A new cateh-and-release purification method using a levulinyl group as a tag and its application to oligosaccharide synthesis

Article abstract of DOI:10.1246/cl.2008.1030

Products possessing a levulinyl group were selectively isolated from reaction mixtures using a new resin-capture method and a polymer-supported aminooxy group. Successive treatment with NaOH in MeOH readily liberated purified products from the resins. Applications of this method to oligosaccharide syntheses are described. Copyright

Full text of DOI:10.1246/cl.2008.1030

1030
Chemistry Letters Vol.37, No.10 (2008)
A New Catch-and-release Purification Method Using a Levulinyl Group as a Tag
and Its Application to Oligosaccharide Synthesis
Minoru Izumi,ꢀ1 Ritsu Okamoto,1 Mizuho Sato,1 Shuhei Nakajima,1 Naomichi Baba,1 and Koichi Fukase2
1Graduate School of Natural Science and Technology, Okayama University, 1-1-1 Tsushimanaka, Okayama 700-8530
2Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043
(Received July 9, 2008; CL-080677; E-mail: mizumi@cc.okayama-u.ac.jp)
Products possessing a levulinyl group were selectively
isolated from reaction mixtures using a new resin-capture meth-
od and a polymer-supported aminooxy group. Successive treat-
ment with NaOH in MeOH readily liberated purified products
from the resins. Applications of this method to oligosaccharide
syntheses are described.
O
O
Ph
O
Ph
O
O
O
O
BnO
BnO
O
7
LevO
OMe
OMe
5 (0.2 mmol)
NaOH
O NH2
6
CH3CO2H, CH2Cl2,
rt, 24 h
MeOH
CH2Cl2
O
N
O
O
O
TFA, H2O
CH2Cl2
Ph
O
O NH2
6
BnO
+
OMe
HO
In organic synthesis, isolation of products is often a tiresome
and time-consuming procedure. Therefore, various techniques
such as polymer-supported synthesis have been developed
for high throughput synthesis.1–7 Catch-and-release purification
based on chemospecific interactions between two functional
groups is a promising method in the phase tag strategy; the
tagged intermediate can be isolated from the reaction mixture
by specific interactions. Various strategies for synthesis of
oligosaccharide have also been developed and reported.8–13 In
the present study, we develop a new catch-and-release purifica-
tion method using a levulinyl group as a tag (Scheme 1).
Although the levulinyl group is stable under acidic condi-
tions, it is readily removed by a reaction with hydrazine
(NH2NH2). Hence, we speculated that compounds containing
a levulinyl group would be trapped by aminooxy (NH2O–)
resins based on imination between carbonyl group and aminooxy
function.14–16
O
N
OMe
4
8
Reuse
Scheme 3.
Table 1. Catch-and-release purification using 2-O-levulinyl-
monosaccharide 5
Yielda
/%
Binding of 5a
Function group
on resin/mmol
Entry Solid-support
/mmol
(3.0 g)
4.5
7.5
7.5
0
0
1
2
3
NH2
(3.0 g)
(3.0 g)
0
0
NH NH2
0.20
100
O
NH2
aCalculated from amount of monosaccharide 4 obtained from
resin after treatment with NaOH in MeOH.
and p-toluenesulfonic acid to give 4,6-benzylidene compound
4. The levulinyl (Lev) group was introduced to the 2-position
by levulinic acid and DIC to give compound 5.
Scheme 2 depicts the synthesis of the monosaccharide pos-
sessing a levulinyl group. Compound 2 was prepared from glu-
cose according to a well-known method.17–19 Ring opening and
then reclosing by the Fischer glycosidation in the presence of
MeOH and HCl afforded methyl 3-O-benzyl-glucoside 3.
Compound 3 was treated with benzaldehyde dimethylacetal
After completing the synthesis, we examined the catch-
and-release of resins using 2-O-levulinyl-monosaccharide 5
(Scheme 3, Table 1). The resins were added to a solution of 5
in dichloromethane, and the mixture was shaken at room temper-
ature for 24 h. Then remaining 5 was removed by simply rinsing
with CH2Cl2. Then solid-supported monosaccharide 7 was treat-
ed with NaOH in CH2Cl2 and MeOH to release monosaccharide
4. Pure 4 was obtained after excess NaOH was removed by an
ion-exchange resin and a short silica-gel column. The amino-
methylated polystyrene did not show absorbability (Entry 1).
Although p-toluenesulfonyl hydrazide polystyrene resin has
been used as a scavenger resin for aldehydes,20 it did not trap
5 (Entry 2). On the other hand, the aminooxy resin21 efficiently
captured compound 5 under acidic conditions (Entry 3). Acetic
acid was more effective as an acid catalyst for oxime formation
than trifluoroacetic acid because imination proceeds at pH 4
(In the case of TFA as acid catalyst, yield was 88%). The resin
could be reused after washing with 10% TFA in MeOH/CH2Cl2
and then MeOH/CH2Cl2 (Scheme 3).22
Levulinyl group
O
O
R
O
R
O
HO
R
O
N
O
O
NH2
Scheme 1.
O
O
PhCH(OMe)2,
HO
5% HCl/MeOH
O
p-TsOH
HO
O
OBn
BnO
reflux, 8 h
CH3CN, rt,
12 h
HO
O
O
OMe
2
3
O
Levulinic acid,
DIC, DMAP
Ph
O
Ph
O
O
O
O
BnO
BnO
CH2Cl2, rt,
4 h
HO
LevO
OMe
This new catch-and-release procedure was then applied
to oligosaccharide syntheses. As shown in Scheme 4, 3 equiv
of glycosyl donor 10 was allowed to react with 1 equiv of glyco-
OMe
5
4
Scheme 2.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.10 (2008)
1031
2001, 40, 4725.
10 S.-Q. Zhang, K. Fukase, M. Izumi, Y. Fukase, S. Kusumoto,
Synlett 2001, 590.
11 T. Miura, K. Goto, D. Hosaka, T. Inazu, Angew. Chem., Int. Ed.
2003, 42, 2047.
12 K. Fukase, M. Takashina, Y. Hori, D. Tanaka, K. Tanaka, S.
Kusumoto, Synlett 2005, 2342, and references therein.
13 J. Bauer, J. Rademann, J. Am. Chem. Soc. 2005, 127, 7296.
14 O. Renaudet, P. Dumy, Org. Lett. 2003, 5, 243.
15 F. Guillaumie, S. F. L. Justesen, K. E. Mutenda, P. Roepstorff,
K. J. Jensen, O. R. T. Thomas, Carbohydr. Res. 2006, 341, 118.
16 K. Larsen, M. B. Thygesen, F. Guillaumie, W. G. T. Willats,
K. J. Jensen, Carbohydr. Res. 2006, 341, 1209.
17 O. T. Schmidt, Methods Carbohydr. Chem. 1963, 2, 318.
18 I. Regnault, P. Villa, G. Ronco, Fr. Patent 89 15985, 1989.
19 M. Morillo, V. Lequart, E. Grand, G. Goethals, A. Usubillaga,
P. Villa, P. Martin, Carbohydr. Res. 2001, 334, 281.
NH
CCl3
BnO
10 (3 equiv)
BnO
BnO
BnO
O
O
DOWEX 50W-X4
Ph
O
HO
HO
O
O
O
CH2Cl2, MeOH,
rt, 6 h
OMe
BnO
BnO
TMSOTf, CH2Cl2,
MS4A, rt, 1 h
LevO
LevO
OMe
5
9
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
O
O
O
+
BnO
O
O
BnO
HO
O
LevO
BnO
O
BnO
LevO
BnO
OMe
11
12
OMe
NH
CCl3
10 (3 equiv)
BnO
BnO
BnO
O
O
BnO
TMSOTf,
CH2Cl2, MS4A,
rt, 1 h
BnO
BnO
BnO
BnO
BnO
BnO
20 PS resin (100–200 mesh, CA. 2.5 mmol/g) is commercially
available from Sigma-Aldrich as a scavenger resin for carbonyl
compounds like as aldehydes.
21 Aminooxy resin (Hydroxylamine Wang resin, 100–200 mesh,
1.5–2.5 mmol/g Novabiochem) is commercially available from
Novabiochem.
O
Purification
O
BnO
O
O
O NH2
CH3CO2H
O
BnO
BnO
HO
OMe
13
88%
22 Procedure for chemical fishing of the levulinylated saccharide 5.
Aminooxy–PS resin (3.0 g, 7.5 mmol) was added to a solution of
dichloromethane of levulinylated monosaccharide 5 (94 mg,
0.20 mmol) and acetic acid (0.1 mL, 1.7 mmol), and stirred at
rt. After 24 h, the resin was filtered, washed with dichloro-
methane twice, and suspended in 6 mL of dichloromethane.
Then 2 mL of 1 M NaOH in MeOH solution was added, and
the mixture was shaken at rt. for 3 h, and filtered. Ion-exchange
resin Dowex 50W-X4 (ca. 200 mg) was added to the filtrate,
which was filtered again. The solution was concentrated in
vacuo. The residue was dissolved in dichloromethane and charg-
ed on a short silica gel column (1 ꢁ 2 cm2). After flushing the
column with 5 mL of dichloromethane, the product was eluted
with CHCl3/MeOH 9:1, and the solvent was removed in vacuo
to give delevulinylated monosaccharide 4 (74 mg, 0.20 mmol,
quant) as a colorless solid.
23 The 1-hydroxysugars were not captured under the present condi-
tions, though free 1-hydroxy sugars were selectively captured by
aminooxy resins for glycomics: Y. Miura, S. Nishimura, Trends
Glycosci. Glycotechnol. 2008, 20, 17, and references therein.
24 Procedure of chemical fishing of mixture of methyl 4,6-bis-O-
(2,3,4-tri-O-benzyl-D-glucopyranosyl)-2-O-levulinyl-3-O-benzyl-
ꢀ-D-glucopyranoside (13). After a mixture of levulinyl-methyl-
glycoside 9 (0.19 g, 0.50 mmol), glycosyl donor 10 (1.03 g,
1.50 mmol), TMSOTf (0.03 g, 0.15 mmol), and molecular sieves
4A (ca. 500 mg) in 2 mL of dichloromethane was stirred on ice
bath, the mixture was stirred at rt. for 3 h. Then K2CO3 was
added to neutralize the solution, which was then filtered. The
same reagents for glycosylation were added to the filtrate on an
ice bath and stirred for 3 h. After 3 h, K2CO3 was added, and then
the solution filtered. Aminooxy–PS resin (3.0 g, 7.5 mmol) and
acetic acid (0.1 mL, 1.7 mmol) were added to the filtrate, and
the mixture was stirred at rt. for 24 h, and then filtered. The resin
was washed with dichloromethane twice, and subsequently sus-
pended in 6 mL of dichloromethane. Then 2 mL of 1 M NaOH
in MeOH solution was added, and the mixture was shaken at
rt. for 3 h, and filtered. Ion exchange resin Dowex 50W-X4 (ca.
200 mg) was added to the filtrate, which was filtered again.
The solution was concentrated in vacuo. The residue was dis-
solved in dichloromethane and charged on a short silica gel col-
umn (1 ꢁ 2 cm2). After flushing the column with 5 mL of di-
chloromethane, the product was eluted with CHCl3/MeOH 9:1,
and the solvent was removed in vacuo to give delevulinylated tri-
saccharide 13 (0.29 g, 0.44 mmol, 88% yield) as a colorless solid;
ESI-MS m=z: Calcd for [(M + Na)þ] 1341.6, found 1341.6.
Scheme 4.
syl acceptor 9 using TMSOTf as an activator in the presence of
molecular sieves 4A. Generally, the glycosylation reaction af-
fords a 1-hydroxy sugar as a by-product via the hydrolysis of
the glycosyl donor. Because 1-hydroxy sugar has a latent alde-
hyde function, it might be captured by the aminooxy resin.23 For-
tunately, in our case, the aminooxy resin did not catch the 1-hy-
droxy sugar formed by the hydrolysis of donor 10. Because gly-
cosylation gave a mixture of disaccharide 11 and trisaccharide
12, glycosylation was repeated. The reaction mixture was then
neutralized with K2CO3 and subsequently filtered. Aminooxy–
polystyrene resin was added to the filtrate to catch levulinyl tri-
saccharide 12 onto the resin. The reagents and by-products with-
out the levulinyl moiety were removed by simply rinsing with
CH2Cl2 to yield the solid-supported trisaccharide, which was
then treated with NaOH in MeOH/CH2Cl2. Excess NaOH was
removed by ion-exchange resin Dowex 50W-X4. Pure delevuli-
nylated trisaccharide of 13 was obtained in 88% yield.24
In conclusion, a new catch-and-release purification using a
levulinyl group as a tag was demonstrated to be simple and very
effective. Because a new free hydroxy function is generated
through this purification procedure, this method can be regarded
as a combination of purification and deprotection. Hence, this
method offers a new approach to purify compounds in organic
synthesis, especially in the field of combinatorial synthesis.
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Published on the web (Advance View) August 30, 2008; doi:10.1246/cl.2008.1030