Stereoselective synthesis of various α-selenoglycosides using in situ production of α-selenolate anion

Article abstract of DOI:10.1016/j.tetlet.2006.12.056

A large variety of α-selenoglycosides, including alkyl and aryl selenoglycosides, selenoglycosyl amino acid and selenodisaccharide have been synthesized in a stereoselective manner. The key precursor of α-anomeric selenolate anion was designed as p-methylbenzoyl selenoglycoside, which was synthesized by the reaction of β-glycosyl chloride with potassium p-methylselenobenzoate. Upon the action of piperazine or methylhydrazine in the presence of Cs₂CO₃, the acyl selenoglycoside produced an anomeric selenolate anion, which reacted in situ with various electrophilic counterparts to yield α-selenoglycoside.

Full text of DOI:10.1016/j.tetlet.2006.12.056

Tetrahedron Letters 48 (2007) 1113–1116
Stereoselective synthesis of various a-selenoglycosides
using in situ production of a-selenolate anion
Masahiro Nanami,a Hiromune Ando,b,* Yumiko Kawai,a
Mamoru Koketsub and Hideharu Ishiharaa,*
aDepartment of Chemistry, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
bDivision of Instrumental Analysis, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Received 8 December 2006; accepted 13 December 2006
Available online 8 January 2007
Abstract—A large variety of a-selenoglycosides, including alkyl and aryl selenoglycosides, selenoglycosyl amino acid and selenodi-
saccharide have been synthesized in a stereoselective manner. The key precursor of a-anomeric selenolate anion was designed as p-
methylbenzoyl selenoglycoside, which was synthesized by the reaction of b-glycosyl chloride with potassium p-methylselenobenzo-
ate. Upon the action of piperazine or methylhydrazine in the presence of Cs2CO3, the acyl selenoglycoside produced an anomeric
selenolate anion, which reacted in situ with various electrophilic counterparts to yield a-selenoglycoside.
Ó 2006 Elsevier Ltd. All rights reserved.
Recently, the broad spectrum of use of aryl selenoglyco-
sides as glycosyl donors has been demonstrated.1 Aryl
selenoglycoside donors can be activated in a chemoselec-
tive manner, and thioglycoside acts as its orthogonal
coupling partner; hence, using aryl selenoglycosides in
the synthesis of certain products appears to be an attrac-
tive option. Moreover, Yamago’s group has extended
the applicability of the selenoglycoside donor to iterative
glycosylation, which successfully delivered an eliciter
active heptasaccharide.2 On the other hand, Pinto’s
group revealed that selenodisaccharides are glycosidase
resistant, suggesting the potential of selenoglycoside as
an alternative type of pseudoglycoside for carbo-
hydrate-based drug development.3 Further, taking into
the account the successful use of selenium-incorporated
nucleotides and peptides for multiwavelength anoma-
lous dispersion (MAD) phasing for X-ray crystallogra-
phy,4 we have been particularly focusing on the
unexplored potential of selenoglycosides as probes in
the structural investigation of carbohydrate–protein
complexes; the results of such an investigation will pro-
vide important information about the molecular basis
underlying cell–cell, cell–virus, and cell–pathogen recog-
nition mediated by carbohydrates.
By taking a step further forward realizing the complete
potential of the contribution of selenoglycoside to glyco-
science, we set an initial aim to establish a synthetic
method capable of designing a large variety of selenogly-
cosides. Previously, we had reported a stereoselective
method for gluco-type b-selenoglycoside synthesis that
features the coupling reaction of its electrophilic coun-
terpart and b-selenolate anion produced in situ from
b-p-methylbenzoyl selenoglycoside in a chemoselective
manner.5 By this method, a wide spectrum of selenogly-
cosides linked to aryl, alkyl, amino acids, and monosac-
charides were successfully synthesized. In this study, we
demonstrate that the principle of our selenoglycosida-
tion can be successfully applied to the synthesis of a-
selenoglycoside.6
To obtain a-p-methylbenzoyl selenoglycoside, we first
examined the synthesis of the key intermediate b-glycosyl
chloride. Among our various attempts at b-chlorination,
Ibatullin’s method provided high yields of tetraacetyl-
glucosyl and galactosyl chlorides; thus, the pentaacetate
of glucose and galactose were reacted with PCl5 in the
presence of BF3ÆOEt2 to yield 1a and 1b, respectively.7
Next, a-p-methylbenzoyl selenoglycoside was synthesized
(Table 1). In a previous study on a-selenoglycoside synthe-
sis,5 b-p-methylbenzoyl selenoglycosides were successfully
produced by the SN2 reaction of b-bromide and potassium
p-methylselenobenzoate under monophasic and biphasic
Keywords: a-Selenoglycoside; Pseudoglycoside; Stereoselective
synthesis.
*
Corresponding authors. Tel./fax: +81 58 293 2617 (H.A.); e-mail:
hando@gifu-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.056

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M. Nanami et al. / Tetrahedron Letters 48 (2007) 1113–1116
Table 1. Examination of the synthesis of a-p-methylbenzoyl selenoglycosides
O
KSe
R1
R1
OAc
O
OAc
O
R2
AcO
2 (3.0 eq)
R2
AcO
Cl
AcO
Se
OAc
1a R1 = H, R2 = OAc
1b R1 = OAc, R2 = H
3a R1 = H, R2 = OAc
3b R1 = OAc, R2 = H
O
Entry
b-Cl
Conditionsa
Solvent
Time (h)
Product
Yield (%)
1
2
3
4
5
6
1a
1a
1a
1a
1a
1b
A
A
A
B
C
A
DMF
Pyr
Diox
DMF
CH2Cl2
DMF
2
3
5.5
7
4
3a
3a
3a
3a
3a
3b
46
34
11
0
0
65
3
Diox = 1,4-dioxane.
a (A) 18-crown-6 (3.0 equiv), rt; (B) nBu4NCl (1.0 equiv), rt; (C) nBu4NSO4H (2.0 equiv), 1 M Na2CO3 aq, rt.
conditions. In contrast, the biphasic reaction of b-chloride
and potassium p-methylselenobenzoate in the presence of
TBAHS did not yield the desired product. The monopha-
sic reaction yielded a complex mixture that contained a-
and b-isomers and unidentified products.8 From this mix-
ture, a single a-isomer 3a was obtained in a 46% yield by
silica gel column chromatography and recrystallization
(entry 1). Although we have examined the in situ anomer-
ization method and the ethereal solvent-assisted a-seleno-
glycosidation, the a-products were not satisfactory
(entries 2–5). Considering these results, the corresponding
a-galactosyl selenoglycoside 3b was prepared under simi-
lar conditions for entry 1 in a moderate yield (entry 6).ꢀ
The a-anomeric configuration of selenoglycosides 3a
and 3b was supported by the doublet signal of the C1 pro-
ton at 6.40 and 6.46 ppm with a coupling constant of
5.2 Hz (J1,2) in 1H NMR spectra, respectively.
the a-acyl selenoglycoside smoothly reacted with pipera-
zine in the presence of Cs2CO3 to produce an anomeric
selenolate anion that in turn reacted in situ with a cou-
pling partner to yield the corresponding a-selenoglyco-
side. In contrast, a-acyl selenolate could not be
produced in the absence of piperazine to recover quanti-
tative amount of a-acyl selenoglycoside and coupling
partner. In a previous paper, we have reported that piper-
azine has been used as the main activator with Cs2CO3;
methylhydrazine was used as the stronger activator for
comparison. In all events, the coupling reactions termi-
nated within 1 min regardless of the type of amine. Con-
sequently, in entries 1–5, p-methylbenzoyl group was
successfully replaced with alkyl and aryl groups, thus giv-
ing high yields of compounds 4–8. As expected, tosylated
serine derivative 99 functioned as a suitable electrophilic
coupling partner to give a-linked selenocysteinyl galacto-
side 1010 in an 85% yield without racemization. For seleno-
disaccharide synthesis, 6-iodo-D-fucose derivative 11,
4-O-triflyl galactoside 13, and 4-O-triflyl glucoside 15
were employed as coupling partners. As a result,
selenodisaccharide sequences Glcpa(1!6)Galp (12),
Glcpa(1!4)Glcp (14), and Galpa(1!4)Galp (16) were
produced in high yields. Compounds 14 and 16 are the
first examples of synthesized a-selenoglycoside that links
to the carbon in the sugar ring. During all the reactions,
the stereochemistry of selenoglycoside linkage was com-
pletely retained, thereby exclusively producing a-ano-
meric products. The configuration of the newly formed
selenoglycosides was confirmed by 1H NMR spectra
(J1,2 = 4.6–5.7 Hz). Additionally, 77Se NMR spectra
demonstrated that the resonance of a-amoneric selenium
ranged from 152.3 to 327.1 ppm.
The available a-acyl selenoglycosides were reacted with
electrophilic coupling partnersꢁ (Table 2). As anticipated,
ꢀ Experimental procedure of 3b synthesis: Potassium p-meth-
ylselenobenzoate 2 (1.29 g, 4.08 mmol) was added to a solution of
compound 1b (500 mg, 1.36 mmol) and 18-crown-6 (1.08 g,
4.08 mmol) in degassed DMF (5.0 mL) under an argon atmosphere.
The mixture was stirred for 3 h at ambient temperature (TLC
monitoring; EtOAc–toluene = 1:3). The reaction mixture was
extracted twice with EtOAc, and the organic layer was washed with
water and brine, dried over Na2SO4, and co-evaporated with toluene
in vacuo. The residue was purified by column chromatography on
silica gel (EtOAc–toluene = 1:9) and recrystallized from diethyl ether
and n-hexane to afford 3b as a pink needle (464 mg, 65%).
ꢁ Typical procedure of a-selenoglycosidation (the case of entry 8):
Cs2CO3 (76.2 mg, 234 lmol) and piperazine (12.1 mg, 140 lmol) were
added to a solution of compound 3a (62.1 mg, 117 lmol) in degassed
DMF (0.5 mL) under an argon atmosphere, and successively a
solution of compound 13 (352 lmol) in degassed DMF (1.0 mL) was
added via cannula. The mixture was stirred for 1 min at ambient
temperature (TLC monitoring; EtOAc–toluene = 1:3). The reaction
mixture was extracted twice with EtOAc, and the organic layer was
washed with 2 M HCl, water, satd Na2CO3 aq and brine, dried over
Na2SO4, and co-evaporated with toluene in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc–tolu-
ene = 1:15) to afford 14 (99.9 mg, 90%).
In the previous paper on b-selenoglycoside synthesis, we
have reported a special case of the formation of asym-
metric diselenodisaccharide and triacetyl glucal during
the reaction of b-p-methylbenzoyl selenoglucoside with
an electrophilic sugar partner.5 We have rationalized
that this was attributable to the antielimination of sele-
nium and acetoxy anion from the corresponding boat
conformer. To confirm the reaction mechanism, b- and
a-p-methylbenzoyl selenoglycosides (12 and 3a) were re-

M. Nanami et al. / Tetrahedron Letters 48 (2007) 1113–1116
1115
Table 2. a-Selenoglycoside formation
electrophile (2.0 eq)
amine (1.2 eq)
Cs2CO3 (2.0 eq)
O
3a (Glc)
3b (Gal)
AcO
DMF
rt
Se
R
1 min
Entry
1
Sugar
Electrophile
Base
Product
Yield (%)
O
Etl
4
97
3a
MeNHNH2
AcO
Se
O
Br
2
3
4
3a
3b
3a
5
6
7
99
95
88
AcO
Piperazine
Se
O
Si
Br
AcO
Se
MeNHNH2
Si
Cl
O
OMe
MeO
AcO
Se
MeNHNH2
O
F
AcO
5
6
3b
3b
8
97
85
NO2
Se
Piperazine
NO2
O
NHFmoc
TsO
NHFmoc
CO2All
9
10
AcO
CO2All
Se
Piperazine
O
I
O
O
AcO
O
O
7
3a
11
12
90
Se
O
O
O
O
O
O
MeNHNH2
TfO
BnO
O
OBn
O
OBn
O
OMP
AcO
8
9
3a
3b
13
15
14
16
90
89
Se
OBn
Piperazine
OMP
BnO
OBn
O
OAc
O
TfO
AcO
Se
OSE
AcO
OAc
O
OAc
OSE
AcO
Piperazine
OAc
MP = p-methoxyphenyl, SE = 2-(trimethylsilyl)ethyl.
acted with piperazine in the presence of Cs2CO3 under
aerobic atmosphere, respectively (Scheme 1). The main
product of the a-acyl selenoglycoside reaction was the
corresponding symmetric diselenide 1911 without glucal
formation, while the main product of the b-acyl seleno-
glycoside was glucal 17 (49%) and symmetric diselenide
186b (51%). In addition, the corresponding asymmetric
diselenodisaccharides were not formed during the a-sele-
noglucosidation conducted at entries 7 and 8 shown in
Table 2. This result strongly supports our proposed
self-decomposition mechanism of b-glucosyl selenolate
anion.
In conclusion, we have demonstrated that a-selenolate
anion could be produced in situ from the corresponding
p-methylbenzoyl selenoglycoside, which reacted rapidly

1116
M. Nanami et al. / Tetrahedron Letters 48 (2007) 1113–1116
Se
OAc
O
AcO
AcO
Se
+
O
-OAc
OAc
O
AcO
17 (49%)
Piperazine
O
AcO
AcO
Se
SeTol
OAc
O
AcO
AcO
O2
OAc
O
AcO
AcO
12
Se
OAc
OAc
Se
Se
AcO
OAc
O
AcO
18 (51%)
OAc
O
OAc
O
AcO
AcO
Piperazine
O2
O
AcO
AcO
O
AcO
Se
AcO
AcO
Se
AcO
Se
Se
SeTol
OAc
3a
OAc
OAc
19 (81%)
O
AcO
Scheme 1. Experiment on degradation of a- and b-glucosyl selenolate anion in the absence of an electrophile. Tol = p-methylbenzoyl.
Synlett 1992, 967–968; (b) Czernecki, R.; Rand-
riamandimby, D. J. Carbohydr. Chem. 1996, 15, 183–
190; (c) Tiwari, P.; Misra, A. K. Tetrahedron Lett. 2006,
47, 2345–2348.
with various electrophiles to produce a large variety of
a-selenoglycosides.
7. Ibatullin, F. M.; Selivanov, S. I. Tetrahedron Lett. 2002,
43, 9577–9580.
Acknowledgment
8. In the mixture the a- and b-isomers were contained in the
1
This work was supported by MEXT of Japan (Grant-in-
Aid for Scientific Research to H.A., No. 16780083).
ratio of 10/3 that was confirmed by H NMR spectrum,
while in the case of galactoside the ratio was 10/0.7.
´
9. Gieselman, M. D.; Xie, L.; van der Donk, W. A. Org.
Lett. 2001, 3, 1331–1334.
10. Spectroscopic data of 10: H NMR (CDCl3, 500 MHz) d
1
References and notes
7.77–7.31 (m, 8H, Ar), 6.05 (d, 1H, J1,2 = 5.7 Hz, H-1),
5.97–5.87 (m, 2H, CH@CH2, NH), 5.45 (m, 1H, H-4Gal),
5.37–5.27 (m, 2H, OCH2CH@CH2), 5.20 (dd, 1H,
J2,3 = 10.9 Hz, H-2Gal), 5.12 (dd, 1H, J3,4 = 2.9 Hz, H-
3Gal), 4.80 (m, 1H, SeCH2CH), 4.70–4.64 (m, 2H,
CH@CH2), 4.87–4.39 (m, 3H, H-5Gal, CH2 of Fmoc),
4.25 (t, 1H, CH of Fmoc), 4.17–4.06 (m, 2H, H-6aGal and
H-6bGal), 3.22–3.00 (2dd, 2H, SeCH2), 2.16–2.00 (4s, 12H,
4Ac); 13C NMR (125 MHz, CDCl3) d 170.3, 170.0, 169.9,
169.8, 158.0, 155.7, 143.8, 143.6, 141.3, 131.3, 127.7, 127.7,
127.7, 127.0, 125.0, 120.0, 120.0, 119.3, 80.5, 68.8, 68.5,
68.1, 67.0, 66.4, 61.7, 54.1, 47.1, 26.3, 20.8, 20.6, 20.6, 20.5;
77Se NMR (95 MHz, CDCl3) d 161.4; m/z (MALDI):
found [M+Na]+ 784.15, C35H39NO17Se calcd for
[M+Na]+ 784.15.
1. Recent papers on glycosylation using aryl selenoglycoside
donor: (a) van Well, R. M.; Ka¨rkka¨inen, T. S.; Kartha, K.
P. R.; Field, R. A. Carbohydr. Res. 2006, 341, 1391–1397;
(b) Litjens, R. E. J. N.; den Heeten, R.; Timmer, M. S. M.;
Overkleeft, H. S.; van der Marel, G. A. Chem. Eur. J.
2005, 11, 1010–1016; (c) Ikeda, K.; Sugiyama, Y.; Tanaka,
K.; Sato, M. Bioorg. Med. Chem. Lett. 2002, 12, 2309–
2311; (d) Yamago, S.; Kokubo, K.; Hara, O.; Masuda, S.;
Yoshida, J.-I. J. Org. Chem. 2002, 67, 8584–8592; (e)
Jiaang, W.-T.; Chang, M.-Y.; Tseng, P.-H.; Chen, S.-T.
Tetrahedron Lett. 2000, 41, 3127–3130.
2. (a) Yamago, S.; Yamada, T.; Hara, O.; Ito, H.; Mino, Y.;
Yoshida, J.-I. Org. Lett. 2001, 3, 3867–3870; (b) Yamago,
S.; Yamada, T.; Ito, H.; Hara, O.; Mino, Y.; Yoshida, J.-I.
Chem. Eur. J. 2005, 11, 6159–6174.
1
11. Spectroscopic data of 19: H NMR (CDCl3, 500 MHz) d
6.01 (d, 2H, J1,2 = 5.7 Hz, H-1, H-10), 5.32 (dd, 2H,
J2,3 = 10.3, J3,4 = 9.7 Hz, H-3, H-30), 5.11 (t, 2H,
J4,5 = 9.7 Hz, H-4, H-40), 4.98 (dd, 1H, H-2, H-20), 4.32
(dd, 2H, Jgem = 12.6, J5,6a = 4.0 Hz, H-6a, H-60a), 4.19
(m, 2H, H-5, H-50), 4.10 (dd, 2H, J5,6b = 2.3 Hz, H-6b, H-
60b), 2.09–2.02 (4s, 24H, 8Ac); 13C NMR (125 MHz,
CDCl3) d 170.5, 169.9, 169.5, 169.4, 83.4, 71.3, 70.7, 70.5,
67.8, 61.2, 20.6, 20.6, 20.6, 20.5; 77Se NMR (95 MHz,
CDCl3) d 322.7; m/z (MALDI): found [M+Na]+ 844.90,
C28H38O18Se2 calcd for [M+Na]+ 845.03.
3. Mehta, S.; Andrews, J. S.; Johnston, B. D.; Svensson, B.;
Pinto, B. M. J. Am. Chem. Soc. 1995, 117, 9783–9790.
4. (a) Obmolova, G.; Ban, C.; Hsieh, P.; Yang, W. Nature
2000, 407, 703–710; (b) Du, Q.; Carrasco, N.; Teplova,
M.; Wilds, C. J.; Egli, M.; Huang, Z. J. Am. Chem. Soc.
2002, 124, 24–25.
5. Kawai, Y.; Ando, H.; Ozeki, H.; Koketsu, M.; Ishihara,
H. Org. Lett. 2005, 7, 4653–4656.
6. Advanced reports on the synthesis of a-selenoglycoside:
(a) Benhaddou, R.; Czernecki, S.; Randriamandimby, D.