Application of 4,5-O,N-oxazolidinone protected thiophenyl sialosyl donor to the synthesis of α-sialosides

Article abstract of DOI:10.1016/j.tetlet.2006.12.061

The synthesis of a novel oxazolidinone sialosyl donor is reported. The introduction of a trans-fused ring enhances reactivity and stereoselectivity in glycosylation reactions for the synthesis of α-sialosides. The oxazolidinone ring can also be removed un

Full text of DOI:10.1016/j.tetlet.2006.12.061

Tetrahedron Letters 48 (2007) 1225–1227
Application of 4,5-O,N-oxazolidinone protected thiophenyl
sialosyl donor to the synthesis of a-sialosides
Michael D. Farris and Cristina De Meo*
Department of Chemistry, Southern Illinois University Edwardsville, Edwardsville, IL 62026, USA
Received 19 July 2006; revised 12 December 2006; accepted 12 December 2006
Available online 8 January 2007
Abstract—The synthesis of a novel oxazolidinone sialosyl donor is reported. The introduction of a trans-fused ring enhances reac-
tivity and stereoselectivity in glycosylation reactions for the synthesis of a-sialosides. The oxazolidinone ring can also be removed
under basic conditions to afford the deprotected amine, which can be further functionalized.
Ó 2006 Elsevier Ltd. All rights reserved.
Sialic acids are a family of 40 naturally occurring 2-keto-
3-deoxy-nononic acids that are mainly found at the
terminal position of glycolipids and glycoproteins. For
this exposed position in the glycan chain, sialic acids
are involved in a wide range of biological phenomena,
such as cell–cell interactions, cell differentiation, tumor
metastasis, and pathogen–host recognition.1,2 The most
widespread member of the sialic acid family, N-acetyl-
neuraminic acid (Neu5Ac) is often linked to galactose
or galactosamine via a(2,3) and a(2,6) glycosidic
linkages. Although extensively explored, the chemical
synthesis of sialosides in a high yield with a complete
stereoselectivity is still a notable challenge.3–5 The pres-
ence of a destabilizing electron-withdrawing carboxylic
group together with a tertiary anomeric center and the
lack of a participating auxiliary often drive glycosyl-
ation reactions toward competitive elimination reac-
tions resulting in a poor stereoselectivity and in the
formation of a 2,3-dehydro derivative. To address these
problems, different strategies have been developed,
primarily focusing on the nature of the leaving group
or promoter. The introduction of participating auxili-
aries at the C-3 positions (indirect methods) also have
been investigated.3,6–8 In addition, modifications of the
C-1 carboxylic group9,10 as well as 1,5-intramolecular
lactamization11 or modifications of the C-5 acetamido
group12 have been reported as alternative strategies to
optimize glycosylation reactions.
mediate for the stereoselective synthesis of a(2,3) and
a(2,6)-linked sialosides. Although the use of oxazolidi-
none protection for glucosamine has been described by
Crich13,14, Kerns,15–17 and Oscarson18 the effect of fused
ring systems on neuraminic acid has not been fully
investigated.19
Thus, compound 220 was prepared in a straightforward
manner starting from the known thioglycoside deriva-
tive 1a as described in Scheme 1. Full deprotection of
1a in the presence of methanesulfonic acid afforded the
free amine intermediate, which was N-functionalized
by treatment with p-nitro-phenyl chloroformate (NPCC)
in an 80% yield, and then O-acetylated to afford 2.
NMR comparison of 2 with 1a showed a strong influence
of the oxazolidinone fused ring on some signals. In
particular, H-3eq is shifted downfield (d = 3.07 ppm)
while H-4 and H-5 are shielded (d = 3.86 and 2.91 ppm,
respectively). In the glycerol chain, H-9 is now
magnetically equivalent, showing a singlet at 4.32 ppm.
AcO
AcO
HN
AcO
AcO
R1R2N
OAc
COOMe
OAc
O
COOMe
SPh
i
O
SPh
AcO
1a R1=H, R2=Ac
1b R1=R2=Ac
O
O
2
Herein we report the application of 4,5-O,N-oxazolidi-
none protected sialosyl donor 2 as a versatile inter-
1c R1=H, R2=TFA
Scheme 1. Reagents and conditions: (i) (a) MsOH, MeOH, 65 °C,
80%; (b) NPCC/NaHCO3, MeCN–H2O, 3 h, 80%; (c) Ac2O/Py, 16 h,
90%.
*
Corresponding author. Tel.: +1 618 650 3170; fax: +1 618 650
3556; e-mail: cdemeo@siue.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.061

1226
M. D. Farris, C. De Meo / Tetrahedron Letters 48 (2007) 1225–1227
Table 2. Glycosylation of donor 2 with acceptors 6–12
To explore the potential of a trans-4,5-cyclic carbamate
as protecting/activating group in sialic acid moiety,
sialosyl donor 2 was then coupled with 1,2:3,4-di-O-iso-
propylidene galactoside acceptor 3 and the results were
compared with different C-5 protected sialyl donors
1a–c (Table 1). All the reactions were performed using
an equimolar amount of donor and acceptor in the pres-
ence of acetonitrile as stereocontrolling solvent, using
NIS/TfOH as promoter. Interestingly, the introduction
of the oxazolidinone ring increases yield and stereoselec-
tivity of the glycosylation reaction (Table 1, entry 4,
90%, 10:1 a:b) when compared with the acetamido-bear-
ing donor 1a or the N-acetylacetamido compound 1b
(entries 1 and 2, respectively). In addition, sialyl donor
2 appears less reactive but more stereocontrolling than
donor 1c (entry 3).
Entry
Acceptor
Product
Yielda
(%)
Ratio
(a:b)b
1c
MeOH
6
13
95
1.7:1
HO
TMS
2
3
14
15
82
a only
7
OH
O
O
O
90
2:1
HO
OMe
8
BnO
BnO
OH
O
4
5
16
17
91
80
6:1
BnO
OMe
Encouraged by these preliminary results, we decided
to investigate the glycosyl donor proprieties of 2 by
coupling with different acceptors, ranging from simple
alcohols (entries 1 and 2), to C-6 (entries 3 and 4) and
C-3 acceptors (entries 5–7, Table 2).
9
OBn
O
HO
HO
1:1.5
BnO
OMe
Coupling with MeOH (entry 1, Table 2) gave a high
yield of methyl glycoside 13 in the ratio 1.7:1. A com-
plete stereoselectivity was observed when 2-trimethyl-
silyl ethanol 7 was used as the acceptor (entry 2).
10
OBz
O
OH
HO
O
6
7
18
19
50
50
a only
a only
TMS
OH
In the series of C-6 acceptors (compounds 3, 8, and 9) all
the glycosylations proceeded with high yields and stereo-
selectivities. In particular, acceptor 9 gave the corre-
sponding disaccharide 16 as 6:1 anomeric mixture in a
91% yield. The best result was obtained by using accep-
tor 3 as reported in Table 1.
11
BnO
HO
OBn
O
OMe
OBn
12
a Isolated yields after Sephadex LH-20.
b Anomeric ratios were determined by 1H NMR analysis.3
To evaluate the glycosyl donor of 2 for the synthesis of
a(2,3) linkages, three differently protected galactoside
acceptors (10–12) were used. Unfortunately, glycosyla-
tion of diol 10 gave mainly the unnatural b anomer.
However, Crich observed the same b-stereoselectivity
in the coupling of donor 1b with acceptor 10.21 Yet, a
complete stereoselectivity was observed when triol 11
was used for the synthesis of sialoside 18 (entry 6); lower
yield than expected (50%) was in part due to disialyla-
tion of 11 in positions 2 and 3, as confirmed by mass
spectrometric analysis of the isolated trisaccharide
c No molecular sieves were used, and 2 equiv of acceptor were required.
(10%). Similar results were previously reported for N-tri-
fluoroacetyl 2-thiomethyl sialyl donor with the same
acceptor.22 To exclude the formation of regioisomers,
we decided to use the sterically hindered, less reactive
2,4,6-substitued acceptor 12. Remarkably, disaccharide
19 was isolated with a 50% yield as a-anomer only (Ta-
ble 2, entry 7), whereas compound 1b failed to give any
glycosylation product,21 while trifluroacetyl derivative
1c gave it in an 84% yield.22
Table 1. Glycosylation of acceptor 3 with donor 1a–c, 2a
The versatility of oxazolidinone protecting group cannot
be proved without a good deprotection method. In the
glucosamine series different methods have been applied
to the selective removal of the fused ring.17,14 In the case
of sialyl donor 2 complete deprotection to afford free
amine 20 was achieved by treatment with barium
hydroxide in ethanol, while sodium methoxide in meth-
anol gave the corresponding N-methoxy carbonyl deriv-
ative 21, as illustrated in Scheme 2.
OH
O
O
NIS/TfOH
O
4a-c, 5
1a-c, 2
+
MS 3Å, MeCN
O
O
3
Entry
Donor
Product
Yieldb
(%)
Ratio
(a:b)c
Reaction
time
1
2
3
4
1a
1b
1c
2
4a
4b
4c
5
Tracec
89
88
90
—
16 h
16 h
10 min
30 min
2:1
5:1
10:1
Thus, disaccharide 5 was fully deprotected and then
N-acetylated to obtain 22 (Scheme 3).
a All glycosylations were performed in CH3CN under argon at ꢀ40 °C.
b Isolated yields.
c Anomeric ratios were determined after column chromatography on
Sephadex LH-20 by 1H NMR analysis.3
The structures of the disaccharides 5, 13–18, and 19 were
confirmed by 1H and COSY NMR experiments, and the

M. D. Farris, C. De Meo / Tetrahedron Letters 48 (2007) 1225–1227
1227
2. Biology of Sialic Acids; Rosenberg, A., Ed.; Plenum Press:
New York, London, 1995.
3. Boons, G. J.; Demchenko, A. V. Chem. Rev. 2000, 100,
4539–4565.
4. Boons, G. J.; Demchenko, A. V. In Carbohydrate-Based
Drug Discovery; Wong, C.-H., Ed.; Wiley, 2003; pp 55–
102.
5. Ress, D. K.; Linhardt, R. J. Curr. Org. Synth. 2004, 1,
31–46.
6. De Meo, C.; Parker, O. Tetrahedron: Asymmetry 2005, 16,
303–307.
7. Meijer, A.; Ellervik, U. J. Org. Chem. 2004, 69, 6249–
6256.
HO
HO
H2N
OH
O
-
CO2
AcO
AcO
HN
OAc
COOMe
a
SPh
HO
20
O
SPh
O
b
HO
HO
HN
2
OH
O
O
COOMe
SPh
MeO2C
HO
21
Scheme 2. Reagents and conditions: (a) Ba(OH)2, EtOH, 65 °C, 16 h,
95%; (b) MeOH, MeONa, 2 h, 90%.
8. Cai, S.; Biao, Y. Org. Lett. 2003, 5, 3827–3830.
9. Haberman, J. M.; Gin, D. Y. Org. Lett. 2001, 3, 1665–
1668.
10. Ishiwata, A.; Ito, Y. Synlett 2003, 9, 1339–1343.
11. Ando, H.; Koike, Y.; Koizumi, S.; Ishida, H.; Kiso, M.
Angew. Chem., Int. Ed. 2005, 44, 2–7.
12. De Meo, C. ACS Symp. Ser., in press.
13. Crich, D.; Vinod, A. U. Org. Lett. 2003, 5, 1297–1300.
14. Crich, D.; Vinod, A. U. J. Org. Chem. 2005, 70, 1291–
1296.
AcO
AcO
HN
OAc
O
HO
HO
AcHN
OH
O
COOMe
-
CO2
a,b
O
O
O
O
O
O
HO
O
O
O
O
22
O
5
O
O
O
Scheme 3. Reagents and conditions: (a) Ba(OH)2, EtOH, 65 °C, 16 h,
95%; (b) Ac2O, MeOH, 5 h, 90%.
15. Benakli, K.; Zha, C.; Kerns, R. J. J. Am. Chem. Soc. 2001,
123, 9461–9462.
16. Kerns, R. J.; Zha, C.; Benakli, K.; Liang, Y.-Z. Tetra-
hedron Lett. 2003, 44, 8069–8072.
17. Wei, P.; Kerns, R. J. Tetrahedron Lett. 2005, 46, 6901–
6905; Wei, P.; Kerns, R. J. J. Org. Chem. 2005, 70, 4195.
18. Boysen, M.; Gemma, E.; Lahmann, M.; Oscarson, S.
Chem. Commun. 2005, 3044–3046.
anomeric configurations were assigned using empirical
rules.3 Thus, the most useful characteristic parameters
to undoubtedly assign anomeric configuration were the
chemical shift of H-30eq (a-glycosides: d 3.10–2.78,
b-glycosides: d 2.60–2.50), the value Dd{H-90a-H-90b}
(a-glycosides:
d 0.1–0.3 ppm, b-glycosides: d 0.6–
19. During the preparation of this manuscript, Takahashi
et al. reported the use of oxazolidinone donor and
acceptor for the synthesis of a(2–8)-linked sialosides, see:
Tanaka, H.; Nishiura, Y.; Takahashi, T. J. Am. Chem.
Soc. 2006, 128, 7124–7125.
0
0
1.0 ppm) and the value of JH-7 ;H-8 coupling constant
(a-glycosides: 6.2–9.6 Hz, b-glycosides: 1.6–3.0 Hz).23
In conclusion, the introduction of 4,5-O,N-oxazolidi-
none protecting group creates a donor whose reactivity
can be in general considered higher than that of
N-acetylacetamido but slightly lower than trifluro-
acetamido derivatives. It has also been demonstrated
that the oxazolidinone fused ring enhances stereoselec-
tivity in glycosylation reactions with a large number of
glycosyl acceptors, although the anomeric selectivity is
also dependent on the nature of acceptor. Thus, high
yields and stereoselectivities can be achieved for the
synthesis of a(2,6) linkages, while an excellent stereo-
selectivity in modest yields have been reported for the
synthesis of a(2,3) linkages. The oxazolidinone ring
can also be removed under basic conditions to afford
the corresponding deprotected amine, which can be
further functionalized.
20. Methyl [2-thiophenyl 7,8,9-tri-O-acetyl-4,5-O,N-carbonyl-
3,5-dideoxy-D-glycero-a-D-galacto-non-2-ulopyranoside]-
onate (2): Rf 0.50 (ethyl acetate/toluene, 1/1 v/v);
26
½aꢁD ꢀ4.90 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.11–7.43 (m, 5H, aromatic), 5.23–5.32 (m, 2H, H-8,
NH), 5.03 (dd, 1H, J7,8 = 9.6 Hz, H-7), 4.33 (s, 2H, H-9),
3.97 (dd, 1H, J6,7 = 1.5 Hz, H-6), 3.8–3.90 (m, 1H, H-4),
3.47 (s, 3H, OCH3), 3.08 (dd, 1H, J3e,4 = 3.6 Hz,
J3e,3a = 10.4 Hz, H-3e), 2.92 (t, 1H, J5,6 = 9.9 Hz, H-5),
2.08 (dd, 1H, H-3a), 2.13, 1.99, (2s, 6H, OCOCH3). HR-
FAB MS [M+Na]+ calcd for C23H27NaNO11S 548.1203,
found 548.1198.
21. Crich, D.; Wenju, L. Org. Lett. 2006, 8, 959–962.
22. De Meo, C.; Demchenko, A. V.; Boons, G. J. Aust. J.
Chem. 2002, 55, 131–134.
23. Selected 1H NMR data for compounds 5a and 14:
O-[Methyl (7,8,9-tri-O-acetyl-4,5-O,N-carbonyl-3,5-dideoxy-
D-glycero-a-D-galacto-non-2-ulopyranosyl)onate]-(2!6)-
1,2:3,4-di-O-isopropylidene-a-D-galactopyranose (5a). 1H
Acknowledgment
0
0
NMR (300 MHz, CDCl3): d 5.11 (dd, 1H, J7 ;8 ¼ 9:7 Hz,
H-70), 4.60 (dd, 1H, J8 ;9 a ¼ 2:7; J9 a;9 b ¼ 9:5 Hz, H-90a),
4.35-4.23 (m, 4H, H-90b), 2.89 (dd, 1H, J3e,4 = 3.4 Hz,
J3e,3a = 12.8 Hz, H-30eq), 2.09 (dd, 1H, H-30ax) ppm.
Methyl [2-(trimethylsilyl)ethyl 7,8,9-tri-O-acetyl-4,5-O,
N-carbonyl-3,5-dideoxy-D-glycero-a-D-galacto-non-2-ulo-
0
0
0
0
We thank Research Corporation-Cottrell College
Science Award for support of this work.
1
pyranoside]onate (14). H NMR (300 MHz, CDCl3): 5.15
References and notes
(dd, 1H, J7,8 = 10.0 Hz, H-7), 4.45–4.38 (m, 2H, H-9), 2.90
(dd, 1H, J3e,4 = 3.6 Hz, J3e,3a = 0.4 Hz, H-3e), 2.05 (dd,
1H, H-3a) ppm.
1. Schauer, R. Sialic Acids: Chemistry, Metabolism and
Function; Springer-Verlag: Wien–New York, 1982; Vol. 10.