Solid-phase synthesis of di-N-acetyl-β-chitobiosyl allosamizoline

Article abstract of DOI:10.2174/157017811799304331

The solid-phase synthesis of di-N-acetyl-β-chitobiosyl allosamizoline 2 was reported. After the 6-O-benzyl allosamizoline 16, NHCbz trichloroacetimidate donors 7, and 14 were synthesized; solid-phase synthesis was performed using the Wang resin as support. The target di-N-acetyl-β- chitobiosyl allosamizoline 2 was obtained by iterative glycosylation reactions, catalytic hydrogenation, acetylation, and deacetylation, respectively.

Full text of DOI:10.2174/157017811799304331

Letters in Organic Chemistry, 2011, 8, 625-627
Solid-Phase Synthesis of Di-N-Acetyl-ꢀ-Chitobiosyl Allosamizoline
Gangliang Huang*
625
College of Chemistry, Chongqing Normal University, Chongqing, 400047, P.R. China
Received April 26, 2011: Revised August 19, 2011: Accepted August 19, 2011
Abstract: The solid-phase synthesis of di-N-acetyl-ꢀ-chitobiosyl allosamizoline 2 was reported. After the 6-O-benzyl
allosamizoline 16, NHCbz trichloroacetimidate donors 7, and 14 were synthesized; solid-phase synthesis was performed
using the Wang resin as support. The target di-N-acetyl-ꢀ-chitobiosyl allosamizoline 2 was obtained by iterative
glycosylation reactions, catalytic hydrogenation, acetylation, and deacetylation, respectively.
Keywords: Allosamidin analogue, di-N-acetyl-ꢀ-chitobiosyl allosamizoline, glycosylation reactions, solid-phase synthesis,
trichloroacetimidate donors, wang resin.
INTRODUCTION
RESULTS AND DISCUSSION
The fungi produce chitinases to modify chitins as the
major cell wall components, and the insects require
chitinases for the partial degradation of their old
exoskeletons. So, it indicates the potential utility of
chitinases as targets for the development of antifungal agents
and biological insecticides (namely chitinase inhibitors). The
allosamidins are just a potent class of pseudodisaccharide
and pseudotrisaccharide chitinase inhibitors. The parent
compound, allosamidin 1 (Fig. 1), was isolated from
Streptomyces fermentations twenty-four years ago [1]. In
1993, Terayama et al. reported in detail that the allosamidin
analogue, i.e. N,N'-diacetyl-ꢀ-chitobiosyl allosamizoline 2,
exhibited inhibitory activity against some chitinases, and it
was synthesized by the conventional organic synthesis
method [2].
Treatment of ꢁ-D-glucosamine hydrochloride salt 3 with
benzyloxycarbonyl (Cbz)-Cl in the presence of NaHCO3/
H2O yielded N-benzyloxycarbonyl protected glucosamine 4
in 88 % yield. Acetylation of compound 4 by means of Ac2O
in pyridine obtained tetraacetate 5 as a mixture of ꢁ/ꢀ
isomers in 4:1. The anomeric acetyl group was selectively
removed using hydrazine acetate in DMF to afford
hemiacetal 6. Reaction of compound 6 with CCl3CN in the
presence of 1,8-diaza[5.4.0]bicycloundec-7-ene (DBU)
exclusively afforded ꢁ-trichloroacetimidate donor 7 in 85 %
yield (Scheme 1).
Treatment of compound 5 with hydrazine acetate in the
presence of DMF obtained hemiacetal 6, 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-benzyloxycar-
bonylamino-ꢀ-D-glucopyranoside 9 in 96 % yield. Treat-
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
OH
OH
O
OH
O
O
O
O
HO
HO
N
NMe2
NMe2
NHAc
NHAc
OH
.
OH
1
OH
OH
OH
O
O
O
O
O
HO
HO
HO
HO
N
NHAc
94
%
yield. Regioselective reductive cleavage of
NHAc
.
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'-
diisopropylcarbodiimide (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).
2
Fig. (1). The structures of allosamidin 1, and di-N-acetyl-ꢀ-
chitobiosyl allosamizoline 2.
The solid-phase synthesis is a rapid and efficient method
to synthesize oligosaccharides [3, 4]. Therefore, it also is
intended to prepare di-N-acetyl-ꢀ-chitobiosyl allosamizoline
2 by solid-phase synthesis. So, it is easier to remove excess
reactants or byproducts in the course of multi-step synthesis.
The solid-phase synthesis of di-N-acetyl-ꢀ-chitobiosyl
allosamizoline 2 was described as follows.
Chlorination of Wang resin with SOCl2 seemed to be ill-
advised, as the resulting hydrogen chloride solution would
likely cleave the acid-labile benzylic ether linkage from the
solid support. Herein, the Wang resin was chlorinated using
triphenylphosphine and triphosgene (BTC) [5] to obtain the
Wang-chlorinated resin 15 in 82 % yield (Scheme 3).
*Address correspondence to this author at the College of Chemistry,
Chongqing Normal University, Chongqing, 400047, P.R. China;
Tel/Fax: (86)0 13068336573; E-mail: huangdoctor226@163.com
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© 2011 Bentham Science Publishers

626 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Gangliang Huang
OH
OH
OAc
HO
HO
O
HO
HO
O
AcO
AcO
O
Cbz-Cl, NaHCO3
Ac2O, Pyridine
OH
OAc
OH
NHCbz
NHCbz
.
NH2 HCl
4
5
3
OAc
OAc
O
AcO
AcO
O
AcO
AcO
.
N2H4 HOAc
CCl3CN, DBU
CCl3
NH
O
OH
NHCbz
6
NHCbz
7
Scheme 1. Synthesis of N-Cbz protected donor 7.
OAc
OAc
O
.
O
a. N2H4
AcO
AcO
HOAc
AcO
NaOMe, MeOH
OAc
AcO
OTBDMS
b. TBDMS-Cl
NHCbz
NHCbz
5
8
Ph
PhCH(OMe)2
O
OH
O
O
O
HO
HO
HO
OTBDMS
OTBDMS
NHCbz
NHCbz
9
10
Ph
OBn
O
O
HO
AcO
O
O
Ac2O, Pyridine
CF3COOH, Et3SiH
OTBDMS
OTBDMS
AcO
NHCbz
12
NHCbz
11
OBn
O
OBn
LevO
LevO
O
a. TBAF, HOAc
b. CCl3CN, DBU
AcO
,
OTBDMS
Lev-OH DIPC AcO
CCl3
NH
O
NHCbz
NHCbz
14
13
Scheme 2. Synthesis of N-Cbz-Donor 14.
O
BTC, Ph3P
O
OH
Cl
Wang resin
Cl
=
Wang-chlorinated resin 15
Scheme 3. Preparation of Wang-chlorinated resin 15.
The Wang resin is a polymer support, and contains a
linker. The C-3 hydroxyl group of compound 16 was
selectively benzylated with the Wang-chlorinated resin 15 by
the way of stannylene methodology [3] to provide the
dibenzylated building block 17 in 45 % yield (Scheme 4).
Glycosylation reactions were performed using 3.0 equiv. of
donor and 1.2 equiv. of trimethylsilyl trifluromethane-
sulfonate (TMSOTf) as promoter for the activation of
trichloroacetimidate donor. At low temperature, TMSOTf-
promoted glycosylation of the trichloroacetimidate donor 14
with the 6-O-benzylallosamizoline alcohol acceptor 17 gave
the corresponding ꢀ-pseudodisaccharide 18 in 72 % yield.
The yield was analyzed by high pressure liquid
chromatography (HPLC) after cleavage of Wang resin with
trifluoroacetic acid from building block 18. Levulinoyl ester
is used as an orthogonal protecting group, which can be
efficiently cleaved to liberate the free hydroxyl site for
further glycosylation. Cleavage of the levulinoyl ester was
performed using hydrazine acetate dissolved in MeOH to
obtain the acceptor 19. After the acceptor 19 was
glycosylated with the donor 7, 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 (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
target pseudotrisaccharide 2 in 75 % yield for the last three
steps. The amino group is protected with Cbz. Due to the
neighboring group participation of Cbz during the
glycosylation reactions, the ꢀ-linkage is easy to form.
In summary, the solid-phase synthesis of di-N-acetyl-ꢀ-
chitobiosyl allosamizoline
2
with NHCbz protected
glycosamine donors has been studied. With Wang resin,

Solid-Phase Synthesis of Di-N-Acetyl-ꢀ-Chitobiosyl Allosamizoline
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
627
OBn
O
OBn
HO
HO
O
Bu2SnO
O
HO
N
NMe2
15 , CsF
N
NMe2
LevO
17
14, TMSOTf
16
OBn
O
OBn
O
O
O
AcO
N
NMe2
NHCbz
18
.
N2H4 HOAc
OBn
OBn
O
HO
O
O
O
AcO
N
NMe2
NHCbz
19
a. 7, TMSOTf
b. H2, Pd/C
c. Ac2O, Pyridine
.
d. NaOMe, MeOH
OH
OH
OH
O
HO
HO
O
O
O
O
HO
HO
NHAc
N
NMe2
NHAc
2
Scheme 4. Solid-phase synthesis of di-N-acetyl-ꢀ-chitobiosyl allosamizoline 2.
[2]
Terayama, H.; Kuzuhara, H.; Takahashi, S.; Sakuda, S.; Yamada,
Y. Synthesis of new allosamidin analog, N,N'-diacetyl-ꢀ-
chitobiosyl allosamizoline and its inhibitory activity against some
chitinases. Biosci. Biotechnol. Biochem., 1993, 57(12), 2067-2069.
Huang, G.L.; Dai, Y.P. Solid-phase synthesis of allosamidin.
Synlett, 2010, 21(10), 1554-1556.
good yields were obtained throughout the iterative
assemblies.
a
[3]
ACKNOWLEDGEMENTS
[4]
Huang, G.L. High-efficiency synthesis of chitooligosaccharides.
Lett. Org. Chem., 2011, 8(1), 70-72.
The present work was supported by Key Foundation
Project of Chongqing Normal University (No. 10XLZ004),
Natural Science Foundation Project of CQ CSTC (No.
[5]
Huang, G.L.; Yang, Q. Efficient synthesis of Wang resin-supported
6-O-benzylallosamizoline. Lett. Org. Chem., 2010, 7(5), 396-398.
CSTC,
2009BB5238),
and
Chongqing
Education
Commission Foundation (No. KJ080810), China.
REFERENCES
[1]
Sakuda, S.; Isogai, A.; Matsumoto, S.; Suzuki, A. Search for
microbial insect growth regulators. II. Allosamidin, a novel insect
chitinase inhibitor. J. Antibiot., 1987, 40, 296-300.