowary, T. L. J. Org. Chem. 2006, 71, 9658.
a-D-glucopyranoside (Scheme 2). The glycosyl sulfoxide 15b was
promoted by Tf2O at À10 °C and then the acceptor was added at
À40 °C. The 1,2-cis product 16 was obtained selectively and no
1,2-trans product was obtained. At last, compound 16 was
transformed into 2-(4-hydroxyphenyl)ethyl-a-D-glucopyranoside
after two-step deprotection in nearly quantitative yield.
8. Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506.
9. Fang, T.; Mo, K. F.; Boons, G. J. J Am Chem Soc 2012, 134, 7545.
10. Kakarla, R.; Dulina, R. G.; Hatzenbuhler, N. T.; Hui, Y. W.; Sofia, M. J. J. Org.
Chem. 1996, 61, 8347.
Conclusions
11. Vincent, S. P.; Burkart, M. D.; Tsai, C. Y.; Zhang, Z.; Wong, C. H. J. Org. Chem.
1999, 64, 5264; Tsukamoto, H.; Kondo, Y. Tetrahedron Lett. 2003, 44, 5247;
Chen, M. Y.; Patkar, L. N.; Chen, H. T.; Lin, C. C. Carbohydr. Res. 2003, 338, 1327;
Chen, M. Y.; Patkar, L. N.; Lin, C. C. J. Org. Chem. 2004, 69, 2884.
12. Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977.
13. Gazdar, M.; Smiles, S. J. Chem. Soc. 1908, 93, 1833; Kaczorowska, K.; Kolarska,
Z.; Mitka, K.; Kowalski, P. Tetrahedron 2005, 61, 8315; Xu, W. L.; Zheng, Y. L.;
Zhang, Q. S.; Zhu, H. S. Synthesis 2004, 2, 227.
We developed a facile and effective method to prepare glycosyl
sulfoxides from thioglycosides by using H2O2 as the oxidant. The
reaction tolerated different types of carbohydrates and a wide
range of protective groups. The oxidation product 15b was used
to synthesize 2-(4-hydroxyphenyl)ethyl-a-D-glucopyranoside with
high stereoselectivity and yield.
14. Schmidt, R. R.; Kast, J. Tetrahedron Lett. 1986, 27, 4007.
15. Xu, L.; Li, X.; Zhang, Q.; Zhu, H. Synthesis 2004, 2, 227.
Acknowledgments
This work was supported by grants from the National Basic
Research Program of China (Grant No. 2012CB822100) and the