Synthesis of N,N-Ac,Boc laurylthio sialoside and its application to O-sialylation

Article abstract of DOI:10.1016/j.tetlet.2007.08.088

The combination of the 5-N-tert-butoxycarbonyl (Boc) group of laurylthio sialoside and cyclopentyl methyl ether (CPME) as a solvent enhanced the reactivity and α-selectivity of the sialyl donor during sialylation. Selective deprotection of the N-Boc group

Full text of DOI:10.1016/j.tetlet.2007.08.088

Tetrahedron Letters 48 (2007) 7431–7435
Synthesis of N,N-Ac,Boc laurylthio sialoside
and its application to O-sialylation
Kiyoshi Ikeda,* Keisuke Miyamoto and Masayuki Sato
Department of Organic Chemistry, School of Pharmaceutical Sciences, University of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka-shi 422-8526, Japan
Received 23 July 2007; revised 23 August 2007; accepted 24 August 2007
Available online 29 August 2007
Abstract—The combination of the 5-N-tert-butoxycarbonyl (Boc) group of laurylthio sialoside and cyclopentyl methyl ether
(CPME) as a solvent enhanced the reactivity and a-selectivity of the sialyl donor during sialylation. Selective deprotection of the
N-Boc group of sialoside, including an acid-sensitive isopropylidene function, was successfully achieved by Yb(OTf)3–SiO2. Trans-
formation of N,N-Ac,Boc into an N-acetylglycolyl group of sialoglycoside was easily performed via selective N-deacylation of the
mixed Ac-N-Boc carbamate, subsequent Boc group removal, and acylation.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
moiety at the nitrogen atom of neuraminic acid residue
after assembling the oligosaccharide backbone.13
N-Acetylneuraminic acid (sialic acid, Neu5Ac) and its
various analogues are critical components of many
glycoconjugates involved in biologically important
ligand–receptor interactions.1 The development of an
efficient method of O-sialylation has been a challenging
task in the field of sialic acid chemistry.2 One important
trend focuses on the utilization of the thioglycoside of
sialic acids for milder and stereoselective O-glycosyl-
ation,3 however, one drawback is the extremely unpleas-
ant odor of thiols employed for thioglycoside
formation.4 Recently, Matsuoka and co-workers
reported thioglycoside of sialic acids with a lauryl moi-
ety to avoid this disadvantage, and its application to
stereoselective O-sialylation.5 Modifications of NHAc
of sialic acid donors have been reported to influence
the reactivity and a-selectivity of sialylation. It is well
recognized that the replacement of the N-acetyl func-
tional group at C-5 with N,N-diacetyl (NAc2),6 N-triflu-
oroacetyl (NTFA),7 N-2,2,2-trichloroethoxycarbonyl
As a part of our program aimed at the development of
new O-sialylation,14 we report the preparation of novel
N,N-diacyl analogues of sialic acid 2 with a laurylthio
moiety as the residual group during sialylation and their
application to stereoselective O-sialylation.
2. Results and discussion
As shown in Scheme 1, three laurylthio glycosides with
NHAc, NAc2, and N,N-Boc,Ac at the C-5 position
(2a, 2b, and 2c, respectively), and a N,N-Boc,Ac phenyl-
thio glycoside 2d were tested for their reactivity and
a-selectivity in sialylation with acceptors. Initially, we
investigated the preparation of 2 to evaluate their poten-
tial for undergoing efficient glycosylation (Scheme 1).
Acetate 1 was treated with 1-dodecanethiol in the pres-
ence of BF3ÆOEt2 in CH2Cl2 to give anomeric mixtures
of thioglycoside 2a5 in 84% yield. N,N-Diacylated
donors 2b15 and 2c16 were successfully prepared by the
treatment of 2a with isopropenyl acetate and PTSA
or with Boc2O and pyridine in 89% or 99% yield.
N,N-Ac,Boc phenylthio glycoside 2d12 was prepared
from 1 in 80% yield over two steps.
(NTroc),8
N-fluorenylmethoxycarbonyl
(Fmoc),9
N-phthaloyl (Npht),10 azido,11 or N,N-Ac,Boc12 in the
sialyl donor results in higher yields and, in some cases,
better a-selectivity during sialylation. Temporary
N-Boc protected the sialyl donor, allowing varying acyl
Keywords: N,N-Ac,Boc laurylthio sialoside; O-sialylation; CPME,
N-Acetylglycolyl sialoglycoside.
Initial glycosylation experiments were carried out with
the reaction of glycosyl donor 2b with p-nitrobenzyl
alcohol 3a17 as an acceptor, and the results are shown
*
Corresponding author. Tel./fax: +81 54 264 5108; e-mail: ikeda@
ys2.u-shizuoka-ken.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.088

7432
K. Ikeda et al. / Tetrahedron Letters 48 (2007) 7431–7435
AcO
OAc
in Table 1. The glycosylation reaction between 2b and
AcO
OAc
1.5 M equiv of 3a using 3.0 M equiv of NIS and 1.0 M -
OAc
SC12H25
CO2Me
equiv of TfOH18 and MS 3 A in CH3CN as expected
˚
i)
AcO
Ac N
AcO
from the assistance of the nitrile solvent effect19 at
À40 °C gave the expected glycoside 4a in 70% yield as
an anomeric mixture with b-anomer as the major prod-
uct (a:b = 1:1.8) (entry 1). Next, the donor property of
2c having an N-Boc moiety was examined and a small
increment of a-selectivity of 2c glycosylation with 3a
was observed (79%, a:b = 1.3:1) (entry 2). Encouraged
by these results, the solvent effect of CPME20 was exam-
ined. High a-selectivity in the condensation of 2c with 3a
in CPME was observed (85%, a:b = 10:1) (entry 3). In
sharp contrast to this, the sialylation of 2a with 3a in
CPME was nonselective, together with the formation
of the 2,3-dehydro glycal derivative (11%) (entry 4).
When Et2O was used as a solvent, both yield and
a-selectivity in sialylation were low (62%, a:b = 2.8:1)
(entry 5). Interestingly, the glycosylation of 2d with 3a
O
O
CO2Me
Ac
N
AcO
AcO
H
R
1
iv)
2a: R = H
ii)
iii)
2b: R = Ac
2c: R = Boc
AcO
OAc
SPh
AcO
O
CO2Me
Boc
N
AcO
Ac
2d
Scheme 1. Reagents and conditions: (i) 1-dodecanethiol, BF3ÆOEt2,
CH2Cl2, rt, 24 h, 84%; (ii) isopropenyl acetate, PTSA, 65 °C, 17 h,
89%; (iii) Boc2O, DMAP, THF, reflux, 4 h, 99%; (iv) (1) thiophenol,
BF3ÆOEt2, CH2Cl2, rt, 24 h, 89%, (2) Boc2O, DMAP, THF, reflux,
20 h, 90%.
Table 1. Glycosylation reaction with C-5 N-protected sialic acid derivatives 2a–d
OAc
AcO
OAc
AcO
R3OH
3a,b
SR2
CO2Me
CO2Me
OR3
AcO
Ac N
AcO
O
O
Ac N
NIS, TfOH
1 AcO
1 AcO
R
R
2a-d: R1= H, Ac, Boc
4a-f: R1 = H, Ac, Boc
R2 = Ph, C12H25
Entry
Glycosyl donor 2
Glycosyl acceptor 3
Conditiona
Product 4
Yieldb (%)
(a/b ratio)
OAc
AcO
CO2Me
OCH2
1
2b
CH3CN, À40 °C
70 (1:1.8)
O2N
CH2OH
AcO
Ac2N
O
O
NO2
3a
3a
AcO
4a
OAc
AcO
AcO
Boc
Ac
CO2Me
OCH2
2
2c
CH3CN, À40 °C
79 (1.3:1)
NO2
N
AcO
4b
4b
3
4
2c
2a
3a
3a
CPME, À40 °C
CPME, À40 °C
85 (10:1)
77 (1:1)
OAc
AcO
CO2Me
OCH2
AcO
AcHN
AcO
O
NO2
4c
4b
5
6
2c
2d
3a
3a
Et2O, À40 °C
62 (2.8:1)
59 (6:1)
CPME, À40 °C
4b
OAc
AcO
CO2Me
OH
AcO
Ac2N
AcO
O
O
O
O
O
7
2b
CH3CN, À40 °C
72 (1:2)
O
O
O
O
O
4d
O
O
3b

K. Ikeda et al. / Tetrahedron Letters 48 (2007) 7431–7435
7433
Table 1 (continued)
Entry Glycosyl donor 2
Glycosyl acceptor 3
Conditiona
Product 4
Yieldb (%)
(a/b ratio)
OAc
AcO
AcO
AcO
CO2Me
8
2c
3b
CH3CN, À40 °C
62 (2.2:1)
O
O
O
N
Boc
Ac
O
O
4e
O
O
9
10
11
2c
2c
2c
3b
3b
3b
CPME, À40 °C
Et2O, À40 °C
CPME, À40 °C
4e
4e
4e
Quant. (a only)
75 (6:1)
47 (5.7:1)c
OAc
AcO
CO2Me
AcO
AcHN
O
O
O
12
2a
3b
CPME, À40 °C
77 (1.9:1)
AcO
O
4f
O
O
O
13
2a
3b
CPME, À80 °C
4f
66 (3.8:1)
a With respect to 2, 1.5 equiv of 3 and 2.0 equiv of NIS and 1.0 equiv of TfOH were used. Reaction time was 16 h.
b Isolated yields. The stereochemistry of 4 was confirmed by 1H NMR (500 MHz) spectral comparison of the chemical shifts of 3Heq signals of
glycosides. Anomeric ratios were determined on the basis of the integration ratios of the 3Heq signals of glycosides in 1H NMR spectroscopy.
c With respect to 2, 1.5 equiv of 3 and 2.0 equiv of NIS and 1.0 equiv of AgOTf were used. Reaction time was 16 h at À40 °C, and 24 h at room
temperature.
catalyzed by NIS/TfOH in CPME at À40 °C gave 4b in
inferior yield (59%) and a-selectivity (a:b = 6:1) (entry
6). Coupling of 2b with 1,2:3,4-di-O-isopropylidene-
a-D-galactose 3b in CH3CN afforded the resulting (2–
6)sialoside 4d in 72% yield (a:b = 1:2) (entry 7). When
the reaction of 2c with 3b was carried out in CH3CN
at À40 °C, an increment of a-selectivity was observed
(62%, a:b = 2.2:1) (entry 8). The sialylation of 2c with
3b in CPME at À40 °C showed remarkable improve-
ment in both the glycosylation yield (quantitative) and
a-selectivity (only a-anomer) (entry 9).21 The reaction
using NIS-AgOTf22 as a promoter in CPME afforded
4e with a-anomer as the major product (47%,
a:b = 5.7:1) (entry 11). Coupling of 2a with 3b in CPME
at À40 °C resulted in the formation of 4f with 77% yield
(a:b = 1.9:1) (entry 12). When the reaction of 2a with 3b
was carried out in CPME at À80 °C, an increment of
a-selectivity was observed (a:b = 3.8:1); however, the
yield of 4f decreased to 66% (entry 13). These results
show that it is important to use the combination of 2c
and CPME for higher yields and a-selectivity during
sialylation.
i) or ii)
4b
4e
4c
4f
iii)
Scheme 2. Reagents and conditions: (i) Yb(OTf)3–SiO2, rt, 48 h, 84%;
(ii) TFA–CH2Cl2 (1:4), rt, 1 h, 96%; (iii) Yb(OTf)3–SiO2, rt, 48 h, 81%.
OAc
AcO
CO2Me
i)
ii)
AcO
O
4b
OCH2
NO2
Boc-N
AcO
H
4g
OAc
AcO
CO2Me
AcO
O
OCH2
NO2
AcOCH2CO-N
H
AcO
4h
Scheme 3. Reagents and conditions: (i) (1) NaOMe, MeOH, rt, 2 h, (2) Ac2O, pyridine, rt, 24 h, 75% over two steps; (ii) (1) TFA–CH2Cl2 (1:4), rt,
1 h; (2) AcOCH2COCl, pyridine, rt, 24 h, 90% over two steps.

7434
K. Ikeda et al. / Tetrahedron Letters 48 (2007) 7431–7435
8. Ando, H.; Koike, Y.; Ishida, H.; Kiso, M. Tetrahedron
Lett. 2003, 44, 6883.
9. Adachi, M.; Tanaka, H.; Takahashi, T. Synlett 2004,
609.
10. Tanaka, K.; Goi, T.; Fukase, K. Synlett 2005, 2958.
11. Yu, C.-S.; Niikura, K.; Lin, C.-C.; Wong, C.-H. Angew.
Chem., Int. Ed 2001, 40, 2900.
Removal of the N-Boc group of 4b with TFA–CH2Cl2
(1:4) or Yb(OTf)3–SiO2 gave 4c in 96% or 84% yield.
Mild and selective deprotection of the N-Boc group of
4e, including an acid-sensitive isopropylidene function
with a catalytic amount of Yb(OTf)3–SiO2, proceeded
smoothly to give 4f in 81% yield (Scheme 2).
23
12. Sherman, A. A.; Yudina, O. N.; Shaskov, A. S.; Menshov,
V. M.; Nifant’ev, N. E. Carbohydr. Res. 2001, 330, 445.
13. Fujita, S.; Numata, M.; Sugimoto, M.; Tomita, K.;
Ogawa, T. Carbohydr. Res. 1992, 228, 347.
N,N-Boc,Ac analogues of sialic acid are of great impor-
tance for synthesizing N-substituted sialosides.12 Thus,
selective N,O-deacetylation of 4b with sodium methox-
ide and successive acetylation with Ac2O and pyridine
gave N-Boc derivative 4g in 75% yield over two steps,
which was deprotected by TFA and subsequently sub-
mitted to N-acylation of the resulting free amino group
with acetyl glycoloyl chloride and pyridine to give the
corresponding N-acetylglycolyl glycoside 4h in 90%
yield over two steps (see Scheme 3).
14. (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; (c) Ikeda, K.; Fukuyo,
J.; Sato, K.; Sato, M. Chem. Pharm. Bull. 2005, 53, 1490.
15. Synthesis and characterization of 2b: A mono-N-acetyl-
ated derivative 2a (130 mg, 0.188 mmol) was dissolved in
isopropenyl acetate (4 mL) and TsOH monohydrate
(7.5 mg, 0.05 mmol) was added. The reaction mixture
was stirred at 65 °C for 17 h, then neutralized with Et3N
and evaporated to dryness. The crude product purified by
silica gel column chromatography using AcOEt–n-hexane
(1:2) gave 2b (123 mg, 89%). 1H NMR (500 MHz, CDCl3)
d: 0.87 (t, 3H, J = 7.0 Hz, –CH3), 1.26–1.31 (m, 18H,
–(CH2)9–), 1.50–1.54 (m, 2H, –SCH2CH2–), 1.97, 2.02,
2.05, 2.11 (s, each 3H, OAc), 2.28, 2.40 (each 3H, s, NAc2),
2.49–2.54 (m, 2H, –SCH2CH2–), 2.67 (dd, 1H, J3eq,4 = 5.2,
J3ax,3eq = 13.7 Hz, H-3eq), 3.79 (s, 3H, OCH3), 4.14–4.22
(m, 2H, H-5, H-9a), 4.66 (dd, 1H, J9b,8 = 2.3, J9a,9b = 12.6
Hz, H-9b), 5.10–5.15 (m, 1H, H-8), 5.24 (dd, 1H,
J7,6 = 1.7, J7,8 = 4.0 Hz, H-7), 5.40 (dd, 1H, J6,5 = 10.0,
J6,7 = 2.0 Hz, H-6), 5.79 (ddd, 1H, J4,5 = J4,3ax = 10.9 Hz,
H-4). Positive FAB MS m/z 718 [M+H]+.
16. Synthesis and characterization of 2c: A solution of 2a
(514 mg, 0.76 mmol), Boc2O (498 mg, 2.28 mmol), and 4-
dimethylaminopyridine (DMAP) (47 mg, 0.38 mmol) in
dry THF (15 mL) was refluxed for 4 h under Ar. The
resulting mixture was concentrated in vacuo. The crude
product purified by silica gel column chromatography
using AcOEt–n-hexane (1:2) gave 2c (583 mg, 99%). 1H
NMR (500 MHz, CDCl3) d: 0.88 (t, 3H, J = 7.0 Hz,
–CH3), 1.24–1.26 (m, 18H, –(CH2)9–), 1.48–1.52 (m, 2H,
–SCH2CH2–), 1.66 (s, 9H, NBoc), 1.95, 2.03, 2.05, 2.07 (s,
each 3H, OAc), 2.35 (s, 3H, NAc), 2.51–2.58 (m, 3H,
–SCH2CH2–, H-3eq), 3.81 (s, 3H, OCH3), 4.19 (dd, 1H,
J9a,8 = 7.9, J9a,9b = 12.8 Hz, H-9a), 4.81 (m, 2H, H-5, H-
3. Conclusion
In summary, we have developed an efficient method to
synthesize a-sialoglycosides by using sialyl donor 2c in
CPME. It should be noted that the combination of both
the long-range assistance20 of the bulky 5-N-Boc group
of 2c and the solvent effect of CPME is critical for effi-
cient a-sialylation. N,N-Boc,Ac glycoside 4b was suc-
cessfully transformed into the corresponding N-acetyl
glycolyl sialoglycoside 4h.
We are currently applying this methodology to the syn-
thesis of other oligosaccharides.
Acknowledgments
This work was financially supported in part by a Grant-
in-Aid for Scientific Research No. 19590103 from the
Ministry of Education, Science, Sports, and Culture of
Japan. The authors also thank MARUKIN BIO, INC.
(Kyoto, Japan) for the generous gift of Neu5Ac. CPME
used in this work was a generous gift from ZEON Cor-
poration, R&D Center.
9b), 5.10–5.13 (m, 1H, H-6, H-8), 5.30 (dd, 1H, J7,6
=
J7,8 = 2.4 Hz, H-7), 5.66 (ddd, 1H, J4,5 = J4,3ax = 10.9 Hz,
J4,3eq = 2.5 Hz, H-4). Positive FAB MS m/z 798
[M+Na]+.
References and notes
1. Rosenberg, A. Biology of Sialic Acids; Plenum: New York,
London, 1995.
2. Boons, G.-J.; Demchenko, A. V. Chem. Rev. 2000, 100,
4539.
3. Hasegawa, A. In Modern Methods in Carbohydrate Syn-
thesis; Khan, S., O’Neill, R., Eds.; Harwood Academic:
New York, 1996; pp 277–300.
4. (a) Matsui, H.; Furukawa, J.-I.; Awano, T.; Nishi, N.;
Sakairi, N. Chem. Lett. 2000, 326; (b) Node, M.; Kumar,
K.; Nishide, K.; Ohsugi, S.; Miyamoto, T. Tetrahedron
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17. Yamada, K.; Fujita, E.; Nishimura, S.-I. Carbohydr. Res.
1998, 305, 443.
18. Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.;
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20. Tokimoto, H.; Fujimoto, Y.; Fukase, K.; Kusumoto, S.
Tetrahedron: Asymmetry 2005, 16, 441.
21. Representative procedure for glycosylation (Table 1, entry
9):
A mixture of the glycosyl donor 2c (39 mg,
5. Matsuoka, K.; Onaga, T.; Mori, T.; Sakamoto, J.-I.;
Koyama, T.; Sakairi, N.; Hatano, K.; Terunuma, D.
Tetrahedron Lett. 2004, 45, 9383.
0.050 mmol), glycosyl acceptor 3b (20 mg, 0.075 mmol),
˚
and 4 A molecular sieves (0.10 g) in CPME (2.0 mL) was
stirred under argon for 6 h at room temperature. NIS
(34 mg, 0.15 mmol) and TfOH (7.5 mg, 0.05 mmol) were
added to the reaction mixture at À40 °C. The reaction
mixture was stirred for 16 h at the same temperature in the
dark. Upon completion, the reaction solution was diluted
6. (a) Demchenko, A. V.; Boons, G.-J. Tetrahedron Lett.
1998, 39, 3065; (b) David, C.; Wenju, L. Org. Lett. 2006,
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7. Meo, D.; Demchenko, A. V.; Boons, G.-J. J. Org. Chem.
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K. Ikeda et al. / Tetrahedron Letters 48 (2007) 7431–7435
7435
with CH2Cl2 and the suspension was filtered off and the
filtrate was washed with aqueous 10% Na2S2O3 solution
and brine and dried over anhydrous MgSO4, and evap-
orated. Column chromatography on silica gel using
AcOEt–n-hexane (1:1) gave 4d (42 mg, quant.) as only
an a-anomer. 1H NMR (CDCl3) d: 1.31, 1.32, 1.40, 1.45 (s,
each 3H, isopropylidene), 1.56 (s, 9H, NBoc), 1.96, 2.03,
2.06, 2.13 (s, each 3H, OAc), 2.36 (s, 3H, NAc), 2.73 (dd,
1H, J3eq,4 = 4.9, J3ax,3eq = 12.9 Hz, H-3eq), 3.78 (s, 3H,
OCH3), 3.80–3.89 (m, 3H, Gal-H-5, 6a, 6b), 4.11–4.37 (m,
3H, H-9a, Gal-H-2,4), 4.59–4.63 (m, 2H, H-5, Gal-H-3),
4.69 (dd, 1H, J9b,8 = 1.7, J9a,b = 10.3 Hz, H-9b), 5.18 (dd,
1H, J6,5 = 7.7, J6,7 = 2.0 Hz, H-6), 5.36–5.40 (m, 2H, H-7,
H-8), 5.51 (d, 1H, JGal-H-1,H-2 = 4.6 Hz, Gal-H-1), 5.70
(ddd, 1H, J4,5 = 5.2, J4,3ax = 10.4 Hz, H-4). Positive FAB
MS m/z 834 [M+H]+, 856 [M+Na]+.
22. Castro, S. W.; Fyvie, W. W.; Hatcher, S. A.; Peczuh, M.
W. Org. Lett. 2005, 4709.
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dron Lett. 1998, 39, 4869.