An efficient synthesis of allosamidin

Article abstract of DOI:10.1055/s-0032-1316547

The solid-phase synthesis of allosamidin was investigated. After two N-benzyloxycarbonyl (Cbz)-protected trichloroacetimidate donors were synthesized, the solid-phase synthesis was performed using polystyrene as support and an o-nitrobenzyl ether tether as linker. The target allosamidin was efficiently obtained by iterative glycosylation reactions, catalytic hydrogenation, acetylation, deacetylation, and photolysis.

Full text of DOI:10.1055/s-0032-1316547

LETTER
▌1829
lAettner Efficient Synthesis of Allosamidin
Solid-Phase Synthesis of Allosamidin
Gangliang Huang,* Shuangquan Shu
College of Chemistry, Chongqing Normal University, Chongqing 400047, P. R. of China
Fax +(86)013068336573; E-mail: huangdoctor226@163.com
Received: 19.04.2012; Accepted after revision: 16.05.2012
a. n-BuLi
Abstract: The solid-phase synthesis of allosamidin was investigat-
ed. After two N-benzyloxycarbonyl (Cbz)-protected trichloroacet-
b. O2
polystyrene
HO
polystyrene
c. Ph3P
imidate donors were synthesized, the solid-phase synthesis was
performed using polystyrene as support and an o-nitrobenzyl ether
tether as linker. The target allosamidin was efficiently obtained by
iterative glycosylation reactions, catalytic hydrogenation, acetyla-
tion, deacetylation, and photolysis.
2
3
O2N
O2N
I
HO
NaBH4
OHC
I
Cs2CO3
I
Cs2CO3
Key words: carbohydrates, solid-phase synthesis, chitinase, inhib-
O
itors, glycosylation
OH
5
4
O2N
HO
The pseudotrisaccharide allosamidin (1) is a potent chitin-
ase inhibitor that demonstrates biological activities
against insects and fungi.1 The synthetic methods used for
compound 1 were reviewed,1–4 but it has mainly been syn-
thesized by traditional organic synthetic methods. With
each synthetic step, the process becomes more complex,
and the cost of mass production increases, which has con-
strained the general use of compound 1 in agriculture. We
have also synthesized allosamidin 1 by a combination of
solid-phase and liquid-phase methods,5 but the target
compound 1 must still be purified by size-exclusion chro-
matography at the last step. Thus, the synthetic methods
applied to allosamidin (1) do not fully take advantage of
O
polystyrene
Ph3P, CCl4
O
6
O2N
Cl
O
polystyrene
Cl
O
7
Scheme 1 Synthesis of chlorinated and polystyrene-bound o-nitro-
benzyl ether 7
the merits of solid-phase synthesis. Thus, if compound 1 α-D-Allosamine hydrochloride salt (8) was prepared ac-
cording to the method described by Jeanloz.6 Treatment of
compound 8 with benzyloxycarbonyl (Cbz) chloride in
the presence of NaHCO3/H2O yielded N-Cbz-protected
allosamine 9 in 85% yield. Acetylation of compound 9 by
treatment with Ac2O in pyridine generated tetraacetate 10
as a mixture of α/β isomers in a ration of 4:1. The anomer-
ic acetyl group was selectively removed by using hydra-
zine acetate in DMF to afford hemiacetal 11. Reaction of
11 with CCl3CN in the presence of 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) exclusively afforded α-trichlo-
roacetimidate donor 12 in 82% yield (Scheme 2).
could be synthesized by solid-phase methods in every
step, the purification process would be simplified to filtra-
tion and washing to remove excess reactants or byprod-
ucts. Towards this end, a solid-phase synthesis of
allosamidin (1) was investigated.
Polystyrene 2 (Scheme 1) was functionalized to phenolic
polystyrene 3 by reaction with n-BuLi, oxygen, and Ph3P,
respectively. The linker, o-nitrobenzyl ether tether, was
utilized because it was easy to attach and cleave. Thus, the
available 5-hydroxy-2-nitrobenzaldehyde (4) was reacted
with 1,3-diiodopropane in N,N-dimethylformamide
(DMF) under alkaline conditions, and then directly re-
duced with NaBH4 to afford iodobenzyl alcohol 5 in 93%
yield for the above two steps. Compound 5 was attached
to phenolic polystyrene 3 through its linker in the pres-
Treatment of compound 10 with hydrazine acetate in the
presence of DMF gave hemiacetal 11, which was used
without further purification. The mixture was then reacted
with tert-butyldimethylsilyl TBDMSCl and imidazole to
ence of Cs2CO3 to afford conjugate 6 in 91% yield, based yield exclusively the β-anomer of the corresponding TB-
on mass gain of the polymer. The chlorination of com- DMS derivative 13. Deacetylation of compound 13 with
pound 6 with Ph3P/CCl4 generated chloride 7 in 86%
yield.
NaOMe/MeOH afforded TBDMS 2-deoxy-N-benzyloxy-
carbonylamino-β-D-allopyranoside 14 in 95% yield.
Treatment of 14 with benzaldehyde dimethylacetal af-
forded the 4,6-O-benzylidene derivative 15, which was
treated with Ac2O and pyridine to obtain acetate 16 in
94% yield. Regioselective reductive cleavage of benzyli-
dene acetal 16 with CF3COOH/Et3SiH at 0 °C afforded 6-
O-benzyl acceptor 17 in 86% yield. Compound 17 was re-
SYNLETT 2012, 23, 1829–1831
Advanced online publication: 22.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316547; Art ID: ST-2012-R0424-L
© Georg Thieme Verlag Stuttgart · New York

1830
G. Huang, S. Shu
LETTER
OH
OH
HO
OAc
O
OAc
NHCbz
10
HO
O
O
AcO
AcO
Ac2O, pyridine
CbzCl, NaHCO3
OH
OH
NH2⋅HCl
8
NHCbz
9
HO
HO
OAc
O
OAc
O
AcO
AcO
AcO
N2H4⋅HOAc
CCl3CN, DBU
CCl3
NH
O
AcO
OH
NHCbz
NHCbz
11
12
Scheme 2 Synthesis of N-Cbz-protected donor 12
acted with levulinic acid in the presence of N,N'-diisopro- ceptor 22. After glycosylation of 22 with donor 12, the
pylcarbodiimide (DIPC) to yield the orthogonally saccharide-bound resin was catalytically hydrogenated to
protected allosamine 18 in 95% yield. The anomeric cleave Cbz and Bn and obtain building block 23 in 96%
TBDMS group was removed by treatment with tetrabutyl- yield. The resulting mixture was then acetylated with
ammonium fluoride (TBAF) in the presence of acetic ac- Ac2O/pyridine and deacetylated with NH3/MeOH, respec-
id, then the crude product was reacted with CCl3CN in the tively. After each of the reactions mentioned above was
presence of DBU to afford the α-trichloroacetimidate do- finished, the resin was filtered and washed. Efficient
nor 19 (Scheme 3).
cleavage of the allosamidin fragment from the resin was
demonstrated by irradiation of building block 24 to afford
target allosamidin 19 in 94% yield, which did not require
further purification by flash column chromatography.
Diol 20 (Scheme 4) was prepared according to the method
described by Griffith and Danishefsky.7 The C-3 hydroxy
group of 20 was selectively benzylated by using stannyl-
ene methodology8 to provide the dibenzylated building In summary, the solid-phase synthesis of allosamidin 1
block 21 in 60% yield. Glycosylation reactions were per- was studied. With polystyrene resin as support and an o-
formed using 3.0 equivalents of donor and 1.2 equivalents nitrobenzyl ether tether as linker, a good yield was ob-
of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as tained by iterative glycosylation reactions, catalytic hy-
promoter to activate the trichloroacetimidate donor. At drogenation, acetylation, deacetylation, and photolysis,
low temperature, TMSOTf-promoted glycosylation of the respectively.
trichloroacetimidate donor 19 with the 6-O-benzylal-
losamizoline alcohol acceptor 21 gave the corresponding
O-perprotected β-pseudodisaccharide in 75% yield. The
Acknowledgment
The work was supported by Open Foundation from Tertiary College
of Chongqing Engineering Research Center of Bioactive Substance
and Ministry of Education Engineering Research Center of Active
Substance & Biotechnology (No. GCZX2012-2), Key Foundation
of Chongqing Normal University (No. 10XLZ004), and Chongqing
Education Commission Foundation (No. KJ080810), China.
product was analyzed by high-pressure liquid chromatog-
raphy (HPLC) after cleavage of polystyrene and linker by
irradiation from the O-perprotected β-pseudodisaccha-
ride. Cleavage of the levulinoyl ester was performed by
using hydrazine acetate dissolved in MeOH to obtain ac-
OAc
O
OAc
NHCbz
10
OAc
AcO
AcO
a. N2H4⋅HOAc
b. TBDMSCl
O
AcO
AcO
OTBDMS
NHCbz
13
Ph
OH
O
O
O
O
PhCH(OMe)2
HO
NaOMe, MeOH
OTBDMS
OTBDMS
OTBDMS
NHCbz
14
NHCbz
15
HO
O
HO
OBn
Ph
HO
O
O
O
CF3COOH, Et3SiH
Ac2O, pyridine
Lev-OH, DIPC
OTBDMS
NHCbz
AcO
NHCbz
AcO
16
17
OBn
O
OBn
LevO
LevO
AcO
O
a. TBAF, HOAc
b. CCl3CN, DBU
OTBDMS
CCl3
NH
O
AcO
NHCbz
NHCbz
18
19
Scheme 3 Synthesis of N-Cbz donor 19
Synlett 2012, 23, 1829–1831
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Synthesis of Allosamidin
1831
References and Notes
OBn
OBn
HO
(1) Huang, G. L. Curr. Org. Chem. 2012, 16, 115.
(2) Huang, G. L. Mini-Rev. Med. Chem. 2012, 12, 665.
(3) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev.
1999, 99, 779.
(4) Andersen, O. A.; Dixon, M. J.; Eggleston, I. M.; vanAalten,
D. M. Nat. Prod. Rep. 2005, 22, 563.
O
a. Bu2SnO
b.
O
HO
HO
O
N
NMe2
N
NMe2
Cl
21
20
a. 19, TMSOTf
b. N2H4⋅HOAc
(5) Huang, G. L.; Dai, Y. P. Synlett 2010, 1554.
(6) Jeanloz, R. W. J. Am. Chem. Soc. 1957, 79, 2591.
(7) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1991,
113, 5863.
OBn
OBn
HO
O
O
O
O
N
NMe2
NHCbz
AcO
22
(8) Huang, G. L.; Yang, Q. Lett. Org. Chem. 2010, 7, 396.
(9) Allosamidin 1: IR (KBr): 3500, 3365, 1652, 1550, 1060 cm–1;
1H NMR (300 MHz, D2O): δ = 5.37 (dd, J = 8.7, 4.9 Hz, 1 H,
H-1), 4.80 (d, J = 8.5 Hz, 1 H, H-1′′), 4.78 (d, J = 8.3 Hz,
1 H, H-1′), 4.37 (dd, J = 8.7, 4.1 Hz, 1 H, H-2), 4.36 (t,
J = 2.9 Hz, 1 H, H-3′), 4.30 (t, J = 5.0 Hz, 1 H, H-3), 4.07 (t,
J = 2.8 Hz, 1 H, H-3′′), 3.92–2.66 (m, 12 H), 3.61 (dd,
J = 12.0, 6.5 Hz, 1 H, H-6′), 3.09 (s, 3 H, NCH3Me), 3.08 (s,
3 H, NCH3Me), 3.67–3.63 (m, 1 H, H-5), 2.09 (s, 3 H,
NHCOCH3), 2.07 (s, 3 H, NHCOCH3); 13C NMR (75 MHz,
D2O): δ = 174.03, 173.79, 160.61, 100.58, 99.92, 86.79,
85.01, 80.48, 76.90, 73.63, 72.59, 70.11, 68.95, 66.40,
64.18, 60.97, 60.84, 59.20, 53.01, 52.63, 51.42, 37.60,
37.41, 22.05; ESI-MS: m/z = 645.2 [M + Na]+.
a. 12, TMSOTf
b. H2, Pd/C
OAc
AcO
O
OH
OH
O
O
O
O
NH2
O
AcO
N
NMe2
NH2
AcO
23
a. Ac2O, pyridine
b. NH3, MeOH
OH
OH
O
HO
O
OH
O
O
O
O
NHAc
HO
NHAc
NMe2
N
24
OH
hν
OH
OH
O
HO
O
OH
O
O
HO
O
NHAc
HO
NHAc
NMe2
N
OH
1
Scheme 4 The solid-phase synthesis of allosamidin 1
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1829–1831

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.