Thiomidoyl approach to the synthesis of α-sialosides

Article abstract of DOI:10.1016/j.tetasy.2004.11.043

Novel sialosyl donors, S-benzoxazolyl (SBox) and S-thiazolyl (STaz) sialosides, have been synthesized and applied to the stereoselective synthesis of α-sialosides. It was also demonstrated that it is possible to selectively activate SBox sialyl donor over

Full text of DOI:10.1016/j.tetasy.2004.11.043

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 303–307
Thiomidoyl approach to the synthesis of a-sialosides
Cristina De Meo* and Olivia Parker
Department of Chemistry, Southern Illinois University at Edwardsville, Edwardsville, IL 62026, USA
Received 8 November 2004; accepted 18 November 2004
Available online 23December 2004
Abstract—Novel sialosyl donors, S-benzoxazolyl (SBox) and S-thiazolyl (STaz) sialosides, have been synthesized and applied to the
stereoselective synthesis of a-sialosides. It was also demonstrated that it is possible to selectively activate SBox sialyl donor over
ethyl thioglycoside, allowing the direct synthesis of disaccharide donors that could be used in subsequent glycosylations without
further manipulations.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
are often plagued with lower yields and stereoselectivi-
ties in comparison with ÔcommonÕ glycosylation reac-
tions.5 In order to cover these gaps, novel sialylation
methods, indirect strategies, and enzymatic approaches
emerged at the turn of the century.5,6 Thus, thioglyco-
sides7 and phosphites8,9 are examples of versatile sialyl
donors that allow mild activation conditions, high stereo-
selectivity, and good yields. Further improvement
came with the discovery of a rather unusual activating
effect of the remote substituent at C-5, such as
trifluoroacetamido.10
Sialic acids are a family of about 50 naturally occurring
2-keto-3-deoxy-nononic acids involved in a wide range
of biological processes.1,2 Sialic acid-containing glyco-
conjugates are involved in a large number of biological
phenomena such as cell–cell adhesion, cell growth regu-
lation, immune response, and oncogenesis.3,4 The C-5-
amino derivative represents the long-known neuraminic
acid, and its amino function can either be acetylated
(Neu5Ac) or glycolylated. Sialic acids normally appear
at the terminal positions of glycoproteins and glycolip-
ids where they are a(2,3)- or a(2,6)- linked to galacto-
sides or a(2,6)- linked to 2-acetamido-galactosyl
residues. The disialosyl structures Neu5Aca(2,8)Neu-
5Ac and Neu5Aca(2,9)Neu5Ac have also been found
as constituents of glycoproteins and glycolipids.
The last decade witnessed an improvement in the meth-
ods and strategies used for convergent oligosaccharide
assembly. Approaches such as armed–disarmed,11
orthogonal,12 semi-orthogonal,13 one-pot,14 and active-
latent,15,16 allow, significantly, shortening of the oligo-
saccharide assembly. The majority of these approaches
are based on selective activation of one donor over an-
other.17 Less attention in that respect has been given
to the convergent synthesis of sialosides, as the number
of approaches for their selective glycosidation is limited
and the overall efficiency not so high.18 For example, for
the synthesis of sialosyl derivatives, multi-step transfor-
mations (removal of protecting group, introduction of a
leaving group) are still required to obtain the disaccha-
ride donor, decreasing the over-all efficiency (Scheme
1a).10,19
The appreciation of the biological importance and ther-
apeutic potential of sialic acid and its derivatives has re-
vealed certain drawbacks in the methods for chemical
sialylation. Introduction of sialic acid residues with a
high regio- and stereoselectivity is a challenging problem
of the contemporary oligosaccharide synthesis. The use
of sialyl donors is complicated by the lack of a partici-
pating substituent at C-3. In addition, the presence of
the deoxy moiety in combination with the electron with-
drawing carboxylate group at the anomeric center make
these derivatives prone to elimination to give 2,3-dehy-
dro derivatives. For these reasons, sialylation reactions
We reasoned that it would be beneficial to develop a new
sialyl donor that could be selectively activated over the
thioglycoside moiety of the glycosyl acceptor for the
direct activation of the latter in the next glycosylation
step (Scheme 1b).
*
Corresponding author. Tel.: +1 618 650 3170; fax: +1 618 650
3556; e-mail: cdemeo@siue.edu
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.043

304
C. De Meo, O. Parker / Tetrahedron: Asymmetry 16 (2005) 303–307
OAc
CO2Me
LG
OAc
AcHN
CO2Me
O
AcO
AcO
O
O
HO
O
O
AcHN
AcO
OR
OR
SR
OAc
AcO
OAc
(a)
OAc
CO2Me
O
AcO
O
O
AcHN
AcO
OAc
OAc
CO2Me
LG
OAc
CO2Me
O
AcO
O
O
AcO
HO
AcHN
AcO
SR
O
O
AcHN
AcO
SR
OAc
OAc
(b)
Scheme 1. (a) Linear approach to the synthesis of sialosides; (b) convergent approach to the synthesis of sialosides.
Recently, a number of new approaches for glycosyl-
ations have emerged.20 Among these, glycosyl thioimi-
dates, S-benzoxazolyl (SBox), and S-thiazolyl (STaz)
were determined to be very stable and stereoselective do-
nors for the D-gluco, D-galacto, and D-manno series.21–23
They also could be activated under mild reaction condi-
tions. Most importantly, they can be activated in the
presence of silver triflate or cupper triflate, allowing
the selective activation of the thioimidoyl glycosyl do-
nors over S-ethyl and O-pentenyl moieties.
curious to find out whether the sialyl chloride could
serve as a suitable precursor for the introduction of
the S-imidoyl moiety. The synthesis of 1a was straight-
forwardly achieved by the treatment of the b-chloro
glycoside of Neu5Ac 2 with potassium 2-mercaptobenz-
oxazolate and [18]crown-6 in acetone to afford 1a in 80%
yield (Scheme 2). Similarly, sialosyl donor 1b was
synthesized from 2 in the presence of sodium 2-merca-
ptothiazolate and [15]crown-5 in 70% yield. The lower
yield for the synthesis of 1b is due to the formation of
the N-linked side product 1c (Fig. 2).
We were interested to find out whether the leaving
groups of this class would be suitable for selective sialyl-
ation. This work describes the synthesis of SBox 1a24
and STaz 1b25 sialosides and their application to stereo-
selective sialylation and convergent oligosaccharide syn-
thesis (Fig. 1).
This side reaction is due to the high basicity and ambi-
dent reactivity of STaz anion.23 In this context, the alter-
native method for the synthesis of 1b by treatment of the
anomeric acetate in the presence of the thiol and Lewis
acid gave lower yield and stereoselectivity.
The glycosyl donor proprieties of 1a and 1b were ini-
tially evaluated by the coupling with the C3and C6
hydroxyl of a series of D-galactosyl acceptors having
different protecting group patterns (3–5, Scheme 3).
2. Results and discussions
Synthesis of the SBox and STaz glycosides can be
achieved by a variety of pathways from acetates, bro-
mides, and by opening of 1,2-anhydro derivatives.
Among these, chlorides received less attention. We were
Coupling of the sialyl donor 1a with acceptor 3 was first
investigated. Thus, different reaction conditions includ-
OAc
OAc
COOMe
COOMe
AcO
AcO
N
N
O
O
AcHN
AcO
AcHN
AcO
S
S
OAc
1b
S
OAc
O
1a
Figure 1.
OAc
Cl
OAc
COOMe
R
AcO
O
AcO
AcHN
AcO
COOMe
O
AcHN
AcO
OAc
OAc
1a,b
2
Scheme 2. Reagents and conditions: (1a), KSBox, acetone, [18] crown-6, rt, 80%; (1b), NaSTaz, acetone, [15] crown-5, rt, 70%.

C. De Meo, O. Parker / Tetrahedron: Asymmetry 16 (2005) 303–307
305
no reaction was observed even at room temperature.
Surprisingly, the same reactions performed in CH2Cl2
still gave good stereoselectivity and yield, (entries 6
and 7).
OAc
COOMe
N
AcO
O
AcHN
AcO
OAc
S
S
1c
Figure 2.
Encouraged by these results, attention was turned to-
ward the synthesis of a(2,3) sialosides: in particular,
reaction of 1a with acceptor 426 gave mainly the a-ano-
mer in the presence of either MeOTf or NIS/TfOH (en-
tries 1 and 2, Table 2). The lower stereoselectivity which
was observed in the presence of AgOTf can be due to the
use of CH2Cl2 as solvent (entry 3). Good stereoselectiv-
ities and moderate yields were also obtained with accep-
tor 527 (entries 4–6). As evident from these results, in a
number of cases excellent stereoselectivity was achieved.
Although a number of reactions resulted in the disac-
charide formation with moderate yield, these results still
represent a creditable achievement, when compared to
other direct sialylation procedures.5
ing temperature, promoter, and solvent were tested.
These results are summarized in Table 1. It should be
noted that sialylation of primary hydroxyls, for example
3, often proceeds with low stereoselectivity, which is
commonly credited to the high reactivity of the glycosyl
acceptor. Thus, sialyl donor 1a gave comparable results
(yield and stereoselectivity) to those achieved by conven-
tional donors, thioglycosides or phosphites. In particu-
lar, activation by MeOTf and NIS/TfOH (entries 1
and 2, respectively) gave the desired disaccharide 6 with
high yields and good stereoselectivity. It is worthy to
mention that no methylation at the acetamido group
was detected when MeOTf was used as the promoter,
a side reaction previously reported for thioglycosides.19
Glycosylations using 1b as sialosyl donor were margin-
ally less efficient: although good yield and stereoselectiv-
ity were observed by reaction of 1b with acceptors 3 and
4 in the presence of MeOTf (entries 7 and 9, Table 2),
Promoters such as AgOTf, Cu(OTf)2, and TfOH were
deactivated by the presence of CH3CN, and, therefore,
OAc
AcHN
CO2Me
OH
O
AcO
O
O
1a,b
O
O
AcO
OAc
O
O
O
O
O
3
O
O
6
OBz
O
HO
OAc
CO2Me
O
OTE
AcO
AcO
OH
HO
1a,b
1a,b
O
OTE
OMe
OH
AcHN
O
OBz
AcO
OAc
HO
4
7
Ph
O
OAc
CO2Me
O
O
OH
O
O
O
OMe
HO
AcHN
AcO
OH
OAc
O
O
5
8
Ph
OTE=O(CH2)2Si(CH3)3
Scheme 3. Synthesis of sialosides 6–8 from (1a) and (1b).
Table 1. Glycosylation reaction between 1a and 3
Entrya
Promoter
Solvent
Temp
Time (h)
Yield
a/b ratiob
1
MeOTf
NIS/TfOH
MeCN
MeCN
MeCN
ꢀ40
16
16
24
24
24
24
16
90
70
2:1
1.6:1
—
2
3AgOTf
ꢀ40
ꢀ40 to rt
ꢀ40 to rt
ꢀ40 to rt
ꢀ40 to 0
ꢀ40
No rxn.
No rxn.
No rxn.
65
4
5
6
7
Cu(OTf)2
TfOH
MeCN
MeCN
DCM
DCM
—
—
Cu(OTf)2
AgOTf
3:1
2:1
55
a
˚
1
In a typical glycosylation procedure, 2 equiv of donor per acceptor were used in the presence of MS 3A .
b Anomeric ratios were obtained by comparison of the integral intensities of the corresponding signals in H NMR spectra; conventional empirical
NMR rules for the assignment of anomeric configurations of sialosides were applied.5

306
C. De Meo, O. Parker / Tetrahedron: Asymmetry 16 (2005) 303–307
Table 2. Glycosylation reaction between 1a, 1b, and 3–5
Entrya
Donor
Acceptor
Promoter
Product
Yield
a/b ratio
1
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
4
4
4
5
5
5
3
3
4
4
5
5
MeOTf
NIS/TfOH
AgOTf
7
7
7
8
8
8
6
6
7
7
8
8
75
60
55
65
60
50
70
77
79
50
19:1
20:1
1.5:1
1.5:1
2:1
2
3
4
MeOTf
NIS/TfOH
AgOTf
5
6
1.2:1
2.3:1
1:1.1
17:1
1:1
7
MeOTf
AgOTf
8
9
MeOTf
AgOTf
10
11
12
b
MeOTf
AgOTf
—
40
1:1
a
˚
All glycosylations were performed in the presence of MS 3A ; glycosylations in the presence of AgOTf required the use of CH2Cl2 as solvent; MeCN
was the solvent of choice for all the other glycosylations.
b No disaccharide was detected, methylated 2,3dehydro derivate was isolated.
OH
O
HO
BzO
OAc
COOMe
O
HO
a
AcO
SEt
1a
O
+
+
AcHN
AcO
O
SEt
BzO
BzO
OAc
BzO
9
10
OBn
O
OAc
COOMe
HO
b
HO
10
AcO
BnO
OBn
O
O
AcHN
AcO
BnO
O
O
O
OMe
BzO
OAc
BnO
BzO
BnO
OMe
11
12
˚
˚
Scheme 4. Reagents and conditions: (a) AgOTf, MS 3A , DCN, ꢀ40 ꢁC, 24 h, 89%, a/b = 1:1; (b) NIS/TfOH, MS 3A , DCM, ꢀ40 ꢁC, 2 h, 70%,
b only.
sialosyl donor 1b gave mainly glycal and N-linked prod-
uct when coupled to less reactive acceptor 5 (entries 11
and 2).
ber of glycosyl acceptors, ranging from highly reactive
primary to less reactive secondary acceptors. The most
attractive feature of thiomidoyl moieties is that they
can be selectively activated over thioglycosides in the
presence of AgOTf as promoter. Based on this concept,
we synthesized a disaccharide donor 10 that could be di-
rectly used for the synthesis of trisaccharide 12. Further
studies in order to improve the stereoselectivity of sialyl-
ations with thioimidoyl donors, by the introduction of a
N-acetylacetamido and N-trifluroacetamido groups at
C-5, are in progress.
As previously mentioned, the possibility to activate thio-
imidoyl sialoside in the presence of thioglycosides was
especially attractive. Indeed, this would allow the syn-
thesis of disaccharides that can be directly used in subse-
quent glycosylation. Based on this concept, 1a was
coupled with galactoside acceptor 928 bearing a thio-
ethyl moiety as leaving group in the presence of AgOTf.
In this case the reaction went to completion after 24 h.
The disaccharide 10 was synthesized with a high yield
of 89%. Subsequently, it was used without further
manipulations as a donor by coupling with acceptor
1129 to obtain a GM3derivative 12 in 70% yield
(Scheme 4).
Acknowledgements
This work was supported by the Southern Illinois Uni-
versity Edwardsville Summer Research Fellowship and
Research Equipment Tool programs.
3. Conclusion
References
To summarize, two novel sialyl donor bearing a thioim-
idoyl moiety as leaving group have been synthesized and
tested in the syntheses of sialosides. SBox and STaz
sialosides proved to be excellent glycosyl donors when
activated with MeOTf and AgOTf. In general, good
yields and stereoselectivities were observed with a num-
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chromatography on silica gel (10% gradient acetone in
toluene) to afford 1a (1.96 g, 80%): Rf 0.43(acetone/
29
1
toluene, 5:5, v/v); ½aꢁD = +15.2 (c 1, CHCl3); H NMR: d;
7.72–7.20 (m, 4H, aromatic), 5.27 (d, 1H, JNH,5 = 9.8 Hz,
NH), 5.23–5.13 (m, 2H, J7,8 = 6.9 Hz, J8,9a = 2.4 Hz,
J8,9b = 5.6 Hz, H-7, 8), 4.92–4.80 (m, 1H, H-4), 4.26 (dd,
1H, J9a,9b = 12.2 Hz, H-9a), 4.12 (dd, 1H, J6,7 = 3.0 Hz,
H-6), 4.05 (dd, 1H, H-9b), 3.95 (dd, 1H, J5,6 = 1.9 Hz,
H-5), 3.72 (s, 3H, OCH3), 2.86 (dd, 1H, J3e,4 = 4.5 Hz,
J3e,3a = 12.8 H-3e), 2.37 (t, 1H, H-3a), 1.97, 1.96, 1.88,
1.86, 1.80 (5s, 15H, NHCOCH3, OCOCH3); 13C NMR: d
171.3, 170.9, 170.6, 170.4, 168.3, 152.9, 142.0, 126.3,
125.1, 120.6, 111.3, 86.8, 75.9, 70.4, 69.5, 67.9, 62.2, 54.0,
49.5, 38.8, 23.5, 21.3, 21.2, 21.1, 20.8; HR-FAB MS
[M+H]+ calcd for C27H33O13N2S 625.1703, found
625.1706.
13. Demchenko, A. V.; De Meo, C. Tetrahedron Lett. 2002,
43, 8819–8822.
14. Zhang, Z.; Ollmann, I. R.; Ye, X. S.; Wischnat, R.;
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24. Experimental data for compound 1a: crown ether (18-
crown-6, 0.14 g, 0.4 mmol) and salt (KSBox, 0.7 g,
4.0 mmol) were added to a solution of 2 (2 g, 4.0 mmol)
in dry acetone (8 mL) under an atmosphere of argon. The
reaction mixture was stirred for 16 h at rt. Upon comple-
tion, the mixture was diluted with CH2Cl2 (30 mL) and
washed with 1% aq NaOH (15 mL) and water (3 · 10 mL),
the organic phase was separated, dried with MgSO4 and
concentrated in vacuo. The residue was purified by column
25. Experimental data for compound 1b: crown ether (15-
crown-5, 0.04 g, 0.2 mmol) and NaSTaz (0.26 g, 2.0 mmol)
were added to a stirred solution of 2 (1.0 mmol) in a dry
acetone (2 mL) under an atmosphere of argon. The
reaction mixture was stirred for 1.5 h at rt. Upon
completion, the mixture was diluted with CH2Cl2
(20 mL) and washed with 1% aq NaOH (10 mL) and
water (3 · 10 mL), the organic phase was separated, dried
with MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (10%
gradient acetone in hexane) to afford 1b (415 mg, 70%): Rf
29
0.78 (acetone/toluene, 5:5, v/v); ½aꢁD = +7.1 (c 1, CHCl3);
1H NMR: d; 5.43–5.27 (m, 2H, J8,9b = 8.5 Hz H-7, 8), 5.21
(d, 1H, JNH,5 = 10.2 Hz, NH), 4.98–4.88 (m, 1H, H-4),
4.44–4.34 (m, 3H, J9a,9b = 11.5 Hz, H-9a, CH2N), 4.26–
4.08 (m, 3H, H-5, 6, 9b), 3.79 (s, 3H, OCH3), 3.47–3.29 (m,
2H, CH2S) 2.77 (dd, 1H, J3e,4 = 4.9 Hz, J3e,3a = 12.4 Hz,
H-3e), 2.22 (t, 1H, H-3a), 2.17, 2.13, 2.12, 2.04, 2.03 (5s,
15H, NHCOCH3, OCOCH3); 13C NMR: d 171.3, 171.2,
170.8, 170.7, 170.6, 168.5, 162.0, 159.3, 145.5, 129.4, 128.6,
125.7, 108.3, 95.2, 89.7, 74.0, 72.6, 71.2, 69.5, 64.6, 61.9,
53.3, 53.1, 38.2, 35.2, 23.2, 21.1, 21.0, 20.8; HR-FAB MS
[M+H]+ calcd for C23H33O12N2S2 593.1475, found
593.1474.
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