A facile method for β-selenoglycoside synthesis using β-p-methylbenzoyl selenoglycoside as the selenating unit

Article abstract of DOI:10.1021/ol051804s

(Chemical Equation Presented) The reaction between α-glycosyl bromides and potassium p-methylselenobenzoate yields β-p-methylbenzoyl selenoglycosides. The acyl selenoglycosides were activated by the action of a secondary amine and Cs₂CO₃ to produce an anomeric selenolate anion, which reacted in situ with various electrophiles to yield novel selenoglycosides while retaining the anomeric stereochemistry.

Full text of DOI:10.1021/ol051804s

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4653-4656
A Facile Method for
â-Selenoglycoside
Synthesis Using -p-Methylbenzoyl
â
Selenoglycoside as the Selenating Unit
Yumiko Kawai,† Hiromune Ando,*,‡ Hideya Ozeki,† Mamoru Koketsu,‡ and
Hideharu Ishihara*,†
Department of Chemistry, Faculty of Engineering, 1-1 Yanagido, Gifu 501-1193,
Japan, and DiVision of Instrumental Analysis, Life Science Research Center, Gifu
UniVersity, 1-1 Yanagido, Gifu 501-1193, Japan
hando@cc.gifu-u.ac.jp
Received July 28, 2005
ABSTRACT
The reaction between
r
-glycosyl bromides and potassium p-methylselenobenzoate yields
â
-p-methylbenzoyl selenoglycosides. The acyl
selenoglycosides were activated by the action of a secondary amine and Cs2CO3 to produce an anomeric selenolate anion, which reacted in
situ with various electrophiles to yield novel selenoglycosides while retaining the anomeric stereochemistry.
The substitution of interglycosidic or intraring oxygen in
carbohydrates with other elements such as carbon, nitrogen,
and other chalcogens is an attractive carbohydrate mimicking
technique.1 Over the last two decades, thioglycosides in
particular have become an important class of “pseudogly-
cosides” due to their notable potential as enzyme inhibitors,2
enzyme-resistant scaffolds,3 synthetic vaccines,4 and so on.
On the other hand, seleno- and telluroglycosides have been
primarily exploited as glycosyl donors for O-glycoside
formation.5 To date, limited information is available on
selenodisaccharide synthesis,6 and there only exists a single
report on the potential inhibitory behavior of selenodisac-
charide by Pinto’s group.
On the basis of our knowledge, to date, (1fn)-linked
selenodisaccharides have been synthesized by Czernecky’s
group6a and Pinto’s group.6b Czernecky’s method exploited
in situ selenolate anion formation by the reduction of
symmetrical diglycosyl diselenide affected with sodium
cyanoborohydride in ethanol-HMPA. This selenolate reacted
with tosylated glycosyl units to yield Glc(1f6)Glc seleno-
disaccharides. On the other hand, Pinto’s group first glyco-
* Corresponding authors.
† Faculty of Engeneering.
‡ Life Science Research Center.
(1) Recent publications on C-glycoside: Kuberan, B.; Sikkander, S. A.;
Tomiyama, H.; Linhardt, R. J. Angew. Chem., Int. Ed. 2003, 42, 2073-
2075. Palomo, C.; Oiarbide, M.; Landa, A.; Gonza´lez-Rego, M. C.; Garc´ıa,
J. M.; Goznza´lez, A.; Odriozola, J. M.; Mart´ın-Pastor, M.; Linden, A. J.
Am. Chem. Soc. 2002, 124, 8637-8643. Brenna, E.; Fuganti, C.; Grasselli,
P.; Serra, S.; Zambotti, S. Chem. Eur. J. 2002, 8, 1872-1878. On
S-glycoside: Thayer, D. A.; Yu, H. N.; Galan, M. C.; Wong, C.-H. Angew.
Chem., Int. Ed. 2005, 44, 4596-4599. Zhu, X.; Pachamuthu, K.; Schmidt,
R. R. Org. Lett. 2004, 6, 1083-1085. Galon´ıc, D. P.; van der Donk, W.
A.; Gin, D. Y. Chem. Eur. J. 2003, 9, 5997-6006. Knapp, S.; Myers, D.
S. J. Org. Chem. 2002, 67, 2995-2999. Cohen, S. B.; Halcomb, R. L. J.
Am. Chem. Soc. 2002, 124, 2534-2543. On selenium: Liu, H.; Pinto, B.
M. J. Org. Chem. 2005, 70, 753-755. Knapp, S.; Darout, E. Org. Lett.
2005, 7, 203-206.
(4) Bousquet, E.; Spadaro, A.; Pappalardo, M. S.; Bernardini, R.; Romeo,
R.; Panza, L.; Ronisvalle, G. J. Carbohydr. Chem. 2000, 19, 527-541.
(5) Ikeda, K.; Sugiyama, Y.; Tanaka, K.; Sato, M. Bioorg. Med. Chem.
Lett. 2002, 12, 2309-2311. Yamago, S.; Kokubo, K.; Hara, O.; Masuda,
S.; Yoshida, J.-I. J. Org. Chem. 2002, 67, 8584-8592. Yamago, S.; Yamada,
T.; Hara, O.; Ito, H.; Mino, Y.; Yoshida, J.-I. Org. Lett. 2001, 3, 3867-
3870. Jiaang, W.-T.; Chang, M.-Y.; Tseng, P.-H.; Chen, S.-T. Tetrahedron
Lett. 2000, 41, 3127-3130. Yamago, S.; Kokubo, K.; Murakami, H.; Mino,
Y.; Hara, O.; Yoshida, J.-I. Tetrahedron Lett. 1998, 39, 7905-7908.
(6) (a) Czernecki, S.; Randriamandimby D. J. Carbohydr. Chem. 1996,
15, 183-190. (b) Mehta, S.; Andrews, J. S.; Johnson, B. D.; Svensson, B.;
Pinto, B. M. J. Am. Chem. Soc. 1995, 117, 9783-9790. (c) Wrede, F. Z.
Physiol. Chem. 1921, 115, 284-304. (d) Schneider, W.; Wrede, F. Ber.
1917, 50, 793-804.
(2) Driguez, H. Chembiochem 2001, 2, 311-318. Driguez, H. Top. Curr.
Chem. 1997, 187, 85-116 and references therein.
(3) Roy, R.; Hernandez-Mateo, F.; Santoyo-Gonzales, F. J. Org. Chem.
2000, 65, 8743-8746.
10.1021/ol051804s CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/22/2005

sylated a selenol mounted on an unanomeric ring carbon of
glycoside with glycosyl trichloroacetimidate in the presence
of a catalytic amount of TMSOTf, producing Glc(1f4)Glc
selenodisaccharide. In the former method, concomitant
deacetylation resulted in disaccharide yield decay (∼70%),
and in the latter method, the oxidation of selenolglycosyl
acceptor in air to form diselenide was a drawback. The novel
method that we have described in this paper can facilitate
the synthesis of â-selenoglycosides by the in situ formation
of anomeric selenolate anion.
Table 1. Synthesis of â-Acylselenoglycosides
entry sugar-Br conditionsa time (h) product yield (%)
1
2
3
4
5
2a
2a
2b
2b
2c
A
B
A
B
B
3
2
3
1.5
3
3a
3a
3b
3b
3c
80
87
75
84
88
Scheme 1. New Selenoglycosylation Described in This Paper
a Key: (A) DMF, rt; (B) nBu4NSO4H (2.0 equiv), 1 M Na2CO3 aq/EtOAc,
rt. Gal ) 2,3,4,6-tetra-O-acetyl-â-D-galactopyranosyloxy.
butylammonium hydrogen sulfate as a phase-transfer catalyst.
Although both conditions produced relatively high yields
(75-88%) of â-acyl selenoglycosides 3 as single isomers
(1H NMR: J1,2 ) 10.2-10.8 Hz; 77Se NMR: 622.8-630.7
ppm), biphasic conditions were employed for large-scale
preparations in view of the efficacy of the workup. It should
be noted that the crystalline acyl selenoglycosides were stable
throughout the 6 months they were stored in a freezer.
The successfully prepared acyl â-selenoglycosides 3a and
3b were linked with various electrophiles 4-11 in the
presence of an amine and Cs2CO3 (Figure 1, Table 2). During
As depicted in Scheme 1, the prominent feature of our
new method is the â-glycosyl p-methylselenobenzoate unit
that behaves as a key selenolate anion precursor. This acyl
selenoglycoside that is activated by the action of a secondary
amine and Cs2CO3 readily produces â-selenolate anion in
situ; the â-selenolate anion immediately reacts with various
electrophiles to yield â-selenoglycosides exclusively. Orig-
inally, this reaction was based on the selective de-O-
acetylation at the anomeric position by hydrazine7 or
piperidine.8 It was well-known that the seleno-carbonyl
bond could be selectively activated to produce selenolate in
the presence of O-acetyl groups because the pKa value of
selenol (10-11) is lower than that of alcohol (∼16).
We first prepared â-glycosyl p-methylselenobenzoates.
Potassium p-methylselenobenzoate 1,9 reported previously,
was used as a selenating reagent. It has a long shelf life in
a freezer and can easily be produced from p-methylbenzoyl
chloride through the reaction sequences depicted in Scheme
2. As shown in Table 1, R-glucosyl, galactosyl, and lactosyl
Figure 1. Coupling partners used in this study. MP ) p-
methoxyphenyl, Tf ) trifluoromethanesulfonyl, SE ) 2-(trimeth-
ylsilyl)ethyl.
Scheme 2. Preparation of Potassium p-Methylselenobenzoate
the screening of a secondary amine to act as an activator,
the smallest volatile aminesdimethylamineswas employed.
In the case of reactions with 4-8, the concomitant adduct
N,N-dimethyl-p-methylbenzamide was not easily separated
from the objective selenoglycosides by silica gel chroma-
tography. Therefore, piperazine was used in entries 1-6
because its corresponding amide could be removed by acidic
bromides 2 (1.0 equiv) reacted with 1 (2.0 equiv) in DMF
and/or under biphasic condition in the presence of tetra-n-
(7) Roush, W. R.; Lin, X.-F. J. Am. Chem. Soc. 1995, 117, 2236-2250.
(8) Bovin, N. V.; Zurabyan, S. E.; Khorlin, A. Y. IzV. Akad. Nauk. SSSR,
Ser. Khim. 1981, 2806-2808.
(9) Ishihara, H.; Hirabayashi, Y. Chem. Lett. 1976, 203-204. Ishihara,
H.; Matsunami, N.; Yamada, Y. Synthesis, 1987, 371-373.
4654
Org. Lett., Vol. 7, No. 21, 2005

14, respectively, in high yields (entries 1-3). Aryl substitu-
tion with 1-fluoro-4-nitrobenzene 7 was also successful in
almost quantitatively producing aryl selenoglycoside 15
(entry 4). The reaction with 1,2-dibromoethane 8 yielded
symmetric diselenoethyl-tethered disaccharide 16 (entry 5).
Further, in the absence of a coupling partner, 3b could be
quantitatively transformed into digalactosyl diselenide 1710
(entry 6). The corresponding R-isomers were not produced
in any of the cases in entries 1-6.
Table 2. Reactions of 3 with Various Electrophiles
During selenodisaccharide formation, we employed O-
triflyl sugars 9-1111 as a glycosyl unit (entries 7-12). The
acyl selenoglucoside 3a was quantitatively incorporated
with 6-O-triflyl-Gal derivative 9 to produce Glcâ(1f6)Gal
selenodisaccharide 18 (entry 7). In this reaction, the use of
excess 9 (4.0 equiv) was critical to suppress the formation
of heterodiselenide 2212 as an inseparable byproduct, which
resulted in the formation of the corresponding glucal and
selenium as concomitant byproducts (Scheme 3). We ratio-
Scheme 3. Proposed Mechanism of Side Reaction during
Selenoglycosylation
nalized the formation of these byproducts as illustrated in
Scheme 3.
Thus, without excess electrophile 9, the remaining â-
selenolate anion decomposes to yield the corresponding
triacetyl glucal and selenium via anti-elimination or it reacts
with the resultant selenoglycoside to yield heterodiselenide
22, triacetyl glucal, and selenium again via anti-elimination.
In any case, in accordance with the proposed mechanism,
galactosyl derivative 3b was free from heterodiselenide
formation, probably because the axially oriented C-4 acetoxy
group prevented the conformational change to boat form by
its steric repulsion with anomeric selenolate. In entries 8-10,
dimethylamine and piperazine smoothly activated 3b to
(10) Daniel, J. R.; Zingaro, R. A. Phosphorus Sulfur 1978, 4, 179-185.
(11) For experimental details of preparation, see the Supporting Informa-
tion.
(12) The structure of compound 22 was supported by MS (MALDI) and
a Yield was calculated on the basis of 8. b 2.0 M solution in THF was
used. DMA ) N,N-dimethylacetamide. PPZ ) piperazine.
1H NMR spectrum of crude 22; m/z (MALDI) found [M + Na]+ 757.03,
1
C26H33O14Se2 calcd for [M + Na]+ 757.05; H NMR (500 MHz, CDCl3)
δ 5.52 (d, J ) 5.2 Hz, 1 H), 5.21 (m, 3 H), 5.10 (t, J ) 9.2 Hz, 1 H), 4.94
(d, J ) 9.7 Hz, 1 H), 4.64 (dd, J ) 2.3, 8.0 Hz, 1 H), 4.31 (m, 2 H), 4.21
(dd, J ) 5.1, 12.6 Hz, 1 H), 4.14 (dd, J ) 2.3, 12.6 Hz, 1H), 4.03 (t, 1 H),
3.74 (m, 1 H), 3.23 (m, 2 H), 2.09-2.01 (4 s, 12 H), 1.59-1.32 (4 s, 12
H). For experimental details, see the Supporting Information.
aqueous workup. Consequently, alkylation with 4, 5, and 6
yielded the corresponding alkyl selenoglycosides 12, 13, and
Org. Lett., Vol. 7, No. 21, 2005
4655

produce a high yield of Galâ(1f6)Gal selenodisaccharide
19. Further, the selenoglycosylation of less reactive 4-O-
triflyl galactosides 10 and 11 successfully achieved seleno-
lactose (Glcâ(1f4)Gal) frames 20 and 21 in high yields.
All outcomes in entries 7-12 also retained the â-anomeric
stereochemistry as confirmed by 1H NMR (J1,2 ) 9.2-10.3
Hz) spectroscopy. Additionally, the resonances of the ano-
meric selenium in 77Se NMR of compounds 18-21 were
observed to lie in the range of 280.8-324.9 ppm, indicating
the presence of acetalic selenium.
In conclusion, p-methylbenzoyl â-selenoglycosides 3 could
be activated under mild conditions to form â-selenolates in
situ, which coupled with various electrophilic partners to
produce â-selenoglycosides 12-21 and 24 in high yields,
each as a single isomer. In particular, the successful delivery
of selenodisaccharide 21 and selenoglycosylamine 24 dem-
onstrated that this method meets the criteria for practical
selenooligosaccharide and selenoglycosyl peptide synthesis.
These syntheses permit only acyl functionality during hy-
droxyl and amine protection because of the lability of
selenoglycoside toward acidic, hydrogenolytic, and oxidative
conditions. The easy preparation and long shelf life of 3
further reinforced the feasibility of this method. The synthesis
of R-selenoglycoside will be reported in due course.
We have been the first to succeed in establishing the
selenoglycosylserine structure (Scheme 4). Thus, Fmoc-
Scheme 4. Synthesis of Selenoglycosyl Serine Derivative
Acknowledgment. We thank Mr. Hidenori Tanaka for
initial examinations on â-acylselenoglycoside synthesis. We
also thank Ms. Yumiko Murase and Ms. Kyoko Sawa for
technical assistance on instrumental analysis. This work was
supported by MEXT of Japan (Grant-in-Aid for Scientific
Research to H.A., No. 16780083) and Mitsubishi Chemical
Corporation Fund (H.A.).
protected â-iodoalanine 23,11 which was prepared from an
Fmoc-Ser derivative, swiftly reacted with selenoacyl galac-
toside 3b to produce â-selenoglycosylated serine 24 with
an 87% yield. Despite the anionic conditions, epimerization
of the R-carbon and cleavage of the Fmoc group did not
occur during the course of the reaction.
Supporting Information Available: Experimental de-
tails, spectral characterization, and copies of 1H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL051804S
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Org. Lett., Vol. 7, No. 21, 2005