Stereoselective synthesis of β-glycosyl esters of cis-cinnamic acid and its derivatives using unprotected glycosyl donors

Article abstract of DOI:10.1016/j.tetlet.2011.08.104

The β-glycosyl esters of cis-cinnamic acid were synthesized directly using Hannesian's unprotected glycosyl donor and the carboxylic acid in toluene. This protocol does not require protecting groups on the glycosyl donors, and high stereoselectivity was a

Full text of DOI:10.1016/j.tetlet.2011.08.104

Tetrahedron Letters 52 (2011) 5688–5692
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of b-glycosyl esters of cis-cinnamic acid
and its derivatives using unprotected glycosyl donors
Kazumasa Matsuo a, Keisuke Nishikawa b, Mitsuru Shindo b,
⇑
a Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, Japan
b Institute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasugako-en, Kasuga 816-8580, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The b-glycosyl esters of cis-cinnamic acid were synthesized directly using Hannesian’s unprotected gly-
cosyl donor and the carboxylic acid in toluene. This protocol does not require protecting groups on the
glycosyl donors, and high stereoselectivity was achieved. The first synthesis of a potent allelochemical,
Received 30 June 2011
Revised 18 August 2011
Accepted 19 August 2011
Available online 26 August 2011
1-O-cis-cinnamoyl-b-D-glucopyranose, is also described.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Natural product
Glycosylation
Glycosyl ester
Allelochemical
Some plants are known to produce growth-regulating com-
pounds, which when released into the environment, affect the
growth and development of other plants. This phenomenon is de-
fined as allelopathy and the related bioactive compounds are called
allelochemicals. Allelochemicals are expected to be an integral part
of the design of potent, environmentally safe herbicides in the
future.1 In 2004, Hiradate and Fujii isolated 1-O-cis-cinnamoyl-
for the removal of the benzylic protecting groups cannot be em-
ployed since the carbon–carbon double bond of the cinnamate
might be damaged in the process. Appropriate deprotection condi-
tions, namely mild enough so as not to cleave and/or migrate the es-
ter, have not been developed for this particular system. After
numerous unsuccessful attempts to deprotect the protected glyco-
syl ester 3 to give the unprotected b-glycosyl cis-cinnamic acid ester
1 (Scheme 1), we decided to use the unprotected glycosyl donors,
b-D-glucopyranose (1) and identified it as a potent allelochemical
derived from Spiraea thunbergii.2 They proposed that the cis-cin-
namic acid (2) might be an essential structure for inhibition, since
both 2 and the glycoside 1 inhibit the lettuce root growth at a com-
parable level (Fig. 1). The glycoside 1 would be readily transformed
into 2 in soil and/or by microorganisms due to the lability of the
glycosyl ester moiety.
For the confirmation of the structure, a structure–activity rela-
tionship study, and a plant physiological study of the natural prod-
uct, the chemical synthesis of a sufficient amount of the glycosyl
ester and its derivatives would be required. Although many kinds
of glycosyl esters are present in nature, their chemical synthesis
has been problematic, because the glycosyl esters are much more
labile than glycosyl ethers. To achieve a regioselective, efficient syn-
thesis of the glycosides, suitable protection of the hydroxyl groups,
which do not participate in the glycosylation, is usually required,
but subsequent deprotection under acidic or basic conditions
would likely cause the cleavage of the glycosyl ester. Furthermore,
in the present case, catalytic hydrogenation or Birch-type reduction
OH
β
O
HO
HO
O
HO
O
1-O-cis-Cinnamoyl-β-D-glucopyranose ( )
1
HO
O
2
cis-Cinnamicacid ( )
⇑
Corresponding author.
E-mail address: shindo@cm.kyushu-u.ac.jp (M. Shindo).
Figure 1. The natural allelochemical 1 and the proposed essential structure 2 for its
bioactivity.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.104

K. Matsuo et al. / Tetrahedron Letters 52 (2011) 5688–5692
5689
unprotected glycosyl donors has not been established so far. Herein,
we report the first selective synthesis of the glycoside 1 via the
b-glycosyl esterification of an unprotected glycosyl donor via a
modified Hannesian protocol.
O
OH
O
O
O
HO
HO
O
O
acid
O
O
HO
O
In order to obtain the b-glycosyl esters selectively, the
O
a
-2-(methoxypyridyl)
ing to the literature. As shown in Scheme 3, tetra-O-acetyl-b-
copyranose 8 was converted into the glycosyl
-chloride 9,5 which
D
-glucopyranoside 4 was prepared accord-
1
D-glu-
3
a
up to 17%
was then treated with silver 3-methoxy-2-pyridoxide 10, prepared
from the 2-hydroxypyridine and silver nitrate, to afford the
Scheme 1. Attempts to deprotect the b-
D
-glycosyl ester.
b-
of b-11 was carried out using HgBr2 at high temperature to give the
-donor (
-11).4a,4d,6 Deacetylation was effected via methanolysis
to afford
-2-methoxypyridyl glucopyranoside 4 in a good yield.6
With the unprotected -glycosyl donor in hand, we then exam-
D
-glucopyranosyl donor 11 in a good yield.4e The anomerization
very few of which have been reported.3 For example, Hannesian and
coworkers reported the stereoselective synthesis of the -glycosyl
a
a
a
a
esters using 2-(methoxypyridyl) D-hexopyranoside 4 as an unpro-
a
tected glycosyl donor (Scheme 2).4 However, they only briefly de-
ined the glycosylation of cis-cinnamic acid (2) (Table 1). According
to the Hannesian’s protocol, the glycosylation was performed in
scribed the b-glycosylation that was employed with benzoic acid
and
provide a 1:3 (
suppression of the
a
-2-methoxypyridyl galactopyranoside 6 in nitromethane to
nitromethane as the solvent at 60 °C to give a 1:1
the glycoside 1 quantitatively (entry 1). In DMF as a polar solvent,
the undesired -1 predominated (entry 2), since the reaction
a/b mixture of
a
:b) ratio.4f Although the key point seems to be
a
ꢀb interconversion of the glycosyl donor by
a
the solvent, the selective synthesis of the b-glycosyl esters using
probably proceeded through an intermediate such as an oxonium
OH
OH
O
O
CH3CN
44 °C
HO
HO
HO
HO
O
N
+
PhCO2H
HO
OH
MeO
O
Ph
57%
(20 equiv.)
β-4
5
α- (α:β = 9:1)
O
OH
HO
OH
HO
O
MeNO2
60 °C
O
HO
PhCO2H
+
O
Ph
HO
HO
HO
O
N
O
β-7 (α:β = 1:3)
(details unknown)
6
α-
MeO
Scheme 2. Hannesian glycosylation in the preparation of the a- and b-glycosyl esters.
N
OAg
OMe
Ag(MOP)
10
OAc
OAc
OAc
ZnCl2
β
MeOCHCl2
O
O
AcO
AcO
O
N
O
AcO
AcO
AcO
AcO
OAc
8
CH2Cl2
reflux
toluene
reflux
OAc
MeO
AcO
Cl
>99%
OAc
9
β-11
85%
xylene
reflux
HgBr2
OH
OAc
O
HO
HO
O
α
NaOMe
MeOH
AcO
AcO
α
HO
AcO
O
N
O
N
95%
α 4 MeO
-
49%
α 11
-
MeO
Scheme 3. Synthesis of
a
-2-(methoxypyridyl) D-glucopyranoside 4.

5690
K. Matsuo et al. / Tetrahedron Letters 52 (2011) 5688–5692
Table 1
Synthesis of the b-D-glycoside of cis-cinnamic acid (2)
OH
OH
β
O
O
HO
HO
HO
O
α
HO
+
HO
HO
CO2H
O
O
N
2
β
-1
MeO
α 4
-
Entry
Solvent
2 (equiv)
4 (M)
Temperature (°C)
Time (h)
a:b
Yield (%)
1
2
3
4
5
6
7
8
MeNO2
DMF
20
100
20
20
20
20
20
100
0.035
0.035
0.035
0.035
0.035
0.035
0.035
0.0035
60
65
44
101
30
100
70
70
3
3
1:1
2:1
1:2
1:2.9
1:4.0
1:3.5
1:8.5
1:15
>99
89
98
CH3CN
Dioxane
CH2Cl2
Toluene
Toluene
Toluene
16
4
48
0.25
3
74
79
65a
52a
91
8
a
The byproducts 12 and 13 were obtained.
OH
O
HO
OH
HO
HO
O
O
HO
HO
O
HO
HO
HO
O
HO
HO
O
N
O
O
HO
HO
12
O
Ph
13
MeO
Table 2
Synthesis of the b-D-glycosides of several carboxylic acids
Table 2 (continued)
OH
Entry Products
Time (h)
a
:b
Yield (%)
OH
β
O
OH
HO
HO
Toluene
α
O
+
RCO2H
HO
HO
O
R
O
HO
HO
O
N
70 °C
0.0035 M
O
HO
HO
14 19
-
O
5
8
1:11 91
HO
O
α-4
MeO
Entry Products
Time (h)
a
:b
Yield (%)
18
F3C
OH
OH
O
HO
O
1
16
1:13 67
1:20 62
1:14 61
HO
O
O
O
O
Ph
O
HO
O
HO
HO
OH
6
8
1:19 98
HO
14
O
19
F3C
CF3
O
HO
2
8
HO
HO
15
O
O
Ph
OH
ion. However, with acetonitrile and dioxane as the solvent, the ra-
tio was reversed to 1:2 and 1:2.9, respectively, in favor of the de-
sired b-anomer (entries 3 and 4). In dichloromethane, although
O
HO
3
16
Ph
HO
HO
the reaction was sluggish due to the low boiling point, the b/a ratio
16
increased up to 4 (entry 5). Less polar solvents would be expected
to improve the ratio because solvent participation could be mini-
mized. By using the much less polar solvent toluene at 100 °C,
the ratio was 1:3.5 (entry 6), and at the lower temperature of
70 °C, a better ratio (1:8.5) was obtained in modest yield (entry
7), in which disaccharides, such as 12 and 13, were detected by
ESI-MS as side products (entries 6 and 7). To avoid this dimeriza-
tion, the reaction was carried out under high-dilution conditions
using 100 equiv of 2 to achieve an excellent yield of b-1 and a
OH
O
HO
HO
4
8
1:8
89
HO
O
I
17

K. Matsuo et al. / Tetrahedron Letters 52 (2011) 5688–5692
5691
R
OH
OH
OH
less polar
solvent
O
O
HO
HO
O
O
HO
HO
O
H
HO
HO
O
R
HO
HO
O
N
N
O
β
HO
O
β-20
MeO
α-4
MeO
SN2-like transition state
A
CH3CN
OH
CH3
OH
OH
O
N
CH3
HO
HO
fast
O
HO
HO
α
N+
O
HO
HO
HO
N
HO
O
R
O
C
-O
HO
N
α-20
O
B
MeO
MeO
OH
RCO2H
-
RCO2
HO
OH
O
slow
HO
MeO
N
HO
O
HO
HO
β-20
R
O
HO
N+
β
HO
O
D
CH3
Scheme 4. Presumed mechanism of the glycosylation using the 2-methoxypyridyl group as the leaving group.4f
much better ratio of 1:15 (entry 8),7 and the excess 2 was recov-
Acknowledgments
ered quantitatively. Due to the instability of the product, which
seems to decompose gradually in aqueous solution, the final puri-
fication was troublesome, for example, HPLC using an ODS column
resulted in decomposition, but using a normal phase HPLC column
with chloroform–methanol eluent to remove a mixture of the
This research was partially supported by a Grant-in-Aid for Sci-
entific Research on (B) (22390002) and the Program for Promotion
of Basic and Applied Research for Innovations in the Bio-oriented
Industry (BRAIN). K.M. additionally acknowledges the support of
the JSPS.
a-isomer and other impurities, the pure compound was success-
fully obtained. The spectra of 1 were identical with those of the
natural product.
Supplementary data
To show the generality of this method, several carboxylic acids
were subjected to the b-glycosylation to afford the b-glucopyrano-
syl esters. As shown in Table 2, the b-glucosides of benzoic acid
(entry 1), 3-phenylpropionic acid (entry 2), trans-cinnamic acid
(entry 3), and the cis-cinnamic acid analogues were obtained in
good yield with excellent b-selectivity (entries 4–6).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.104.
References and notes
According to Hannesian’s description of the mechanism of the
1. Allelopathy; Macias, F. A., Galindo, J. C. G., Molinillo, J. M. G., Cutler, H. G., Eds.;
CRC press: Florida, 2004.
glycosylation by 2-methoxypyridyl group as a leaving group,4f
2. (a) Hiradate, S.; Morita, S.; Sugie, H.; Fujii, Y.; Harada, J. Phytochemistry 2004, 65,
731–739; (b) Hiradate, S.; Morita, S.; Furubayashi, A.; Fujii, Y.; Harada, J. J. Chem.
Ecol. 2005, 31, 591–739.
3. For an example, see: (a) Pfander, H.; Laderach, M. Carbohydr. Res. 1982, 99, 175–
179; For a recent review of glycosylation, see: (b) Zhu, X.; Schmidt, R. Angew.
Chem., Int. Ed. 2009, 48, 1900–1934.
4. (a) Hanessian, S. Can. Pat. Appl., 2100821, 1995.; (b) Hanessian, S.; Conde, J. J.;
Khai, H. H.; Lou, B. Tetrahedron 1996, 52, 10827–10834; (c) Hanessian, S.; Lu, P.-
P.; Ishida, H. J. Am. Chem. Soc. 1998, 120, 13296–13300; (d) Hanessian, S.; Lou, B.
Chem. Rev. 2000, 100, 4443–4463; (e) Hanessian, S.; Saavedra, O. M.; Mascitti, V.;
Marterer, W.; Oeinhold, R.; Mak, C.-P. Tetrahedron 2001, 57, 3267–3280; (f)
Hanessian, S.; Mascitti, V.; Lu, P.-P.; Ishida, H. Synthesis 2002, 1959–
1968.
the
a-glycosyl esterification would be promoted by protonation
of the pyridyl moiety by the nucleophile (the carboxylic acid)
and a subsequent SN2-like reaction by the carboxylate would result
in the formation of the b-glycosyl ester (Scheme 4). When a
relatively polar solvent like acetonitrile was used, the intermediate
C would be partially generated through the transition state B, and
the resulting C and the anomer D would be in rapid equilibrium.
Since the
than the b-anomer C, the
based on the Curtin–Hammett principle.
a-anomer D would react with the nucleophile slower
a-glycosyl ester would also be generated
5. (a) Jansson, K.; Magnusson, G. Tetrahedron 1990, 46, 59–64; (b) Jansson, K.;
Noori, G.; Magnusson, G. J. Org. Chem. 1990, 55, 3181–3185; (c) Lee, J.-C.; Chang,
S.-W.; Liao, C.-C.; Chi, F.-C.; Chen, C.-S.; Wen, Y. –S.; Wang, C.-C.; Kulkarni, S.-S.;
Puranik, R.; Liu, Y.-H.; Hung, S.-C. Chem. Eur. J. 2004, 10, 399–415; (d) Steinmann,
A.; Thimm, J.; Thiem, J. Eur. J. Org. Chem. 2007, 5506–5513.
In conclusion, we have achieved the first efficient synthesis of
the potent allelochemical, the b-glycosyl ester of cis-cinnamic
acid, by means of the stereoselective glycosylation using unpro-
tected glycosyl donors via a modified Hannesian protocol. This
method has high generality and is very useful for the synthesis
of bioactive b-glycosyl esters in the structure–activity relation-
ship studies.
6. Preparation of
a-4: To a solution of b-11 (0.260 g, 0.571 mmol) in xylene
(29 mL) was added HgBr2 (0.103 g, 0.285 mmol). The mixture was refluxed for
2 h, and filtered through a pad of Celite. The filtrate was washed with water and
dried over Na2SO4. The residue was purified by column chromatography

5692
K. Matsuo et al. / Tetrahedron Letters 52 (2011) 5688–5692
(30–40% EtOAc–hexane) to give
colorless foam. To a solution of
a
-11 (0.128 g, 0.281 mmol, 49% yield) as a
7. Representative procedure of the b-glycosylation: 1-O-cis-cinnamoyl-b-
D-
a
-11 (46 mg, 0.10 mmol) in MeOH (1.0 mL) was
glucopyranose (1): suspension of -4 (10.0 mg, 34.8 mol) in toluene
A
a
l
added sodium methoxide (1.1 mg, 20
at room temperature. After the mixture was evaporated, the residue was
l
mol). The mixture was stirred for 15 min
(10 mL) was treated with cis-cinnamic acid (2) (0.516 g, 3.48 mmol) and the
reaction mixture was stirred for 8 h at 70 °C. At this temperature, the mixture
was gradually clear. After the mixture was evaporated, the residue was purified
by silica-gel column chromatography (5–10% MeOH–CHCl3) to remove the
excess carboxylic acid, followed by HPLC (Mightysil Si 60, 10 ꢂ 250 mm, 5%
purified by silica-gel column chromatography (15% MeOH–CHCl3) to give
a
+92.0
-4
(27 mg, 95% yield): colorless needles (MeOH–Et2O): mp 128–132 °C; ½a D25
ꢁ
(c 0.50, MeOH); 1H NMR (400 MHz, CD3OD) d: 3.43 (dd, J = 6.4 Hz, 6.0 Hz, 1H),
3.62 (dd, J = 6.4 Hz, 2.4 Hz, 1H), 3.64–3.69 (m, 2H), 3.74 (ddd, J = 6.8 Hz, 2.8 Hz,
2.0 Hz, 1H), 3.93 (t, J = 6.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 5.2 Hz,
MeOH–CHCl3, flow rate 5.0 mL/min) to give 1 (9.8 mg, 32
l
mol, 91% yield,
a
:b = 1:15) as a colorless oil. ½a D25
ꢁ
+20.00 (c 0.10, MeOH); 1H NMR (600 MHz,
3.2 Hz, 1H), 7.31 (dd, J = 5.2 Hz, 0.8 Hz, 1H), 7.68 (dd, J = 3.2 Hz, 0.8 Hz, 1H); 13
C
CD3OD) d: 3.32–3.44 (m, 4H), 3.68 (dd, J = 12.0 Hz, 5.4 Hz, 1H), 3.84 (dd,
J = 12.0 Hz, 2.4 Hz, 1H), 5.54 (d, J = 7.8 Hz, 1H), 6.02 (d, J = 12.6 Hz, 1H), 7.09 (d,
J = 12.6 Hz, 1H), 7.33–7.36 (m, 3H), 7.67–7.68 (m, 2H); 13C NMR (150 MHz,
CD3OD) d: 62.3 (t), 71.1 (d), 73.9 (d), 78.1 (d), 78.9 (d), 95.7 (d), 119.4 (d), 129.1
(d), 130.4 (d), 131.3 (d), 135.9 (s), 146.4 (d), 166.1 (s); IR (KBr): 3379, 2928,
1735, 1626, 1166, 1070 cmꢀ1; MS (ESI) m/z: 333 ([M+Na]+), 333 (100%).
NMR (100 MHz, CD3OD) d: 56.4 (q), 62.4 (t), 71.4 (d), 73.1(d), 75.0 (d), 75.2 (d),
95.3 (d), 119.8 (d), 120.7 (d), 137.9 (d), 146.5 (s), 154.0 (s); IR (KBr): 3392, 3273,
2941, 1602, 1581, 1471, 1440, 1288, 1211, 999 cmꢀ1
; MS (FAB) m/z: 288
([M+H]+), 126 (100%); HRMS (FAB) calcd for C12H18NO7 ([M+H]+): 288.1083,
found: 288.1080.