Preparation of sialyl donors carrying functionalized ester substituents: Effects on the selectivity of glycosylation

Article abstract of DOI:10.1055/s-2003-40332

Methylthio sialyl donors having various ester substituents were prepared systematically. Nucleophilic displacement of methyl ester with Ph₃SiSH and Cs₂C₃ followed by in situ alkylation with RX or esterification with R-OH/DCC afforded these compounds in good yields. Glycosylations promoted by NIS-TfOH were examined in order to examine the effect of substituent of the ester portion. When conducted in CH₃CN, enhanced α-selectivities were observed for cyanomethyl, 2-cyanoethyl, 2-cyanobenzyl, and 2-nitrobenzyl esters, implying that these substituents are effective enhancing the solvent effect of acetonitrile, possibly by stabilizing the β-oriented nitrilium ion.

Full text of DOI:10.1055/s-2003-40332

LETTER
1339
Preparation of Sialyl Donors Carrying Functionalized Ester Substituents:
Effects on the Selectivity of Glycosylation
Preparationof
Sia
k
lyl
D
onors ihiro Ishiwata, Yukishige Ito*
RIKEN (The Institute of Physical and Chemical Research), 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
Fax +81(48)4624680; E-mail: yukito@postman.riken.go.jp
Received 28 April 2003
Dedicate to the memory of Professor Raymond U. Lemieux.
Gin.9 Such an approach is potentially attractive, because
C-1 carboxylate should be masked in any event. Further-
more, Neu5Ac esters that can be detached under non-hy-
drolytic conditions would be valuable for the synthesis of
Abstract: Methylthio sialyl donors having various ester substitu-
ents were prepared systematically. Nucleophilic displacement of
methyl ester with Ph3SiSH and Cs2CO3 followed by in situ alkyla-
tion with RX or esterification with R-OH/DCC afforded these com-
pounds in good yields. Glycosylations promoted by NIS–TfOH complex oligosaccharides and glycopeptides. In this pa-
were examined in order to examine the effect of substituent of the
ester portion. When conducted in CH3CN, enhanced a-selectivities
were observed for cyanomethyl, 2-cyanoethyl, 2-cyanobenzyl, and
Ph3SiSH-Cs2CO3 mediated methyl ester cleavage as the
2-nitrobenzyl esters, implying that these substituents are effective
per, we wish to report 1) the systematic preparation of var-
ious esters of Neu5Ac methylthio glycoside using
key reaction, and 2) their use as glycosyl donors to ex-
enhancing the solvent effect of acetonitrile, possibly by stabilizing
plore the possibility to enhance the a-selectivity by pe-
ripheral participation (Scheme 1). In particular, nitrile-
containing substituents are of primary interest, consider-
ing well-known solvent effect of acetonitrile,3 posing that
a-selective sialylation would be possible in a non-part-
icipating solvent.
the b-oriented nitrilium ion.
Key words: sialic acid, glycosylation, stereoselective, substituent
effect, selective deprotection
Sialic acids, most typically N-acetylneuraminic acid
(Neu5Ac), are important constituents of biologically im-
portant glycoconjugates,1 and the chemical synthesis of
Neu5Ac glycosides has been investigated with substantial
success.2 In order to overcome the difficulty inherent to
the synthesis of Neu5Ac glycosides that solely exist with
stereoelectronically disfavored a-configuration, various
approaches have been reported. These exploits either 1)
the solvent effect of CH3CN,3 2) participation of the C-3
auxiliary,4 or 3) fine-tuning the reactivity by changing
NHAc to NAc2,5 N3,6 or NHTFA.7
In order to eliminate the complexity that may arise from
the stereochemistry of Neu5Ac donors, known methyl es-
ter 1a3a,10 was selected as the starting material, because
this compound is obtainable in a pure a-form as a crystal-
line solid. For chemoselective cleavage of the methyl es-
ter, SN2 type reaction should be most appropriate.11 For
this purpose, the use of Ph3SiSH attracted to our attention.
This reagent, readily available from triphenylsilane and
sulfur,12 has been known as a powerful nucleophile,13 yet
being a stable solid. We expected that the thiolate derived
from it might well have an enough reactivity to promote
the methyl ester cleavage in an SN2 fashion. Thus, 1a was
Recently, substituent effects of the ester portion of
Neu5Ac donors have been investigated by Takahashi8 and
HO
O
X
O
O
O
O
OAc
X
AcO
O
OAc
C
AcO
C
2
O
O
SMe
AcNH
AcO
AcNH
AcO
O
promoter
OAc
OAc
3
1
Xδ+
OAc
AcO
Oδ+
O
C
AcNH
AcO
OAc
?
O
Scheme 1
Synlett 2003, No. 9, Print: 11 07 2003.
Art Id.1437-2096,E;2003,0,09,1339,1343,ftx,en;S03003ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1340
A. Ishiwata, Y. Ito
LETTER
Table 1 Preparation of Various Esters
treated with Ph3SiSH in DMF in the presence of Cs2CO3
and a catalytic amount of 2,6-di-t-butyl-4-cresol. In fact,
smooth formation of carboxylate was observed under
these conditions. Subsequent in situ alkylation cleanly
gave esters 1b and 1d–j in high yield as summarized in
Table 1. On the other hand, for the preparation of cyano-
ethyl ester 1c (entry 2), reaction with 3-bromopropioni-
trile was not successful, presumably due to its base-
sensitivity. In this case, an indirect route using DCC me-
diated esterification of carboxylic acid (1k, isolated in
96% yield) was adopted. (Scheme 2).14
1) Ph3SiSH
OAc
AcO
CsCO3 /
DMF
OAc
AcO
CO2R
SMe
CO2Me
SMe
O
O
AcNH
AcO
AcNH
AcO
2) RX
OAc
1b–j
OAc
(entry 1, 3–9)
or
1a
ROH-DCC
(entry 2)
Entry
1
RX or ROH
Temp/Time
Yield
(%)
With a series of Neu5Ac donors in hand, glycosylations
with benzyl 2,3,4-tri-O-benzyl-b-D-glucopyranoside
(2A)15 and 1,2-4,5-di-O-isopropylidene-fructopyranose
(2B)16 were examined. The former was selected as a typi-
cal primary alcohol, while the latter was chosen because
of its simple NMR pattern that allowed straightforward
interpretations of spectra to assess a/b ratio of sialylated
products.
1
2
3
4
5
6
7
8
9
b
c
d
e
f
BrCH2CN
0 °C–r.t./3 h
0 °C–r.t./12 h
0 °C/4 h
85
84
97
76
86
77
82
92
80
HOCH2CH2CN
BrCH2COPh
BrCH2CO2Me
0 °C/4 h
BrCH2CO2-t-Bu
BrCH2C6H4CN-(2-)
BrCH2C6H4NO2-(2-)
0 °C/ 1 d
0 °C/4 h
Reactions with 2A were first examined in non-participat-
ing medium CH2Cl2 using N-iodosuccinimide (NIS) and
triflic acid (TfOH) (Table 2). Although it was initially
hoped that a-selective glycosylation might be possible by
the internal participation of functionalized ester substitu-
ents, beneficial substituent effect was observed in neither
case, in terms of a-selectivity (entries 1–9) and b-isomers
were obtained as the major products.
g
h
i
0 °C/4 h
ClCH2C6H4OMe-(2-) 40 °C/1 d
ClCH2C(Me)=CH2 40 °C/ 1 d
j
When secondary alcohol 2B was used as the acceptor sub-
strate, manifested effects were observed for cyanomethyl
(entry 20) and cyanoethyl (entry 21) esters. Clearly, these
results compare favorably with that obtained by standard
methyl ester (entry 19).
On the other hand, when CH3CN was used as the solvent,
increments of a-selectivity were observed in several cas-
es. For instance, esters having nitrile (entries 12, 15) ester
(entry 14), and nitro (entry 16) functionalities gave higher
selectivity than methyl ester. In the cases of nitrile-con-
taining substituents, the distances between anomeric car-
bon and nitrogen seemed to be important, implying that
nitrile group participates the oxocarbenium ion, either di-
rectly or indirectly (vide infra). Namely, 2-cyanobenzyl
carrying donor afforded highest selectivity (enry 15) and
2-cyanoethyl ester (entry 12) gave slightly higher selec-
tivity than methyl (entry 10) and cyanomethyl (entry 11)
counterparts. On the other hand, p-electornic (entry 18)
and alkoxy (entry 17) groups were ineffective.
For the present, straightforward interpretation of these re-
sults can not be provided. Obviously, results obtained in
CH2Cl2 suggest that these substituents are not able to as-
sist a-selective reaction through direct participation. To
explain the enhanced selectivities observed in CH3CN,
more plausible would be the indirect participation, which
stabilize the kinetically generated b-nitrilium ion,17 there-
by retarding its anomerization (Scheme 3).18 Further par-
ticipation of acetonitrile or succinimide (by-product
accompanies NIS reaction) to these cyclic intermediates
might be possible.
Ph3SiSH, Cs2CO3
2,6-di-t-butylcresol
OAc
AcO
CO2H
SMe
OAc
AcO
CO2Me
SMe
DMF, 80 °C
O
O
AcNH
AcO
AcNH
AcO
OAc
then
acidic work-up
OAc
1a
96%
1k
HO
DCC
CN
OAc
AcO
CO2Cs
1c
O
SMe
AcNH
AcO
OAc
RX
1b, d-j
Scheme 2
Synlett 2003, No. 9, 1339–1343 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Preparation of Sialyl Donors
1341
Me
Xδ+
O
O
OAc
AcO
Nδ+
OAc
X
AcO
NIS
TfOH
O
SMe
Oδ+
O
α > β
AcNH
AcO
AcNH
AcO
OAc
MeCN
O
OAc
O
HO
X: CN (1b,c,g), NO2 (1h)
Scheme 3
For the reaction with secondary alcohol, cyanoethyl ester give 4,22 with complete preservation of acetyl and phthal-
seemed to be the best compromise between selectivity and imide groups.
yield and further investigations using more biologically
In conclusion, systematic preparations of methylthio
Neu5Ac donors having modified esters were carried out
and their effects on the selectivity of glcosylations with
primary and secondary alcohols were examined. In
CH3CN, enhanced a-selectivities were observed for cya-
nomethyl, 2-cyanoethyl, 2-cyanobenzyl, and 2-nitroben-
zyl esters, implying that these substituents are effective
relevant acceptors, 2C19 (Gal), 2D20 (bGal1→4Glc), and
2E21 (bGal1→4GlcN) were performed with this donor
(Scheme 4). As expected, all reactions afforded a-glyco-
sides as the major products in satisfactory yields (entries
1, 3, 5), and enhancement of selectivity was observed (en-
tries 2, 4, 6) compared to methyl ester (Table 3).
Besides pronounced a-selectivity, the use of cyanoethyl enhancing the solvent effect of acetonitrile, possibly by
ester would be attractive from practical point of view, be- stabilizing the b-oriented nitrilium ion.
cause it is removable under non-hydrolytic conditions.
This feature would be valuable for the synthesis of gangli-
osides, complex-type oligosaccharides, and glycopep-
Acknowledgment
Financial support from the Mizutani Foundation for Glycoscience
and a Grant-in-Aid for Scientific Research from the Japan Society
for the Promotion of Science (Grant No. 13480191) are acknowl-
edged. The authors thank Dr. Hiroko Akao for her help and Ms.
Akemi Takahashi for technical assistance.
tides, where methyl ester cleavage often complicates the
synthetic scheme. In fact, removal of cyanoethyl ester
proceeded smoothly in the presence of DBU in CH2Cl2 to
OAc
AcO
CO2R
O
OAc
AcO
CO2R
OBn
O
O
AcNH
AcO
O
SMe
AcNH
AcO
OAc
HO OBn
OAc
OBn
O
HO OBn
2C-E
HO
O
3aC-E (R = Me)
1a or 1c
(1.2 equiv.)
or
3cC-E (R = CH2CH2CN)
C
D
2/3a/3c
E
OBn
O
OBn
O
OMe
O
BnO
O
BnO
OAll
OBn
NPhth
OBn
OAc
AcO
CO2H
OBn
O
Ac2O
pyridine
OBn
O
DBU
CH2Cl2
r.t. 1 h
3cE
O
O
O
BnO
OAll
AcNH
AcO
OAc
NPhth
OBn
AcO
99%
4
Scheme 4
Synlett 2003, No. 9, 1339–1343 ISSN 1234-567-89 © Thieme Stuttgart · New York

1342
A. Ishiwata, Y. Ito
LETTER
Table 2 Glycosylation Reactions Using Neu5Ac Thioglycosides
OAc
AcO
CO2R
O
O
AcNH
AcO
1
a
b
c
d
e
f
R
O
HO
OAc
O
Me
OAc
AcO
CO2R
SMe
3 (α)
2A,B
CH2CN
+
O
CH2CH2CN
CH2COPh
AcNH
AcO
OAc
O
AcO
NIS, TfOH
MS3A, –40 °C
O
OAc
O
CH2CO2Me
CH2CO2t-Bu
CH2C6H4CN-(2-)
CH2C6H4NO2-(2-)
CH2C6H4OMe-(2-)
CH2C(Me)=CH2
CO2R
AcNH
AcO
1a–j
OAc
g
h
i
3 (β)
O
OBn
O
BnO
BnO
OBn
HO
O
O
OH
j
O
O
2A
2B
Entrya
1
1
a
b
c
e
f
2
1:2
Solventb
D
Time (h)
Yield (%)
77
Product
3aA
3bA
3cA
3eA
3fA
a:bc
1:9.6
1:5
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
1.2:1
1.3:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1:1.6
1:1.6
1.2:1
1:1.6
1:1.6
1.2:1
8
2
D
1.5
8
90
3
D
85
b only
1:4
4
D
1.1
8
85
5
D
54
1:21
1:10
1:11
1:11
1:15
3:1
6
g
h
i
D
8
77
3gA
3hA
3iA
7
D
8
73
8
D
8
69
9
j
D
8
81
3jA
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
a
b
c
e
f
N
8
83
3aA
3bA
3cA
3eA
3fA
N
1.5
8
88
3:1
N
87
4:1
N
8
78
3.6:1
8.7:1
31:1
8.5:1
2.7:1
2.6:1
3.0:1
8.0:1
17:1
2.6:1
2.4:1
14:1
N
8
56
g
h
i
N
8
39
3gA
3hA
3iA
N
8
81
N
8
21
j
N
8
85
3jA
a
b
c
d
e
h
N
2
40
3aB
3bB
3cB
3dB
3eB
3bB
N
2
44
N
8
31
N
2.5
2
24
N
<5
15
N
8
a All reactions were performed in the presence of 1.5–1.7 equiv of NIS and 0.8–1.2 equiv of TfOH, except entries 18, 19, 21, and 22, where 0.3
equiv of TfOH was used.
b D: CH2Cl2, N; CH3CN.
c Determined by 400 MHz 1H NMR.
Synlett 2003, No. 9, 1339–1343 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Preparation of Sialyl Donors
1343
Table 3 Stereoselective Glycosylation; Comparison of Methyl (1a)
and Cyanoethyl (1c) Esters
(10) (a) This compound was prepared from corresponding 2-SAc
derivative: Hasegawa, A.; Nakamura, J.; Kiso, M. J.
Carbohydr. Chem. 1986, 5, 11. (b) With Et2NH and MeI in
DMF: Angus, D. I.; von Itzstaein, M.; Kiefel, M. J.
Carbohydr. Res. 1994, 259, 293.
Entrya
1
a
c
a
c
a
c
2
Product Yield (%) a:bb
1
2
3
4
5
6
C
C
D
D
E
E
3aC
3cC
3aD
3cD
3aE
3cE
56
63
49
51
52
54
8.4:1
13:1
9.1:1
15:1
(11) Salomon, C. J.; Matta, E. G.; Mascaretti, O. A. Tetrahedron
1993, 49, 3691.
(12) Birkofer, L.; Ritter, A.; Goller, H. Chem. Ber. 1963, 3289.
(13) Brittain, J.; Gareau, Y. Tetrahedron Lett. 1993, 34, 3363.
(14) Typical procedure (compound 1h): To the solution of
compound 1a (209 mg, 0.401 mmol), 2,6-di-t-butyl-4-cresol
(18 mg, 0.08 mmol) and Ph3SiSH (352 mg, 1.20 mmol) in
dry DMF (5 mL) was added Cs2CO3 (352 mg, 1.08 mmol)
and the mixture was stirred at 80 °C for 8 h. After cooling
down to ice-water temperature, 2-nitrobenzyl bromide (261
mg, 1.21 mmol) was added and stirring continued for 4 h at
0 °C. The reaction was saturated aq KHSO4 and extracted
with EtOAc. The organic layer was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was
purified by flash chromatography (hexane–EtOAc, 10:1–
1:2) to give compound 1h (212 mg, 82%).
11:1
19:1
a All reactions were performed in the presence of 1.7 equiv of NIS
and 1.0 equiv of TfOH.
b Determined by 400 MHz 1H NMR.
(15) Petit, J. M.; Jaquinet, J.-C.; Sinaÿ, P. Carbohydr. Res. 1980,
82, 130.
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(22) NMR (CD3OD, 400 MHz) d 1.72 (1 H, t, J = 12.0 Hz, H-
3Neu5Ac), 1.85, 1,86, 1.97, 1.98, 1.99, and 2.10 (each 3 H, s,
6Ac), 2.71 (1 H, dd, J = 12.0 Hz, 4.0 Hz, H-3Neu5Ac), 3.37–
3.42 (1 H, m, H-6Gal), 3.52–3.60 (3 H, m, H-5Gal, H-6Glc, H-
2Gal), 3.83–3.88 (3 H, m, H-6Glc, H-6¢Glc, H-5Gal), 3.97–4.09
(3 H, m, H-4Glc, CH2=CHCH2, H-5Neu5Ac), 4.09 (1 H, dd, J =
11.2 Hz, 8.4 Hz, H-2Gal), 4.14 (1 H, dd, J = 12.4 Hz, 5.2 Hz,
H-9Neu5Ac), 4.14 (1 H, dd, J = 12.4 Hz, 5.2 Hz, H-9Neu5Ac),
4.17–4.25 (2 H, m, H-9Neu5Ac, CH2CH=CH2), 4.28 (1 H, dd,
J = 11.2 Hz, 8.4 Hz), 4.39 (1 H, d, J = 12.0 Hz, Bn), 4.41 (1
H, dd, J = 12.4 Hz, 3.2 Hz, H-9Neu5Ac), 4.49 (1 H, d, J = 12.4
Hz, Bn), 4.54 (1 H, d, J = 12.0 Hz, Bn), 4.59 (1 H, d, J = 12.0
Hz, Bn), 4.69 (1 H, dd, J = 9.6 Hz, 2.4 Hz, H-3Gal), 4.76 (1
H, d, J = 12. 0 Hz, Bn), 4.81 (1 H, d, J = 7.2 Hz, H-1Gal),
4.88–4.96 (2 H, m, Bn), 4.98–5.03 (1 H, m, CH2CH=CH2),
5.03–5.23 (2 H, m, CH2CH=CH2, H-4Neu5Ac), 5.16 (1 H, d, J
= 8.4 Hz, H-1Gal), 5.18 (1 H, d, J = 12.4 Hz, Bn), 5.38 (1 H,
d, J = 2.4 Hz, H-4Gal), 5.39 (1 H, dd, J = 8.0, 2.4 Hz, H-
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7Neu5Ac), 5.66–5.77 (2 H, m, H-8Neu5Ac, CH2CH=CH2), 6.82–
7.90 (24 H, m, Ar).
Synlett 2003, No. 9, 1339–1343 ISSN 1234-567-89 © Thieme Stuttgart · New York