Use of phenyl 2-alpha-selenoglycosides of N-acetylneuraminic acid as a glycosyl donor for the glycosylation reactions.

Article abstract of DOI:10.1016/S0960-894X(02)00400-6

Phenyl 2-alpha-selenoglycosides of Neu5Ac were successfully prepared from the corresponding peracetylated chloro derivative of Neu5Ac 1 and phenylselenol in the presence of N,N-di-isopropylethylamine in excellent yields. The reaction of with various alcoh

Full text of DOI:10.1016/S0960-894X(02)00400-6

Bioorganic & MedicinalChemistry Letters 12 (2002) 2309–2311
Use of Phenyl 2-ꢀ-Selenoglycosides of N-Acetylneuraminic Acid
as a Glycosyl Donor for the Glycosylation Reactions
Kiyoshi Ikeda,* Yuji Sugiyama, Kiyoshi Tanaka and Masayuki Sato
School of Pharmaceutical Sciences, University of Shizuoka, Yada 52-1, Shizuoka 422-8526, Japan
Received 23 April2002; accepted 4 June 2002
Abstract—Phenyl2- a-selenoglycosides of Neu5Ac 2 were successfully prepared from the corresponding peracetylated chloro deri-
vative of Neu5Ac 1 and phenylselenol in the presence of N,N-di-isopropylethylamine in excellent yields. The reaction of 2 with
various alcohols was effectively catalyzed by NIS/TfOH or DMTST to produce a variety of glycosides in moderate yields. Selective
activation of 2 over phenyl2- a-thioglycoside of Neu5Ac 6 with AgOTf/K2CO3 was also achieved. # 2002 Elsevier Science Ltd. All
rights reserved.
N-Acetylneuraminic acid (Neu5Ac), sialic acid and its
various analogues play essential roles in a variety of
biochemicaland biool gicalprocesses. 1 The development
of an efficient method of O-sialylation has been a
challenging task in the field of sialic acid chemistry.2
Selenium-substituted carbohydrates are gaining increased
attention with regard to the use of stereocontrolled glyco-
sylations.3 Many useful glycosylation reactions, originally
developed using sulfur chemistry, may be carried out
more selectively with the selenium analogues using
appropriate thiophilic reagents. However, to the best of
our knowledge, there has been only one report4 of the
synthesis of selenoglycosides of Neu5Ac to date, and no
application to glycosylation reactions was described.
Herein we report a novelprocedure for the synthesis of
phenyl2- a-selenoglycosides of Neu5Ac 2 and their
application to the glycosylation reaction.
Faillard and Rothermel reported the synthesis of 2a
using phase-transfer catalysis4 from 1b and phenylselenol
in a moderate yield (entry 3). We succeeded in stereo-
selective preparation of a-glycosides 2a,b8 through SN2
displacement of the chloro group in 1b,c with phenyl-
selenol in the presence of N,N-di-isopropylethylamine6
Initially we focused on a search for an efficient method
of synthesizing selenoglycosides 2. Treatment of per-
acetylated chloro derivative of Neu5Ac 1a with phe-
nylselenol5 in the presence of boron trifluoride etherate6
resulted in the elimination of HCl to afford 2,3-dehydro
derivative 5 in 56% yield (entry 1, Table 1). Next, reaction
of 1b with sodium phenylselenolate under Williamson
reaction conditions7 gave a-selenoglycoside of Neu5Ac
2a in only 20% yield, together with 5 (entry 2).
Table 1. Preparation of a-selenoglycosides of Neu5Ac
Entry Glycosyl donor
Conditions
a-Selenoglycoside (%)
1
2
3
4
5
1a
1b
1b
1b
1c
PhSeH, BF3OEt2
PhSeSePh, NaH
PhSeH, BnEt3N+ClÀ
PhSeH, iPr2NEt
2a (0)
2a (20)
2a (60)
2a (97)
2b (92)
PhSeH, iPr2NEt
*Corresponding author. Tel.: +81-054-264-5108; fax: +81-054-264-
5108; e-mail: ikeda@ys2.u-shizuoka-ken.ac.jp
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00400-6

2310
K. Ikeda et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2309–2311
Table 2. NIS-TfOH or DMTST promoted glycosylations of selenoglycoside of Neu5Aca
Entry
1
Donor 2
Acceptor 3
Promoters
NIS-TfOH
Solvent/temp.
Products
Yield (%) (a/b)b
2a
CH3CN/À40 ꢀC
4a
44 (3/1)
3a
3a
3a
3a
3a
2
3
4
5
2a
2a
2a
2b
NIS-TfOH
NIS-TfOH
DMTST
CH2Cl2/À40 ꢀC
Ether/À40 ꢀC
4a
4a
4a
4b
60 (1/4)
67 (1/1)
80 (2/1)
55 (2/1)
CH3CN/À40 ꢀC
CH3CN/À40 ꢀC
NIS-TfOH
6
2a
NIS-TfOH
CH3CN/À25 ꢀC
4c
69 (2/1)
3b
3b
7
8
2a
2a
NIS-TfOH
DMTST
CH3CN/À40 ꢀC
CH3CN/À40 ꢀC
4c
4d
42 (4/1)
50 (3/1)
3c
3c
9
2a
2a
NIS-TfOH
NIS-TfOH
CH3CN/À40 ꢀC
CH3CN/À40 ꢀC
4d
4e
40 (4/1)
23 (7/1)
10
3d
11
2a
NIS-TfOH
CH3CN/À40 ꢀC
4f
12 (3/1)
3e
aWith respect to 2, 1.2 equiv of 3 and 3.0 equiv of promoter were used. Reaction time was 15 h.
bIsolated yields. The anomeric ratios were determined by comparison of the intensities of the H-3eq signals of the glycosides in 1H NMR (270 MHz)
spectroscopy.
in almost quantitative yields (entries 4 and 5). Next,
glycosylations of 2 with alcohols were examined. As
summarized in Table 2, the reactions of glycosyl donors
2 with alkyl alcohols 3a–e were activated by N-iodo-
succinimide (NIS)-TfOH9 or dimethyl(methylthio)-
sulfonium triflate (DMTST)10 as promoters to give the
corresponding O-glycosides (4a–f) in moderate yields.
Anomeric stereochemistry of the resulting glycosides
was markedly affected by the solvent and the reaction
temperature. Thus, a relatively large amount of a-gly-
cosides was obtained in acetonitrile, as expected from
the more significant solvent participation of acetonitrile
than dichloromethane or ether (entries 1, 2 and 3).11
The ratio of a-glycosides at À40 ꢀC was larger than that
of the reaction at À25 ꢀC (entries 6 and 7). The most
promising yield was achieved when DMTST was used
as a promoter in acetonitrile at À40 ꢀC (entry 4).12 For
comparison of the donor 2a with the corresponding
sulfur analogue 6, the competitive glycosylation was
carried out using the reported conditions13 of silver tri-
flate as a promoter in the presence of potassium car-
bonate. This experiment resulted in recovery of 93% of
compound 6 concomitant with the formation of 4a
(44%, a/b=1:2) from 2a (Scheme 1).
Thus, the efficient activation of selenoglycoside of Neu5Ac
over the thioglycoside of Neu5Ac was achieved.
Scheme 1. Selective activation of selenolglycoside of Neu5Ac.

K. Ikeda et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2309–2311
2311
In summary, the selenoglycosides of Neu5Ac were effi-
ciently prepared in this study, and these were shown to
act as a versatile glycosyl donor.
H-7,8), 7.31–7.36 (m, 2H, aromatic–H), 7.39–7.42 (m, 2H,
aromatic–H), 7.62–7.64 (m, 1H, aromatic–H). FAB-MS m/z
632 (M+H)+. Anal. calcd for C26H33NO12Se: C, 49.53; H,
5.28; N, 2.22. Found: C, 49.43; H, 5.56; N, 2.22. Compound
2b as a white amorphous powder: 1H NMR (CDCl3) d 1.84 (s,
3H, NHAc), 1.94, 2.02, 2.05, 2.11 (s, each 3H, OAc), 2.87 (dd,
1H, J3eq,3ax=13.0 Hz, J3eq,4=4.6 Hz, H-3eq), 3.88 (dd, 1H,
J6,7=2.2 Hz, J6,5=10.3 Hz, H-6), 3.97 (q, 1H, J5,4=10.3 Hz,
H-5), 4.17 (dd, 1H, J9a,8=5.9 Hz, J9a,9b=12.4 Hz, H-9a), 4.37
(dd, 1H, J9b,8=2.7 Hz, H-9b), 4.78 (m, 1H, H-4), 5.01 (s, 2H,
-OCH2Ph), 5.19 (br s, 1H, H-8), 5.27 (dd, 1H, J7,8=6.5 Hz,
H-7), 7.27–7.39 (m, 9H, aromatic–H), 7.54–7.57 (m, 1H, aro-
matic–H). FAB-MS m/z 708 (M+H)+. Anal. calcd for
C32H37NO12Se: C, 54.39; H, 5.28; N, 1.98. Found: C, 54.27;
H, 5.18; N, 2.19.
Acknowledgements
The authors thank Marukin Chuyu Co., Ltd. (Kyoto,
Japan) for the generous donation of Neu5Ac. This work
was supported in part by a Grant-in-Aid for Scientific
Research (No. 13672223) from the Ministry of Education,
Science, Sports and Culture of Japan.
9. Konradsson, P.; Mootoo, D. R.; McDevitt, R. E.; Fraser-
Reid, B. J. Chem. Soc. Chem. Commun. 270.
References and Notes
10. (a) Fugedi, P.; Garegg, P. J. Carbohydr. Res. 1986, 149, c9.
(b) Kanie, O.; Kiso, M.; Hasegawa, A. J. Carbohydr. Chem.
1988, 7, 501.
1. Rosenberg, A., Ed. Biology of Sialic Acids. Plenum: New
York, London, 1995.
2. Boons, G.-J.; Demchenko, A. V. Chem. Rev. 2000, 100,
4539.
11. Hasegawa, A.; Nagahama, T.; Ohki, H.; Hotta, K.; Ish-
ida, H.; Kiso, M. J. Carbohydr. Chem. 1991, 10, 493.
12. Typicalprocedure for a-glycoside of 4a: To a stirred
solution of compound 2a (49 mg, 0.078 mmol) and p-nitro-
benzyl alcohol (13 mg, 0.094 mmol) in CH3CN (3 mL) in the
3. (a) Ito, Y.; Ogawa, T. Tetrahedron Lett. 1987, 28, 6221. (b)
Idem. Tetrahedron Lett. 1988, 29, 3987. (c) Ito, Y.; Numata,
M.; Sugimoto, M.; Ogawa, T. J. Am. Chem. Soc. 1989, 111,
8508. (d) Ikeda, K.; Akamatsu, S.; Achiwa, K. Carbohydr.
Res. 1989, 189, c1.
4. Rothermel, J.; Faillard, H. Carbohydr. Res. 1990, 208, 251.
5. Pinto, B. M.; Mehta, S. J. Org. Chem. 1993, 58, 3269.
6. Marra, A.; Sinay, P. Carbohydr. Res. 1989, 187, 35.
7. Gal l ic, J. L.; Lubineau, AJ. . Carbohydr. Chem. 1991, 10, 263.
8. Spectral data and elemental analysis data of compounds
2a and 2b are shown below. Compound 2a as a white amor-
phous powder: 1H NMR (CDCl3) d 1.86 (s, 3H, NHAc), 2.01,
2.05, 2.06, 2.14 (s, each 3H, OAc), 2.85 (dd, 1H, J3eq,3ax=12.7
Hz, J3eq,4=4.6 Hz, H-3eq), 3.57 (s, 3H, CO2Me), 3.88 (br d,
1H, J6,5=10.3 Hz, H-6), 4.00 (q, 1H, J5,4=10.3 Hz, H-5), 4.19
(dd, 1H, J9a,8=4.6 Hz, J9a,9b=12.4 Hz, H-9a), 4.39 (m, 1H,
H-9b), 4.79 (m, 1H, H-4), 5.11 (br d, 1H, NH), 5.28 (br m, 2H,
˚
presence of 4A MS (0.3 g) was added DMTST (60 mg, 0.23
mmol) at À40 ꢀC under Ar. After stirring for 15 h at the same
temperature, the reaction mixture was filtered through a Celite
545 pad, and evaporated. Column chromatography on silica
gelusing CH Cl2–methanol(10:1) gave compound 4a (39 mg,
2
1
80%) as a white powder: IR (film) 1745, 1666, 1523 cmÀ1; H
NMR (CDCl3) d 1.89 (s, 3H, NHAc), 2.03, 2.06, 2.12, 2.14 (s,
each 3H, OAc), 2.70 (dd, 1H, J3eq,3ax=12.4 Hz, J3eq,4=3.1
Hz, H-3eq), 3.70 (s, 3H, CO2Me), 4.01–4.08 (m, 2H, H-5,6),
4.55, 4.93 (d, each 1H, Jgem=13.5 Hz,–CH2C6H4p-NO2), 5.14
(br d, 1H, NH), 5.39 (m, 1H, H-8), 7.52 (d, 2H, J=7.8 Hz,
aromatic–H), 8.20 (d, 2H, aromatic–H). FAB-MS m/z 627
(M+H)+.
13. Mehta, S.; Pinto, B. M. Tetrahedron Lett. 1991, 32, 4435.