Solid-phase synthesis of allosamidin

Article abstract of DOI:10.1055/s-0029-1219932

The solid-phase synthesis of allosamidin is described. After the NHCbz trichloroacetimidate donors were synthesized, solid-phase synthesis was performed using the Wang resin as support. The target allosamidin was obtained by iterative glycosylation reactions, catalytic hydrogenation, acetylation, and deacetylation, respectively. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219932

1554
LETTER
Solid-Phase Synthesis of Allosamidin
Synthesisof
Allos
a
a
midin ng Liang Huang,* Yue Peng Dai
College of Chemistry, Chongqing Normal University, Chongqing 400047, P. R. of China
E-mail: huangsome@hotmail.com
Received 23 March 2010
solid-phase synthesis. After some protocols for the syn-
thesis of allosamidin by solution-phase methodology have
been reported,2 we also intend to prepare the allosamidin
by solid-phase synthesis. So, it is easier to remove excess
Abstract: The solid-phase synthesis of allosamidin is described.
After the NHCbz trichloroacetimidate donors were synthesized,
solid-phase synthesis was performed using the Wang resin as sup-
port. The target allosamidin was obtained by iterative glycosylation
reactions, catalytic hydrogenation, acetylation, and deacetylation, reactants or byproducts in the course of multistep synthe-
respectively.
sis of allosamidin.
Key words: allosamidin, solid-phase synthesis, trichloroacetim-
idate donors, Wang resin, glycosylation reactions
The most important concept behind the oligosaccharide
synthesis is the glycosylation reaction to involve glycosyl
donor and glycosyl acceptor. The retrosynthetic analysis
of allosamidin 1 is shown in Scheme 1. It indicated that
The fungi produce chitinases to modify chitins as the ma-
jor cell wall components, and the insects require chitin-
ases 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 allosami-
dins are just a potent class of pseudodisaccharide and
pseudotrisaccharide chitinase inhibitors. The parent com-
pound, allosamidin (1, Figure 1), was isolated from Strep-
tomyces fermentations twentytwo years ago.1 It contains
two N-acetylhexosamine residues with the unusual D-
allo-configuration and a novel aminocyclitol (i.e., al-
losamizoline 2), joined by two b-(1→4) glycosidic bonds.
Its unique chemical structure made allosamidin an attrac-
tive synthetic target, resulting in many publications about
the total syntheses of allosamidin 1.2 The choice of gly-
cosidation method to assemble the component units of the
allosamidin constitutes the essential difference between
each of the reported total syntheses. Ensuring exclusive b-
selectivity is the primary goal of these glycosylation
methods.
our synthetic strategy for allosamidin 1 was in reverse or-
der for the installation of subunits 3, 5, and 8. The Wang
resin is a polymer support, and contains a linker.4 The C-
3 hydroxy group of diol 8 can be selectively benzylated
with the Wang-chlorinated resin 7 by the way of stan-
nylene methodology5 to provide the dibenzylated building
block 6. It also has shown the effectiveness of the glycosyl
trichloroacetimidates as donors3b in the glycosidic bond
formation. Levulinoyl ester is used as an orthogonal pro-
tecting group, which can be efficiently cleaved to liberate
the free hydroxy site for further glycosylation. The amino
group is protected with benzyloxycarbonyl (Cbz). Due to
the neighboring-group participation of Cbz during the
glycosylation reaction, the b-linkage is easy to form. The
Cbz, Wang resin, and Bn can be removed by hydrogeno-
lysis at the end of synthesis.
a-D-Allosamine hydrochloride salt 9 was prepared with
the approach that described by Jeanloz.6 Treatment of
compound 9 with CbzCl in the presence of aqueous
NaHCO3 yielded N-benzyloxycarbonyl-protected al-
losamine 10 in 85% yield. Acetylation of compound 10 by
means of Ac2O in pyridine obtained tetraacetate 11 as a
mixture of a/b isomers in a 4:1 ratio. The anomeric acetyl
group was selectively removed using hydrazine acetate in
DMF to afford hemiacetal 12. Reaction of compound 12
with CCl3CN in the presence of 1,8-diaza[5.4.0]bicy-
cloundec-7-ene (DBU) exclusively afforded a-trichloro-
acetimidate donor 3 in 82% yield (Scheme 2).
The solid-phase synthesis is a rapid and efficient method
to synthesize oligosaccharides.3 However, up to now,
there is no report for the preparation of allosamidin by
OH
O
OH
O
OH
O
O
O
HO
HO
N
NMe2
NHAc
NHAc
OH
OH
OH
1
Treatment of compound 11 with hydrazine acetate in the
presence of DMF obtained hemiacetal 12, which was used
without further purification. Then, the mixture was react-
ed with TBDMSCl and imidazole to yield exclusively the
b-anomer of the corresponding TBDMS derivative 13.
Deacetylation of compound 13 with NaOMe/MeOH af-
forded TBDMS 2-deoxy-N-benzyloxycarbonylamino-b-
D-allopyranoside 14 in 95% yield. Treatment of com-
pound 14 with benzaldehyde dimethylacetal afforded the
4,6-O-benzylidene derivative 15. Compound 15 was
treated with Ac2O and pyridine to obtain acetate 16 in
HO
HO
O
N
NMe2
2
Figure 1 Structures of allosamidin 1 and allosamizoline 2
SYNLETT 2010, No. 10, pp 1554–1556
x
x
.x
x
.2
0
1
0
Advanced online publication: 10.05.2010
DOI: 10.1055/s-0029-1219932; Art ID: S01310ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Allosamidin
1555
OH
OH
O
OH
O
O
O
O
HO
HO
N
NMe2
NHAc
NHAc
OH
OH
1
OBn
OAc
O
HO
OBn
AcO
O
O
O
O
NHCbz
O
AcO
CCl3
NH
O
N
NMe2
AcO
NHCbz
3
4
Wang resin-type
OBn
O
OBn
HO
LevO
O
O
N
NMe2
CCl3
O
O
AcO
NHCbz
5
NH
6
OBn
O
HO
HO
O
Cl
N
NMe2
8
Wang-chlorinated resin 7
Scheme 1 Retrosynthetic analysis of allosamidin 1
Ac2O,
pyridine
OH
CbzCl,
NaHCO3
OH
OAc
O
HO
O
HO
HO
O
AcO
AcO
OH
OAc
OH
HO
.
NHCbz
10
NHCbz
11
.
NH2 HCl
9
OAc
O
OAc
O
CCl3CN,
DBU
AcO
AcO
AcO
AcO
N2H4 HOAc
CCl3
NH
O
OH
NHCbz
NHCbz
12
3
Scheme 2 Synthesis of NCbz-protected donor 3
OAc
O
94% yield. Regioselective reductive cleavage of ben-
zylidene acetal 16 with CF3COOH/Et3SiH7 at 0 °C afford-
ed 6-O-Bn acceptor 17 in 86% yield. Compound 17 was
treated with levulinic acid in the presence of N,N¢-diiso-
propylcarbodiimide (DIPC) to yield the orthogonally pro-
tected allosamine 18 in 95% yield.8 The anomeric
TBDMS group was removed using tetrabutylammonium
fluoride (TBAF) in the presence of acetic acid.9 Then, the
crude product was reacted with CCl3CN in the presence of
DBU to afford the a-trichloroacetimidate donor 5
(Scheme 3).
OAc
NaOMe,
MeOH
.
a. N2H4⋅HOAc
O
AcO
AcO
AcO
OAc
OTBDMS
O
b. TBDMSCl
NHCbz
11
NHCbz
13
AcO
Ph
PhCH(OMe)2
O
OH
O
O
HO
OTBDMS
O
OTBDMS
NHCbz
15
OBn
NHCbz
14
HO
HO
HO
Ph
Ac2O,
pyridine
O
O
TFA,
Et3SiH
O
OTBDMS
OTBDMS
NHCbz
17
NHCbz
16
AcO
AcO
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)10 to ob-
tain the Wang-chlorinated resin 7 in 82% yield
(Scheme 4).
OBn
O
a. TBAF,
AcOH
OBn
O
LevO
Lev-OH,
DIPC
LevO
AcO
OTBDMS
CCl3
NH
b. CCl3CN,
DBU
O
AcO
NHCbz
18
NHCbz
5
Scheme 3 Synthesis of NCbz donor 5
Synlett 2010, No. 10, 1554–1556 © Thieme Stuttgart · New York

1556
G. L. Huang, Y. P. Dai
LETTER
O
BTC, Ph3P
O
OH
Cl
Cl
=
Wang resin
Wang-chlorinated resin 7
Scheme 4 Preparation of Wang-chlorinated resin 7
OBn
N
OBn
The diol 8 (Scheme 5) was prepared with the approach
that described by Griffith and Danishefsky.11 The C-3 hy-
droxy group of compound 8 was selectively benzylated by
the way of stannylene methodology5 to provide the diben-
zylated building block 6 in 45% yield. Glycosylation re-
actions were performed using 3.0 equivalents of donor
and 1.2 equivalents of trimethylsilyl trifluoromethane-
sulfonate (TMSOTf) as promoter for the activation of tri-
chloroacetimidate donor. At low temperature, TMSOTf-
promoted glycosylation of the trichloroacetimidate donor
5 with the 6-O-benzylallosamizoline alcohol acceptor 6
gave the corresponding b-pseudodisaccharide 19 in 68%
yield. The yield was analyzed by HPLC after cleavage of
Wang resin with trifluoroacetic acid from building block
19. Cleavage of the levulinoyl ester was performed using
hydrazine acetate dissolved in MeOH to obtain the accep-
tor 4.12 After the acceptor 4 was glycosylated with the do-
nor 3, resin was washed, filtered, and dried under the
vacuum overnight. The saccharide-bound resin was cata-
lytically hydrogenated to cleave the Cbz, Wang resin, and
Bn (90% yield). Then, the resulting mixture was acetylat-
ed 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 pseudot-
risaccharide 113 in 71% yield for the last three steps.
HO
Bu2SnO
O
HO
HO
O
O
NMe2
7, CsF
N
NMe2
LevO
6
8
TMSOTf
5,
OBn
O
OBn
N
O
O
O
NMe2
NHCbz
AcO
19
N2H4⋅HOAc
OBn
O
OBn
HO
O
O
O
N
NMe2
NHCbz
AcO
4
a. 3, TMSOTf
b. H2, Pd/C
c. Ac2O, pyridine
d. NaOMe, MeOH
OH
O
OH
O
O
OH
HO
O
O
HO
NHAc
HO
N
NMe2
NHAc
HO
1
In summary, the solid-phase synthesis of allosamidin 1
with NHCbz-protected allosamine donors has been stud-
ied. With Wang resin, good yields were obtained through-
out the iterative assemblies.
Scheme 5 Solid-phase synthesis of allosamidin 1
(7) DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C.
Tetrahedron Lett. 1995, 36, 669.
(8) Melean, L. G.; Love, K. R.; Seeberger, P. H. Carbohydr.
Res. 2002, 337, 1893.
(9) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
6190.
(10) Rivero, I. A.; Somanathan, R.; Hellberg, L. H. Synth.
Commun. 1993, 23, 711.
Acknowledgment
This work was supported by Natural Science Foundation Project of
CQ CSTC (No. CSTC, 2009BB5238), China.
(11) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1991,
113, 5863.
(12) Reichardt, N.-C.; Martin-Lomas, M. Angew. Chem. Int. Ed.
2003, 42, 4674.
(13) Allosamidin 1
References and Notes
(1) Sakuda, S.; Isogai, A.; Matsumoto, S.; Suzuki, A. J. Anibiot.
1987, 40, 296.
(2) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev.
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MHz, D2O): d = 5.37 (dd, 1 H, H-1), 4.80 (d, 1 H, H-1¢¢), 4.78
(d, 1 H, H-1¢), 4.37 (dd, 1 H, H-2), 4.36 (t, 1 H, H-3¢), 4.30
(t, 1 H, H-3), 4.07 (t, 1 H, H-3¢¢), 3.92–2.66 (m, 12 H), 3.61
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MHz, D2O): d = 174.03, 173.79, 160.61, 100.58, 99.92,
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(3) (a) Tanaka, K.; Fujimoto, Y.; Tanaka, S.; Mori, Y.; Fukase,
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Synlett 2010, No. 10, 1554–1556 © Thieme Stuttgart · New York

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