Convergent and convenient total synthesis of phytoalexin-elicitor active heptasaccharide by one-pot sequential glycosylation

Article abstract of DOI:10.1246/cl.2002.730

Convergent and convenient total synthesis of branched hepta-β-glucoside 1 having phytoalexin-elicitor activity was efficiently accomplished by way of two one-pot sequential glycosylation reactions. Trisaccharide 8 was synthesized in high yield by TfOH-catalyzed one-pot glycosylation using three component monosaccharides and subsequent selective deprotection of a 6′-O-TBDPS group. The second one-pot glycosylation of trisaccharide 8 with the three monosaccharides smoothly proceeded to afford heptaglucoside 11 stereoselectively in 48% total yield based on monosaccharide 3. The targeted compound 1 was obtained in high yield after the removal of the protecting groups.

Full text of DOI:10.1246/cl.2002.730

730
Chemistry Letters 2002
Convergent and Convenient Total Synthesis of Phytoalexin-Elicitor Active Heptasaccharide
by One-Pot Sequential Glycosylation
Teruaki Mukaiyama, Kazuhiro Ikegai, Takashi Hashihayata, Ko¯ichi Kiyota, and Hideki Jona
The Kitasato Institute, Center for Basic Research, TCI, 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
(Received April 12, 2002; CL-020314)
Convergent and convenient total synthesis of branched
constructed by TfOH-catalyzed one-pot glycosylation using
three component monosaccharides, 2, 4, and 6. Next, three
independent glycosylation reactions, the armed-disarmed glyco-
sylation using a pair of reactivity-tuned thioglucosides9 (3 and 5)
as well as orthogonal glycosylation8 using the combination of
glucosyl fluoride 2 and thioglucoside 3 were employed in one-pot
for the formation of fully protected heptasaccharide 11. The
stereochemistry of glycosylation reactions was supposed to be
controlled by the assist of neighboring effect of 2-O-benzoyl
protecting group.
hepta-ꢀ-glucoside 1 having phytoalexin-elicitor activity was
efficiently accomplished by way of two one-pot sequential
glycosylation reactions. Trisaccharide 8 was synthesized in high
yield by TfOH-catalyzed one-pot glycosylation using three
component monosaccharides and subsequent selective deprotec-
tion of a 60-O-TBDPS group. The second one-pot glycosylation of
trisaccharide 8 with the three monosaccharides smoothly
proceeded to afford heptaglucoside 11 stereoselectively in 48%
total yield based on monosaccharide 3. The targeted compound 1
was obtained in high yield after the removal of the protecting
groups.
P. Albersheim et al. reported in 1984 that the elicitor-active
hexa-ꢀ-D-glucopyranosyl-D-glucitol, isolated from the mycelial
walls of Phytophthora megasperma f. sp. Glycinea, induces
antibiotic phytoalexin accumulation in soybeans.1 Since then,
chemical synthesis of phytoalexin elicitor related ꢀ-glucans have
drawn much attention because of their complex branched
structures and biological activities.2{4
Recently, several one-pot sequential glycosylation re-
actions4;5 for convenient synthesis of linear trisaccharides were
reported from our laboratory6;7 by utilizing orthogonal proper-
ties8 of donor and acceptor glycosides: that is, the combination of
glycosyl fluorides (or glycosyl phenylcarbonates) and thioglyco-
sides. Such one-pot procedures certainly reduced the number of
laborious and time-consuming purification processes of inter-
mediate saccharides. Therefore, it is important to show its
extended usefulness byapplying the above-mentioned methods to
synthesis of complex branched oligosaccharides besides pre-
viously reported linear ones. In this communication, we would
like to report convergent and convenient total synthesis of methyl
heptaglucoside 1 by one-pot sequential glycosylation.
Scheme 1. One-pot synthesis of trisaccharide unit 8.
Glucosyl fluoride 2 having 2-O-para-methylbenzoyl group
( p-MeBz) was prepared easily by treating the corresponding 1-O-
hydroxyl sugar10 with diethylaminosulfurtrifluoride (DAST)11 in
CH2Cl2. ꢁ-Ethylthio glucosides 3 and 4 corresponding to 3, 6-
branching positions were synthesized from ethyl 2-O-benzoyl-
4,6-O-benzylidene-3-O-chloroacetyl-1-thio-ꢁ-D-glucopyrano-
side12 by standard protecting group manipulations.
In the first place, synthesis of trisaccharide unit 8 was carried
out according to our previously reported one-pot procedure:7 that
is, TfOH-catalyzed glycosylation13 of thioglucoside 4 having a
free hydroxyl group at C-3 with glucosyl fluoride 2 to form the
corresponding disaccharide, which in turn was followed by
glycosylation of methyl glucoside 6 using NIS-TfOH promoter
system14 to give the corresponding silylated trisaccharide 7 in
high yield (86% based on 4). The desired trisaccharide unit 8 was
obtained in 93% yield after selective deprotection of the tert-
butyldiphenylsilyl (TBDPS) group on treatment with tetra-n-
butylammonium fluoride (TBAF) in the presence of acetic acid.
The second one-pot glycosylation of ‘‘4-units’’ was studied
in detail. In the first step, the double glycosylation of diol 3 having
thioglycosidic linkage with 2 molar amount of 2 was attempted in
the presence of 30 mol% of TfOH and molecular sieves 5A (MS
5A), and terminal branched trisaccharide 9 was afforded directly
in excellent yield (Scheme 2). Next, the armed-disarmed
glycosylation with thus formed trisaccharide 9 was examined
using several disarmed thioglycoside acceptors by the promotion
of NIS-TfOH at low temperature (À60 to À50 ꢀC). The desired
tetrasaccharide 10a, however, was not obtained when ꢀ-
phenylthio glycoside 5a was used as an acceptor since self-
coupling of 5a exclusively took place, and trisaccharide 9 was
recovered. Tetraglucoside 10b was also obtained in poor yield
even though less activated ꢀ-glycoside 5b having p-ClBz group
Figure 1. The structure of the hepta-ꢀ-D-glucoside 1 and component
saccharides employed.
Two one-pot glycosylation reactions were involved in
synthetic strategy for hepta-ꢀ-glucoside 1 (Scheme 1, 3).
According to our previously reported procedure,7 it was
considered that methyl triglucoside 8 should rapidly be
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
731
was used. On the other hand, it was found that tetrasaccharide 10c
was obtained in 51% yield by only changing the anomeric group
from ꢀ-phenylthio to ꢁ-ethylthio. It should be noted that the ꢁ-
ethylthio glycoside 5c might have been stabilized by the anomeric
effect,15 and that it has lower reactivity than the corresponding ꢀ-
phenylthio glycoside 5a. After screening several protective
groups, the desired tetraglucoside 10e was synthesized in high
yield (total 76% yield based on 3) when p-CF3Bz protected ꢁ-
ethylthio glucoside 5e was used (Entry 5).
subsequent hydrogenolysis.16
It is noted that convergent and convenient total synthesis of
methyl hepta-ꢀ-glucoside 1 having phytoalexin-elicitor activity
was accomplished by one-pot sequential glycosylation reactions.
Fully protected heptasaccharide 11 was rapidly assembled in only
three steps from the component monosaccharides by two one-pot
reactions. It is also noted that the significant reactivity difference
was observed between ꢁ-ethylthio- and ꢀ-phenylthio-glucosides,
which indicated that reactivity tuning of thioglycoside donors is
controlled by their anomeric configurations.
The present research is partially supported by Grant-in-Aids
for Scientific Research from Ministry of Education, Culture,
Sports, Science and Technology. The authors wish to thank Mr.
Hirokazu Ohsawa, Dr. Shigeru Nakajima, and Ms. Chihiro
Suzuki-Sato, Banyu Pharmaceutical Company, for their kind help
concerning mass-spectrometry, NMR, and optical rotation
analysis.
Scheme 2. Double glycosylation of diol 3 with 2.
Table 1. The second one-pot glycosylation of four units
References and Notes
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3
4
R. Verduyn, M. Douwes, P. A. M. van der Klein, E. M. Mosinger, G. A.
¨
Based on the above results, one-pot heptasaccharide synth-
esis using four building blocks was attempted as shown inScheme
3. First, TfOH-catalyzed double glycosylation of 3 with 2,
followed by the armed-disarmed coupling with p-CF3Bz-
protected 5e afforded tetraglucoside 10e as a major product,
which was confirmed by TLC monitoring. Next, the glycosylation
of the above mentioned trisaccharide unit 8 with 10e was tried by
successively adding NIS. As a result, four glycosidic linkages
were formed sequentially in one-pot manners and fully protected
heptaglucoside 11 was obtained stereoselectively in 48% yield
(based on 3). Finally, the protected 11 was converted to the final
product 1 in 95% yield by saponification of Bz groups and
van der Marel, and J. H. van Boom, Tetrahedron, 49, 7301(1993).
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5
6
7
8
9
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16 Spectroscopic data for compound 1 are in fully agreement with those
reported by J. H. van Boom et al.3 Selected 1H NMR (600 MHz, D2O,
285 K, ꢂ ¼ TMS); ꢂ 4.34 (1H, d, J ¼ 8:4 Hz), 4.37 (3H, t, J ¼ 8:4 Hz),
4.58 (1H, d, J ¼ 7:8 Hz), 4.59 (1H, d, J ¼ 7:8 Hz), 4.63 (1H, d,
J ¼ 3:6 Hz) (anomeric positions); Selected 13C NMR (125 MHz, D2O,
ꢂ ¼ TMS); ꢂ 99.01, 102.19, 102.41, 102.45, 102.52, 102.62, 102.65
(anomeric positions); ESI-HRMS: [M+NH4]þ calculated for
20
C
43H78NO36, 1184.4304; found 1184.4308; ½ꢁꢁ
¼ À3:98 ꢀ (c 1.0,
D
H2O); FT-IR (KBr): 764, 1033, 3410 cmÀ1
.
Scheme 3. One-pot synthesis of heptasaccharide 11.