Novel glycosylation reactions using glycosyl thioimidates of N-acetylneuraminic acid as sialyl donors

Article abstract of DOI:10.1016/j.bmcl.2006.02.037

Novel sialyl donors 4 bearing a thioimidolyl moiety as the leaving group were successfully prepared from the corresponding arylthio derivatives 3 and a peracetylated chloro derivative of Neu5Ac 2 in the presence of N,N-di-isopropylethylamine with moderate

Full text of DOI:10.1016/j.bmcl.2006.02.037

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2618–2620
Novel glycosylation reactions using glycosyl thioimidates
of N-acetylneuraminic acid as sialyl donors
Kiyoshi Ikeda,* Misato Aizawa, Kazuki Sato and Masayuki Sato
School of Pharmaceutical Sciences, University of Shizuoka, Surugaku-Yada 52-1, Shizuoka 422-8526, Japan
Received 4 December 2005; revised 6 February 2006; accepted 15 February 2006
Available online 3 March 2006
Abstract—Novel sialyl donors 4 bearing a thioimidolyl moiety as the leaving group were successfully prepared from the correspond-
ing arylthio derivatives 3 and a peracetylated chloro derivative of Neu5Ac 2 in the presence of N,N-di-isopropylethylamine with
moderate yields. The reaction of 4 with various alcohols 5 was effectively activated by AgOTf as the promoter to give the corre-
sponding O-sialosides 6 with good yields. Selective activation of 4a over 4-pentenyl 2-glycoside of Neu5Ac 7 with AgOTf was also
achieved.
Ó 2006 Elsevier Ltd. All rights reserved.
N-Acetylneuraminic acid (sialic acid, Neu5Ac) and its
various analogs play essential roles in a variety of bio-
chemical and biological processes.1 The development
of an efficient method of O-sialylation has been a chal-
lenging task in the field of sialic acid chemistry.2 Recent
analysis has focused on the utilization of metal triflate
salts as activators for milder and stereoselective O-glyco-
sylation.3 Recently, AgOTf or Cu(OTf)2 promoted
O-sialylation using S-benzoxazolyl and S-thiazolyl
glycoside derivatives of Neu5Ac has been reported.4
As part of our program aimed at the development of
new O-sialylation reaction,5 we demonstrated the utility
of glycosyl thioimidates of Neu5Ac based on a variation
of the remote activation concept6 in the synthesis of
O-sialoside.7 Here, we report the preparation of sialyl
donors bearing a thioimidolyl moiety and their applica-
tion to stereoselective O-sialylation.
temperature with 95%, 58%, 49%, and 56% yields,
respectively (Scheme 1). Faillard and Rothermel have
reported the synthesis of 4a using phase-transfer cataly-
sis10 from 2a and 3a with only a moderate yield of 53%.
Compound 4e was also synthesized from 2b prepared
from 1b and 2a with a 63% yield.
We started our investigation on the glycosylation of 4a
with p-nitrobenzyl alcohol 5a11 as an acceptor. The gly-
cosylation reaction between 4a and 1.5 equiv of 5a
using 2.0 equiv of AgOTf12 in CH2Cl2 at room temper-
ature gave the expected glycoside 6a13 with an 89% yield
as an anomeric mixture with b-anomer as the major
product (Table 1, entry 1). Next, glycosylations of other
glycosyl donor 4b–d with 5a were examined. As summa-
rized in Table 1, the reactions of 4b–d with 5a were acti-
vated by AgOTf as a promoter to give 6a with 72%,
63%, and 64% yields, respectively (entries 2–4). Different
reaction conditions including promoters and solvents
Synthesis of 4a–d was achieved by pathways from 2a,
which was easily prepared from 1a with AcCl. We suc-
ceeded in stereoselective preparation of a-sialosides
4a,8 4b,4 4c, and 4d through SN2 displacement of the
chloro group in 2 with 2-mercaptobenzothiazole 3a, 2-
mercaptobenzoxazole 3b, 2-mercaptobenzimidazole 3c,
and 2-mercapto-5-nitro-benzimidazole 3d in the pres-
ence of N,N-di-isopropylethylamine9 in CH2Cl2 at room
were tested. The reaction using Cu(OTf)2 or MeOTf15
14
as promoters afforded 6a with 48% and 36% yields,
respectively (entries 6 and 7). These results show the
superiority of AgOTf to Cu(OTf)2 or MeOTf as promot-
ers. The solvent effect was then examined using CH3CN
and CH2Cl2. A relatively large amount of a-glycosides
was obtained in CH3CN with a-anomer as the major
product (a/b = 2:1), as expected from the assistance of
the nitrile solvent effect,16 compared to the use of
CH2Cl2 (entries 5,17 7, 9, and 10). Encouraged by these
results, we next examined the coupling of 4a with bio-
logically relevant acceptors, galactose derivatives 5b,
5c, and 5d. The reaction of 4a with 5b promoted
Keywords: Sialic acid; O-Sialylation; Thioimidolyl group; Silver
triflate.
*
Corresponding author. Tel./fax: +81 54 264 5108; e-mail:
ikeda@ys2.u-shizuoka-ken.ac.jp
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.02.037

K. Ikeda et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2618–2620
2619
Scheme 1. Synthesis of 4.
Table 1. Glycosylation reactions between 4a–e and 5a–d
Entry Glycosyl donor Glycosyl acceptor Conditiona
Product
Yield (%)
(a/b)b
1
4a
AgOTf, rt, CH2Cl2
89 (1:6)
2
3
4
5
6
7
4b
4c
4d
4a
4a
4a
5a
5a
5a
5a
5a
5a
AgOTf, rt, CH2Cl2
AgOTf, rt, CH2Cl2
AgOTf, rt, CH2Cl2
6a
6a
6a
72 (1:7)
63 (1:8)
64 (1:8)
71 (2:1)
48 (1:9)
36 (2:1)
AgOTf, À20 °C to 0 °C, CH3CN 6a
Cu(OTf)2, rt, CH2Cl2 6a
MeOTf, À20 °C to 0 °C, CH3CN 6a
8
4a
AgOTf, rt, CH2Cl2
54 (1:3)
9
4a
4e
5b
5a
AgOTf, À20 °C to 0 °C, CH3CN 6b
AgOTf, À20 °C to 0 °C, CH3CN
54 (2:1)
41 (2:1)
10
11
12
4a
4a
AgOTf, rt, CH2Cl2
AgOTf, rt, CH2Cl2
33 (1:2)
41 (1:3)
Troc: Cl3CCH2OC(O)–, C14: CH3(CH2)12C(O)–
a With respect to 4, 1.5 equiv of 5 and 2.0 equiv of promoter were used. Reaction time was 15 h.
1
b Isolated yields. The stereochemistry of 6 was confirmed by H NMR (500 MHz) spectral comparison of the chemical shifts of 3Heq signals of the
glycosides. The anomeric ratios were determined on the basis of the integration ratios of the 3Heq signals of the glycosides in 1H NMR
spectroscopy.
by AgOTf in CH2Cl2 at room temperature gave the cor-
responding Neu5Ac(2–6)Gal 6b with a 54% yield (entry
8). When CH3CN was used as the solvent at À40 °C, an
increase of a-selectivity was observed with a-anomer as
the major product (54%, a/b = 2:1) (entry 9). It should
be noted that no glycosylation4 of 4b with 5b in the

2620
K. Ikeda et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2618–2620
5. (a) Ikeda, K.; Sugiyama, Y.; Tanaka, K.; Sato, M. Bioorg.
Med. Chem. Lett. 2002, 12, 2309; (b) Ikeda, K.; Torisawa,
Y.; Nishi, T.; Minamikawa, J.; Tanaka, K.; Sato, M.
Bioorg. Med. Chem. 2003, 11, 3073.
6. Hanessian, S.; Bacquet, C.; Lehong, N. Carbohydr. Res.
1980, 80, C17.
7. Ikeda, K.; Aizawa, M.; Sato, M. Abstracts of Papers, 30th
Symposium on Progress in Organic Reactions and Syn-
theses, Sapporo, Japan, October 19–20, 2004; The Phar-
maceutical Society of Japan, p 98.
8. Experimental data of 4a: N,N-di-isopropylethylamine
(0.529 g, 4.1 mmol) was added to a solution of 2a
(1.67 g, 3.28 mmol) and 3a (0.457 g, 2.73 mmol) in dry
dichloromethane (20 ml) under an atmosphere of argon.
The reaction mixture was stirred for 16 h at room
temperature. Upon completion, the mixture was con-
centrated in vacuo and the residue was purified by
column chromatography on silica gel (AcOEt) to afford
4a (1.66 g, 95%): 1H NMR (CDCl3) d: 1.87, 1.98, 1.99,
2.02, 2.04 (s, each 3H, NHCOCH3, OCOCH3), 2.29 (dd,
1H, J3ax,4 = 11.5 Hz, J3ax,3eq = 13.2 Hz, H-3ax), 2.91 (dd,
1H, J3eq,4 = 4.6 Hz, H-3eq), 3.77 (s, 3H, OCH3), 4.02
(ddd, 1H, J5,4 = J5,6 = J5,NH = 10.3 Hz, H-5), 4.13 (dd,
1H, J6,7 = 1.7 Hz, H-6), 4.15 (dd, 1H, J9a,8 = 5.5 Hz,
J9a,9b = 12.6 Hz, H-9a), 4.37 (dd, 1H, J9b,8 = 2.3 Hz, H-
9b), 4.89–4.94 (m, 1H, H-4), 5.18–5.20 (m, 1H, NH),
5.28–5.37 (m, 1H, H-8), 5.29 (d, 1H, J7,8 = 7.5 Hz, H-7),
7.42–7.51 (m, 2H, aromatic-H), 7.89, 8.05 (d, each 1H,
J = 7.5 Hz, aromatic-H). Positive FAB-MS m/z 641
[M+H]+. HR-FAB-MS Calcd for C27H33O12N2S2
(M+H)+: 641.1475. Found: 641.1483.
Scheme 2. Selective activation of 4a in the presence of O-pentyl
glycoside of Neu5Ac 7.
presence of AgOTf in CH3CN was observed. The glyco-
sylation of 4a with 5c afforded the resulting (2–6)sialoside
6c with a moderate yield of 33% (entry 11). Coupling of 4a
with 5d gave 6d with a 41% yield (entry 12).
To evaluate the applicability of 4a to the armed–
disarmed like coupling reaction,18 we performed com-
petitive glycosylation of 4a with the 4-pentenyl 2-glyco-
side of Neu5Ac 7.19 The glycosylation of 4a in the
presence of 7 with 5b was carried out using AgOTf in
CH2Cl2 at room temperature to give 6b with a 43% yield
(a/b = 1:6) together with the recovery of 89% of 7
(Scheme 2). The selective activation of 4a over 7 was
achieved in the presence of AgOTf.
In summary, we have developed an efficient method
for the preparation of novel sialyl donors bearing a
thioimidolyl moiety and demonstrated their utility
toward synthesizing various a-sialosides. We are
currently applying this methodology to the synthesis of
other oligosaccharides.
9. Marra, A.; Sinay, P. Carbohydr. Res. 1989, 187, 35.
10. Rothermel, J.; Faillard, H. Biol. Chem. Hoppe-Seyler
1988, 370, 1077.
11. Yamada, K.; Fujita, E.; Nishimura, S.-I. Carbohydr. Res.
1998, 305, 443.
12. Mehta, S.; Pinto, B. M. Tetrahedron Lett. 1991, 32, 4435.
13. Representative procedure for glycosylation (Table 1, entry
1):
0.072 mmol), glycosyl acceptor 5a (16 mg, 0.108 mmol),
A mixture of the glycosyl donor 4a (46 mg,
Acknowledgment
˚
and 4 A molecular sieves (0.25 g) in CH2Cl2 (2.0 ml) was
stirred under argon for 1 h. Freshly conditioned AgOTf
(37 mg, 0.144 mmol) was added and the reaction mixture
was stirred for 17 h at room temperature and then diluted
with CH2Cl2. The precipitates were filtered off through a
pad of Celite and concentrated to give the crude product,
which was purified on a preparative-TLC with a solvent
system of AcOEt to give the glycoside 6a (40 mg, 70%) as a
mixture of a/b anomers.
This work was partly supported by the Japan Health
Science Foundation.
References and notes
1. Rosenberg, A. Biology of Sialic Acids; Plenum: New York,
London, 1995.
14. Mukaiyama, T.; Nakatsuka, T.; Shoda, S.-I. Chem. Lett.
1979, 487.
2. (a) Boons, G.-J.; Demchenko, A. V. Chem. Rev. 2000, 100,
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2004, 609; (c) Ando, H.; Koike, Y.; Ishida, H.; Kiso, M.
Tetrahedron Lett. 2003, 44, 6883; (d) Ando, H.; Koike, Y.;
Koizumi, S.; Ishida, H.; Kiso, M. Angew. Chem., Int. Ed.
2005, 44, 6759; (e) Tanaka, K.; Goi, T.; Fukase, K. Synlett
2005, 2958.
3. (a) Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503; (b)
Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-. L.
Chem. Rev. 2002, 102, 2227.
15. Lonn, H. J. Carbohydr. Chem. 1987, 6, 301.
16. Hasegawa, A.; Nagahama, T.; Ohki, H.; Hotta, K.;
Ishida, H.; Kiso, M. J. Carbohydr. Chem. 1991, 10, 493.
17. It was reported that sialylation of 5a (1.5 equiv) with
methyl peracetylated Neu5Ac (2.0 equiv of Bi(OTf)3 and
2.0 equiv of BF3ÆOEt2, CH3CN, rt) gave 6a in 27% yield
and a/b = 57:43.5b
18. Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-
Reid, B. J. Am. Chem. Soc. 1988, 110, 5583.
4. Cristina, De. M.; Olivia, P. Tetrahedron: Asymmetry 2005,
16, 303.
19. Ikeda, K.; Fukuyo, J.; Sato, K.; Sato, M. Chem. Pharm.
Bull. 2005, 53, 1490.