A facile method for synthesizing selenoglycosides based on selenium-transfer to glycosyl imidate

Article abstract of DOI:10.1016/j.tetlet.2014.01.151

A facile reaction for constructing selenoglycosides has been developed based on the transacetalization reaction between a selenoacetal and a glycosyl imidate. Glycosyl imidates were activated with TMSOTf to produce oxocarbenium ion, which reacted with benzyloxymethyl alkyl (aryl) selenide, providing alky (or aryl) selenoglycosides in high yields. Furthermore, this reaction was utilized in the synthesis of 2-(trimethylsilyl)ethylselenoglycoside, which, upon treatment with TBAF in the presence of an electrophile, was transformed into other selenoglycosides.

Full text of DOI:10.1016/j.tetlet.2014.01.151

Tetrahedron Letters 55 (2014) 1920–1923
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile method for synthesizing selenoglycosides based
on selenium-transfer to glycosyl imidate
a
Tatsuya Suzuki a,b, Naoko Komura a,b, Akihiro Imamura a, Hiromune Ando a,b, , Hideharu Ishida ,
⇑
Makoto Kiso a,b,
⇑
a Department of Applied Bioorganic Chemistry, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan
b Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile reaction for constructing selenoglycosides has been developed based on the transacetalization
reaction between a selenoacetal and a glycosyl imidate. Glycosyl imidates were activated with TMSOTf
to produce oxocarbenium ion, which reacted with benzyloxymethyl alkyl (aryl) selenide, providing alky
(or aryl) selenoglycosides in high yields. Furthermore, this reaction was utilized in the synthesis of 2-(tri-
methylsilyl)ethylselenoglycoside, which, upon treatment with TBAF in the presence of an electrophile,
was transformed into other selenoglycosides.
Received 27 December 2013
Revised 28 January 2014
Accepted 30 January 2014
Available online 7 February 2014
Keywords:
Selenoglycoside
Selenoacetal
Ó 2014 Elsevier Ltd. All rights reserved.
Transacetalization
Carbohydrate mimetics
Organoselenium compounds have broad applications in organic
synthesis, where the dual characteristics of selenium as both a
nucleophile and an electrophile are deliberately utilized. Recently,
organoselenium compounds have also emerged as crucial therapeu-
tic compounds that exhibit antiviral and anticancer activities.1
Among organoselenium compounds, seleno-carbohydrates have
been widely utilized as glycosyl donors in oligosaccharide synthesis,
where an arylselenyl group introduced at the anomeric position
functions as a leaving group during glycosylation.2 In crystallogra-
phy, by taking advantage of the anomalous dispersion of selenium
in response to X-ray irradiation, the methylselenoglycoside of N-
acetylglucosamine was successfully utilized as a carbohydrate li-
gand mimetic in X-ray structural determination of carbohydrate-
binding protein with multi-wavelength anomalous dispersion
(MAD) phasing.3 On the basis of a similar principle, dodecyl-b-sele-
nomaltoside has been successfully utilized as a selenium agent for
MAD phasing in X-ray structural analysis of a membrane protein
and as a detergent for stabilizing the protein in water.4
sponding dialkyl (aryl) diselenide upon reaction with a hydride
reducing agent,6 Zn–ZnCl2,7 or InI.8 Alternatively, reaction of glyco-
syl halide with acyl selenolates can provide acyl selenoglycosides.9
Recent studies have shown that p-methylbenzoylselenoglycosides
could be converted into a variety of selenoglycosides chemoselec-
tively.10 Arylselenoglycosides are obtained from glycosyl acetate
by treatment with arylselenol generated in situ in the presence
2a
of BF3ꢀOEt2
or by treatment with Me2Sn(SePh)2 and Bu2
Sn(OTf)2.11 Furthermore, the conversion of glycals into phenylsele-
noglycosides has been successfully demonstrated. However, the
application of these methods in the modification of oligosaccha-
rides as seleno-glycosyl donors or as seleno-carbohydrate
mimetics remains difficult, mainly due to poor compatibility with
the chemistry used in oligosaccharide synthesis. Therefore, a meth-
od for preparing selenoglycosides that is highly compatible with
oligosaccharide synthesis is necessary to extend the potential of
The introduction of selenium at the anomeric position of a
monosaccharide can be achieved by treating a glycosyl halide with
selenium under sodium borohydride reduction conditions,5 or with
alkyl (aryl) selenolate, which is generated in situ from the corre-
Scheme 1. Outline of selenoglycoside formation through transacetalization
between selenoacetal and glycosyl imidate.
⇑
Corresponding authors. Tel./fax: +81 58 293 3452 (H.A.).
E-mail address: hando@gifu-u.ac.jp (H. Ando).
http://dx.doi.org/10.1016/j.tetlet.2014.01.151
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

T. Suzuki et al. / Tetrahedron Letters 55 (2014) 1920–1923
1921
Inspired by the transacetalization reaction between a glycosyl
imidate and a thioglycoside in the presence of a catalytic amount
of Lewis acid—a reaction that was often observed as an undesired
side reaction during glycosylation12—we envisioned a selenoglyco-
side formation method that utilizes a simple mix selenoacetal and
a glycosyl imidate (Scheme 1).
We expected that selenium-transfer to an oxocarbenium ion
would occur more efficiently than sulfur transfer, due to higher
nucleophilicity of selenium. Benzyloxymethyl alkyl selenide
(BOMSeR) was designed as a selenoacetal, in which the benzyl
group functions as an electron-donating group and as a UV-sensi-
tive group, to facilitate the monitoring of reactions by thin layer
chromatography. The synthesis of BOMSeMe 1 and BOMSePh 2
was carried out by following a straightforward procedure for the
Scheme 2. Synthesis of bezyloxymethyl alky (aryl) selenides 1–3.
selenoglycosides, not only as synthetic intermediates but also as
carbohydrate mimetics. In this Letter, we report a new synthetic
method for selenoglycosides that also allows for the modification
of oligosaccharides.
Table 1
Results for reactions of selenoacetal 1–3 with various glycosyl imidates 4 to 10
Entry
1
Reagent
Glycosyl imidate
Solvent
CH2Cl2
Temp (°C)
ꢁ40
Product
Yield (%)
99
1
2
3
1
1
CH2Cl2
ꢁ40
ꢁ40
11 (b only)
80
87
CH2Cl2-EtCN (1:1)
4
5
2
2
EtCN
ꢁ80
ꢁ20
90
93
CH2Cl2
6
7
8
2
3
3
CH2Cl2-EtCN (1:1)
0
92
98
85
CH2Cl2
ꢁ40
9 (
a:b = 20:1)
CH2Cl2-EtCN (1:1)
0

1922
T. Suzuki et al. / Tetrahedron Letters 55 (2014) 1920–1923
reactivity to that of 1 and 2, providing high yields of the correspond-
ing mono- and oligo-saccharyl selenoglycosides 16 and 17.16
By the reported reaction of the 2-(trimethylsilyl)ethylselenyl
group with TBAF to generate selenolate anion,13,17 selenoglycoside
16 could be converted into glycosyl selenolate, which reacted in
situ with electrophiles 18 and 20 to yield seleno-disaccharide 19
and glycosyl selenocystein 21,18 respectively in high yields while
retaining the anomeric stereochemistry (Scheme 3).
In conclusion, transacetalization using BOMSeR (1–3) and gly-
cosyl imidates has been shown to be an efficient, facile method
for synthesizing various selenoglycosides. Since selenium-transfer
proceeds under conditions similar to the conditions for imidate
glycosidation, this method will be a reliable option for the synthe-
sis of oligosaccharyl selenoglycosides. In addition, we demon-
strated that 2-(trimethylsilyl)ethyl selenoglycoside served as a
synthetic equivalent of glycosyl selenolate, which will be useful
Scheme 3. Conversion of 2-(trimethylsilyl)ethylselenoglycoside into other
selenoglycosides.
for synthesizing
oligosaccharides.
a selenoglycoside between the residues of
alkylation of selenium: commercially available diselenides were
reacted with BOMCl in the presence of NaBH4 in THF-EtOH at room
temperature, affording 1 and 2, respectively (Scheme 2). Similarly,
di-2-(trimethylsilyl)ethyl diselenide13 was successfully converted
into the corresponding selenoacetal, thus giving 3 (BOMSeSE) in
77% yield.14
Acknowledgement
The iCeMS is supported by the World Premier International
Research Center Initiative (WPI), MEXT, Japan. This work was
financially supported in part by MEXT of Japan (a Grant-in-Aid
for Scientific Research (B) No. 22380067 to M.K., and a Grant-in-Aid
for Young Scientists (A) No. 23688014, and Grant-in-Aid on Inno-
vative Areas No. 24110505, Deciphering sugar chain-based signals
regulating integrative neuronal functions to H.A.). We thank Ms.
Yumiko Kawai (Gifu Univ.) for various initial examinations on the
activation of selenoglycosides, and Ms. Kiyoko Ito (Gifu Univ.) for
providing technical assistance.
Next, we reacted the selenoacetals with glycosyl imidates. The
optimized reaction conditions and the results obtained are sum-
marized in Table 1.à In entry 1,
a-tetrabenzylgalactosyl imidate 4
and BOMSeMe 1 were reacted at ꢁ40 °C by the catalytic action of
TMSOTf in the presence of acid-washed molecular sieves (AW-300)
in CH2Cl2. This reaction produced b-methylselenoglycoside 11. To
obtain the best yield of 11 (99%), 2.0 equiv of 1 and 0.6 equiv of
TMSOTf were used. When using 1.0 equiv of 1, the yield decreased
to 74% and benzyl b-glycoside was obtained in 9% yield as a byprod-
uct. In entry 2, the b-isomer of 4 (5) also provided exclusively b-sele-
noglycoside 11 in high yield. In contrast, the reaction of disaccharyl
imidate 6 with 1 in CH2Cl2 produced an anomeric mixture of seleno-
References and notes
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4653–4656; (b) Nanami, M.; Ando, H.; Kawai, Y.; Koketsu, M.; Ishihara, H.
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G.-J. Carbohydr. Res. 2000, 329, 709–715; (c) Li, Z.; Gildersleeve, J. C. J. Am. Chem.
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glycosides 12 (90%,
a:b = 87:3), which were inseparable by chro-
matographic methods. Therefore, in entry 3, nitrile solvent was
used as the co-solvent to direct b-selectivity,15 thereby giving 12
as a single isomer in 87% yield. Similar to BOMSeMe, BOMSePh 2
produced selenoglycosides in high yields. Thus, sialyl imidate 7
and glucosaminyl imidate 8 were converted into phenyl selenoglyco-
sides 13 and 14 in high yields, respectively (entries 4 and 5). Further-
more, the conversion of tetrasaccharyl imidate
9
into
phenylselenoglycoside 15 was accomplished in excellent yields (en-
try 6). In entries 7 and 8, BOMSeSE 3 was shown to possess similar
Typical procedure for the synthesis of BOMSeR (the case of BOMSePh 2): Sodium
borohydride (132 mg, 3.50 mmol) and ethanol (3.2 mL) were added to a solution of
diphenyldiselenide (500 mg, 1.61 mmol) in THF (6.4 mL) at 0 °C under argon
atmosphere, and the reaction mixture was stirred for 10 min. Then, BOMCl (500 lL,
3.63 mmol) was added, and stirring was continued for 1.5 h at ambient temperature.
Completion of reaction was confirmed by TLC analysis (CHCl3/n-hexane = 1/1). After
quenched by addition of satd aq NH4Cl (10 mL), the mixture was extracted with
CH2Cl2 three times. The combined organic solution was dried over Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel column chromatography
(CHCl3/n-hexane = 1/10) to give 2 (621 mg, 77%) as a colorless syrup.
à
Typical procedure for selenoglycoside formation with BOMSeR (the case of entry 3 of
Table 1): A mixture of selenoacetal 2 (75 mg, 269
135 mol), and AW-300 (135 mg) in CH2Cl2 was stirred for 30 min under argon
atmosphere, and cooled to ꢁ40 °C, to which TMSOTf (16.4 L, 81 mol) was then
lmol), glycosyl imidate 4 (100 mg,
l
13. Tani, K.; Murai, T.; Kato, S. J. Am. Chem. Soc. 2002, 124, 5960–5961.
l
l
14. Spectroscopic data of compound 3; ½a D
ꢂ
ꢁ2.7° (c 1.0, CHCl3); 1H NMR (500 MHz,
added. The reaction mixture was stirred for 1 h at ꢁ40 °C as the progress of the
reaction was monitored by TLC analysis (EtOAc/n-hexane = 1/4). After satd aq Na2CO3
(1.0 mL) was added to quench the reaction, the mixture was diluted with CHCl3,
filtered through a pad of Celite and washed with CHCl3. The combined filtrate and
washings were washed with satd aq NaHCO3, and the organic layer was dried over
Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column
chromatography (EtOAc/n-hexane = 1/8) to give 11 (98 mg, 99%) as a colorless syrup.
CDCl3) d 7.34–7.28 (m, 5 H, Ph), 5.06 (s, 2 H, SeCH2O), 4.61 (s, 2 H, PhCH2), 2.76
(s, 2 H, CH2CH2TMS), 1.04 (s, 2 H, CH2TMS), 0.27 (s, 9 H, TMS); 13C NMR
(125 MHz, CDCl3) d 195.2, 144.3, 136.9, 129.4, 127.2, 21.7, 21.4, 18.9, ꢁ1.9;
77Se-NMR (95 MHz, CDCl3)
d
258.1; m/z (ESI): found [M+Na]+ 325.0501,
C
13H22OSe calcd for [M+Na]+ 325.0497.
15. (a) Schmidt, R. R.; Rücker, E. Tetrahedron Lett. 1980, 21, 1421–1424; (b)
Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett. 1984, 25, 1379–1382.

T. Suzuki et al. / Tetrahedron Letters 55 (2014) 1920–1923
24.7° (c 1.0, CHCl3);
1923
16. Spectroscopic data of selected compounds; compound 12; ½a D
ꢂ
1H NMR (500 MHz, CDCl3) d 8.12-7.42 (m, 10 H, Ph), 6.02 (d, 1 H, J2,NH = 7.0 Hz,
NHc), 5.57 (m, 1 H, H-8b), 5.49 (t, 1 H, J1,2 = J2,3 = 10.0 Hz, H-2a), 5.36–5.34 (m, 2
H, H-4c, H-4d), 5.22 (dd, 1 H, J6,7 = 2.5 Hz, J7,8 = 10.0 Hz, H-7b), 5.15 (d, 1 H,
J1,2 = 8.5 Hz, H-1c), 5.12 (dd, 1 H, J1,2 = 8.0 Hz, J2,3 = 10.0 Hz, H-2d), 5.07–5.04 (m,
2 H, H-1a, NHb), 4.98–4.94 (m, 2 H, H-3c, H-3d), 4.87 (m, 1 H, H-4b), 4.66–4.60
(m, 2 H, H-6aa, H-1d), 4.46 (dd, 1 H, J3,4 = 2.5 Hz, H-3a), 4.35 (dd, 1 H, J5,6b = 6.5
Hz, Jgem = 12.5 Hz, H-6ba), 4.26 (dd, 1 H, J8,9a = 2.0 Hz, Jgem = 12.5 Hz, H-9ab),
4.16–4.09 (m, 2 H, H-6ac, H-6bc), 4.02–3.98 (m, 2 H, H-9bb, H-5d), 3.92–3.75
(m, 10 H, H-4a, H-5a, H-5b, H-6b, H-5c, H-6ad, H-6bd, COOMe), 3.38 (m, 1 H, H-
2c), 2.83–2.73 (m, 3 H, H-3axb, TMSCH2CH2), 2.23–1.80 (m, 37 H, H-3eqb, Ac),
0.95–0.90 (m, 2 H, TMSCH2), ꢁ0.06 (s, 9 H, TMS); 13C NMR (125 MHz, CDCl3) d
172.1, 170.9, 170.6, 170.4, 170.4, 170.3, 170.2, 170.0, 170.0, 169.2, 168.3, 165.9,
165.3, 133.2, 133.1, 130.2, 129.9, 129.8, 129.5, 128.4, 128.4, 101.1, 98.9, 97.7,
78.3, 74.1, 73.8, 73.8, 71.8, 70.8, 70.7, 70.4, 70.1, 69.0, 68.8, 67.3, 66.7, 66.4,
64.1, 62.6, 62.2, 60.8, 55.1, 53.7, 52.7, 49.1, 36.8, 31.7, 29.6, 29.2, 23.9, 23.1,
21.3, 20.8, 20.8, 20.7, 20.6, 20.5, 20.4, 20.2, 19.6, 18.1, -1.9; 77Se NMR (95 MHz,
CDCl3) d 343.6; m/z (ESI): found [M+Na]+ 1665.4460, C71H94N2O35SeSi calcd for
[M+Na]+ 1665.4464.
1H NMR (500 MHz, CDCl3) d 7.99–7.33 (m, 10 H, Ph), 5.79 (d, 1 H, J3,4 = 3.0 Hz,
H-4a), 5.74 (t, 1 H, J1,2 = J2,3 = 10.0 Hz, H-2a), 5.53 (dd, 1 H, H-3a), 5.43 (m, 1 H,
H-8b), 5.36 (dd, 1 H, J6,7 = 1.6 Hz, J7,8 = 9.3 Hz, H-7b), 5.02–4.95 (m, 2 H, H-1a, H-
4b), 4.92–4.89 (m, 2 H, NH, Cl3CCH2), 4.50 (d, 1 H, Jgem = 12.0 Hz, Cl3CCH2), 4.39
(dd, 1 H, J8,9a = 2.4 Hz, Jgem = 12.4 Hz, H-9ab), 4.22 (dd, 1 H, J5,6 = 10.8 Hz, H-6b),
4.17–4.10 (m, 2 H, H-5a, H-9bb), 3.85–3.80 (m, 4 H, H-6aa, COOMe), 3.62 (m, 1
H, H-5b), 3.49 (dd, 1 H, J5,6b = 8.0 Hz, Jgem = 10.7 Hz, H-6ba), 2.59 (dd, 1 H,
J3ax,4 = 4.7 Hz, Jgem = 12.9 Hz, H-3axb), 2.22–2.00 (m, 18 H, Ac, SeCH3), 1.88 (t, 1
H, J3eq,4 = 12.9 Hz, H-3eqb); 13C NMR (125 MHz, CDCl3) d 170.7, 170.5, 170.3,
169.8, 169.7, 167.8, 165.5, 165.3, 154.0, 133.2, 133.2, 129.8, 129.6, 129.3, 129.2,
128.3, 99.1, 95.4, 77.2, 76.4, 74.5, 72.5, 72.1, 68.6, 68.0, 67.9, 67.7, 67.3, 63.1,
62.6, 60.4, 53.0, 51.5, 38.0, 31.5, 22.6, 21.0, 20.8, 20.6, 14.2, 14.1, 2.6; 77Se NMR
(95 MHz, CDCl3)
C
d
209.4; HRMS: m/z (ESI): found [M+Na]+ 1136.0998,
44H50Cl3NO21Se calcd for [M+Na]+ 1136.0998; Spectroscopic data of
compound 15; ½a D
ꢂ
ꢁ4.9° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) d 8.14–
7.22 (m, 15 H, Ph), 5.55 (m, 1 H, H-8b), 5.36–5.34 (m, 2 H, H-4c, H-4d), 5.28–
5.24 (m, 2 H, H-2a, NHc), 5.18–5.15 (m, 3 H, H-7b, H-1c, H-2d), 5.07–5.04 (m, 2
H, H-1a, NHb), 4.99–4.95 (m, 2 H, H-3c, H-3d), 4.75 (m, 1 H, H-4b), 4.61–4.56 (m,
2 H, H-6aa, H-1d), 4.48 (dd, 1 H, J3,4 = 2.5 Hz, J2,3 = 9.5 Hz, H-3a), 4.38 (dd, 1 H,
J5,6a = 6.0 Hz, Jgem = 11.4 Hz, H-6ba), 4.22 (dd, 1 H, J8,9a = 2.4 Hz, Jgem = 12.5 Hz,
H-9ab), 4.14–4.10 (m, 2 H, H-6ac, H-6bc), 4.00 (dd, 1 H, J5,6a = 5.4 Hz, Jgem = 11.6
Hz, H-6ad), 3.85–3.80 (m, 5 H, H-5a, H-5b, H-9bb, H-5c, H-6bd), 3.76 (s, 3 H,
COOMe), 3.74–3.69 (m, 3 H, H-4a, H-6b, H-5d), 2.95 (m, 1 H, H-2c), 2.73 (dd, 1 H,
J3ax,4 = 4.4 Hz, Jgem = 13.1 Hz, H-3axb), 2.18–1.78 (m, 37 H, H-3eqb, Ac); 13C
NMR (125 MHz, CDCl3) d 171.9, 171.1, 170.8, 170.6, 170.3, 170.3, 170.1, 169.9,
169.9, 169.1, 168.3, 165.8, 164.8, 136.4, 133.1, 130.2, 130.1, 130.0, 129.6, 128.4,
128.4, 128.2, 128.2, 127.4, 101.3, 98.3, 97.4, 81.0, 77.6, 77.2, 76.4, 74.1, 74.0,
72.7, 71.8, 70.8, 70.8, 70.4, 69.5, 69.5, 69.0, 69.0, 68.8, 67.4, 66.8, 66.4, 63.7,
62.7, 62.3, 60.9, 60.4, 55.2, 53.8, 52.6, 49.1, 36.9, 31.7, 29.6, 29.2, 24.0, 23.0,
21.3, 21.0, 20.9, 20.8, 20.7, 20.7, 20.6, 20.5, 20.3, 20.1, 14.2; 77Se NMR (95 MHz,
CDCl3) d 426.0; m/z (ESI): found [M+Na]+ 1641.4069, C72H86N2O35Se calcd for
17. Garud, D. R.; Ando, H.; Kawai, Y.; Ishihara, H.; Koketsu, M. Org. Lett. 2007, 9,
4455–4458.
18. Spectroscopic data of compound 21;
½
a D
ꢂ
ꢁ32.2° (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) d 7.77–7.30 (m, 8 H, Ar), 5.98 (d, 1 H, J = 8.0 Hz, NH), 5.90
(m, 1 H, CH of Allyl), 5.40 (m, 1 H, H-4), 5.36–5.25 (m, 3 H, CH@CH2 of Allyl, H-
2), 5.01 (dd, 1 H, J3,4 = 3.4 Hz, J2,3 = 10.3 Hz, H-3), 4.74 (d, 1 H, J1,2 = 9.7 Hz, H-1),
4.67–4.66 (m, 3 H, CH–CH2 of Allyl, CH of Cys), 4.55 and 4.35 (2 dd, 2 H, CH2 of
Fmoc), 4.26 (dd, 1 H, CH of Fmoc), 4.11–4.03 (m, 2 H, H-6a, H-6b), 3.80 (m, 1 H,
H-5), 3.32 and 3.10 (2 dd, 2 H, CH2 of Cys), 2.10–1.94 (4 s, 12 H, 4 Ac); 13C NMR
(125 MHz, CDCl3) d 170.2, 170.1, 170.0, 169.7, 169.7, 155.9, 143.8, 143.6, 141.2,
131.4, 131.4, 127.7, 127.1, 125.1, 124.9, 120.0, 120.0, 118.9, 77.8, 75.8, 71.4,
67.6, 67.1, 66.9, 66.3, 61.5, 54.3, 47.0, 24.9, 20.8, 20.5, 20.5, 20.4; 77Se NMR
(95 MHz, CDCl3) d 280.0; m/z (ESI): found [M+Na]+ 784.1479, C35H39NO13Se
calcd for [M+Na]+ 784.1479.
[M+Na]+ 1641.4069; Spectroscopic data of compound 17; ½a D
ꢂ 5.2° (c 1.1, CHCl3);