O-sialylation with N-acetyl-5-N,4-O-carbonyl-protected thiosialoside donors in dichloromethane: Facile and selective cleavage of the oxazolidinone ring

Article abstract of DOI:10.1021/jo062431r

An N-acetyl-5-N,4-O-carbonyl-protected thiosialoside donor, the structure of which has been defined through X-ray crystallography, was prepared and tested in couplings to a wide range of acceptors. This donor gives excellent yields and α-selectivities in

Full text of DOI:10.1021/jo062431r

O-Sialylation with N-Acetyl-5-N,4-O-Carbonyl-Protected
Thiosialoside Donors in Dichloromethane: Facile and
Selective Cleavage of the Oxazolidinone Ring
David Crich* and Wenju Li
Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
dcrich@uic.edu
ReceiVed NoVember 26, 2006
An N-acetyl-5-N,4-O-carbonyl-protected thiosialoside donor, the structure of which has been defined
through X-ray crystallography, was prepared and tested in couplings to a wide range of acceptors. This
donor gives excellent yields and R-selectivities in linking with various primary alkyl and carbohydrate
acceptors under the N-iodosuccinimide and trifluoromethanesulfonic acid in situ activation method at
-40 °C in dichloromethane. The favorable affect of the oxazolidinone substructure for R-sialylation is
illustrated by a comparison study with a N,N-diacetylsialyl donor, which exhibited inferior yields and
R-selectivities. The sialylation selectivity is independent of the anomeric configuration of the donor, but
is highly related to the reaction temperature under the NIS/TfOH activation method. In contrast to the
NIS/TfOH method, the Ph2SO/Tf2O promotion gives â-selective couplings in dichloromethane. The
oxazolidinone of the N-acetyl-5-N,4-O-carbonyl protected sialosides, both R- and â-anomers, could be
cleaved cleanly by treatment with sodium methoxide under mild conditions without removal of the
acetamide.
Introduction
challenge owing to the inherent obstacles in sialic acid’s unique
structure: the hindered C-2-ketal carbon and the methylene C-3
ring carbon, prone to 2,3-elimination.
Progress in sialylation methodologies can be characterized
into several categories: the application of various leaving
groups, such as halides,3 sulfides,4 xanthates,5 phosphates,6
hydroxyl groups,7 and N-phenytrifluoroacetimidates;8 introduc-
tion of auxiliary participating groups at the C-3 position,
Sialic acids have been known for more than half a century
as important residues incorporated in a wide spread of oligosac-
charides and glycoconjugates with important functional roles
in mammalian biology.1 Among the more than 30 naturally
occurring derivatives of sialic acids, N-acetylneuraminic acid
(Neu5Ac) is the most common one and is present in a variety
of glycosidic linkages, most typically R-(2,3) and R-(2,6)
linkages to galactose (or lactose), as well as R-(2,8) or R-(2,9)
linkages in polysialic acids. Over the years considerable efforts
have been spent on the development of methodologies and
strategies for efficient R-sialoside installation allowing for the
chemical, enzymatic, or chemoenzymatic synthesis of complex
sialoconjugates.2 However, R-sialylation remains a formidable
(2) (a) Boons, G. J.; Demchenko, A. V. Chem. ReV. 2000, 100, 4539-
4565. (b) Ress, D. K.; Linhardt, R. J. Curr. Org. Synth. 2004, 1, 31-46.
(c) Boons, G. J.; Demchenko, A. V. In Carbohydrate-based Drug DiscoVery;
Wong, C. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vol. 1, pp
55-102. (d) Kiso, M.; Ishida, H.; Ito, H. In Carbohydrates in Chemistry
and Biology; Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim,
Germany, 2000; Vol. 1, pp 345-365. (e) Halcomb, R. L.; Chappell, M. D.
In Glycochemistry: Principles, Synthesis, and Applications; Wang, P. G.,
Bertozzi, C. R., Eds.; Dekker: New York, 2001; pp 177-220. (f) Toshima,
K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531. (g) Boons, G. J. Contemp.
Org. Synth. 1996, 3, 173-200. (h) Roy, R. Top. Curr. Chem. 1997, 187,
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Khan, S. H., O’Niell, R. A., Eds.; Harwood: Amsterdam, The Netherlands,
1996; pp 277-300. (j) Hasegawa, A.; Kiso, M. In PreparatiVe Carbohydrate
Chemistry; Hanessian, S., Ed.; Dekker: New York, 1997; pp 357-379.
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927-928. (b) Paulsen, H.; Tietz, H. Carbohydr. Res. 1984, 125, 47-64.
(1) (a) Schauer, R. Sialic Acids: Chemistry, Metabolism and Function;
Springer-Verlag: New York, 1982; Vol. 10. (b) Sialobiology and Other
NoVel Forms of Glycosylation; Inoue, Y., Lee, Y. C., Troy, F. A., II, Eds.;
Gakushin: Osaka, Japan, 1999. (c) Biology of the Sialic Acids; Rosenberg,
A., Ed.; Plenum: New York, 1995. (d) Mammen, M.; Choi, S. K.;
Whitesides, G. M. Angew. Chem., Int. Ed. 1998, 37, 2754-2794. (e)
Simanek, E. E.; McGarvey, G. J.; Jablonwski, J. A.; Wong, C. H. Chem.
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10.1021/jo062431r CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/06/2007
J. Org. Chem. 2007, 72, 2387-2391
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Crich and Li
includinghalogen,9sulfide,10 selenide,10b oroxygensubstituents;10e,11
the use of C-1 neighboring group participations;12 modification
of the amino protective groups at the C-5 position;13 and the
development of new promotors, such as NIS/TfOH,14 NIS/
TMSOTf,15 DMTST,16 NBS/Bu4NOTf,17 and Ph2SO/Tf2O.7,18
carbonates in glucose,20 and 3,4-O-carbonates in rhamnopyra-
nose21 can have dramatic affects on glycosylations, whether
present in donors or acceptors. During the course of our
investigation, Takahashi and co-workers described a related
study on the use of 5-N,4-O-oxazolidinones as sialic acid donors
(2) and acceptors (3,4), and achieved an elegant synthesis of
R-(2f8)-oligosialosides by this means.22 Our donor 1 differs
from 2 by the presence of the N-acetamido group, which we
included because of the known beneficial effects of double
nitrogen protection,13 and to facilitate deprotection.
Results and Discussion
Donor 1 was prepared from 523 on a gram scale following
the protocol employed for the introduction of N-acetyl-2-N,3-
O-carbamates to the glusosamine series (Scheme 1).19g,h The
anomer 9 was prepared analogously from 723(Scheme 1). Both
1 and 9 are crystalline solids and showed excellent shelf-
stability.
We directed our efforts in the R-sialylation field to the
investigation of a new thiosialoside donor 1 featuring N-acetyl-
5-N,4-O-carbonyl protection based on the knowledge that fused
structures like 2-N,3-O-carbamates in glycosamine,19 2,3-O-
SCHEME 1. Preparation of Donors 1 and 9
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Wong, C. H. J. Am. Chem. Soc. 1999, 121, 734-753. (b) Nicolaou, K. C.;
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5918.
First, the coupling of 1 with two alkyl alcohols, 1-octanol
and 1-adamantanol, was surveyed under the diphenyl sulfoxide
and triflic anhydride activation conditions in the presence of
the hindered base 2,4,6-tri-tert-butylpyrimidine (TTBP) devel-
oped for other thiosialoside donors.18 In both cases, â sialosides
were obtained predominantly (Table 1, entries 1 and 2).
Couplings to carbohydrate acceptors also showed unfavorable
R-selectivities (Table 1, entries 3 and 4). The anomeric
stereochemistry of all coupling products is assigned on the basis
of the chemical shifts of the sialic acid H-3eq24 and the3JC1,H-3ax
coupling constants.25 The fused oxzolidinone structure does not
affect the distinct difference of the3JC1,H-3ax coupling constants
between R- and â-anomers.
(10) (a) Erce´govec, T.; Magnusson, G. J. Org. Chem. 1995, 60, 3378-
3384. (b) Ito, Y.; Ogawa, T. Tetrahedron 1990, 46, 89-102. (c) Marti-
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(d) Erce´govec, T.; Magnusson, G. J. Org. Chem. 1996, 61, 179-184. (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.
(11) Okamoto, K.; Kondo, T.; Goto, T. Tetrahedron 1987, 43, 5919-
5928.
(12) (a) Takahashi, T.; Tsukamoto, H.; Yamada, H. Tetrahedron Lett.
1997, 38, 8223-8226. (b) Danishefsky, S. J.; DeNinno, M. P.; Chen, S. J.
Am. Chem. Soc. 1988, 110, 3929-3940. (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.
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Chem. 2005, 48, 875-883. (c) Meijer, A.; Ellervik, U. J. Org. Chem. 2004,
69, 6249-6256. (d) De, Meo, C.; Demchenko, A. V.; Boons, G. J. J. Org.
Chem. 2001, 66, 5490-5498. (e) Tanaka, H.; Adachi, M.; Takahashi, T.
Chem. Eur. J. 2005, 11, 849-862. (f) Ando, H.; Koike, Y.; Ishida, H.;
Kiso, M. Tetrahedron Lett. 2003, 44, 6883-6886. (g) Lu, K. C.; Tseng,
S.-Y.; Lin, C. C. Carbohydr. Res. 2002, 337, 755-760. (h) Yu, C. S.;
Niikura, K.; Lin, C. C.; Wong, C. H. Angew. Chem., Int. Ed. 2001, 40,
2900-2903. (i) Scneider, R.; Freyhardt, C. C.; Schmidt, R. R. Eur. J. Org.
Chem. 2001, 9, 1655-1661. (j) Tanaka, K.; Goi, T.; Fukase, K. Synlett
2005, 2958-2962.
(19) (a) Benakli, K.; Zha, C.; Kerns, R. J. J. Am. Chem. Soc. 2001, 123,
9461-9462. (b) Kerns, R. J.; Zha, C.; Benakli, K.; Liang, Y. Z. Tetrahedron
Lett. 2003, 44, 8069-8072. (c) Wei, P.; Kerns, R. J. Tetrahedron Lett.
2003, 44, 8069-8072. (d) Wei, P.; Kerns, R. J. J. Org. Chem. 2005, 70,
4195-4198. (e) Boysen, M.; Gemma, E.; Lahmann, M.; Oscarson, S. Chem.
Commun. 2005, 3044-3046. (f) Manabe, S.; Ishii, K.; Ito, Y. J. Am. Chem.
Soc. 2006, 128, 10666-10667. (g) Crich, D.; Vinod, A. U. Org. Lett. 2003,
5, 1297-1300. (h) Crich, D.; Vinod, A. U. J. Org. Chem. 2005, 70, 1291-
1296. (i) Mendlik, M. T.; Tao, P.; Hadad, C. M.; Coleman, R. S.; Lowary,
T. L. J. Org. Chem. 2006, 71, 8059-8070.
(14) Hasegawa, A.; Nagahama, T.; Ohki, H.; Hotta, K.; Ishida, H.; Kiso,
M. J. Carbohydr. Chem. 1991, 10, 493-498.
(15) (a) Kiso, M.; Hasegawa, A. In Neoglycoconjugates; Lee, Y., Lee,
R., Eds.; Academic Press: New York, 1994; Vol. 242, pp 173-183. (b)
Terada, T.; Kiso, M.; Hasegawa, A. J. Carbohydr. Chem. 1993, 12, 425-
440. (c) Terada, T.; Ishida, H.; Kiso, M.; Hasegawa, A. J. Carbohydr. Chem.
1995, 14, 751-768. (d) Terada, T.; Toyoda, T.; Ishida, H.; Kiso, M.;
Hasegawa, A. J. Carbohydr. Chem. 1995, 14, 769-790.
(20) Crich, D.; Jayalath, P. J. Org. Chem. 2005, 70, 7252-7259.
(21) Crich, D.; Vinod, A. U.; Picione, J. J. Org. Chem. 2003, 68, 8453-
8458.
(22) Tanaka, H.; Nishiura, Y.; Takahashi, T. J. Am. Chem. Soc. 2006,
128, 7124-7125.
(23) Marra, A.; Sinay¨, P. Carbohydr. Res. 1989, 187, 35-42.
(24) Dabrowski, U.; Friebolin, H.; Brossmer, R.; Supp, M. Tetrahedron
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1995, 43, 1536-1542.
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34, 2187-2190.
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Tetrahedron Lett. 1988, 29, 6317-6320. (b) Prytulla, S.; Lauterwein, J.;
Klessinger, M.; Thiem, J. Carbohydr. Res. 1991, 215, 345-349.
(18) Crich, D.; Li, W. Org. Lett. 2006, 8, 959-962.
2388 J. Org. Chem., Vol. 72, No. 7, 2007

R-Sialylation
TABLE 1. Ph2SO/Tf2O-Promoted Couplings of 1
TABLE 3. NIS/TfOH-Promoted Couplings of 1 with Simple
Alcohols
a Isolated yields. b Determined by 1H NMR analysis of the crude reaction
mixture. c Isolated ratio.
a Isolated yields. b Determined by 1H NMR analysis of the crude reaction
mixture.
TABLE 2. Ph2SO/Tf2O-Promoted Couplings of 14
TABLE 4. The Effect of Temperature on the Sialylation of 1
reaction
temp, °C
reaction
time
yield,a %
entry
(R:â)b
1
2
3
-25
-40
-78
20 min
2 h
90 (1.6:1)
91 (3.3:1)
no activation
a Isolated yields. b Determined by 1H NMR analysis of the crude reaction
mixture.
TABLE 5. NIS/TfOH-Promoted Couplings of 1 with Sugar
Acceptors
a Isolated yields. b Determined by 1H NMR analysis of the crude reaction
mixture.
Under the same Ph2SO/Tf2O preactivation conditions, the N,
N-diacetyl-protected sialoside donor 14 provided higher R-se-
lectivities (Table 2, entries 1-3) than 1 in couplings to the same
acceptors, indicating that the oxazolidinone group is detrimental
to R-sialylation under the Ph2SO/Tf2O activation conditions.
When the NIS/TfOH activation method was applied to
sialylations with 1 in CH2Cl2 at -40 °C, we found that excellent
yields and R-selectivities were obtained with 1-octanol (Table
3, entry 1), benzyl alcohol (Table 3, entry 2), and 3â-cholestanol
(Table 3, entry 3). With the tertiary alcohol 1-adamantanol the
R-selectivity dropped somewhat but the yield was still excellent
(Table 3, entry 4).
The influence of temperature on the sialylation of 1 under
the NIS/TfOH activation method in dichloromethane was studied
with 1-adamantanol as the acceptor. The results show that higher
R-selectivity could be achieved at lower temperature (Table 4,
entries 1 and 2), but at the expense of reduced reaction rate. At
-78 °C, no activation was observed over a period of several
hours (Table 4, entry 3).
A series of carbohydrate acceptors were then coupled with 1
by the standard NIS/TfOH promotion method in dichlo-
romethane at -40 °C. Sialylation of methyl 2,3,4-tri-O-benzyl-
R-D-glucopyranoside afforded the corresponding disaccharide
12 cleanly as a single R anomer (Table 5, entry 1). Excellent
yields and R-selectivities were also obtained with methyl 1,2;3,4-
di-O-isopropylidene-R-D-galactopyranoside and methyl 2,3,4-
a Isolated yields. b Determined by 1H NMR analysis of the crude reaction
mixture. c Isolated ratio. d Coupled to the 3-OH.
tri-O-benzyl-R-D-galactopyranoside (Table 5, entries 2 and 3)
both affording important linkage types. With the secondary sugar
acceptors, methyl 2,3-O-isopropylidene-R-L-rhamnopyranoside
and methyl 2,4,6-tri-O-benzyl-â-D-galactopyranoside, good
J. Org. Chem, Vol. 72, No. 7, 2007 2389

Crich and Li
TABLE 6. NIS/TfOH-Promoted Couplings of 14
TABLE 8. Selective Cleavage of the Oxazolidinones in Sialosides
a Isolated yields. b Determined by 1H NMR analysis of the crude reaction
mixture.
TABLE 7. NIS/TfOH-Promoted Couplings of 9
a Isolated yields. b Determined by 1H NMR analysis of the crude reaction
mixture.
yields were obtained but the reactions gave predominantely
â-sialosides (Table 5, entries 4 and 5). In the regioselective 3-O-
sialylation of methyl 2,6-di-O-benzyl-â-D-galactopyranoside, a
greater population of R-anomer was obtained, but there still
remains room for improvement (Table 5, entry 6).
The favorable affects of the 5-N,4-O-carbonyl protecting
system under the NIS/TfOH conditions are illustrated by
comparison of Table 3, entry 1 and Table 5, entry 2 with
corresponding couplings to the N,N-diacetyl-protected donor 14
presented in Table 6. It is also noteworthy that couplings with
1 generally proceed faster under the NIS/TfOH conditions than
those to 14, and typically afford higher yields owing to a reduced
propensity for glycal formation.
To probe the effect of anomeric configuration of the donor
on sialylation, we tested the sialylations of R-anomeric isomer
9 under these NIS/TfOH promotion conditions in CH2Cl2.
Comparable yields and selectivities were obtained in couplings
with the same alcohols as for donor 1 (Table 7). Clearly these
sialylaion reactions proceed through a common intermediate
whose constitution is independent of the original anomeric
configuration of the donors.
5-N,4-O-carbonyl-protected sialosides could be removed selec-
tively by treatment with sodium methoxide in methanol at room
temperature, affording the desired N-acetamido products easily
and cleanly (Table 8). This result parallels Oscarson’s report
on the deprotection of glycosides of N-acetyl-2-N,3-O-oxazo-
lidinone-protected 4,6-di-O-benzyl-D-glucosamine, which gives
the N-acetyl-glycosides directly.19e This deprotection method
does not depend on the anomeric configuration of substrates,
and renders application of the N-acetyl-5-N,4-O-carbonyl system
especially attractive for the synthesis of complex sialoconjugates
and oligosialosides by eliminating harsh conditions for oxazo-
lidinone cleavage and the extra steps for reinstalling the
acetamido group.
Further studies on the properties of N-acetyl-5-N,4-O-
carbonyl-protected thiosialosides and their applications in the
synthesis of various sialosides are underway in our laboratory.
Experimental Section
The hydrolysis of oxazolidinones typically requires harsh
conditions often involving treatment with barium or lithium
hydroxide in hot aqueous ethanol, which results in the con-
comitant removal of the acetamide group for N-acetyloxazoli-
dinones.26 Exceptions have been described but these appear to
be limited to the â-series of glucosamine-based N-acetyloxazoli-
dinones.19c,e,h We found that the oxazolidinone of the N-acetyl-
Methyl (Phenyl 5-amino-5-N,4-O-carbonyl-3,5-dideoxy-2-thio-
D-glycero-â-D-galacto-non-2-ulopyranoside)onate (6). A stirred
solution of methyl (phenyl 5-acetamideo-4,7,8,9-tetra-O-acetyl-3,5-
dideoxy-2-thio-â-D-glycero-D-galacto-2-nonulopyranosid)onate (5)23
(5.00 g, 8.57 mmol, 1.00 equiv) in methanol (80 mL) was treated
with methanesulfonic acid (1.68 mL, 25.7 mmol, 3.0 equiv) at room
temperature, and then refluxed under Ar for 24 h. After being cooled
to room temperature, the reaction mixture was quenched with excess
triethylamine, and then concentrated under reduced pressure. The
concentrate and NaHCO3 (3.60 g, 42.8 mmol, 5.0 equiv) were
(26) Kang, S. H.; Choi, H.; Kim, J. S.; Young, J. H. Chem. Commun.
2000, 227-228.
2390 J. Org. Chem., Vol. 72, No. 7, 2007

R-Sialylation
dissolved in CH3CN (30 mL) and H2O (60 mL) and cooled to 0
°C. To the vigorously stirred mixture was added 4-nitrophenyl
chloroformate (4.32 g, 21.4 mmol, 2.5 equiv) in CH3CN (30 mL)
slowly through a dropping funnel, after which stirring was continued
for 3 h at 0 °C. The resulting mixture was extracted with ethyl
acetate (3 × 100 mL) and the combined extracts were washed with
brine, and then dried over Na2SO4 and concentrated. The residue
was purified by silica gel column chromatography, eluting with
EtOAc then EtOAc/MeOH from 10/1 to 5/1 to give the title
procedure as for 1. Mp 148-149 °C (EtOAc/Et2O/hexanes). [R]14
D
1
+13.4 (c 1.1, CHCl3). H NMR (500 MHZ, CDCl3) δ 7.56-7.26
(m, 5H), 5.54 (dd, J ) 1.5, 6.0 Hz, 1H), 5.34 (dt, J ) 3.0, 7.0 Hz,
1H), 4.42 (dd, J ) 3.0, 12.5 Hz, 1H), 4.34 (dd, J ) 1.5, 9.5 Hz,
1H), 4.19 (dd, J ) 7.0, 12.0 Hz, 1H), 3.98-3.92 (m, 1H), 3.59
(dd, J ) 9.0, 11.0 Hz, 1H), 3.58 (s, 3H), 3.10 (dd, J ) 3.5, 12.0
Hz, 1H), 2.45 (s, 3H), 2.16 (s, 3H), 2.11 (t, J ) 13.0 Hz, 1H), 2.07
(s, 6H); 13C NMR (125 MHz, CDCl3) δ 171.9, 170.7, 170.2, 170.1,
3
168.1 (C-1, JC-1,H-3ax ) 7.50 Hz), 153.4, 136.6, 130.2, 129.0,
compound (6) as white foam (2.67 g, 6.68 mmol, 78% after two
128.3, 87.7, 75.7, 72.5, 70.5, 62.6, 59.1, 53.1, 36.7, 24.7, 21.1, 21.0,
20.9. Anal. Calcd for C25H29NO12S: C, 52.90; H, 5.15; N, 2.47.
Found: C, 53.13; H, 5.11; N, 2.47.
1
steps). [R]14 -186.0 (c 3.2, MeOH). H NMR (500 MHZ, CD3-
D
OD) δ 7.61-7.59 (m, 2H), 7.39-7.35 (m, 3H), 4.69 (dd, J ) 1.5,
10.0 Hz, 1H), 4.62 (dt, J ) 4.0, 12.5 Hz, 1H), 3.83 (dd, J ) 2.5,
11.0 Hz, 1H), 3.75-3.69 (m, 2H), 3.60 (s, 3H), 3.62-3.57 (m,
2H), 2.88 (dd, J ) 4.0, 13.0 Hz, 1H), 2.42 (dd, J ) 13.5, 15.0 Hz,
1H); 13C NMR (125 MHz, CD3OD) δ 169.1, 161.1, 136.3, 129.6,
129.3, 128.7, 89.6, 77.8, 74.4, 70.7, 69.8, 63.5, 58.0, 52.1, 37.0.
ESIHRMS calcd for C17H21N1O8SNa ([M + Na]+) 422.08804,
found 422.08939.
Coupling Protocol with Ph2SO/Tf2O/TTBP in Dichlo-
romethane. A solution of donor 1 (0.11 mmol, 1 equiv), diphenyl
sulfoxide (0.32 mmol, 3 equiv), TTBP (0.22 mmol, 2 equiv), and
activated 4 Å powdered sieves in anhydrous dichloromethane (2
mL) was stirred for 1 h at room temperature under an argon
atmosphere, and then cooled to -78 °C, followed by addition of
Tf2O (0.12 mmol, 1.1 equiv). After 10 min, a solution of the
acceptor (0.22 mmol, 2 equiv) in dichloromethane (1 mL) was
added. The reaction mixture was stirred for 1-6 h at -78 °C and
then warmed to room temperature, diluted with dichloromethane,
filtered through Celite, washed with saturated aqueous NaHCO3,
dried over Na2SO4, and concentrated under reduced pressure. The
glycosides were isolated by column chromatography on silica gel
eluting with THF/Hex systems to afford the sialosides.
Coupling Protocol with NIS/TfOH in Dichloromethane. A
solution of donor 1 (61.3 mg, 0.11 mmol, 1.0 equiv), acceptor (0.16
mmol, 1.5 equiv), and activated 5 Å powdered molecular sieves
(216 mg, 2.0 g/mmol) in anhydrous dichloromethane (2 mL) was
stirred overnight under an argon atmosphere, and then cooled to
-40 °C followed by addition of NIS (58.3 mg, 0.26 mmol, 2.4
equiv) and TfOH (9.5 µL, 0.11 mmol, 1.0 equiv). The reaction
mixture was stirred at -40 °C for 20 min to 2 h until the
disappearance of the donor on TLC, then quenched with triethy-
lamine (22.6 µL, 0.16 mmol, 1.5 equiv) and warmed to room
temperature. The mixture was diluted with dichloromethane, filtered
through Celite, washed with 20% aqueous Na2S2O3 solution, dried
over Na2SO4, and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel eluting with
THF/Hex system to afford the sialosides.
Methyl (Phenyl 5-amino-5-N,4-O-carbonyl-3,5-dideoxy-2-thio-
D-glycero-R-D-galacto-non-2-ulopyranoside)onate (8). 8 was
prepared from 723 following the same procedure as for 6. [R]15
D
+23.1 (c 3.1, MeOH). 1H NMR (500 MHZ, CD3OD) δ 7.58-7.56
(m, 2H), 7.44-7.41 (m, 1H), 7.38-7.35 (m, 2H), 4.06-4.01 (m,
1H), 3.85-3.79 (m, 3H), 3.69-3.60 (m, 2H), 3.59 (s, 3H), 3.56
(dd, J ) 2.0, 9.0 Hz, 1H), 3.12 (dd, J ) 4.0, 12.0 Hz, 1H), 2.23 (t,
J ) 12.5 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ 169.1, 160.9,
136.4, 130.0, 128.6, 87.9, 78.31, 78.28, 71.6, 70.0, 63.2, 57.0, 52.3,
36.7. ESIHRMS calcd for C17H21N1O8SNa ([M + Na]+) 422.08804,
found 422.08929.
Methyl (Phenyl 5-acetamido-7,8,9-tri-O-acetyl-5-N,4-O-car-
bonyl-3,5-dideoxy-2-thio-D-glycero-â-D-galacto-non-2-ulopyra-
noside)onate (donor 1). A solution of compound 6 (2.67 g, 6.68
mmol) in pyridine (20 mL) was treated with Ac2O (24 mL) and
stirred at room temperature overnight, then concentrated under
reduced pressure. The residue was dissolved in anhydrous CH2-
Cl2, treated with EtN(i-Pr)2 (11.6 mL, 66.8 mmol, 10 equiv), and
cooled to 0 °C before acetyl chloride (3.87 mL, 53.4 mmol, 8 equiv)
was added dropwise, then the mixture stirred at 0 °C for 1 h. After
warming to room temperature, the resulting solution was poured
into saturated aqueous NaHCO3 solution, the organic layer was
separated, the aqueous layer was extracted twice with CH2Cl2, and
the combined organic phase was washed with brine, dried over Na2-
SO4, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluting with
EtOAc/Hex (1:1) to give donor 1 as a yellowish solid (3.49 g, 92%),
which can be further purified by recrystalization from EtOAc/Et2O/
Hex to afford white needle crystals. Mp 152-153 °C (EtOAc/Et2O/
hexanes). [R]14D -117 (c 0.8, CHCl3). 1H NMR (500 MHZ, CDCl3)
δ 7.47-7.31 (m, 5H), 5.52 (t, J ) 2.0 Hz, 1H), 4.96 (td, J ) 1.5,
8.5 Hz, 1H), 4.86 (dd, J ) 2.5, 9.0 Hz, 1H), 4.76 (dt, J ) 4.0, 13.0
Hz, 1H), 4.34 (dd, J ) 2.5, 12.0 Hz, 1H), 3.86 (dd, J ) 8.0, 11.5
Hz, 1H), 3.73 (dd, J ) 9.0, 11.5 Hz, 1H), 3.60 (s, 3H), 2.88 (dd,
J ) 3.5, 13.0 Hz, 1H), 2.49 (s, 3H), 2.32 (t, J ) 12.5 Hz, 1H),
2.12 (s, 3H), 2.05 (s, 3H), 1.93 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 172.5, 171.3, 170.4, 169.8, 167.8 (C-1, 3JC-1,H-3ax ) 2.50
Hz), 153.6, 136.8, 130.2, 129.2, 128.2, 88.3, 75.7, 75.1, 73.9, 72.7,
62.9, 59.6, 52.8, 36.0, 24.8, 21.2, 20.85, 20.76. Anal. Calcd for
C25H29NO12S: C, 52.90; H, 5.15; N, 2.47. Found: C, 53.01; H,
5.15; N, 2.45.
Procedure for the Selective Cleavage of Oxazolidinones. To
a solution of sialoside (0.1 mmol, 1.0 equiv) in methanol (2 mL)
was added a few drops of sodium methoxide solution in methanol
(∼70 µL, 0.3 mmol, 3.0 equiv) at room temperature. The mixture
was stirred at room temperature for 30 min followed by treatment
with Amberlyst 15 ion-exchange resin for 5 min. The mixture was
diluted with methanol and filtered through a sintered funnel packed
with Celite and silica gel. The filter pad was rinsed with methanol
(3 × 5 mL) after filtration. The combined filtrates were concentrated
under reduced pressure to afford the deprotected N-acetamido-
sialosides in quantitative yield without further purification.
Acknowledgment. We thank Dr. D. J. Wink for X-ray
crystallography of donor 1, and the NIH (GM 62160) for
financial support of this work.
Supporting Information Available: X-ray crystal structure of
1, full characterization data, and copies of NMR spectra for new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
Methyl (Phenyl 5-acetamido-7,8,9-tri-O-acetyl-5-N,4-O-car-
bonyl-3,5-dideoxy-2-thio-D-glycero-R-D-galacto-non-2-ulopyra-
noside)onate (donor 9). 9 was prepared from 8 following the same
JO062431R
J. Org. Chem, Vol. 72, No. 7, 2007 2391