4
construction. When adapted to sialyl-hemiketal donors such
(89%, entry 2), C2-R-selectivity was not significantly
enhanced. Similar results were obtained when methyl 2,3,4-
tri-O-benzyl-R-D-glucopyranoside (7) was employed as the
acceptor (entries 4 and 5) using less nucleophilic diaryl
sulfoxides such as bis(m-trifluoromethylphenyl) sulfoxide
as 4,7,8,9-tetra-O-acetyl-N-acetylneuraminic acid methyl
ester (3, Scheme 2), this method provides a versatile approach
(
entry 4, 77%; 1:2 R/â) and (p-nitrophenyl)(phenyl) sulfoxide
Scheme 2
6
,7
(entry 5, 66%, 2:1 R/â).
To augment R-selectivity in dehydrative sialylation, C1-
neighboring group participation was explored employing the
C1-N,N-dimethyl glycolamide protective group recently
8
,9
introduced by us. This sialyl C1-protective group (i.e., 8,
Scheme 3) has been shown to enhance R-selectivity in
Scheme 3
to dehydrative sialylation. In situ generation of a diaryl
sulfoxide bis(triflate) intermediate 4 would lead to rapid
activation of the C2-hemiketal within 3 to afford the C2-
sialyloxosulfonium species 5, an electrophile that represents
a novel class of reactive sialyl donor. Subsequent anomeric
bond formation with an appropriate nucleophilic acceptor
(
Nu-H) leads to the formation of the sialyl conjugate 6. Initial
investigations to assess the feasibility of direct dehydrative
sialylation involved treatment of a solution of 3 and Ph SO
in CH Cl at -78 °C with Tf O, followed by the addition of
-propanol as a model sialyl acceptor (3 equiv). Subsequent
stirring of the reaction for 2 h at -50 °C led to the formation
of sialoside 6 (Nu ) -OCHMe , entry 1) in 98% yield (1:2
R/â). Similar results were also obtained when methyl 2,3,4-
tri-O-benzyl-R-D-glucopyranoside (7) was employed as the
sialyl acceptor to form the corresponding Neu5Ac(2f6)-
Glu sialoside (72%, entry 3).
2
2
2
2
2
sialylation with a variety of coupling methods, presumably
via generation and nucleophilic displacement of a â-sialyl-
C2-imidate cation donor 10, formed via dissociation of the
putative anomeric C2-sulfoxide in 9. This strategy is distinct
from the more common approach of C3-neighboring group
2
10
participation in that multistep incorporation and removal
of a transient C3-auxiliary is not necessary.
Although these early results establish the feasibility of
dehydrative sialylation with C2-hemiketal sialyl donors,
anomeric selectivity favors the non-natural â-glycosidic
linkage, indicating that the predominant coupling pathway
does not proceed through invertive displacement at C2 of a
putative â-oxosulfonium intermediate 5 (Scheme 2). Dehy-
drative sialylation of 2-propanol was also investigated in
propionitrile (entry 2) in the hopes that the formation of a
reactive â-nitrilium intermediate (similar to that invoked in
sialylations in acetonitrile solvent with C2-thio-sialoside
(5) (a) Hasegawa, A.; Ohki, H.; Nagahama, T.; Ishida, H.; Kiso, M.
Carbohydr. Res. 1991, 212, 277-281. (b) Birberg, W.; L o¨ nn, H. Tetra-
hedron Lett. 1991, 32, 7453, 7457.
(6) Use of electron-rich diarylsulfoxides such as bis(p-methoxyphenyl)
sulfoxide led to incomplete activation of the C2-hemiketal, presumably a
result of the attenuated electrophilicity of the sulfonium 4 (Ar ) p-
methoxyphenyl) relative to that of 4 (Ar ) Ph).
(7) No products arising from acceptor addition to the cationic imidate
carbon were observed.
(8) Haberman, J. M.; Gin, D. Y. Org. Lett. 2001, 3, 1665-1668.
(9) For another approach to the enhancement of R-selectivity in sialyl-
ations via C1-auxiliaries, see: Takahashi, T.; Tsukamoto, H.; Yamada, H.
Tetrahedron Lett. 1997, 38, 8223-8226.
5
donors) would lead to improved R-selectivity. Although a
comparable yield of the sialyl conjugate 6 was obtained
(
10) (a) Erc e´ govic, T.; Magnusson, G. J. Org. Chem. 1995, 60, 3378-
3384. (b) Okamoto, K.; Kondo, T.; Goto, T. Tetrahedron 1987, 43, 5909-
918. (c) Ito, Y.; Ogawa, T. Tetrahedron 1990, 46, 89-102. (d) Marti-
5
chonok, V.; Whitesides, G. M. J. Am. Chem. Soc. 1996, 118, 8187-8191.
(e) Castro-Palomino, J. C.; Tsvetkov, Y. E.; Schmidt, R. R. J. Am. Chem.
Soc. 1998, 120, 5434-5440. (f) Hossain, N.; Magnusson, G. Tetrahedron
Lett. 1999, 40, 2217-2220.
(
4) (a) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997,
1
1
19, 7597-7598. (b) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000,
22, 4269-4279.
2540
Org. Lett., Vol. 5, No. 14, 2003