Thioester-assisted α-sialylation reaction

Article abstract of DOI:10.1016/j.tetlet.2008.05.154

α-Selective sialylation reactions were carried out using novel sialic acid building blocks that possess a thioester auxiliary. In contrast to other arylthio- and benzylthioester derivatives, sialyl phosphite 1a (with the phenylthioester moiety) was employed as the α-selective building block, and was reacted with various primary alcohols, including the C6-OH group of galactose and glucose, with moderate to excellent α-selectivities. For C3-OH of the galactose, 4,6-di-O-benzylgalactal afforded desired α-linkage with excellent selectivity.

Full text of DOI:10.1016/j.tetlet.2008.05.154

Tetrahedron Letters 49 (2008) 5111–5114
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Thioester-assisted
a
-sialylation reaction
*
Shinya Hanashima, Shoji Akai, Ken-ichi Sato
Material and Life Chemistry, Faculty of Engineering, Kanagawa University, 3-27-1, Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Selective sialylation reactions were carried out using novel sialic acid building blocks that possess a
thioester auxiliary. In contrast to other arylthio- and benzylthioester derivatives, sialyl phosphite 1a
(with the phenylthioester moiety) was employed as the -selective building block, and was reacted with
various primary alcohols, including the C6–OH group of galactose and glucose, with moderate to excel-
lent -selectivities. For C3–OH of the galactose, 4,6-di-O-benzylgalactal afforded desired -linkage with
excellent selectivity.
Received 7 April 2008
Revised 22 May 2008
Accepted 26 May 2008
Available online 12 June 2008
a
a
a
Keywords:
Sialic acid
Glycosylation
Thioester
Auxiliary
Ó 2008 Elsevier Ltd. All rights reserved.
Galactal
Sialic acids have been found on the non-reducing terminus of
various glycans on cell surfaces. Sialylated glycolipids and glyco-
proteins on cell membranes are closely associated with physiolog-
ical processes involving cell adhesion, signal transduction, and
fertilization.1 Some kinds of sialylated glycans are known as cancer
antigens and play a significant role in malignant transformation
and metastasis.2 Several infectious bacteria and viruses also inter-
act with these glycans in their entry stage.3
tionalities were introduced on the carboxylic acid moiety at the
C1-position through an alternate approach.7 Specifically, building
blocks that possess –(CH2)2CN7b or –CH2CONMe2
have favored
7c,d
the formation of the
a-sialoside, presumably through intermedi-
ates that coordinate with the auxiliaries. Furthermore, such ester
functionalities can be deprotected via mild hydrolysis during the
final global deprotection step. To date, however, satisfactory yield
and stereoselectivity have yet to be achieved in the formation of
Chemical synthesis of sialic acid-terminated glycans requires
a naturally occurring sialyl-a(2-3)-galactose unit.
investigations of
a
-selective sialic acid building blocks.4 Upon an
To improve the stereoselectivity in C1-participation strategy,
novel sialic acid building blocks 1a–e, which possess a thioester
moiety at the C1-position, were employed. Presumably, the auxil-
iary group would augment the ‘nitrile effect’,8 in which, upon acti-
vation of the building block, the thioester moiety would stabilize
the proposed five-membered intermediate in the presence of the
nitrile solvent (Fig. 1). In this Letter, we initially described tuning
of thioester auxiliaries from the points of stability, yield, and
stereoselectivity in the glycosylation with C6–OH of the galacto-
side 6. Furthermore, the applicability of building block 1a in sialyl-
ation reactions was investigated using several acceptor alcohols.
First, building blocks 1a–e, which possess benzylthio and aryl-
thio moieties, were synthesized from phenylthioglycoside 29
(Scheme 1).10 Prior to the introduction of the thioester moieties,
the methyl ester group of 2 was selectively removed using LiCl in
pyridine,11 then treatment with acid provided carboxylic acid 3
in 91% yield. Liberated carboxyl group of 3 was activated by using
chloroformic chloride, and succeeding addition of thiols to give the
corresponding thioester building blocks 4a–e in moderate yields.12
Although sialylation reactions using thioglycoside 4a were
performed by the treatment with NIS and TfOH, the reactions did
not proceed due to the sluggish activation rate of 4a. From this
activation of the leaving group at the C2-position, the resulting
oxocarbenium ion is destabilized by the electron-withdrawing
ester group on the anomeric center. As a consequence, the less
reactive tertiary anomeric center becomes susceptible to elimina-
tion to give a C2,3-dehydro sialic acid derivative. Furthermore,
the C3-deoxy structure can cause difficulty in controlling the
stereoselectivity in the sialylation reactions.
To address these issues, recent advances in sialic acid building
blocks have provided two solutions: first, the use of C5-amino
protecting groups,5 such as N-TFA,5b carbamate,5d–f and C4,5-oxa-
zolidinone5g–i groups, have been shown to improve the reactivity
as well as the stereoselectivity of
a-sialylation reactions. Second,
the use of C3-participating groups, such as OH,6a Br,6b SR,6c–e and
(O–(C@S)R)6f was shown to assist in the stereoselective formation
of
a-sialoside through a three- or five-membered ring intermediate.
The use of such building blocks, however, would require an
additional step to remove the participating group in order to
generate the deoxy moiety, and therefore, the participating func-
* Corresponding author. Tel.: +81 45 481 5661x3853; fax: +81 45 413 9770.
E-mail address: satouk01@kanagawa-u.ac.jp (K. Sato).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.154

5112
S. Hanashima et al. / Tetrahedron Letters 49 (2008) 5111–5114
AcO
OAc
TMSOTf
EtCN
AcO
OAc
AcO
OAc
N
N
COSR
O
S
R
AcO
AcHN
O
O
O
AcO
AcHN
OP(OBn)2
AcO
AcHN
S
O
R
AcO
O
P
AcO
AcO
1: R = Ar, Bn
H
OBn
Nu
OBn
Figure 1. Structure of novel sialic acid building block 1 and plausible reaction mechanism.
AcO
OAc
AcO
OAc
AcO
OAc
(d) (BnO)2PNEt2,
-tetrazole,
CH2Cl2,
COR
(c) NBS,
acetone/H2O
COS R
OH
OP(OBn)2
COS R
1
H
AcO
AcO
AcHN
O
AcO
AcHN
O
SPh
AcHN
O
AcO
AcO
AcO
2: R = OMe
3: R = OH
(a) LiCl,pyridine
reflux, 91%
1a: R = Ph, 74%
1b: R = Bn, 83%
1c: R = Ph
1d: R = Ph
1e: R = Ph
5a: R = Ph, 94%
5b: R = Bn, 59%
5c: R = Ph
5d: R = Ph
5e: R = Ph
p
p
p
OMe, 72%
Me, 65%
NO2, 62%
p
p
p
OMe, 93%
Me, 88%
NO2, 87%
(b) ClCOOEt,
Et3N, CH2Cl2,
4a: R = SPh, 81%
4b: R = SBn, 75%
4c: R = SPh
4d: R = SPh
4e: R = SPh
0
oC, then
p
p
p
OMe, 74%
Me, 64%
NO2, 82%
RSH, Et3N,
0
oC to r.t.
Scheme 1. Reagents and conditions for the synthesis of 1a–e.
result, the anomeric phenylthio moiety was substituted with a
more reactive phosphite group.13 Hydrolysis for the phenylthio
group of 4a–e was achieved using NBS under acetone/H2O condi-
tions to afford 5a–e.14 Subsequently, the phosphite leaving group
was introduced using N,N-diethyldibenzylphosphoramidite with
1H-tetrazole13b to afford desired 1a–e.
To investigate the effects of the thioester moieties, sialylation
reactions between building blocks 1a–f (1.0 equiv) and the C6–
OH of galactoside 6 (1.5 equiv) were carried out (Table 1).15 In all
cases, phosphites 1a–f were readily activated using catalytic
amounts of TMSOTf at À40 °C in propionitrile (EtCN).16 According
to our results, phenylthioester 1a (entry 2) and benzylthioester
1b (entry 3) gave good yields as well as better selectivities, in com-
parison to the corresponding methyl ester 1f (entry 1). Based on
this result, further investigations were demonstrated to study the
electron-donating/withdrawing substituents on the thiophenyl
aromatic system. Sialylation reactions involving building blocks
1c, 1d, and 1e (entries 4–6, respectively) proceeded smoothly to
afford the corresponding disaccharides in moderate to good yields.
With respect to the stereoselectivity, p-methoxyphenylthioester 1c
(entry 4) and p-tolylthioester 1d (entry 5) exhibited moderate
-selectivities ( /b = 4.5–4.7:1). In contrast, thioester 1e (entry
6), which possesses an electron-withdrawing nitro function,
resulted in low selectivity ( /b = 2.5:1). Among these entries, phen-
ylthioester 1a demonstrated good -selectivity and yield, and was
selected as the optimal building block for further sialylation reac-
tions with various acceptor alcohols. Furthermore, 1a exhibited
the best conversion along the preparation scheme from 3 to 1a.
a
a
a
a
Results of the sialylation reactions of 1a (a/b = 1:4) with various
acceptor alcohols are shown in Table 2. First, to examine the con-
version rate of 1a, sialylation reactions were carried out using ex-
cess amounts of n-octanol, cyclohexanol, and 1-adamantanol. As
shown in entry 1, the use of n-octanol 8 provided glycoside 15 in
91% yield with moderate
use of cyclohexanol 9, which was chosen as a simple secondary
alcohol, readily provided glycoside 16 in 87% yield ( /b = 4.2:1).
a-selectivity (a/b = 6:1). Similarly, the
a
In contrast, 1-adamantanol 10 afforded glycoside 17 in low yield
(entry 5), presumably due to the steric hindrance.
Next, sialylation reactions between 1a and the C6–OH group of
galactoside and glucoside were investigated. In the case of galacto-
Table 1
The sialylation reactions using novel sialic acid building blocks 1a–f
O
OH
AcO
OAc
O
AcO
O
OAc
COR
O
O
OP(OBn)2
O
6
AcO
AcHN
O
AcO
(1.5 equiv)
O
O
O
CO
R
AcHN
AcO
AcO
O
O
O
TMSOTf (0.2 equiv),
MS4A, EtCN , −40 oC, 1 h
7
1a-f
(1.0 equiv)
Entry
1
R
Yield (%)
a
/b Ratioa
OMe (1f)
7f, 90
3.8:1
2
3
4
5
6
SPh (1a)
SBn (1b)
SPhpOMe (1c)
SPhpMe (1d)
SPhpNO2 (1e)
7a, 89
7b, 92
7c, 77
7d, 87
7e, 74
5.8:1
5.2:1
4.5:1
4.7:1
2.5:1
a
a
/b Ratio was determined by 1H NMR spectra.

S. Hanashima et al. / Tetrahedron Letters 49 (2008) 5111–5114
5113
side 11, which features a 4,6-diol, the reaction readily proceeded to
provide 18 in 87% yield with excellent -selectivity ( /b = 9:1, en-
try 2).17 The use of glucose acceptor 12 provided desired sialoside
19 in 57% yield with moderate selectivity ( /b = 5:1, entry 3).
Finally, reactions involving naturally occurring (2-3)-linkages
contrast, the use of galactal 14,19 which possesses an exposed
nucleophilic C3-OH, as the acceptor substrate,20 proceeded
smoothly to afford disaccharide 21 in 81% yield with excellent
a
a
a
selectivity (entry 7,
a/b = 9:1), which were better than those of 1f
a
and 14 (56%, /b = 3.5:1).
a
of galactose derivatives were carried out. Although galactose diol
acceptor 13 possesses a relatively reactive C3–OH group, desired
disaccharide 20 was produced in merely 31% yield (entry 6).18 In
In summary, sialic acid thioester building blocks 1a–e were syn-
thesized from 2 in three steps involving thioesterification, hydroly-
sis, and introduction of the phosphite group. The resulting
Table 2
Glycosylation reaction of 1a with various acceptor alcohols
AcO
OAc
AcO
OAc
8-14 (1.0 equiv)
OP(OBn)2
COSPh
TMSOTf
COSPh
OR
AcO
AcHN
AcO
AcHN
O
O
MS4A,
EtCN, −40 o
AcO
AcO
1a (1.2 equiv)
Products
AcO
C
Entry
1
Acceptor
Time
Yield (%)
91a
a/b Ratio
OAc
COSPh
HO
30 min
6:1
4.2:1
8:1
9:1
5:1
ad
AcO
AcHN
O
8
O-Ocyl
15
AcO
AcO
OAc
COSPh
O-Cy
HO
87a
27a
87
AcO
AcHN
2
3
4
5
6
1 h
1 h
1 h
1 h
3 h
O
9
AcO
16
AcO
OAc
COSPh
O-Ad
OH
AcO
AcHN
O
AcO
10
17
AcO
OAc
OH
COSPh
HO
O
HO
BzO
AcO
AcHN
O
O
OSE
O
BzO
OSE
AcO
OBz
11
OBz
18
AcO
OAc
COSPh
O
OH
O
AcO
57b
O
BnO
BnO
AcHN
OMP
AcO
AcO
O
OBn
12
BnO
OMP
BnO
19
OBn
AcO
OAc
COSPh
OBn
OBn
HO
HO
13
HO
AcO
AcHN
31b
O
O
O
O
OMP
O
OMP
OBz
OBz
20
AcO
OAc
OBn
BnO
COSPh
OBn
BnO
O
AcO
AcHN
7
1 h
1 h
81
9:1
HO
O
O
56c
3.5:1c
AcO
14
21
a
3.0 equiv of acceptor was used to determine conversions.
CH3CN/CH2Cl2 = 1:2 was used for solvent due to solubility of the MP glycosides.
Donor 1f (methyl ester) was used.
b
c
d
a
-Anomer was isolated as a major product. SE: 2-trimethylsilylethyl, MP: p-methoxyphenyl.

5114
S. Hanashima et al. / Tetrahedron Letters 49 (2008) 5111–5114
4. Recent reviews for chemical sialylation reactions: (a) Boons, G.-J.; Demchenko,
A. V. Chem. Rev. 2000, 100, 4539–4566; (b) Halcomb, R. L.; Chappell, M. D. J.
Carbohydr. Chem. 2002, 21, 723–768; (c) Ando, H.; Imamura, A. Trends Glycosci.
Glycotechnol. 2004, 16, 293–303.
thioester building blocks were subjected to sialylation reactions
(Table 1), in which phenylthioester 1a exhibited the best -selec-
tivity in EtCN, and was chosen for the subsequent sialylation reac-
a
5. (a) Demachenko, A. V.; Boons, G.-J. Tetrahedron Lett. 1998, 39, 3065–3068; (b)
De Meo, C.; Demachenko, A. V.; Boons, G.-J. J. Org. Chem. 2001, 66, 5490–5497;
(c) Yu, C.-S.; Niikura, K.; Lin, C.-C.; Wong, C.-H. Angew. Chem., Int. Ed. 2001, 40,
2900–2903; (d) Ando, H.; Koike, Y.; Ishida, H.; Kiso, M. Tetrahedron Lett. 2003,
44, 6883–6886; (e) Tanaka, H.; Adachi, M.; Takahashi, T. Chem. Eur. J. 2005, 11,
849–862; (f) Ikeda, K.; Miyamoto, K.; Sato, M. Tetrahedron Lett. 2007, 48, 7431–
7435; (g) Tanaka, H.; Nishiura, Y.; Takahashi, T. J. Am. Chem. Soc. 2006, 128,
7124–7125; (h) Farris, M. D.; De Meo, C. Tetrahedron Lett. 2007, 48, 1225–1227;
(i) Crich, D.; Li, W. J. Org. Chem. 2007, 72, 7794–7797.
tions with various acceptor alcohols. For primary acceptor alcohols,
1a afforded
acceptors, galactal 14 was reacted with 1a to give desired sialoside
21 with good -selectivity. As to the presumable reaction mecha-
a-sialosides in good yield. In the case of secondary
a
nism, sialic acid building block 1a was activated by TMSOTf, then
stable five-membered intermediate was immediately formed with
nitrile solvent that approaches from b-face by the ‘nitrile effect’
6. (a) Okamoto, K.; Kondo, T.; Goto, T. Tetrahedron 1987, 43, 5919–5928; (b)
Okamoto, K.; Kondo, T.; Goto, T. Tetrahedron 1987, 43, 5909–5918; (c) Ito, Y.;
Numata, M.; Sugimoto, M.; Ogawa, T. J. Am. Chem. Soc. 1989, 111, 8508–8510;
(d) Ercegovic, T.; Magnusson, G. J. Org. Chem. 1995, 60, 3378–3384; (e)
Martichonok, V.; Whitesides, G. M. J. Am. Chem. Soc. 1996, 118, 8187–8191; (f)
Castro-Palomino, C. J.; Tsvetkov, E. Y.; Schmidt, R. R. J. Am. Chem. Soc. 1998, 120,
5434–5440.
7. (a) Takahashi, T.; Tsukamoto, H.; Yamada, H. Tetrahedron Lett. 1997, 38, 8223–
8226; (b) Ishiwata, A.; Ito, Y. Synlett 2003, 1339–1343; (c) Haberman, J. M.; Gin,
D. Y. Org. Lett. 2001, 3, 1665–1668; (d) Haberman, J. M.; Gin, D. Y. Org. Lett.
2003, 5, 2539–2541.
(Fig. 1). Finally, the acceptor alcohol attacks from the
form resulting -sialoside dominantly.
a-face to
a
Acknowledgments
This work was supported by the ‘Science Frontier Project of
Kanagawa University’ from the Ministry of Education, Science,
Sports and Culture, Japan, and by Grants-in-Aid for Scientific
Research for Young Scientists B (No. 20710171 to S.H.) from Japan
Society for the Promotion Science (JSPS). We thank Ms. A. Masuda
(Kanagawa University) for technical assistance.
8. (a) Kanie, O.; Kiso, M.; Hasegawa, A. J. Carbohydr. Chem. 1988, 7, 501–506; (b)
Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990, 694–696.
9. Cao, S.; Meunier, S. J.; Andersson, F. O.; Letellier, M.; Roy, R. Tetrahedron:
Asymmetry 1994, 5, 2303–2312.
10. Ethylthio ester was also synthesized, but the production yields through the
preparation steps were low because of the labile ethylthio moiety.
11. (a) Ren, C.-T.; Chen, C.-S.; Yu, Y.-P.; Tsai, Y.-F.; Lin, P.-Y.; Chen, Y.-J.; Zou, W.;
Wu, S.-H. Chem. Eur. J. 2003, 9, 1085–1095; (b) Fujita, S.; Numata, M.; Sugimito,
M.; Tomita, K.; Ogawa, T. Carbohydr. Res. 1994, 263, 181–196.
12. Tokuyama, H.; Yokoshima, S.; Lin, S.-C.; Li, L.; Fukuyama, T. Synthesis 2002,
1121–1123.
13. (a) Martin, T. J.; Schmidt, R. R. Tetrahedron Lett. 1992, 33, 6123–6126; (b)
Kondo, H.; Ichikawa, Y.; Wong, C.-H. J. Am. Chem. Soc. 1992, 114, 8748–
8750.
Supplementary data
Synthetic procedures, spectroscopic data, and 1H and 13C NMR
spectra of compounds 1a, 1b, 1c, 1d, 1e, 3, 4a, 4b, 4c, 4d, 4e, 7a,
7b, 7c, 7d, 7e, 16, 17, 18, 19, 20, and 21. Supplementary data asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.05.154.
14. For the synthesis of 5b carrying benzylthioester, partial decomposition was
confirmed in this conditions.
15. The phosphite 1f13 carrying methyl ester was also prepared to compare the
effect of ester moiety.
References and notes
16. The reaction was also carried out in CH2Cl2, but undesirable b-anomer was
1. (a) Angata, T.; Varki, A. Chem. Rev. 2002, 102, 439–469; (b) Furuhata, K. Trends
Glycosci. Glycotechnol. 2004, 16, 143–169.
2. (a) Higashi, H.; Hirabayashi, Y.; Fukui, Y.; Naiki, M.; Matsumoto, M.; Ueda, S.;
Kato, S. Cancer Res. 1985, 45, 3796–3802; (b) Devine, P. L.; Clark, B. A.; Birrell, G.
W.; Layton, G. T.; Ward, B. G.; Alewood, P. F.; McKenzie, F. C. Cancer Res. 1991,
51, 5826–5836.
3. (a) Suzuki, Y.; Nagao, Y.; Kato, H.; Matsumoto, M.; Nerome, K.; Nakajima, K.;
Nobusawa, E. J. Biol. Chem. 1986, 261, 17057–17061; (b) Higa, H. H.; Rogers, G.
N.; Paulson, J. C. Virology 1985, 144, 279–282; (c) Masuda, H.; Suzuki, T.;
Sugiyama, Y.; Horiike, G.; Murakami, K.; Miyamoto, D.; Jwa Hidari, K. I.-P.; Ito,
T.; Kida, H.; Kiso, M.; Fukunaga, K.; Ohuchi, M.; Toyoda, T.; Ishihama, A.;
Kawaoka, Y.; Suzuki, Y. FEBS Lett. 1999, 464, 71–74.
dominantly provided (a/b ratio = 0.5–0.8/1; data were not shown).
17. Produced inseparable mixture of 18a/18b was capable for separation after
acetylation.
18. The resulting mixture of this reaction was accompanied by several side
products. MALDI-TOF mass spectra suggested that intralactonized byproducts
between C1-carboxylic acid of sialic acid residue and C4–OH of galactose
residue were observed.
19. Love, K.-R.; Andrade, R. B.; Seeberger, P. H. J. Org. Chem. 2001, 66, 8165–8176.
20. Hanashima, S.; Castagner, B.; Esposito, D.; Nokami, T.; Seeberger, P. H. Org. Lett.
2007, 9, 1777–1779.