70
Letters in Organic Chemistry, 2011, 8, 70-72
High-Efficiency Synthesis of Chitooligosaccharides
Gangliang Huang*
College of Chemistry, Chongqing Normal University, Chongqing, 400047, China
Received October 18, 2010: Revised December 05, 2010: Accepted December 07, 2010
Abstract: The solid-phase synthesis of chitooligosaccharides is described. After the NHCbz trichloroacetimidate donors 6
and 14 were synthesized; solid-phase synthesis was performed using the Wang resin as support. The illustrated tetra-N-
acetyl-chitotetraose 1 was obtained by iterative glycosylation reactions, catalytic hydrogenation, acetylation, and
deacetylation, respectively.
Keywords: Chitooligosaccharides, solid-phase synthesis, trichloroacetimidate donors, Wang resin, glycosylation reactions.
INTRODUCTION
ment of compound 9 with benzaldehyde dimethylacetal
afforded the 4,6-O-benzylidene derivative 10. Compound 10
was treated with Ac2O and pyridine to obtain acetate 11 in
94% yield. Regioselective reductive cleavage of benzylidene
acetal 11 with CF3COOH/Et3SiH at 0°C afforded 6-O-Bn
acceptor 12 in 85% yield. Compound 12 was treated with
levulinic acid in the presence of N,N’-diisopropylcar-
bodiimide (DIPC) to yield the orthogonally protected
glucosamine 13 in 94% yield. The anomeric TBDMS group
was removed using tetrabutylammonium fluoride (TBAF) in
the presence of acetic acid. Then, the crude product was
reacted with CCl3CN in the presence of DBU to afford the ꢀ-
trichloroacetimidate donor 14 (Scheme 2).
Chitooligosaccharide (COS) is a kind of oligosaccharide
which is made from chitin or chitosan by chemical or
enzymatic decomposing method [1, 2]. COSs having N-
acetyl analogues are of special interest in the agricultural and
biomedical fields, because they exhibit strong bactericidal,
fungicidal [3], and antitumour activities [4]. They also can
be used as plant growth regulator [5].
The solid-phase synthesis is a rapid and efficient method
to synthesize oligosaccharides [6, 7]. So, we also intend to
prepare the chitooligosaccharides by solid-phase synthesis. It
is easier to remove excess reactants or byproducts in the
course of multi-step synthesis of chitooligosaccharides.
Herein, the illustrated tetra-N-acetyl-chitotetraose 1 was
synthesized by solid-phase method. The method is highly-
efficient, and it can be used to synthesize other COSs.
Glycosylation reactions were performed using 3.0 equiv.
of donor and 1.2 equiv. of trimethylsilyl trifluromethan-
esulfonate (TMSOTf) as promoter for the activation of
trichloroacetimidate donor. The Wang resin is a polymer
support, and contains a linker [8]. At low temperature,
TMSOTf promoted the glycosylation of trichloroacetimidate
donor 14 with Wang resin, and the levulinoyl ester was
cleaved using hydrazine acetate dissolved in MeOH to give
the corresponding building block 15 in 86% yield (Scheme
3). The yield was analyzed by high pressure liquid
chromatography (HPLC) after cleavage of Wang resin with
trifluoroacetic acid from building block 15. Iterating the
above process for two times obtained building block 16.
TMSOTf promoted the glycosylation of trichloroacetimidate
donor 6 with building block 16 to give building block 17.
The resin was washed, filtered, and dried under the vacuum
overnight. The saccharide bound resin was catalytically
hydrogenated to cleave the Cbz, Wang resin, and Bn (about
91% yield). Then, the resulting mixture was acetylated with
Ac2O/pyridine and deacetylated with NaOMe/MeOH,
respectively, to obtain a crude product. The crude product
was purified by size-exclusion chromatography on Biogel P4
to afford the corresponding illustrated tetra-N-acetyl-
chitotetraose 1 [9] in 77% yield for the last three steps. It
indicated that the synthetic strategy for compound 1 was in
reverse order for the installation of subunits 6 and 14. In
addition, due to the neighboring group participation of Cbz
during the glycosylation reaction, the ꢁ-linkage is easy to
form in compound 1.
RESULTS AND DISCUSSION
Treatment of ꢀ-D-glucosamine hydrochloride salt 2 with
benzyloxycarbonyl (Cbz)-Cl in the presence of
NaHCO3/H2O yielded N-benzyloxycarbonyl protected
glucosamine 3 in 88% yield. Acetylation of compound 3 by
means of Ac2O in pyridine obtained tetraacetate 4 as a
mixture of ꢀ/ꢁ isomers in 4:1. The anomeric acetyl group
was selectively removed using hydrazine acetate in DMF to
afford hemiacetal 5. Reaction of compound 5 with CCl3CN
in the presence of 1,8-diaza[5.4.0]bicycloundec-7-ene
(DBU) exclusively afforded ꢀ-trichloroacetimidate donor 6
in 85% yield (Scheme 1).
Treatment of compound 4 with hydrazine acetate in the
presence of DMF obtained hemiacetal 7, which was used
without further purification. Then, the mixture was reacted
with tert-butyldimethylsilyl (TBDMS)-Cl and imidazole to
yield exclusively the ꢁ-anomer of the corresponding
TBDMS derivative 8. Deacetylation of compound 8 with
NaOMe/MeOH afforded TBDMS 2-deoxy-N-benzyloxy-
carbonylamino-ꢁ-D-glucopyranoside 9 in 96% yield. Treat-
*Address correspondence to this author at the College of Chemistry,
Chongqing Normal University, Chongqing, 400047, China; Tel: (86)0
13068336573; Fax: (86)0 13068336573; E-mail: huangdoctor226@163.com
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.
Huang, Gangliang
