Combination of solid phase and solution phase synthesis of oligosaccharides using sonication

Article abstract of DOI:10.1016/j.tetlet.2010.06.027

An approach that combines solid phase and solution phase synthesis of oligosaccharides via the assistance of sonication has been developed. By employing the traceless linker, the designed oligosaccharides can be obtained in pure form and, more importantly

Full text of DOI:10.1016/j.tetlet.2010.06.027

Tetrahedron Letters 51 (2010) 4323–4327
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Tetrahedron Letters
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Combination of solid phase and solution phase synthesis of
oligosaccharides using sonication
*
Christabel T. Tanifum, Jianjun Zhang, Cheng-Wei T. Chang
Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An approach that combines solid phase and solution phase synthesis of oligosaccharides via the assis-
tance of sonication has been developed. By employing the traceless linker, the designed oligosaccharides
can be obtained in pure form and, more importantly, ready for incorporation to aglycons of interest via
‘Click’ chemistry or amide linkage. The overall strategy will facilitate the studies of roles of carbohydrates
in bioactive compounds.
Received 20 May 2010
Revised 28 May 2010
Accepted 7 June 2010
Available online 19 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The superb biocomplexity of carbohydrates makes oligosaccha-
rides the most prevalent bio-molecules in nature. As a result, the
synthesis of oligosaccharides has been the focus of carbohydrate
synthesis pursued by researchers from different areas.1–4 Solid
phase synthesis of oligosaccharides is one of the most significant
achievements in the methodology development for complex carbo-
hydrate synthesis.5,6 To achieve the complete transformation of so-
lid phase reaction, the soluble reagents, such as glycosyl donors,
are often used in excess. Since the syntheses of glycosyl donors
could be labour intensive and resource consuming, increasing the
efficiency of glycosylation may have a significant impact on the
complex carbohydrate synthesis.
ture. Following the washing of resin, the glycosylated adducted
with monosaccharide can be cleaved from the resin using NaN3
also with the assistance of sonication (Table 1). By employing this
simple protocol, a panel of monosaccharides with 6-azidohexyl
anomeric group can be prepared and ready for further applications
via ‘Click’ chemistry. The stereoselectivity of glycosylation, in gen-
eral, is governed by the neighbouring group assistance and the nat-
ure of the monosaccharides. Interestingly, the xylopyranose donor
offered only the
a glycoside rather than the expected b glycoside
(entry 4). Due to the absence of C-6 group, xylopyranose is known
to be more flexible in its conformation. Sonication is likely to pro-
vide additional energy that overcomes the conformation-related
Sonication has been employed for enhancing the efficiency of
glycosylation in solution phase synthesis.7,8 When glycosylation
is carried out under sonication, we have discovered that the reac-
tion can be shortened and the yields can be improved. Therefore,
we wish to explore the possible use of sonication in the solid phase
synthesis of oligosaccharides. We selected toluenesulfonyl chloride
polystyrene resin for our study (Scheme 1). Using 1,6-hexanediol
as the spacer and following the glycosylation, the product can be
traceless removed using NaN3 leaving the carbohydrate with an
azido terminal ready to be incorporated onto targets of interest
via ‘Click’ chemistry or amide linkage.9
We began with the synthesis of monosaccharide using various
glycosyl acetates as the donors and BF3–OEt2 as the activating
agent. Glycosyl acetates can be easily prepared and serve as cost
effective glycosyl donors. However, glycosyl acetates are also
known for their relatively low reactivity towards glycosylation.
Such a deficiency presents even a greater challenge in using these
glycosyl donors for solid phase synthesis. The glycosylation was
conducted with the assistance of sonication at ambient tempera-
neighbouring group assistance and generates the a glycoside.
HO(CH2)6OH
O
S
O
S
TEA, DMAP
CH2Cl2, rt
O(CH2)6OH
Cl
O
O
toluenesulfonyl
chloride polystyrene
1
O
(RO)n
O
O
O
(RO)n
O
S
(CH2)6
X
3
activating agent
sonication
O
2
O
NaN3
(RO)n
O
4
(CH2)6 N3
sonication
* Corresponding author. Tel.: +1 2 435 797 3545; fax: +1 2 435 797 3390.
E-mail address: tom.chang@usu.edu (C.-W.T. Chang).
Scheme 1. Strategy for solid phase carbohydrates synthesis.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.027

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C.-W.T. Chang et al. / Tetrahedron Letters 51 (2010) 4323–4327
Table 1
Glycosylation using monosaccharide donors
1) 1, BF3-OEt2, CH2Cl2
O
sonication
O
(AcO)n
ambient temp. 20 - 25 min.
(AcO)n
4a-h
O
2) NaN3, DMF
sonication
ambient temp. 15 min.
OAc
3a-h
(CH2)6 N3
Entry
Glycosyl donor
Product
Yield18 (%)
a
b ratioa
b only
only
1/1
only
only
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
Pentaacetyl
Pentaacetyl
Pentaacetyl
Tetraacetyl
Tetraacetyl
Tetraacetyl
D
D
D
-glucopyranose (3a)
-mannopyranose (3b)
-galactopyranose (3c)
4a8a
4b8a
4c8a
4d
14
55
70
58
75
65
25
32
14
55
70
58
75
65
25
32
a
D
-xylopyranose (3d)
-rhamnopyranose (3e)
-fucopyranose (3f)
a
a
L
4e8a
4f8a
4g
D
b only
a
a
Acetyl 3-O-acetyl-2,4-di-O-benzyl-
Acetyl 2-O-acetyl-3,4-di-O-benzyl-
L
-rhamnopyranose (3g)
-rhamnopyranose (3h)
only
only
L
4h
Pentaacetyl
Pentaacetyl
Pentaacetyl
Tetraacetyl
Tetraacetyl
Tetraacetyl
D
D
D
-glucopyranose (3a)
-mannopyranose (3b)
-galactopyranose (3c)
4a8a
4b8a
4c8a
4d
b only
only
1/1
a
D
-xylopyranose (3d)
-rhamnopyranose (3e)
-fucopyranose (3f)
a
a
only
only
L
4e8a
4f8a
4g
D
b only
a
a
Acetyl 3-O-acetyl-2,4-di-O-benzyl-
Acetyl 2-O-acetyl-3,4-di-O-benzyl-
L
-rhamnopyranose (3g)
-rhamnopyranose (3h)
only
only
L
4h
a
The a
b ratio is determined by 1H NMR.
13. A branched trimannoside 19 containing 1,6- and 1,2-glycosidic
bonds can also be synthesised using donors 148b and 178b
(Scheme 4).
OAc
O
AcO
AcO
1) 1, BF3-OEt2, CH2Cl2
sonication
OAc
O
OAc
ambient temp. 30 min.
The synthesis of oligosaccharide consisting of L-rhamnose has
O
2) NaN3, DMF
sonication
also been attempted using the same strategy. We focused on the
rhamnose donors with 2-O- and 3-O- acetyl groups due to their
presence in the tetrasaccharide antigen found in anthrax
(Fig. 1).12 Using a convergent approach, various trirhamnosides
can be assembled and used as the synthesis of analogues of anthrax
antigen.
OAc
AcO
ambient temp. 20 min.
OAc
OAc
O
maltose
50%
AcO
AcO
OAc
OAc
O
Rhamnose derivatives, 20,14 21,11c 22,15 23,16 and 24,17 were
synthesised from the modified procedures. Initial studies using
sonication protocol for attaching rhamnose donor on resin fol-
lowed by methoanolysis confirm the successful synthesis of the de-
sired acceptors, 25 and 26 (Scheme 5). Unfortunately, the attempt
to attach the second rhamnose was unsuccessful affording only
compound 4g after several trials. It is possible that the anomeric
acetyl group on either 23 or 24 can undergo transesterification
and acetylate the free OH on acceptor.
O
O(CH2)6N3
AcO
5
OAc
1) 1, BF3-OEt2, CH2Cl2
sonication
OAc
O
OAc
ambient temp. 30 min.
AcO
AcO
O
O
AcO
OAc
2) NaN3, DMF
sonication
OAc
cellobiose
OAc
ambient temp. 20 min.
29%
An alternative approach combining solid phase and solution
phase synthesis was adopted (Scheme 6). In this approach, com-
pound 24 was employed as the glycosyl donor and the mono-
rhamnoside was prepared using sonication-assisted solid phase
strategy. After cleaving from the resin, the second and the third
glycosylation using compound 27 as the glycosyl donor was
accomplished leading to the synthesis of the trirhamnoside, com-
pound 29, which can serve as an important precursor for the syn-
thesis of anthrax tetrasaccharide reported in the literature.11a–d
In conclusion, we have demonstrated that sonication can also
be applied to the solid phase synthesis of oligosaccharides. By
employing the traceless linker, the designed oligosaccharides can
be obtained in pure form and, more importantly, ready for incorpo-
ration to aglycons of interest via ‘Click’ chemistry or amide linkage.
In the event where solid phase synthesis cannot yield satisfactory
results, a combination of solid phase and solution phase approach
may serve as a valuable alternative. The overall strategy will facil-
itate the studies of roles of carbohydrates in bioactive compounds.
A typical experimental procedure is as followed: the resin is
allowed to swell in anhydrous methylene chloride for 1 h after
which the glycosyl donor (3–6 equiv) is added followed by Lewis
acid and the reaction mixture is sonicated for 20–25 min at ambi-
OAc
O
OAc
O
AcO
AcO
O
AcO
O(CH2)6N3
OAc
6
OAc
Scheme 2. Glycosylation using disaccharide donors.
Similar effect is noted for galactopyranose as well which results in
the decrease of stereoselectivity (entry 3). Disaccharide donor can
also be utilised in a similar fashion (Scheme 2).
Encouraged with this result, we further investigated the synthe-
sis of more complex trisaccharides. We decided to focus on
D
-mannose- and L-rhamnose-based oligosaccharides due to their
emerging significance in recent studies.10,11 We employed manno-
pyranosyl acetate 78a as the donor (Scheme 3). Following the son-
ication-assisted glycosylation, the 2-O-acetyl group was removed
with NaOMe, and then the second glycosylation was conducted
in a similar fashion. Release of the disaccharide was accomplished
using NaN3 and the desired disaccharide was obtained. Since we
have previously prepared the disaccharide donor, 1113, a similar
approach leads to the synthesis of trimannosides with 1,2-linkages,

C.-W.T. Chang et al. / Tetrahedron Letters 51 (2010) 4323–4327
4325
OAc
O
OAc
O
1, BF3.OEt2, CH2Cl2
30 min, sonication
BnO
BnO
BnO
BnO
BnO
BnO
7
OAc
O(CH2)6O
8
OAc
O
BnO
1) NaOMe, MeOH
BnO
BnO
2) 7, BF3.OEt2, CH2Cl2
30 min, sonication
NaN3, DMF
O
sonication, 20 min
BnO
9
O
BnO
BnO
OAc
O
BnO
O(CH2)6O
BnO
BnO
O
BnO
O
BnO
BnO
50% from 1
O(CH2)6N3
10
1) NaOMe, MeOH
2) NIS, TMSOTf, CH2Cl2
OBn
O
AcO
BnO
BnO
OBn
O
AcO
BnO
BnO
O
BnO
O
BnO
BnO
O
BnO
OAc
O
O
BnO
BnO
BnO
11
BnO
BnO
SPh
sonication, 45 min
AcO
O
BnO
8
O
O(CH2)6O
BnO
BnO
OBn
O
O(CH2)6O
12
BnO
BnO
O
BnO
O
NaN3, DMF
sonication, 20 min
BnO
BnO
50% from 1
O
BnO
O
BnO
BnO
13
O(CH2)6N3
Scheme 3. Solid phase synthesis of di- and trimannosides.
OH
OAc
O
OAc
O
AcO
AcO
1, BF3.OEt2, CH2Cl2
O
BnO
BnO
BnO
BnO
HO
sonication
HO
14
OAc
O(CH2)6O
15
O
OAc
O
AcO
BnO
BnO
O
OH
O
HO
HO
17
BnO
BnO
NaOMe
MeOH
SPh
O
NIS, TMSOTf, CH2Cl2
sonication, 50 min
16
OH
O(CH2)6O
O
HO
OAc
O
AcO
OAc
O
O
AcO
BnO
BnO
OH
O
O
BnO
BnO
OH
NaN3, DMF
O
O
sonication, 30 min
N
O
18
BnO
BnO
H HO
OMe
O(CH2)6O
Figure 1. Anthrax tetrasaccharide.
OAc
O
AcO
OAc
O
AcO
BnO
BnO
ent temperature. After that the resin is washed with methylene
chloride followed by methanol and methylene chloride again
(three times). Then the resin is dried under vacuum. The dried re-
sin is swelled in DMF, followed by addition of NaN3 (2 equiv) and
the mixture is sonicated for 30 min and filtered through Celite
(twice) to remove the solids. The solvent was evaporated and the
desired product can be obtained. If the crude product is not pure
BnO
BnO
O
O
O
44% from 1
BnO
BnO
19
O(CH2)6N3
Scheme 4. Solid phase synthesis of branched trimannosides.

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C.-W.T. Chang et al. / Tetrahedron Letters 51 (2010) 4323–4327
OMe
O
BnO
OH
20
OH
BnBr, NaOH
Bu4N+-HSO4
-
CH2Cl2, H2O
OMe
OMe
O
O
BnO
BnO
+
OH
OBn
21
22
OBn
OH
75 %
15%
Ac2O, cat. H2SO4
CH2Cl2, HOAc
0oC to r.t.
Ac2O, cat. H2SO4
CH2Cl2, HOAc
0oC to r.t.
99%
72%
1
OAc
O
OAc
O
BF3-OEt2, CH2Cl2
sonication, 15 min
BnO
BnO
OAc
OBn
OBn
OAc
23
24
1) NaOMe, MeOH
CH2Cl2
2) 23, BF3-OEt2
CH2Cl2, sonication
3) NaN3, DMF
sonication
1
1
BF3-OEt2, CH2Cl2
BF3-OEt2, CH2Cl2
sonication, 15 min
sonication, 15 min
4g
1) NaOMe, MeOH
CH2Cl2
2) NaN3, DMF
sonication
1) NaOMe, MeOH
CH2Cl2
2) NaN3, DMF
sonication
O(CH2)6N3
O(CH2)6N3
O
O
HO
BnO
BnO
BnO
OH
25
26
OBn
80% from 1
36% from 1
Scheme 5.
1) 1, BF3-OEt2, CH2Cl2
sonication, 15 min.
2) NaOMe, MeOH
CH2Cl2
3) NaN3, DMF
sonication
O(CH2)6N3
OAc
O
BnO
O
BnO
BnO
80%
26
BnO
24
OH
NH
C
OAc
1) BF3-OEt2, CH2Cl2
O
CCl3
O
BnO
68%
AcO
27
OBn
2) NaOMe, MeOH
CH2Cl2
O(CH2)6N3
O(CH2)6N3
O
BnO
O
1) BF3-OEt2, CH2Cl2
27
BnO
BnO
BnO
O
2) NaOMe, MeOH
CH2Cl2
O
O
BnO
O
65%
BnO
O
HO
OBn
28
OBn
O
BnO
HO
29
OBn
Scheme 6.

C.-W.T. Chang et al. / Tetrahedron Letters 51 (2010) 4323–4327
4327
9. For recent examples: (a) Ziegler, T.; Hermann, C. Tetrahedron Lett. 2008, 49,
2166–2169; (b) Cheng, L.; Chen, Q.; Du, Y. Carbohydr. Res. 2007, 342, 975–981;
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enough, it can be further purified by a flash column (gradient Hex/
EtOAc from 100:0 to 70:30). For the reaction carried out with phe-
nylthioglycosides as the donors, longer reaction time was needed
to enable the reaction to proceed. Since the overall yield can be af-
fected by the loading efficiency of 1,6-hexanediol linker, repeating
the loading step for the preparation of 1 is recommended.
10. For examples of D-mannose-based publications: (a) Danishefsky, S. J.; Allen, J.
R. Angew. Chem., Int. Ed. 2000, 39, 836–863; (b) Janeway, C. A., Jr.; Medzhitov, R.
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Acknowledgement
We acknowledge the support from Department of Chemistry
and Biochemistry, Utah State University.
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Supplementary data
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Supplementary data (spectroscopic information for the synthes-
ised compounds) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2010.06.027.
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D
-
-
mannopyranoside as the glycosl donor and phentlthiol 3,4,6-tri-O-benzyl-
D
mannopyranoside as the glycosyl acceptor. Both acceptor and donor and the
experimental procedure can be found in Ref. 8b.
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18. The low yield of some examples is likely due to the loading efficiency of 1,6-
hexanediol linker on sulfonyl resin and incomplete glycosylation as 6-
azidohexanol was obtained as the by-product in several syntheses. Therefore,
repeating the loading step for the preparation of 1 is recommended.