Applicability of methyl 2,3,4-tri-O-benzoyl-1-methanesulfonyl-α-d-glucopyranuronate as a novel quaternary glucuronyl reagent for tertiary amines

Article abstract of DOI:10.3987/COM-07-11289

Applicability of a methyl 2,3,4-tri-O-benzoyl-1-methanesulfonyl-α-D-glucopyranuronate 3 as a novel quaternary glucuronyl reagent was investigated. The reaction of 3 with an aromatic tertiary amines such as pyridine derivatives or imidazole derivatives proceeded to give quaternary N-glucuronides in a moderate yields, but the reaction of 3 with an aliphatic tertiary amine did not occur. In case of the reaction of 3 with nicotine which has aromatic and aliphatic tertiary amines in the molecule, the reaction proceeded selectively on the pyridine ring to give the corresponding N-glucuronide. The present reagent was considered to be useful for the formation of N-quaternary glucuronide from aromatic tertiary amines.

Full text of DOI:10.3987/COM-07-11289

HETEROCYCLES, Vol. 75, No. 5, 2008
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HETEROCYCLES, Vol. 75, No. 5, 2008, pp. 1213 - 1223. © The Japan Institute of Heterocyclic Chemistry
Received, 5th December, 2007, Accepted, 1st February, 2008, Published online, 5th February, 2008. COM-07-11289
APPLICABILITY OF METHYL 2,3,4-TRI-O-BENZOYL-1-METHANE-
SULFONYL-α-D-GLUCOPYRANURONATE
AS
A
NOVEL
QUATERNARY GLUCURONYL REAGENT FOR TERTIARY AMINES
Ichiro Araya*a,b and Hiroyuki Akita b
a
Research Center, Kyorin Pharmaceutical Co, Ltd., 1848, Nogi, Nogi-machi,
Shimotsuga-Gun, Tochigi, 329-0114, Japan.
E-mail: ichirou.araya@mb.kyorin-pharm.co.jp
b
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi,
Chiba 274-8510, Japan.
Abstract – Applicability of a methyl 2,3,4-tri-O-benzoyl-1-methanesulfonyl-
α-D-glucopyranuronate 3 as a novel quaternary glucuronyl reagent was
investigated. The reaction of 3 with an aromatic tertiary amines such as pyridine
derivatives or imidazole derivatives proceeded to give quaternary N-glucuronides
in a moderate yields, but the reaction of 3 with an aliphatic tertiary amine did not
occur. In case of the reaction of 3 with nicotine which has aromatic and aliphatic
tertiary amines in the molecule, the reaction proceeded selectively on the pyridine
ring to give the corresponding N-glucuronide. The present reagent was considered
to be useful for the formation of N-quaternary glucuronide from aromatic tertiary
amines.
INTRODUCTION
In a study of metabolites of pharmaceuticals, quaternary glucuronidation of tertiary amines is a significant
role in the metabolic eliminations of pharmaceuticals containing a tertiary amine group. It is important to
synthesize an authentic sample of glucuronate derived from candidate compounds for drugs in order to
confirm its structure and pharmacological activities. There have been many reports concerning the
synthesis of β-N-quaternary glucuronide of tertiary amines using methyl 2,3,4-tri-O-acetyl-1-bromo-
α-D-glucopyranuronate (1). In this case, the preparation of α-N-glucuronides is not reported.1 The reaction
of 1 with aliphatic tertiary amines such as H1 antihistamine and tricyclic antidepressant drugs gave
β-N-glucuronides in moderate yield after deprotection of protecting groups.2 In contrast, in case of the
reaction of 1 with aromatic tertiary amines, there are a few report of chemical synthesis. The reaction of 1

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HETEROCYCLES, Vol. 75, No. 5, 2008
with pyridine,3 1-phenylimidazole4 and nicotine derivatives5 is reported to give the corresponding
N-glucuronide, respectively in low yields. These results seem to be low reactivity and stability of 1, and
less basicity of aromatic tertiary amine. In our initial investigation, 4-(2-methyl-1H-imidazol-1-yl)-2,2-
diphenylbutanamide (2) possessing an imidazole moiety as a new type of treatment for urinary
incontinence was not reacted with 1 in many reaction conditions, but 2 was reacted with methyl
2,3,4-tri-O-benzoyl-1-methanesulfonyl-α-D-glucopyranuronate (3) in CHCl3 under reflux condition to
afford the corresponding N-glucuronide in moderate yields.6 In addition, compound 3 is stable under the
room temperature for 3 months, while compound 1 was necessarily stored in the refrigerator. In the
present study, we describe applicability of this newly prepared compound 3 for N-glucuronidation.
RESULTS AND DISCUSSION
First, synthesis of methyl 2,3,4-tri-O-benzoyl-1-methanesulfonyl-α-D-glucopyranuronate (3) as a new
glycosyl donor is shown in Chart 1. By applying the reported method,7 1,2,3,4-tetra-O-benzoyl-β-D-
glucopyranouronate (4) was synthesized from D-(+)-glucurono-3,6-lactone. Compound (4) was treated
with methansulfonic acid in CH2Cl2 to afford α-methansulfonate (3) as a white powder in 49% yield.
MeO2C
MeO2C
O
MeSO3H
O
BzO
BzO
BzO
BzO
OBz
CH2Cl2
49%
BzO
OMs
OBz
3
4
Chart 1
Next, we examined the quaternary glucuronidation reaction of aromatic tertiary amines using 1.2
equivalent of 3 in CHCl3 under reflux for 24 h. Counter ion of the generated N-quanternary compounds
might be hydroxyl ion because the reaction mixture was treated with water. Elemental analysis of the
products was not successful, while molecular weight of N +-quaternary part of the each compound was
determined by Electrospray Ionization Mass spectrum (ESI-MS). The results were summarized Table 1.
In case of the reaction of 3 with many aromatic tertiary amines, the reaction proceeded to give the
corresponding N-glucuronides in moderate yield. In case of methylpyridine derivatives, effect of
substitution patterns of methyl group of pyridine was not found (entries 2~4) and the reaction proceeded
even in 2-methylpyridine with steric hindrance. In addition, pyridine congeners possessing
electron-donating group such as the hydroxyl or hydroxylmethyl groups (entries 5-6), and the
electron-withdrawing groups such as the ethoxycarbonyl group and the amide group (entries 9-10) were
reacted with 3 to give the corresponding N-glucuronides. However, in case of CN group (entry 11), the
reaction did not proceed and only 3-cyanopyridine (5k) was recovered. This was considered due to the

HETEROCYCLES, Vol. 75, No. 5, 2008
1215
low basicity of 5k. In case of the reaction of 3 with 4-dimethylaminopyridine (5l), the reaction exclusively
proceeded to afford N-glucuronide (6l) along with hydrolysis of ester group in 87% yield.
Table 1. N -Glucuronidation of pyridine derivatives
MeO2C
O
BzO
BzO
BzO
OMs
MeO2C
BzO
BzO
O2C
X
X
O
O
3
NMe2
+
BzO
BzO
+
N
N
N
CHCl3
reflux
BzO
OBz
-
OH
5a-l
6a-k
6l
Entry
X
Time(h)
Yield (%)
Anomeric proton Config.
8.21 (d, 9.2Hz)
1
2
5a
5b
H
24
24
6a 52
6b 42
β
2-Me
7.74 (d, 7.3Hz)
β
3-Me
4-Me
3-OH
8.32 (d, 9.2Hz)
3
4
5
5c
5d
5e
24
24
24
6c 50
6d 54
6e 80
β
8.26 (d, 9.2Hz)
β
7.27 (d, 8.0Hz)
β
3-CH2OH
3-Cl
7.66 (d, 9.2Hz)
6
7
24
24
24
24
24
63
70
5f
6f
β
1)
5g
6g
-
-
8.53 (d, 8.8Hz)
8
5h
5i
3-F
6h 32
β
3-CO2Et
3-CONH2
8.53 (d, 9.2Hz)
9
6i
6j
70
70
β
1)
10
5j
-
-
-
-(N.R)
87
-
11 5k
12
5l
3-CN
48
24
6k
6l
4-NMe2
6.01 (d, 9.0Hz)
β
1) Anomeric proton of this compound is not able to assign.
1
The β-configuration at the anomeric position of the N-glucuronide was determined by using H-NMR
analysis. For eight compounds (entries 1-6,8,9) examined in the present work, a doublet at δ 6.01-8.53 (J
= 7.3-9.2 Hz) was seen on the 1H-NMR spectrum and was assigned to the anomeric proton (C1-H) of the
glucuronate moiety. Because coupling constant for α- and β-anomers of various types of glucuronides are
reported to appear in the range of about 2 to 4 Hz and about 7 to 10 Hz, respectively.1 The experimentally
determined coupling constants indicate that these compounds have a β-configuration at the anomer center.
The reaction of 3 with 1-butylimidazole (7a), 1-phenylimidazole (7b), 1-benzyl-2-methylimidazole (7c)
gave the corresponding N-glucuronides (8a, 8b, 8c), respectively in good yields. (Table 2) Furthermore
the reaction of 3 with imidazole (7d) afforded the tertiary N-glucuronide (8d) in 88% yields. The

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HETEROCYCLES, Vol. 75, No. 5, 2008
conjugated position of the glucuronide moiety on the imidazole ring of 8c was confirmed by a heteronuclear
multiple bond connectivity (HMBC) spectrum as shown in Figure 1. The HMBC method demonstrated
two connectivities 1) C(5)-carbon atom of the imidazole ring and the anomeric proton (C1-H), 2)
C(4)-carbon atom of the imidazole ring and methyene proton of the benzyl moiety. These results were
consistent with the above structure. (Figure 1) Applicability for other compounds such as heterocycles
Table 2. N -Glucuronidation of imidazole derivatives
R2
R2
CO2Me
OBz
3
O
R1
N
N
R1
N
N
OBz
Me
CHCl3
reflux
OH-
BzO
CO2Me
OBz
145
N
O
7 (a-d)
8 (a-d)
OH-
N
OBz
5.44(d) H
120
OBz
123
R1
R2
Yield (%)
Anomeric Proton
H
7.44(d)
8c
n-Bu
Ph
7.43 (d, 9.4Hz)
7.71 (d, 9.4Hz)
7a
7b
7c
7d
H
H
8a 72
8b 78
8c 47
8d 88
: key HMBC correlation
Figure 1
Bn
H
CH3
H
7.74 (d, 9.3Hz)
5.67 (d, 9.2Hz)
nitrogen-containing aromatic bicyclic heterocycles and aliphatic amines was carried out and the results
were shown in Table 3. In case of aromatic bicyclic heterocycles, isoquinoline (9a) and 1-methylbenz-
imidazole (12) was reacted with 3 to give the N-glucuronides 10a (53% yield) and 13 (73% yield).
However, in case of the electron-withdrawing groups binding isoquinoline, the reaction of 3 with 9b did
not proceed. In case of the reaction of 3 with aliphatic amines including primary (16), secondary (17) and
tertiary amines (18, 19), compound 3 was decomposed to afford a complex mixture at 0 °C. (Table 3)
Table 3. N -Glucuronidation of other amines
X
R
Substrate
Substrate
Yield (%) Anomeric Proton
10a
6.64 (d, J=8.9Hz)
Yield (%)
complex mixt.
complex mixt.
-
-
H
9a
9b
53
16
17
NH2
N
R
N.R.
CN
N
H
R
complex mixt.
N.R.
-
-
H
11a
11b
complex mixt.
complex mixt.
N
18
19
CN
N
N
12 NMe
-
-
-
13
73
7.48 (d, J=9.4Hz)
X
complex mixt.
O
S
14
15
N
complex mixt.

HETEROCYCLES, Vol. 75, No. 5, 2008
1217
These results indicate that moderate basicity of substrates is important to proceed the reaction. Then we
investigated the reaction of 3 with nicotine (20) which has aromatic and aliphatic tertiary amines in the
molecule. The reaction selectively proceeded on the pyridine ring to give N-glucuronide (21) along with
hydrolysis of ester group in 61% yield. (Chart 2)
In the present study, we investigated the scope and limitation of the N-glucuronidation using a newly
synthesized quaternary glucuronyl reagent 3 for tertiary amines. This reagent 3 is available from
glucurono-D-lactone in three steps and can be safely stored at room temperature. The N-glucuronidation is
not applicable to aliphatic tertiary amines because 3 is susceptible to decomposition in the present of
strong basic amines. The N-glucuronidation using 3 is applicable to many aromatic tertiary amines having
moderate basicity. Finally, it is possible to obtain N-glucuronides of aromatic tertiary amines by removing
the protective group of quaternary salt thus obtained under alkaline conditions.6
MeO2C
O
BzO
BzO
BzO
O2C
OMs
3
O
BzO
N
N
BzO
Me
CHCl3
reflux
62%
OBz
MeN
N
21
20
Chart 2
EXPERIMENTAL
Melting points were determined with a Yanagimoto micromelting point apparatus and are uncorrected.
Elemental analyses are within ±0.3% of the theoretical values and were determined by a Yanaco CHN
coder MT-5. Infrared spectra were recorded with a JASCO FT/IR-5300 spectrometer. Mass spectrometry
(MS) and high-resolution MS (HRMS) were performed with JEOL JMS SX-102A or JEOL JMS-T100LP
1
mass spectrometer. H-NMR spectra were obtained on a JEOL EX-400 (400 MHz) spectrometer. Spectra
were run in either CDCl3 or CD3OD using TMS as internal standard. Splitting patterns are indicated as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. Columm chromatography
was performed with silica gel (Merck: silica gel 60 with particle size 0.040–0.063 mm).
Methyl 2,3,4-tri-O-benzoyl-1-methanesulfonyl-α-D-glucopyranuronate (3)
To a solution of methyl 1,2,3,4-tetra-O-benzoyl-β-D-glucopyranouronate 47 (44.3 g, 72.4 mmol) in
anhydrous CH2Cl2 (300 mL) was added methansulfonic acid (55.8 g, 581 mmol) and the whole mixture
was stirred for 45 min at rt. The reaction was quenched with 5 % aqueous sodium hydrogen carbonate
(1400 mL). The organic layer was separated, and the aqueous layer was extracted two times with CH2Cl2.
The combined organic solution was washed with water, dried over sodium sulfate (Na2SO4), and

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HETEROCYCLES, Vol. 75, No. 5, 2008
concentrated under reduced pressure. The residue was purified by silica gel column chromatography
(CH2Cl2: hexane: AcOEt=10:5:1) and crystallized from a mixed solvent of CH2Cl2/hexane (1:2) to give a
25
colorless solid 3 (20.6 g, 49%). 3: mp 139-140 °C (decomp). [α]D 63.7 (c 0.3, CHCl3). IR (KBr) cm-1:
1763, 1731, 1272, 707. 1H-NMR (CDCl3) δ: 3.11 (3H, s), 3.70 (3H, s), 4.79 (1H, d, J=9.8 Hz), 5.54 (1H,
dd, J=3.4, 9.8 Hz), 5.75 (1H, t, J=9.8 Hz), 6.17 (1H, t, J=9.8 Hz), 6.41 (1H, d, J=3.4 Hz), 7.31-7.57 (9H,
13
m), 7.88-7.99 (6H, m). C-NMR (CDCl3) δ: 39.5, 53.1, 68.7, 69.1, 69.5, 70.8, 95.9, 128.4, 128.4, 128.5,
128.5, 128.5, 128.6, 129.7, 129.8, 129.9, 133.5, 133.6, 133.8, 165.0, 165.2 165.3, 166.7. FAB-MS m/z:
597 (M-H)-. Anal. Calcd for C29H26O12S (MW: 598.58): C, 58.19; H, 4.38. Found: C, 58.20; H, 4.30.
1-(2,3,4-Tri-O-benzoyl-6-methyl–β-D-glucopyranuronosyl)pyridinium hydroxide (6a)
A solution of pyridine (15.8 mg, 0.20 mmol) and 3 (144 mg, 0.24 mmol) in anhydrous CHCl3 (1 mL) was
refluxed for 24 h under argon. After cooling, the reaction mixture was diluted with CH2Cl2 (2 mL), then
washed with water (2 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (CH2Cl2: MeOH=5:1) to give the title compound 6a as a
25
white powder (62.0 mg, 52%). 6a: mp 140-144 °C (decomp). [α]D -5.0 (c 0.4, CHCl3). IR (KBr) cm-1:
3422, 1734, 1261, 710. 1H-NMR (CDCl3) δ: 3.65 (3H, s), 5.31 (1H, d, J=9.9 Hz), 5.79 (1H, t, J=9.3 Hz),
5.90 (1H, t, J=9.6 Hz), 6.45 (1H, t, J=9.4 Hz), 7.24-7.28 (2H, m), 7.35 (2H, t, J=7.8 Hz), 7.40-7.45 (3H,
m), 7.49-7.54 (1H, m), 7.54-7.59 (1H, m), 7.87-7.80 (4H, m), 8.01-8.09 (4H, m), 8.34 (1H, d, J=9.2 Hz),
8.52 (1H, t, J=7.8 Hz), 9.86 (2H, d, J=5.6 Hz). MS (ESI) m/z: 582[M-OH]+. HR-MS (ESI) m/z: 582.17577
(Calcd for C33H28NO9: 582.17641).
1-(2,3,4-Tri-O-benzoyl-6-methyl– β-D-glucopyranuronosyl)-2-methylpyridinium hydroxide (6b)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (6b) from
2-methylpyridine (18.6 mg, 0.20 mmol) to give 6b (42.0 mg, 42%) as pale brownish amorphous foam. 6b:
25
1
[α]D -6.9 (c 0.4, CHCl3). IR (KBr) cm-1: 3415, 1734, 1258, 711. H-NMR (CDCl3) δ: 3.40 (3H,s), 3.62
(3H, s), 5.76 (1H, t, J=9.4 Hz), 5.89 (1H, t, J=9.8 Hz), 6.07 (1H, d, J=10.0 Hz), 6.59 (1H, t, J=9.5 Hz),
7.24-7.31 (2H, m), 7.34-7.43 (5H, m), 7.51-7.57 (2H, m), 7.74 (1H, d, J=7.3Hz), 7.80-7.82 (4H, m),
8.01-8.03 (3H, m), 8.37-8.40 (2H, m), 9.42 (1H, br s). MS (ESI) m/z: 596[M-OH]+. ESI-MS m/z:
596.19188 (Calcd for C34H30NO9: 596.19206).
1-(2,3,4-Tri-O-benzoyl-6-methyl–β-D-glucopyranuronosyl)-3-methylpyridinium hydroxide (6c)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (6c) from
3-methylpyridine (18.6 mg, 0.20 mmol) to give 6c (61.0 mg, 50 %) as white powder. 6c: mp 133-136 °C
25
1
(decomp). [α]D -23.6 (c 0.3, CHCl3). IR (KBr) cm-1: 3415, 1734, 1258, 711. H-NMR (CDCl3) δ: 2.53
(3H,s), 3.64 (3H, s), 5.32 (1H, d, J=9.9 Hz), 5.72 (1H, t, J=9.3 Hz), 5.86 (1H, t, J=9.6 Hz), 6.47 (1H, t,
J=9.3 Hz), 7.25-7.29 (1H, m), 7.32-7.44 (6H, m), 7.50-7.58 (2H, m), 7.82 (2H, d, J=7.3 Hz), 7.89-7.93
(3H, m), 8.02 (2H, d, J=7.3 Hz), 8.27 (1H, d, J=7.8 Hz), 8.32 (1H, d, J=9.2 Hz), 9.60 (1H, s), 9.68 (1H, d,

HETEROCYCLES, Vol. 75, No. 5, 2008
1219
J=6.1 Hz). MS (ESI) m/z: 596 [M-OH]+.ESI-MS m/z: 596.19148 (Calcd for C34H30NO9: 596.19206).
1-(2,3,4-Tri-O-benzoyl-6-methyl–β-D-glucopyranuronosyl)-4-methylpyridinium hydroxide (6d)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (6d) from
4-methylpyridine (18.6 mg, 0.20 mmol) to give 6d (66.0 mg, 54 %) as pale brownish powder. 6d: mp
24
1
137-142 °C (decomp). [α]D -20.6 (c 0.3, CHCl3). IR (KBr) cm-1: 3415, 1734, 1280, 711. H-NMR
(CDCl3) δ: 2.67 (3H,s), 3.64 (3H, s), 5.28 (1H, d, J=10.0 Hz), 5.75 (1H, t, J=9.3 Hz), 5.86 (1H, t, J=9.6
Hz), 6.43 (1H, t, J=9.4 Hz), 7.25-7.29 (2H, m), 7.36 (2H, t, J=7.8 Hz), 7.41-7.45 (3H, m), 7.50-7.58 (2H,
m), 7.78-7.82(4H, m), 7.88 (2H, dd, J=8.3, 1.1 Hz), 8.00-8.02 (2H, m), 8.26 (1H, d, J=9.2 Hz), 9.66 (2H,
d, J=6.7 Hz). MS (ESI) m/z: 596 [M-OH]+. HR-MS (ESI) m/z: 596.19222 (Calcd for C34H30NO9:
596.19206).
1-(2,3,4-Tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)–3-hydroxypyridinium hydroxide (6e)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (6e) from
3-hydroxypyridine (19.0 mg, 0.20 mmol) to give 6e (98.0 mg, 80 %) as pale yellow powder. 6e: mp
25
1
149-153 °C (decomp). [α]D -7.4 (c 0.3, CHCl3). IR (KBr) cm-1: 3423, 1735, 1261, 710. H-NMR
(CDCl3) δ: 3.67 (3H, s), 5.23 (1H, d, J=9.8 Hz), 5.80 (1H, t, J=9.2 Hz), 5.89 (1H, t, J=9.6 Hz), 6.36 (1H, t,
J=9.4 Hz), 7.24-7.32 (4H, m), 7.38-7.46 (5H, m), 7.50-7.56 (2H, m), 7.76-7.85 (5H, m), 7.99-8.01 (2H, m),
8.46 (1H, d, J=5.6 Hz), 8.78 (1H, s). MS (ESI) m/z: 598 [M-OH]+. ESI-MS m/z: 598.17064 (Calcd for
C33H28NO10: 598.17132).
1-(2,3,4-Tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)-3-hydroxymethylpyridinium hydroxide
(6f)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (6f) from
3-hydroxymethylpridine (21.8 mg, 0.20 mmol) to give 6f (79.0 mg, 63 %) as colorless amorphous foam.
25
6f: [α]D -21.5 (c 0.4, CHCl3). IR (KBr) cm-1: 3396, 1734, 1261, 710. 1H-NMR (CDCl3) δ: 3.69 (3H, s),
4.68 (2H, dd, J=19.7, 15.1 Hz), 5.36 (1H, d, J=10.0 Hz), 5.98-6.04 (2H, m), 6.41 (1H, t, J=9.4 Hz),
7.23-7.33 (5H, m), 7.39-7.49(4H, m), 7.53-7.57 (1H, m), 7.66 (1H, d, J=9.2 Hz), 7.79 (2H, dd, J=8.4, 1.2
Hz), 7.84 (2H, dd, J=8.3, 1.2 Hz), 7.90 (1H, dd, J=7.8, 6.2 Hz), 8.00 (2H, dd, J=8.4, 1.3 Hz), 8.48 (1H, d,
J=8.1 Hz), 9.40 (1H, d, J=6.1 Hz), 9.67 (1H, s). MS (ESI) m/z: 612 [M-OH]+. HR-MS (ESI) m/z:
612.18668 (Calcd for C34H30NO10: 612.18697).
1-(2,3,4-Tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)-3-chloropyridinium hydroxide (6g)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (6g) from
3-chloropyridine (22.7 mg, 0.20 mmol) to give 6g (89.0 mg, 70 %) as yellow powder. 6g: mp 122-126 °C
25
1
(decomp). [α]D -37.9 (c 0.3, CHCl3). IR (KBr) cm-1: 3405, 1734, 1261, 710. H-NMR (CDCl3) δ: 3.65
(3H, s), 5.28 (1H, d, J=9.8 Hz), 5.72 (1H, t, J=9.3 Hz), 5.89 (1H, t, J=9.4 Hz), 6.44 (1H, t, J=9.3 Hz),
7.25-7.58 (12H, m), 7.93-7.81 (5H, m), 8.01-8.08 (3H, m), 8.42-8.47 (2H, m), 9.74 (1H, s), 10.15 (1H, d,

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HETEROCYCLES, Vol. 75, No. 5, 2008
J=6.1 Hz). MS (ESI) m/z: 616 [M-OH]+. HR-MS (ESI) m/z: 616.13648 (Calcd for C33H27 ClNO9:
616.13743).
1-(2,3,4-Tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)-3-fluoropyridinium hydroxide (6h)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (6h) from
3-fluoropyridine (19.4 mg, 0.20 mmol) to give 6h (40.0 mg, 32 %) as white powder. 6h: mp 139-143 °C
25
1
(decomp). [α]D -6.4 (c 0.4, CHCl3). IR (KBr) cm-1: 3409, 1734, 1278, 710. H-NMR (CDCl3) δ: 3.64
(3H, s), 5.26 (1H, d, J=9.5 Hz), 5.77 (1H, t, J=9.0 Hz), 5.91 (1H, t, J=9.2 Hz), 6.41 (1H, t, J=9.2 Hz),
7.22-7.57 (9H, m), 7.80 (2H, d, J=9.4 Hz), 7.88 (2H, d, J=9.4 Hz), 8.01 (2H, d, J=8.1 Hz), 8.16-8.21 (1H,
m), 8.34-8.37 (1H, m), 8.53 (1H, d, J=8.8 Hz), 9.82 (1H, s), 10.06 (1H, d, J=5.9 Hz). MS (ESI) m/z: 600
[M-OH]+. HR-MS (ESI) m/z: 600.16750 (Calcd for C33H27FNO9: 600.16698).
1-(2,3,4-Tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)-3-ethoxycarbonylpyridinium hydroxide
(6i)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (6i) from
3-ethoxycarbonylpyridine (30.2 mg, 0.20 mmol) to give 6i (94.0 mg, 70 %) as pale brownish amorphous
foam. 6i: [α]D25 3.9 (c 0.3, CHCl3). IR (KBr) cm-1: 3444, 1735, 1261, 709. 1H-NMR (CDCl3) δ: 1.46 (3H,
t, J=7.1 Hz), 3.66 (3H, s), 4.48-4.57 (2H, m), 5.28 (1H, d, J=9.7 Hz), 5.73 (1H, t, J=9.2 Hz), 5.91 (1H, t,
J=9.4 Hz), 6.43 (1H, t, J=9.2 Hz), 7.26-7.59 (8H, m), 7.81-7.95 (5H, m), 8.03 (2H, d, J=7.3 Hz), 8.14 (1H,
t, J=7.0 Hz), 8.53 (1H, d, J=9.2 Hz), 9.01 (1H, d, J=8.0 Hz), 9.99 (1H, s), 10.46 (1H, d, J=5.9 Hz). MS
(ESI) m/z: 654 [M-OH]+. HR-MS (ESI) m/z: 654.19653 (Calcd for C36H32NO11: 654.19753).
1-(2,3,4-Tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)-3-carbamoylpyridinium hydroxide (6j)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (6i) from
3-carbamoylpyridine (24.4 mg, 0.20 mmol) to give 6j (88.0 mg, 70 %) as white powder. 6j: mp
25
1
147-149 °C (decomp). [α]D 27.4 (c 0.3, CHCl3). IR (KBr) cm-1: 3406, 1735, 1262, 710. H-NMR
(CDCl3) δ: 3.66 (3H, s), 5.19 (1H, d, J=8.2 Hz), 6.01-6.11 (2H, m), 6.43 (1H, t, J=8.1 Hz), 6.71(1H, br),
7.25-7.56 (9H, m), 7.84-7.89 (5H, m), 7.97-7.99(2H, m), 8.12 (1H, br s), 9.38 (2H, br s), 9.61 (1H, br s),
11.09 (1H, br s). MS (ESI) m/z: 625 [M-OH]+. HR-MS (ESI) m/z: 625.18268 (Calcd for C34H29N2O10:
625.18222).
1-(2,3,4-Tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)-4-dimethylaminopyridinium hydroxide
(6l)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (6l) from
4-dimethylaminopyridine (24.4 mg, 0.20 mmol) to give 6l (109 mg, 87 %) as white powder. 6l: mp
25
1
182-183 °C (decomp). [α]D -88.7 (c 0.3, CHCl3). IR (KBr) cm-1: 3423, 1730, 1282, 711. H-NMR
(CD3OD) δ: 3.23 (6H, s), 4.49 (1H, d, J=9.9 Hz), 4.85 (3H, s), 5.86-5.95 (2H, m), 6.01 (1H, d, J=9.0 Hz),
6.10 (1H, t, J=9.5 Hz), 7.00 (2H, d, J=7.9 Hz), 7.29-7.33 (2H, m), 7.37- 7.41 (4H, m), 7.45-7.49 (1H, m),

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7.51-7.58 (2H, m), 7.78-7.85 (4H, m), 7.94-7.96 (2H, m), 8.53 (2H, d, J=8.1 Hz). MS (ESI) m/z: 611
[M-OH]+. HR-MS (ESI) m/z: 611.20368 (Calcd for C34H31N2O9: 611.20295).
1-Butyl-3-(2,3,4-tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)imidazolium hydroxide (8a)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (8a) from
1-butylimidazole (24.8 mg, 0.20 mmol) to give 8a (93.0 mg, 72 %) as pale brownish amorphous foam. 8a:
[α]D25 36.9 (c 0.5, CHCl3). IR (KBr) cm-1: 3419, 1734, 1262, 711. 1H-NMR (CDCl3) δ: 0.77 (3H, t, J=7.3
Hz), 1.09–1.17 (2H, m), 1.67–1.74 (2H, m), 3.63 (3H, s), 4.12–4.24 (2H, m), 4.99 (1H, d, J=9.9 Hz), 5.79
(1H, t, J=8.5 Hz), 5.84 (1H, t, J=9.5 Hz), 6.27 (1H, t, J=9.5 Hz), 7.26–7.31 (2H, m), 7.36-7.46 (6H, m),
7.50–7.58 (2H, m), 7.81–7.83 (3H, m), 7.92-7.99 (4H, m), 11.18 (1H, s). IR (KBr) cm-1: 3419, 1734, 1262,
711. MS (ESI) m/z: 627 [M-OH]+. HR-MS (ESI) m/z: 627.23415 (Calcd for C35H35N2O9: 627.23425).
1-Phenyl-3-(2,3,4-tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)imidazolium hydroxide (8b)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (8b) from
1-phenylimidazole (28.8 mg, 0.20 mmol) to give 8b (104 mg, 78 %) as white powder. 8b: mp 151-153 °C
25
1
(decomp). [α]D 32.0 (c 0.3, CHCl3). IR (KBr) cm-1: 3407, 1734, 1260, 711. H-NMR (CDCl3) δ: 3.63
(3H, s), 5.09 (1H, d, J=9.9 Hz), 5.82 (1H, t, J=9.6 Hz), 5.95 (1H, t, J=9.4 Hz), 6.33 (1H, t, J=9.3 Hz),
7.28–7.64 (18H, m), 7.71 (1H, d, J=9.4 Hz), 7.83 (2H, d, J=7.4 Hz), 7.94-8.03 (6H, m), 11.77 (1H, s). MS
(ESI) m/z: 6487[M-OH]+. HR-MS (ESI) m/z: 647.20274 (Calcd for C37H31N2O9: 647.20295).
Benzyl-2-methyl-3-(2,3,4-tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)imidazolium hydroxide
(8c)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (8c) from
1-benzyl-2-methylimidazole (34.4 mg, 0.20 mmol) to give 8c (65.0 mg, 47 %) as pale brownish
amorphous foam. 8c: [α]D25 -4.4 (c 0.1, CHCl3). IR (KBr) cm-1: 3406, 1733, 1279, 711. 1H-NMR (CDCl3)
δ: 3.04 (3H, s), 3.58 (3H, s), 5.44 (2H, dd, J=21.5, 15.6 Hz), 5.56 (1H, d, J=10.1 Hz), 5.69 (1H, t, J=9.5
Hz), 5.78 (1H, t, J=9.8 Hz), 6.40 (1H, t, J=9.6 Hz), 7.12 (2H, dd, J=7.9, 1.5 Hz), 7.24-7.44 (12H, m),
7.49-7.56 (3H, m), 7.74 (1H, d, J=9.3 Hz), 7.82-7.79 (4H, m), 7.90 (1H, d, J=2.3 Hz), 7.98-8.00 (2H, m).
MS (ESI) m/z: 675 [M-OH]+. HR-MS (ESI) m/z: 675.23330 (Calcd for C39H35N2O9: 675.23425).
1-(2,3,4-Tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)imidazole (8d)
A solution of imidazole (27.2 mg, 0.40 mmol) and 3 (120 mg, 0.20 mmol) in anhydrous CHCl3 (1 mL)
was refluxed for 48 h under argon. The reaction mixture was diluted with CH2Cl2 (2 mL), then washed
with water (2 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (AcOEt:hexane=1:1) to give the title compound 8d as a white
25
powder (100 mg, 88 %).8d: mp 211-213 °C (decomp). [α]D 19.3 (c 0.3, CHCl3). IR (KBr) cm-1: 3445,
1
1734, 1263, 707. H-NMR (CDCl3) δ: 3.70 (3H, s), 4.55 (1H, d, J=9.9 Hz), 5.67 (1H, d, J=9.2 Hz), 5.83
(1H, t, J=9.7 Hz), 5.93 (1H, t, J=9.4 Hz), 6.06 (1H, t, J=9.6 Hz), 7.07 (1H, s), 7.25-7.56 (11H, m), 7.70

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(1H, s), 7.77 (2H, d, J=7.4 Hz), 7.84 (2H, t, J=7.6 Hz), 7.95 (2H, d, J=7.3 Hz). MS (ESI) m/z: 571 [M+H]+.
HR-MS (ESI) m/z: 571.17154 (Calcd for C31H27N2O9: 571.17165).
1-(2,3,4-Tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)isoquinolinium hydroxide (10a)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (10a) from
isoquinoline (25.8 mg, 0.20 mmol) to give 10a (69.0 mg, 53 %) as pale brownish powder. 10a: mp
25
1
138-140 °C (decomp). [α]D -28.1 (c 0.3, CHCl3). IR (KBr) cm-1: 3422, 1732, 1261, 709. H-NMR
(CD3OD) δ: 3.66 (3H, s), 5.06 (1H, d, J=10.0 Hz), 6.01 (1H, t, J=9.8 Hz), 6.14 (1H, t, J=9.3 Hz), 6.40 (1H,
t, J=9.6 Hz), 6.64 (1H, t, J=8.9 Hz), 7.26–7.31 (4H, m), 7.36-7.51 (4H, m), 7.56–7.60 (1H, m), 7.66–7.68
(2H, m), 7.78–7.80 (2H, m), 7.93–7.95 (2H, m), 8.06–8.10 (1H, m), 8.30–8.31 (2H, m), 8.51 (2H, t, J=7.1
Hz), 8.98–8.96 (1H, m), 10.38 (1H, s). MS (ESI) m/z: 632 [M-OH]+. HR-MS (ESI) m/z: 632.19163 (Calcd
for C37H30NO9: 632.19206).
3-Methyl-1-(2,3,4-tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl–1-yl)benzimidazolium hydroxide
(13)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (13) from
1-methylbenzimidazole (26.4 mg, 0.20 mmol) to give 13 (95.0 mg, 73 %) as pale brownish amorphous
25
1
foam. 13: [α]D -49.0 (c 0.4, CHCl3). IR (KBr) cm-1: 3413, 1734, 1258, 710. H-NMR (CDCl3) δ: 3.65
(3H, s), 4.10 (3H, s), 5.10 (1H, d, J=9.6 Hz), 5.91 (1H, t, J=9.5 Hz), 6.07 (1H, t, J=9.3 Hz), 6.32 (1H, t,
J=9.3 Hz), 7.26–7.35 (4H, m), 7.41–7.58 (6H, m), 7.49 (1H, d, J=8.9 Hz), 7.66-7.89 (8H, m), 8.01 (2H, t,
J=4.2 Hz), 8.37 (1H, d, J=8.3 Hz), 11.88 (1H, s). MS (ESI) m/z: 635 [M-OH]+. HR-MS (ESI) m/z:
635.20369 (Calcd for C36H31N2O9: 635.20295).
1-(2,3,4-Tri-O-benzoyl-6-methyl-β-D-glucopyranuronosyl)-3-((S)-1-methyl-pyrrolidin-2-yl)-
pyridinium hydroxide (21)
The same procedure as the synthesis of 6a was applied for the synthesis of the title compound (21) from
(S)-nicotine (24.4 mg, 0.20 mmol) to give 21 (80.0 mg, 62 %) as pale yellow powder. 21: mp 134-137 °C
25
1
(decomp). [α]D -78.7 (c 0.3, CHCl3). IR (KBr) cm-1: 3419, 1732, 1280, 710. H-NMR (CDCl3) δ:
1.46-1.55 (1H, m), 1.70-1.87 (2H, m), 1.98-2.11 (4H, m), 3.13 (1H, t, J=7.6 Hz), 3.37 (1H, t, J=8.1 Hz),
4.93 (1H, d, J=7.9 Hz), 5.89 (1H, t, J=9.0 Hz), 6.06 (1H, d, J=7.6 Hz), 6.18 (1H, t, J=8.1 Hz), 6.72 (1H, d,
J=9.2 Hz), 7.25-7.29 (4H, m), 7.36-7.51 (5H, m), 7.74 (2H, d, J=7.3 Hz), 7.87-7.90 (3H, m), 8.08 (2H, d,
J=7.2 Hz), 8.34 (1H, d, J=8.1 Hz), 9.35(1H, s), 9.90 (1H, d, J=6.1 Hz). MS (ESI) m/z: 651 [M-OH]+.
HR-MS (ESI) m/z: 651.23405 (Calcd for C37H35N2O9: 651.23425).
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