α-Selective sialylations with N-acetyl-5-N,4-O-oxazolidinone- protected p-toluenethiosialoside

Article abstract of DOI:10.1055/s-0028-1087539

A novel N-acetyl-5-N,4-O-oxazolidinone-protected p-toluenethiosialoside was readily prepared from sialic acid and p-toluenethiol. It was demonstrated that the p-toluenethiosialoside could be successfully applied to the α-selective sialylations with variou

Full text of DOI:10.1055/s-0028-1087539

LETTER
425
a-Selective Sialylations with N-Acetyl-5-N,4-O-Oxazolidinone-Protected
p-Toluenethiosialoside
a-Selective Si
e
Department of Chemistry, Beijing Normal University, Beijing 100875, P. R. of China
Fax +86(10)58802075; E-mail: gwxing@bnu.edu.cn
Received 18 August 2008
vent, it was synthesized via a comparatively longer syn-
thetic route from pentaacetate derivative of Neu5Ac.15
Abstract: A novel N-acetyl-5-N,4-O-oxazolidinone-protected p-
toluenethiosialoside was readily prepared from sialic acid and p-tol-
uenethiol. It was demonstrated that the p-toluenethiosialoside could
be successfully applied to the a-selective sialylations with various
glycosyl acceptors in good yields. In the coupling of N-acetyl-5-
N,4-O-oxazolidinone-protected p-toluenethiosialoside and gluco
alcohol, a quantitative reaction yield and high a-selectivity were ob-
tained in dichloromethane–acetonitrile (2:1) at –40 °C.
p-Toluenethiosialoside (4) is a common donor for sialyla-
tion, which can be easily derivated to other kinds of useful
sialyl donors.18,20 Since p-methyl-phenyl group has a
greater electron-donating property compared to phenyl
group, toluenethioside should be more reactive than phe-
nylthioside.19 Furthermore, p-toluenethiol is a nonvolatile
solid (mp 40–44 °C) instead of the liquid thiophenol (mp
–15 °C), which can efficiently reduce the odor problem
during its transformation into sulfide sialyl donor. Based
on these facts, herein, we report the synthesis of a novel
N-acetyl-5-N,4-O-oxazolidinone-protected p-toluenethio-
sialoside 1 and its application into sialylation with various
sugar acceptors.
Key words: p-toluenethiosialoside, oxazolidinone, sialic acid
N-Acetylneuraminic acid (Neu5Ac) is the best-known
naturally occurring derivative of the sialic acid family,
which is abundant on the mammalian cell surface. Many
biological studies illustrate the significant importance of
sialic acid in cell differentiation, charged molecules trans-
portation, and pathogen-host recognition, which are in-
volved in the numerous cellular events in high animals
and human being. N-Acetylneuraminic acid frequently
occupies the terminal position of glycan chains on glyco-
proteins and glycolipids via a-glycosidic linkage and is
considered as the antennae of glycoconjugates.1 Over the
years, various sialylation strategies2 were developed to
construct the natural a-linkage, and mainly focused on the
use of various leaving groups, such as sulfide,3 xanthate,4
phosphite,5 and trifluoroacetimidate,6 as well as pro-
moters including NIS/TfOH,7 NIS/TfOH/TMSOTf,8
TBAOTf,9 and Ph2SO/Tf2O.10,11 In addition, some indi-
rect chemical methods for sialylations such as participat-
ing auxiliaries at C-312,2b and modifications of C-513 using
N-Ac2, N-TFA, N-Troc, etc. have also been investigated.
AcO
AcO
AcO
AcO
SPh
CO2Me
OAc
OAc
CO2Me
STol
O
O
AcN
AcN
O
O
O
O
1
2
AcO
AcO
S
OAc
OAc
AcO
CO2Me
STol
AcO
AcO
O
O
CO2Me
AcN
O
AcHN
O
3
4
Figure 1
In order to prepare donor 1, sialoside 4 was first prepared
from Neu5Ac and p-toluenethiol as described in the liter-
ature.20 Deacetylation of 4 with MsOH in MeOH under
reflux afforded the free amine intermediate, which was
then transformed into 5-N,4-O-carbonyl-protected deriva-
tive 5 by treatment with 4-nitrophenyl chloroformate in
60% yield (two steps). All the hydroxy groups in 5 and the
amino nitrogen in the oxazolidinone were successively
acetylated with acetic anhydride and pyridine then acetyl
chloride and N,N-diisopropylethylamine to produce donor
1 in 80% yield (Scheme 1).21 The solid-state structure of
1 has been confirmed by single-crystal X-ray diffraction
(Figure 2).24
Recently, 5-N,4-O-oxazolidinone as a protective group of
the sialyl donor was introduced by several research
groups.14–17 In particular, Crich et al. devised N-acetyl-5-N,4-
O-carbonyl-protected phenylthiosialoside 2 (Figure 1),14
and 1-adamantanylthiosialosides 3.15 These two novel sia-
lyl donors were successfully used in the a-sialylation and
a satisfactory reaction yield and a/b product ratio, respec-
tively, were obtained. Unfortunately, it was noted that 2
failed in the glycosylation with secondary sugar acceptors
promoted by NIS/TfOH in nitrile solvents at –40 °C in or-
der to increase the a-selectivities of the sialylations by
means of the nitrile effect.15 Although 3 afforded a good
a-selective sialylation at low temperature in nitrile sol-
Initially, the donor 1 property was investigated with gluco
alcohol 6 bearing a primary free 6-hydroxy group as the
acceptor. To a stirring mixture of 1 and 6 (1.2 equiv), and
SYNLETT 2009, No. 3, pp 0425–0428
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087539; Art ID: W13108ST
x
x.
x
x.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

426
F.-f. Liang et al.
LETTER
OAc
OAc
smoothly and a quantitative product yield and the highest
a/b product ratio (6.5:1) were observed (Table 1, entry 3),
suggesting that the best solvent to use was a CH2Cl2–
MeCN mixture. In addition, decreasing the reaction tem-
perature to –75 °C gave the a-anomer as the only product
but in a lower reaction yield (63%, Table 1, entry 4).
Higher temperature (–20 °C) was useful to improve the
reaction yield (92%, Table 1, entry 6). However, the prod-
uct yield was the highest when the reaction was carried
out at –40 °C (Table 1, entry 5). Therefore we used the
reaction conditions described in entry 5 of Table 1 for the
following sialylations with various sugar acceptors.
OH
OH
OH
ref. 20
CO2Me
STol
HO
AcO
O
O
CO2H
AcHN
AcHN
HO
AcO
OH
4
Neu5Ac
OH
CO2Me
STol
1) MeOH, MsOH, reflux
HO
O
2) 4-O2NC6H4OCOCl
NaHCO3, H2O–MeCN, 0 °C
2 steps: 60%
HN
O
O
5
OAc
OAc
CO2Me
STol
1) Ac2O, pyridine, r.t.
AcO
O
AcN
2) DIPEA, AcCl
CH2Cl2, 0 °C
2 steps: 80%
O
O
1
Table 2 illustrates the results of our efforts to explore the
sialylation reactions between donor 1 and various alcohol
acceptors.22 Besides methyl 2,3,4-tri-O-benzyl-a-D-
glucopyranoside (6), it was found that excellent yields
(>90%) and good a-selectivities (a/b >6:1) were obtained
with other primary alcohols such as methyl 1,2:3,4-di-O-
isopropylidene-a-D-galactopyranoside (8) and 1-octanol
(9, Table 2, entries 1–3). For secondary sugar acceptors,
diosgenin (10) and 3b-cholestanol (11), both afforded the
desired linkage types with a/b >10. In the case of 3b-
cholestanol 11, the product yield was low (51%) due to its
poor solubility in the CH2Cl2–MeCN mixture used. In the
regioselective 3-O-sialylation of methyl 2,6-di-O-benzyl-
b-D-galactopyranoside (12), the a-anomer was the major
product (a/b = 1.8:1). The ratio was much higher than in
the case of donor 2 used for the sialylation (a/b = 1:1.3),14
indicating that p-toluenethiosialoside 1 was a better sialyl
donor than phenylthiosialoside 2. Similarly, with 2,4,6-
tri-O-benzyl-b-D-galactopyranoside (13) as the acceptor,
compared with the unsatisfactory product a/b ratio (1:8)14
of the known donor 2, a much improved a-selectivity (a/
b = 1.2:1) was obtained for the reaction. For the sterically
hindered acceptor, coupling of 1 and 1-adamantanol (14)
also gave the major a-anomer in 76% isolated yield.
Scheme 1 Synthesis of donor 1
Figure 2 The X-ray crystallographic structure of 1
4 Å molecular sieves in acetonitrile at –40 °C under argon
was added trifluoromethanesulfonic acid and N-iodosuc-
cinimide. Thin-layer chromatography indicated the reac-
tion was finished in 20 minutes. The expected product 7
was achieved in high yield (93%) and an a/b ratio of 5.4:1
(Table 1, entry 1). We then further examined the solvent
effect on the glycosylation. The results showed that using
2:1 CH2Cl2–MeCN as the solvent, the reaction went
Table 1 The Effect of Solvent and Temperature on the Sialylation of Donor 1
AcO
OAc
CO2Me
O
OH
AcO
AcO
OAc
CO2Me
STol
O
AcO
O
NIS, TfOH
4 Å MS
BnO
BnO
AcN
O
O
+
AcN
O
O
BnO
BnO
OMe
O
BnO
O
BnO
OMe
7
6
1
Entry
Solvent
MeCN
CH2Cl2
Temp (°C)
–40
Time (min)
Yield (%)a
a/bb
5.4:1
3.9:1
6.5:1
a
1
2
3
4
5
6
20
20
20
60
60
60
93
–40
90
CH2Cl2–MeCN (2:1)
CH2Cl2–MeCN (2:1)
CH2Cl2–MeCN (2:1)
CH2Cl2–MeCN (2:1)
–40
quant.
63
–75
–40
quant.
92
6.2:1
6.3:1
–20
a Isolated yields.
b Determined by 1H NMR analysis.
Synlett 2009, No. 3, 425–428 © Thieme Stuttgart · New York

LETTER
a-Selective Sialylations
427
Table 2 Sialylation of Various Alcohol Acceptors with Donor 1
OAc
OAc
OAc
OAc
O
CO2Me
CO2Me
OR
AcO
AcO
NIS, TfOH
O
+
O
ROH
STol
AcN
O
AcN
O
CH2Cl2–MeCN (2:1), –40 °C
O
1
Entry
Acceptor
Product
Yield (%)a
quant.
a/bb
OH
O
BnO
BnO
1
7d
6.2:1
BnO
OMe
6
OH
O
O
15d
16d
95
92
a
O
2
3
O
O
8
HO
>10:1
6
9
O
O
4
5
1723
80
51
>10:1
>10:1
HO
10
C8H17
18d
HO
11
OH
OBn
O
19d
20d
21d
72
81
76
1.8:1c
1.2:1
3.3:1
OMe
6
7
8
HO
OBn
12
OBn
OBn
O
OMe
OBn
HO
13
HO
14
a Isolated yields.
b Determined by 1H NMR analysis.
c Coupled to the 3-OH.
d The 1H NMR data have good consistence with those reported in ref. 14
.
In conclusion, p-toluenethiosialoside 1 was designed enethiosialoside was successfully applied to the a-selec-
based on the known thioglycoside 2 and 4. Since p-tolu- tive sialylations with various glycosyl acceptors in good
enethiol is a nonvolatile solid, donor 1 could be more yields. In some cases, p-toluenethiosialoside 1 proves to
readily prepared than phenylthiosialoside 2. In the cou- be a better sialyl donor than phenylthiosialoside 2, espe-
pling of 1 and 6, excellent product yield and a-selectivity cially in the regioselective 3-O-sialylation of galactopyra-
were observed with CH2Cl2–MeCN (2:1) as reaction me- noside 12 and the glycosyaltion of tribenzyl
dia at –40 °C. In this letter, the results also demonstrated galactopyranoside 13.
that N-acetyl-5-N,4-O-oxazolidinone-protected p-tolu-
Synlett 2009, No. 3, 425–428 © Thieme Stuttgart · New York

428
F.-f. Liang et al.
LETTER
(18) (a) Cao, S.; Meunier, S. J.; Andersson, F. O.; Letellier, M.;
Roy, R. Tetrahedron: Asymmetry 1994, 5, 2303. (b) Ye,
X.-S.; Huang, X.-F.; Wong, C.-H. Chem. Commun. 2001,
974. (c) Lin, C.-C.; Huang, K.-T.; Lin, C.-C. Org. Lett. 2005,
7, 4169.
(19) Roy, R.; Andersson, F. O.; Letellier, M. Tetrahedron Lett.
1992, 33, 6053.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The project was financially supported by the National Natural Sci-
ence Foundation of China (20502002) and Beijing Municipal Com-
mission of Education. The authors are grateful to Prof. Guo-fu Zi
for helpful discussion on the X-ray crystallography.
(20) Yu, C.-S.; Niikura, K.; Lin, C.-C.; Wong, C.-H. Angew.
Chem. Int. Ed. 2001, 40, 2900.
(21) Donor 1 was prepared similarly as literature described.14
Compound characterization data for 5: 1H NMR (500 MHz,
CD3OD): d = 7.47 (d, J = 7.7 Hz, 2 H), 7.22 (d, J = 7.7 Hz,
2 H), 4.06 (dt, J = 11.9, 3.3 Hz, 1 H), 3.83 (m, 3 H), 3.67–
3.69 (m, 2 H), 3.67 (s, 3 H), 3.55 (d, J = 8.8 Hz, 1 H), 3.14
(dd, J = 11.7, 3.6 Hz, 1 H, H-3eq), 2.38 (s, 3 H), 2.21 (t,
J = 12.2 Hz, 1 H, H-3ax). 13C-APT NMR (125 MHz,
CD3OD): d = 169.1, 160.9, 140.5, 136.3, 129.3, 125.1, 87.8,
78.3, 78.2, 71.5, 70.0, 63.1, 57.1, 52.2, 36.6, 19.9. HRMS:
m/z calcd for C18H23NO8SNa [M + Na]+: 436.10421; found.
436.10364.
References and Notes
(1) (a) Sialic Acids: Chemistry, Metabolism and Function, Vol.
10; Schauer, R., Ed.; Springer: New York, 1982.
(b) Biology of Sialic Acid; Rosenberg, A., Ed.; Plenum Press:
New York, 1995. (c) Traving, C.; Schauer, R. Cell. Mol. Life
Sci. 1998, 54, 1330. (d) Lehmann, F.; Tiralongo, E.;
Tiralongo, J. Cell. Mol. Life Sci. 2006, 63, 1331.
(2) For reviews, see: (a) Okamoto, K.; Goto, T. Tetrahedron
1990, 46, 5835. (b) Boons, G.-J.; Demchenko, A. V. Chem.
Rev. 2000, 100, 4539. (c) Hasegawa, A.; Kiso, M. In
Preparative Carbohydrate Chemistry; Hanessian, S., Ed.;
Marcel Dekker: New York, 1997, 357.
(3) For recent examples, see: (a) Ando, H.; Koike, Y.; Ishida,
H.; Kiso, M. Tetrahedron Lett. 2003, 44, 6883.
(b) Matsuoka, K.; Onaga, T.; Mori, T.; Sakamoto, J.-I.;
Koyama, T.; Sakairi, N.; Hatano, K.; Terunuma, D.
Tetrahedron Lett. 2004, 45, 9383.
(4) (a) Marra, A.; Sinaÿ, P. Carbohydr. Res. 1990, 195, 303.
(b) Martichonok, V.; Whitesides, G. M. J. Org. Chem. 1996,
61, 1702.
(5) (a) Martin, T. J.; Schmidt, R. R. Tetrahedron Lett. 1992, 33,
6123. (b) Kondo, H.; Ichikawa, Y.; Wong, C. H. J. Am.
Chem. Soc. 1992, 114, 8748.
(6) Yu, B.; Cai, S. Org. Lett. 2003, 5, 3827.
(7) Yoshida, M.; Uchimura, A.; Kiso, M.; Hasegawa, A.
Glycoconjugate J. 1993, 10, 3.
(8) Zhang, Z.; Niikura, K.; Huang, X.-F.; Wong, C.-H. Can. J.
Chem. 2002, 80, 1051.
Compound 1: 1H NMR (500 MHz, CDCl3): d = 7.45 (d,
J = 7.9 Hz, 2 H), 7.18 (d, J = 7.9 Hz, 2 H), 5.55 (d, J = 5.8
Hz, 1 H), 5.38 (m, 1 H), 4.45 (dd, J = 12.2, 2.6 Hz, 1 H), 4.36
(d, J = 9.4 Hz, 1 H), 4.23 (m, 1 H), 3.98 (m, 1 H), 3.65 (s, 3
H), 3.63 (m, 1 H), 3.10 (dd, J = 12.1, 3.5 Hz, 1 H, H-3eq),
2.48 (s, 3 H), 2.39 (s, 3 H), 2.19 (s, 3 H), 2.14 (m, 1 H, H-
3ax), 2.11 (s, 3 H), 2.10 (s, 3 H). 13C-APT NMR (125 MHz,
CDCl3): d = 171.9, 170.6, 170.3, 170.0, 168.2, 153.4, 140.6,
136.3, 129.7, 124.7, 87.8, 77.4, 75.7, 72.6, 70.7, 62.5, 59.1,
53.1, 36.5, 24.7, 21.3, 21.1, 20.9, 20.8. HRMS: m/z calcd for
C26H31NO12SNa [M + Na]+: 604.14647; found. 604.14590.
(22) General Sialylation Procedure (with the Coupling
Between 1 and 6 as Example)
To a mixture of donor 1 (40.0 mg, 0.07 mmol, 1.0 equiv),
acceptor 6 (38.4 mg, 0.08 mmol, 1.2 equiv), and activated 4
Å powdered MS, was added anhyd CH2Cl2–MeCN (2:1, 3
mL). The resulted solution was stirred for 0.5 h at r.t. under
Ar, and then cooled to –40 °C followed by addition of NIS
(37.7 mg, 0.17 mmol, 2.4 equiv) and TfOH (6.0 mL, 0.07
mmol, 1.0 equiv). The reaction was stirred at –40 °C for 1 h.
After quenched with Et3N (0.1 mL), the mixture was diluted
with CH2Cl2, filtered through Celite, washed with 20% aq
Na2S2O3 solution, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by column
chromatography on SiO2 eluting with hexane–EtOAc
system to give the coupling product.
(9) Nagao, Y.; Nekado, T.; Ikeda, K.; Achiwa, K. Chem. Pharm.
Bull. 1995, 43, 1536.
(10) Crich, D.; Li, W. Org. Lett. 2006, 8, 959.
(11) Crich, D.; Wu, B. Tetrahedron 2008, 64, 2042.
(12) (a) Ito, Y.; Ogawa, T. Tetrahedron 1990, 46, 89.
(b) Hossain, N.; Magnusson, G. Tetradron Lett. 1999, 40,
2217.
(13) For recent review, see: De Meo, C.; Priyadarshani, U.
Carbohydr. Res. 2008, 343, 1540.
(14) Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387.
(15) Crich, D.; Li, W. J. Org. Chem. 2007, 72, 7794.
(16) Farris, M. D.; De Meo, C. Tetrahedron Lett. 2007, 48, 1225.
(17) Tanaka, H.; Nishiura, Y.; Takahashi, T. J. Am. Chem. Soc.
2006, 128, 7124.
(23) Compound 17: 1H NMR (500 MHz, CDCl3): d = 5.60 (d,
J = 7.2 Hz, 1 H), 5.40 (dt, J = 6.9, 2.8 Hz, 1 H), 5.34 (d,
J = 3.1 Hz, 1 H), 5.12 (m, 1 H), 4.55 (d, J = 9.4 Hz, 1 H),
4.42–4.33 (m, 2 H), 4.13 (m, 1 H), 4.01 (m, 1 H), 3.79 (s,
3 H), 3.71 (t, J = 9.8 Hz, 1 H), 3.62 (m, 1 H), 3.48–3.35 (m,
2 H), 2.90 (dd, J = 12.0, 3.2 Hz, 1 H, H-3eq), 2.49 (s, 3 H),
2.15 (s, 3 H), 2.12 (s, 3 H), 2.03 (s, 3 H), 1.01 (s, 3 H), 0.96
(d, J = 6.9 Hz, 3 H), 0.79 (s, 3 H), 0.78 (d, J = 5.7 Hz, 3 H).
(24) CCDC 693369 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Synlett 2009, No. 3, 425–428 © Thieme Stuttgart · New York