Synthesis and anticancer activity of novel chiral D-glucose derived bis-imidazoles and their analogs

Article abstract of DOI:10.1016/S0008-6215(01)00154-9

A series of novel D-glucose derived bis-imidazoles and their analogs, which possess potential in bioorganic and supramolecular chemistry, were designed and synthesized from methyl α-D-glucoside through protection, bis-bromination, N-alkylation and deprotection. All new compounds were characterized by HRMS, ¹H, ¹³C and DEPT NMR spectroscopy as well as elemental analysis. The ¹H-¹H and ¹H-¹³C 2D NMR spectra for some compounds were also recorded. Some regular features of ¹³C and ¹H NMR spectra were summarized. The anticancer activity of some compounds was evaluated.

Full text of DOI:10.1016/S0008-6215(01)00154-9

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Carbohydrate Research 333 (2001) 313–326
Note
Synthesis and anticancer activity of novel chiral
D-glucose derived bis-imidazoles and their analogs
Chenghe Zhou, Alfred Hassner*
Department of Chemistry, Bar-Ilan Uni6ersity, Ramat-Gan 52900, Israel
Received 20 February 2001; accepted 29 May 2001
Abstract
A series of novel
D
-glucose derived bis-imidazoles and their analogs, which possess potential in bioorganic and
supramolecular chemistry, were designed and synthesized from methyl a-D-glucoside through protection, bis-bromi-
1
nation, N-alkylation and deprotection. All new compounds were characterized by HRMS, H, 13C and DEPT NMR
1
spectroscopy as well as elemental analysis. The H–1H and 1H–13C 2D NMR spectra for some compounds were also
1
recorded. Some regular features of 13C and H NMR spectra were summarized. The anticancer activity of some
compounds was evaluated. © 2001 Published by Elsevier Science Ltd.
1
Keywords: Carbohydrates; Glucosides; Imidazoles; Organic synthesis; Biological activity; H and 13C NMR
1. Introduction
cyclic aralkyl,10 aliphatic multi-ether,11
bisphenol A diether,12 aromatic ether and
alkanoyl piperazine derivatives have been
reported.1,4,8,13
It is well known that sugars play important
roles in biological systems and this has at-
tracted a great deal of recent attention. Inter-
est in development of sugar derivatives as
drugs and artificial receptors14,15 has been
growing in recent years.
This led us to develop chiral sugar derived
bis-imidazole compounds as target molecules.
These novel molecules possess potential as
precursors for the synthesis of sugar imida-
zolium macrocyclic receptors. In this report
Bis-imidazole compounds not only possess
potential as desensitizing agents,1 as protein
analogs2 and artificial multi-dentate ligands to
bind metal ions3 and as good precursors for
the synthesis of imidazolium cyclophanes4,5
which play wide roles as artificial receptors in
molecular recognition, catalysis and self-orga-
nization,6 but also many of them exhibit bio-
logical activities as anti-cancer, anti-viral,
anti-fungal and anti-bacterial agents.7,8 Most
of these compounds possess antibacterial ac-
tivity and some possess a stronger ability to
kill bacteria than some drugs being used in
hospitals.8 Various types of non-chiral bis-imi-
dazoles such as alkyl,5h aralkyl,2,5g,7a,9 hetero-
we employed
designed and synthesized a series of novel
chiral -glucose derived bis-imidazole com-
D
-glucose as a starting material,
D
* Corresponding author. Tel.: +972-3-5318320; fax: +
972-3-5351250.
E-mail address: hassna@mail.biu.ac.il (A. Hassner).
pounds and their analogs (Scheme 1) and
investigated their anticancer activity.
0008-6215/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0008-6215(01)00154-9

314
C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
Scheme 1. Synthesis of glucose bis-imidazole compounds and their analogs.
2. Results and discussion
Reaction of aralkyl dibromide, for example
xylylene bromide, with the bis-hydroxy sugar
2 under similar reaction conditions gave
mainly cyclic compounds, for instance, com-
pound 10 (Fig. 1) was obtained in 75% yield.
D
-Glucoside bis-alkyl bromides (3a–c).—
The synthesis of -glucoside bis-alkyl bro-
D
mides (3a–c) was carried out by the reaction
of the sodium salt of the bis-hydroxy sugar 2
with an excess of v-dibromides. The reaction
of bis-hydroxy sugar 2 with alkyl dibromides
at 0–25 °C readily gave the corresponding
bis-bromoalkyl sugars 3a–c as main products,
only a small amount of mono-bromoalkyl
Using
dibenzo-18-crown-6
and
tetra-
butylammonium bromide as phase transfer
catalysts and sodium hydroxide as the base,
the reaction of either alkyl or aralkyl dibro-
mides with bis-hydroxy sugar 2 in N,N-
dimethylformamide only gave one 1+1
cyclization products 9 or 10 and no other
products were observed. The above facts stress
the importance of choosing the proper reac-
D
-glucoside and cyclization products were ob-
tained. At temperatures higher than 60 °C,
this reaction mainly resulted in cyclization
products. For example, reaction of compound
2 with 1,4-dibromobutane at 60 °C produced
the cyclic compound 9 (Fig. 1) in 58% yield.
Under the same reaction conditions, 1,4-di-
bromohexane gave complex products, while
1,2-dibromoethane or 1,3-dibromopropane
surprisingly yielded less of the desired prod-
ucts and most of the sugar was recovered.
Fig. 1.

C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
315
Deprotection of
D
-glucoside bis-imidazoles
tion conditions in order to be able to deter-
mine whether open chain or cyclization prod-
ucts are obtained.
and their analogs.—The 4,6-O-benzylidene
group of the protected sugar bis-imidazoles
4a–h was very easily cleaved with dilute hy-
drochloric acid, acetic acid or trifluoroacetic
acid to afford the partially deprotected methyl
D
-Glucoside bis-alkyl imidazoles and their
-glucoside
analogs (4a–h).—The synthesis of
D
bis-alkyl imidazole 4a was performed by the
a- -glucoside bis-imidazoles (5a–h) in almost
D
dropwise addition of the bis-bromoalkyl
quantitative yields. The deprotection of the
methoxy group required stronger acid concen-
tration, higher reaction temperature and
longer hydrolysis time. Concentrated hydro-
chloric acid–water (2/1, v/v) at 60 °C could
deprotect the methoxy group and afford the
totally deprotected sugar bis-imidazoles, but
different sugar bis-imidazole compounds dis-
played very different results. For example, the
totally deprotected compound 6a was ob-
tained from 4a in excellent yield, while under
the same reaction conditions 4c produced a
low yield of 6c, which is difficult to purify.
D
-glucoside (3a) to the sodium salt of imida-
zole. The strong base particularly favors the
synthesis of sugar bis-imidazoles. This indi-
cates that the alkylation of the imidazole an-
ions occurs rapidly at the nitrogen atom, while
quaternarization byproducts are effectively
suppressed. Addition of the sugar dibromide
all at once, instead of dropwise, decreased the
yield of 4. Under the same conditions, the
reaction of several imidazole derivatives in-
cluding 2-methylimidazole, and benzimidazole
with a series of -glucoside bis-alkyl bromides
D
(3a–c) also produced target bis-imidazole and
bis-benzimidazole derivatives 4b, 4d–e and
4g–h in good yields. By contrast, the reaction
gave low yields of 4 in the absence of base or
when a weak base such as potassium carbon-
ate was used.
1
13
Moreover, as expected, the H, C and DEPT
NMR spectra clearly suggest that the fully
deprotected sugar bis-imidazole is a mixture
1
containing a and b anomers. The H NMR
signals indicated that the amount of these two
configurations in the mixture is about equal.16
For the deprotection of the sugar bis-imida-
zole derivatives 4a–h, if hydrochloric acid is
used as the deprotecting reagent, the workup
is very simple. After the reaction is complete,
the solvents were evaporated and the residue
was washed with petroleum ether (30–60 °C)
to remove benzaldehyde and this afforded the
pure hydrochlorides 5 or 6 of deprotected
sugar bis-imidazole compounds. These hydro-
chloric acid salts increase the stability of the
deprotected sugar bis-imidazole, and also re-
sult in good solubility of the products in wa-
ter. This high solubility in water is useful in
biological activity tests. However, if trifl-
uoroacetic acid is employed as the hydrolytic
reagent, due to the formation of trifl-
uoroacetic acid salt, it was very difficult to
remove completely trifluoroacetic acid in or-
der to obtain the pure sugar bis-imidazoles.
The salts 5 and 6 were neutralized with
ammonium hydroxide to produce the corre-
Though the bis-imidazoles 4a–b, 4d–e and
4g–h were prepared efficiently by the above
method, it was not easy to obtain nitroimida-
zole derivatives 4c and 4f by N-alkylation.
Under the above conditions, the reaction of
2-methyl-5-nitroimidazole and its benzo
analog gave complicated products. Their an-
ions are insoluble in non-hydroxylic solvents
while in hydroxylic solvents the alkyl halides 3
are hydrolyzed or may lead to alkenes. We
developed an alternative approach by separat-
ing the alkylating agent from the basic
medium using a phase transfer catalytic proce-
dure to prepare bis-nitroimidazole and bis-ni-
trobenzimidazole compounds 4c and 4f. This
method involves suspension of potassium car-
bonate in acetonitrile with the nitroimidazole
or nitrobenzimidazole, the sugar dibromide 3
and tetrabutylammonium iodide. These reac-
tion conditions gave relatively good yields of
the
D
-glucoside bis-nitroimidazole (4c) and
bis-nitrobenzimidazole (4f). Tetrabutylammo-
nium iodide is effective because the counter
cation is only loosely bound to the azole
anion.
sponding free
D
-glucose bis-imidazoles (7 and
8). The imidazoles 7 and 8 were soluble in
water, but their solubility in water is much
lower than that of their salts 5 and 6. Chloro-

316
C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
quence: C-2\C-4\C-5. The presence of a
2-methyl group in 4b–c and 5b–c resulted in
large downfield chemical shifts of the imida-
zolyl 2-carbons, while the nitro group cause a
large downfield shift (\15 ppm) for the C-4
signal in 4c and 5c. Though the substitutents
form is not very effective to extract them from
water. Instead, after neutralization the mix-
ture was evaporated to dryness, and the solid
residue was washed with chloroform. The
combined chloroform washings were concen-
trated to afford pure compounds 7 and 8. It is
advisable to keep compounds 5 and 6 rather
than compounds 7 and 8 for long-time
storage.
13
affect the C chemical shifts of the imidazolyl
ring in -glucose bis-imidazole compounds, all
D
imidazolyl 13C signals appear in a similar
chemical shift sequence. However, for 13C
NMR spectra of benzimidazolyl compounds a
different situation was observed. For the benz-
imidazolyl compounds 4d–e and 5d–e the
chemical shifts (ppm) are C-2\C-9\C-8\
C-5\C-6\C-4\C-7, while the 2-methyl-5-
nitrobenzimidazolyl 13C signals in 4f and 5f
are in the order C-8\C-5\C-2\C-9\C-
6\C-7\C-4. No large differences are found
in 13C chemical shifts for all the corresponding
OCH2, BrCH2 and NCH2 groups in various
13C NMR spectra.—13C NMR spectra of
3–8 were consistent with the assigned struc-
tures. When the 13C chemical shifts of 3 are
compared with those of the unsubstituted
methyl a-
D
-glucoside (2), the bromoalkyl sub-
stituted
D
-glucosides 3a–c display a downfield
shift for the C-2, C-3, C-4 and C-6 signals,
and upfield shifts for all other sugar carbons.
The magnitude of these shifts is dependent on
their positions in the
Br atoms of the bis-bromoalkyl
(3a–c) were replaced by an imidazolyl group,
the resulting bis-imidazole -glucosides and
D
-glucosides. When the
D
-glucosides
D
-glucoside derivatives.
D
1H NMR spectra.—In comparison with the
their analogs 4a–h enhance a small upfield
shift for almost all the methoxy carbons, C-6,
C-5 and C-4, as well as most of C-2 and C-1
signals. The chemical shift pattern (ppm) was
observed as C-1\C-4\C-2\C-3\C-6\
C-5\OMeꢀC.17
bis-hydroxy
tuted bis-bromoalkyl
D
-glucoside (2), the 2,3-substi-
-glucosides (3a–c)
D
show small downfield shifts for H-1 (0.13–
0.17 ppm), H-4 (0.06–0.08 ppm), H-5 (0.04–
0.07 ppm), equatorial H-6eq (0.02–0.05 ppm),
axial H-6ax (0.05–0.11 ppm), and OMeꢀH
(0.04–0.08 ppm) and show only significant
upfield shifts for H-2 (0.19–0.20 ppm) and
H-3 (0.20–0.22 ppm). All the anomeric H-1
signals in 4a–h give small coupling constants
J values (3.0–3.6 Hz), this demonstrating that
The deprotected
D
-glucose derivatives 5a–h
and 6–8a display a slightly different 13C chem-
ical shift pattern with their chemical shifts
(ppm) in the order C-1\C-4\C-2\C-3\
C-5\C-6\OMeꢀC.17 Compounds 5a–h
showed large upfield shifts for C-3 (6.47–
6.78ppm) and C-6 (8.42ꢀ8.60ppm), while C-
5 showed a large downfield shift (6.85–
7.01ppm) compared to 4. For the totally de-
these
D
-glucose derivatives possess the a
configuration. Thus, substitution does not re-
sult in a change of the a-
D
-glucoside
configuration.
protected bis-imidazole
chloride (6a), 13C and DEPT NMR spectra
gave two sets of 13C data for the
-glucose
D
-glucoside hydro-
In
D
-glucosides 5a–h, all H-1 protons dis-
play significant downfield signals (0.07–0.29
ppm) and all equatorial H-6eq give large up-
field shifts (between 0.27 and 0.46 ppm). The
D
moiety, indicating the presence of both a and
b configurations. Compared with the b
configuration of 6a, almost all these corre-
totally deprotected
D
-glucose bis-imidazole
(6a) showed two types of anomeric H-1 sig-
nals in a 1:1 ratio at 5.36 and 4.65 ppm, J 2.6
and 8.1 Hz, respectively. This clearly indicates
two configurations for 6a, the small J value
belonging to the a configuration, and the large
J value to the b configuration. Compared with
the protected compound 4a, the H-1 signal for
the a configuration of 6a displays a large
downfield shift (0.69 ppm), while the 1-proton
sponding
D
-glucose carbons of a configuration
of 6a exhibit upfield chemical shifts.18
D
-Gluc-
ose bis-imidazole dihydrochlorides (5a and 6a)
show a higher field chemical shifts as com-
pared to corresponding free compounds 7a
and 8a.
All imidazolyl groups in the bis-imidazole
D
-glucosides showed a 13C chemical shift se-

C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
317
3. Experimental
for the b configuration gave no significant
upfield shift. Compounds 7a and 8a showed
higher field chemical shifts of the 1-proton
than their corresponding hydrochlorides 5a
and 6a.
General methods.—All air- and moisture-
sensitive reactions were carried out in flame-
dried, Ar-flushed, two necked flasks sealed
with rubber septa, and the reagents were in-
troduced with a syringe. Tetrahydrofuran
(THF) was freshly distilled from sodium–ben-
zophenone. N,N-Dimethylformamide was dis-
tilled from barium oxide after it was dried by
solid potassium hydroxide. Chromatography
was done on E. Merck silica gel 60 (230–400
mesh), and pre-coated E. Merck Silica Gel
plates (60 F254) were used for thin-layer chro-
matography (TLC). Analytical TLC was visu-
alized with I2 and UV light, or by spraying the
plates with (5:100, g/g) phospho-molybdic
acid–EtOH or (5:100, g/g) KMnO4–EtOH
The proton chemical shifts (ppm) of imida-
zolyl groups are in the order H-2\H-4\H-
5. The deprotected hydrochloride compounds
5a–c, 5g–h and 6a give large downfield shifts
compared to 4a–c and 4g–h or to 7a and 8a.
For benzimidazolyl protons, the chemical
shifts (ppm) order is H-2\H-4\H-7\H-
5\H-6\MeꢀH. The protons of all the 2-po-
sition OCH2 groups show a smaller chemical
shift than those of 3-position OCH2 groups,
1
whereas, the H spectra of 2-position BrCH2
and NCH2 groups (linked via a carbon bridge
to the
D
-glucoside) display a larger chemical
1
13
and briefly heating. H and C NMR spectra
were recorded on a Bruker AM-300, 600 or
Varian-500 instrument with Me4Si as the in-
ternal standard; Ph=phenyl ring, Im=imida-
shift than those of 3-position BrCH2 and
NCH2 groups.
Biological acti6ity.—Anticancer activity of
-glucose derived bis-imidazoles 5a–f and 6a
D
zolyl
ring,
Bim=benzimidazolyl
ring.
was evaluated at the National Institute of
Health (NIH) Bethesda, MD, USA. The com-
pounds were tested over a range of concentra-
tions (10−4–10−8 M). Of these seven
Coupling constants were determined directly
1
from H NMR spectra. Mass spectra (CI or
FAB) were measured on a Finnigan MAT
4510 or Autospec spectrometer. Melting
points were determined on a Electrothermal
Digital melting point apparatus and are un-
corrected. Optical rotations were measured on
a Perkin–Elmer 141 or Dip-1000 digital polar-
imeter with a path length of 0.1 or 0.5 dm.
The concentration for optical rotation is given
compounds, only
D
-glucose bis(5,6-dimethyl)-
benzimidazole hydrochloride derivative 5e
showed significant activity in three cell lines,
at one dose essay: NCI-H460 (lung cancer)
13% cell growth (reduced from 100), in
MCF7 (breast) 2%, in SF-268 (CNS) essay
−70%. Other biological activities are being
tested.
in g/100 mL. Methyl 4,6-O-benzylidene a-
glucopyranoside (2) was prepared from methyl
a-
-glucopyranoside (1).19 All other chemicals
D
-
Conclusions.—In summary, we have suc-
cessfully developed a practical method for the
D
and reagents were obtained from commercial
synthesis of a series of novel chiral
D
-glucose
suppliers
purification.
and
used
without
further
derived bis-imidazoles (4–8), have summa-
1
rized their regular features of H and 13C
Methyl 2,3-O-bis(4-bromobutyl)-4,6-O-ben-
-glucopyranoside (3a).—To a
NMR spectra and have evaluated their anti-
cancer activities. Carefully controlled condi-
tions are necessary to obtain the bis-bromo-
alkyl derivative 3 in order to avoid formation
of cyclization products. As expected, depro-
zylidene-h-
D
well-stirred suspension of NaH (200 mg 60%,
5 mmol) in dry DMF (5 mL), solid methyl
4,6-O-benzylidene-a-
D
-glucopyranoside
(2)
(400 mg, 1.4 mmol) was added slowly as a
powder. The resulting mixture was stirred for
60 min, and then cooled to 0 °C with ice.
1,4-Dibromobutane (5 mL) was added. After
4 h, the reaction was allowed to reach 60 °C
until the reaction was complete (TLC, 100:1
CHCl3–acetone). Ice-water (50 g) was added
tection of the a- -glucoside 4a leads to a
D
mixture of a and b anomers 6a in a 1:1 ratio.
Further applications, for instance, as multi-
dentates to bind metal ions and as precursors
for synthesis of gluco-imidazolium macro-
cycles, are currently under investigation.

318
C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
5), 55.32 (OCH3), 33.85, 33.77 (BrCH2),
32.55, 29.38, 29.20, 24.82, 24.73 (CH2);
and the mixture was extracted with CHCl3
(2×40 mL). The combined CHCl3 solutions
were washed with water, dried over Na2SO4
and then concentrated under reduced pres-
sure. The residue was subjected to column
chromatography on silica gel using (100:1–5)
CHCl3–acetone as eluent to give methyl 2,3-
CIHRMS,
m/z
579.0913
[M+H]+
([C24H36Br2O6 +H] requires 579.0957). Anal.
Calcd for C24H36Br2O6: C, 49.67; H, 6.25.
Found: C, 49.77; H, 6.21.
Methyl 2,3-O-bis(6-bromohexyl)-4,6-O-ben-
zylidene-h-
D
-glucopyranoside
(3c).—Com-
O-bis(4-bromobutyl)-a- -glucoside (3a) as an
D
oil (490 mg, 63.6%); [h]2D4 +36.57° (c 7.0,
CHCl3); 1H NMR (300 MHz, CDCl3): l
7.49–7.46 (m, 2 H, Ph H-2,6), 7.38–7.35 (m, 3
H, Ph H-3,4,5), 5.53 (s, 1 H, PhꢀCH), 4.82 (d,
1 H, J1,2 3.6 Hz, H-1), 4.27 (dd, 1 H, J6eq,6ax 9,
J5,6a 3.7 Hz, H-6eq), 3.85–3.65 (m, 7 H, 2
OCH2, H-3, H-5 and H-6ax), 3.58–3.43 (m, 6
H, H-4, BrCH2, OCH3), 3.37–3.33 (m, 3 H,
H-2 and BrCH2), 2.01–1.87 (m, 4 H, CH2),
pound 3c was prepared according to the
procedure reported for the preparation of 3a.
Starting from 1,6-dibromohexane (15 mL), the
bis-hydroxy sugar 2 (1.2 g, 4.25 mmol), NaH
(1.0 g 60%, 25 mmol) and DMF (10 mL), the
pure 2,3-O-bis(6-bromohexyl) sugar (3c) (1.82
g, 70.6%) was obtained as an oil; [h]D22
+
1
37.57° (c 7.0, CHCl3); H NMR (300 MHz,
CDCl3): l 7.47–7.44 (m, 2 H, Ph H-2,6),
7.36–7.31 (m, 3 H, Ph H-3,4,5), 5.50 (s, 1 H,
PhꢀCH), 4.78 (d, 1 H, J1,2 3.6 Hz, H-1), 4.24
(dd, 1 H, J6eq,6ax 9.45, J5,6eq 3.9 Hz, H-6eq),
3.80–3.59 (m, 7 H, 2OCH2, H-3, H-5 and
H-6ax), 3.46 (t, 9 Hz, 1 H, H-4), 3.40 (s, 3 H,
OCH3), 3.37 (t, 6.9 Hz, 2 H, BrCH2), 3.32 (dd,
1 H, H-2), 3.28 (t, 6.9 Hz, 2 H, BrCH2),
1.92–1.41 (m, 16 H, CH2); 13C NMR (75
MHz, CDCl3): l 137.52 (Ph C-1), 128.89 (Ph
C-4), 128.17 (Ph C-3,5), 126.05 (Ph C-2,6),
101.29 (PhꢀCH), 98.95 (C-1), 81.95 (C-4),
80.46 (C-2), 78.23 (C-3), 73.03 (OCH2), 71.80
(OCH2), 69.08 (C-6), 62.40 (C-5), 55.29
(OCH3), 33.86, 33.83 (BrCH2), 32.79, 32.73,
30.07, 29.86, 28.00, 27.99, 27.94, 25.82, 25.18
(CH2); CIHRMS m/z 607.1280 [M+H]+
([C26H40Br2O6 +H] requires 607.1270). Anal.
Calcd for C26H40Br2O6: C, 51.33; H, 6.63.
Found: C, 51.19; H, 6.59.
13
1.79–1.65 (m, 4 H, CH2); C NMR (75 MHz,
CDCl3): l 137.36 (Ph C-1), 128.98 (Ph C-4),
128.26 (Ph C-3,5), 126.03 (Ph C-2,6), 101.38
(PhꢀCH), 98.78 (C-1), 82.03 (C-4), 80.33 (C-
2), 78.23 (C-3), 72.11 (OCH2), 70.95 (OCH2),
69.07 (C-6), 62.37 (C-5), 55.33 (OCH3), 33.76,
33.58 (BrCH2), 29.61, 29.48, 28.84, 28.62
(CH2); CIHRMS, m/z 550.0532 [M]+
(C22H32Br2O6 requires 550.0566). Anal. Calcd
for C22H32Br2O6: C, 47.84; H, 5.84. Found: C,
47.79; H, 5.84.
Methyl
benzylidene-h-
2,3-O-bis(5-bromopentyl)-4,6-O-
-glucopyranoside (3b).—Com-
D
pound 3b was prepared according to the
procedure for 3a from 1,5-dibromo pentane (5
mL), the bis-hydroxy sugar 2 (800 mg, 2.83
mmol), NaH (500 mg 60%, 12.5 mmol) and
DMF (5 mL). The pure 2,3-O-bis(5-bro-
mopentyl) sugar (3b) (1.25 g, 76.4%,) was
obtained as an oil; [h]2D5 +39.74° (c 7.8,
CHCl3); 1H NMR (300 MHz, CDCl3): l
7.49–7.46 (m, 2 H, Ph H-2,6), 7.38–7.35 (m, 3
H, Ph H-3,4,5), 5.52 (s, 1 H, PhꢀCH), 4.80 (d,
1 H, J1,2 3.6 Hz, H-1), 4.26 (dd, 1 H, J6eq,6ax 9,
J5,6eq 3.8 Hz, H-6eq), 3.83–3.63 (m, 7 H,
2OCH2, H-3, H-5 and H-6ax), 3.48 (t, J4,5 9 Hz
1 H, H-4), 3.42 (s, 3 H, OCH3), 3.40 (t, 6.6
Hz, 2 H, BrCH2), 3.32 (dd, 1 H, H-2), 3.28 (t,
6.9 Hz, 2 H, BrCH2), 1.92–1.41 (m, 12 H,
CH2); 13C NMR (75 MHz, CDCl3): l 137.45
(Ph C-1), 128.95 (Ph C-4), 128.22 (Ph C-3,5),
126.05 (Ph C-2,6), 101.35 (PhꢀCH), 98.92 (C-
1), 81.95 (C-4), 80.44 (C-2), 78.23 (C-3), 72.84
(OCH2), 71.68 (OCH2), 69.09 (C-6), 62.40 (C-
Methyl
4,6-O-benzylidene-h-
2,3-O-bis[4-(N-imidazolyl)butyl]-
-glucopyranoside (4a).
D
—To a well-stirred suspension of NaH (670
mg 60%, 16.7 mmol) in dry DMF (5 mL),
imidazole (680 mg, 10 mmol) was added
slowly. The resulting mixture was stirred for
20 min, and then allowed to rise to 50–60 °C.
A solution of
D
-glucoside dibromide (3a, 1.1
g, 2 mmol) in THF (20 mL) was added drop-
wise for 3–5 h. After the reaction was com-
plete, ice-water (30 mL) was added. The
mixture was extracted with CHCl3 (2×30
mL). The organic layer was combined, dried
with Na2SO4 and concentrated under reduced
pressure. The residue was subjected to column

C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
319
3 H, Im 2ꢀCH3), 2.13 (s, 3 H, Im 2ꢀCH3),
1.67–1.62 (m, 4 H, CH2), 1.48–1.37 (m, 4 H,
chromatography on silica gel using CH2Cl2–
MeOH as eluent affording the pure -glu-
D
13
CH2); C NMR (75 MHz, CDCl3): l 144.16,
coside bis-imidazole (4a) as a syrup (605 mg,
1
57.5%); [h]2D5 +20.11° (c 9.3, CHCl3); H
144.10 (Im C-2), 137.27 (Ph C-1), 128.99 (Ph
C-4), 128.17 (Ph C-3,5), 126.82, 126.62 (Im
C-4), 125.98 (Ph C-2,6), 118.99, 118.88 (Im
C-5), 101.42 (PhꢀCH), 98.48 (C-1), 81.76 (C-
4), 80.26 (C-2), 78.14 (C-3), 72.24 (OCH2),
70.85 (OCH2), 68.93 (C-6), 62.27 (C-5), 55.20
(OCH3), 45.67, 45.54 (NCH2), 27.49, 27.40,
27.01, 26.94 (CH2), 12.91, 12.81 (Im 2ꢀCH3);
CIHRMS m/z 555.3170 [M+H]+ ([C30H42-
N4O6+H] requires 555.3183). Anal. Calcd for
C30H42N4O6: C, 64.96; H, 7.63; N, 10.10.
Found: C, 64.85; H, 7.67; N, 10.18.
NMR (600 MHz, CDCl3): l 7.36 (s, 1 H, Im
H-2), 7.33–7.32 (m, 2 H, Ph H-2,6), 7.23–7.20
(m, 4 H, Ph H-3,4,5 and Im H-2), 6.90 (bs, 1
H, Im H-4), 6.85 (bs, 1 H, Im H-4), 6.78 (bs,
1 H, Im H-5), 6.64 (bs, 1 H, Im H-5), 5.38 (s,
1 H, PhꢀCH), 4.67 (d, 1 H, J1,2 3.5 Hz, H-1),
4.13 (dd, 1 H, J6eq,6ax 10, J5,6eq 4.5 Hz, H-6eq),
3.81 (t, 7 Hz, 2 H, NCH2), 3.67–3.63 (m, 4 H,
H-5, NCH2, and one proton of OCH2), 3.60–
3.56 (m, 3 H, H-3, H-6ax and one proton of
OCH2), 3.49–3.46 (m, 2 H, OCH2), 3.36 (dd, 1
H, J3,4=J4,5 9 Hz, H-4), 3.29 (s, 3 H, OCH3),
3.20 (dd, 1 H, J2,3 9 Hz, H-2), 1.72–1.61 (m, 4
H, CH2), 1.43–1.40 (m, 2 H, CH2), 1.37–1.33
Methyl 2,3-O-bis[4-(N-(2-methyl-4-nitro)-
imidazolyl)butyl]-4,6-O-benzylidene-h- -gluco-
D
pyranoside (4c).—A mixture of 2-methyl-5-ni-
troimidazole (162 mg, 1.2 mmol), dry potas-
sium carbonate (677 mg, 4.8 mmol), the
13
(m, 2 H, CH2); C NMR (150 MHz, CDCl3):
l 137.33 (Ph C-1), 136.99 (Im C-2), 136.87 (Im
C-2), 129.11 (Im C-4), 129.02 (Ph C-4), 128.93
(Im C-4), 128.20 (Ph C-3,5), 126.02 (Ph C-
2,6), 118.79 (Im C-5), 118.72 (Im C-5), 101.44
(PhꢀCH), 98.49 (C-1), 81.80 (C-4), 80.22 (C-
2), 78.11 (C-3), 72.12 (OCH2), 70.78 (OCH2),
68.94 (C-6), 62.29 (C-5), 55.21 (OCH3), 46.61,
46.49 (NCH2), 27.92, 27.78, 26.92, 26.84
(CH2); CIHRMS m/z 527.2870 [M+H]+
([C28H38N4O6+H] requires 527.2860). Anal.
Calcd for C28H38N4O6: C, 63.86; H, 7.27; N,
10.64. Found: C, 63.88; H, 7.26; N, 10.69.
Methyl2,3-O-bis[4-(N-(2-methyl)imidazolyl)-
D
-glucoside dibromide 3a (316 mg, 0.57
mmol), tetrabutylammonium iodide (50 mg)
and MeCN (5 mL) was stirred at 80 °C. After
the reaction was complete (TLC, EtOAc), the
mixture was cooled and water (30 mL) was
added. The resulting solution was extracted
with CHCl3 (3×30 mL). All the combined
CHCl3 solutions were washed with water,
dried with anhyd MgSO4 and then concen-
trated under reduced pressure. The remaining
crude product was subjected to column chro-
matography on silica gel using CH2Cl2–
MeOH as eluent affording the corresponding
pure desired bis-nitroimidazole 4c as a syrup
(248 mg, 67.4%); [h]2D6 +26.58° (c 15.8,
butyl]-4,6-O-benzylidene-h- -glucopyranoside
D
(4b).—Prepared according to the procedure
reported for 4a. Starting from NaH (800 mg
60%, 20 mmol), the sugar dibromide 3a (555
mg, 1.01 mmol) and 2-methylimidazole (500
1
CHCl3); H NMR (300 MHz, CDCl3): l 7.79
(s, 1 H, Im H-5), 7.54 (s, 1 H, Im H-5),
7.43–7.41 (m, 2 H, Ph H-2,6), 7.34–7.31 (m, 3
H, Ph H-3,4,5), 5.51 (s, 1 H, PhꢀCH), 4.85 (d,
1 H, J1,2 3.6 Hz, H-1), 4.26 (dd, 1 H, J6eq,6ax 9,
J5,6eq 3.9 Hz, H-6eq), 4.01 (t, J 7 Hz, 2 H,
NCH2), 3.81–3.73 (m, 7 H, NCH2, OCH2,
H-3, H-5 and H-6ax), 3.68 (t, J 6 Hz, 2 H,
OCH2), 3.51 (t, 1 H, J3,4=J4,5 9 Hz, H-4),
3.44 (s, 3 H, OCH3), 3.38 (dd, 1 H, J2,3 9 Hz,
H-2), 2.42 (s, 3 H, Im 2ꢀCH3), 2.27 (s, 3 H, Im
2ꢀCH3), 1.92–1.77 (m, 4 H, CH2), 1.65–1.47
(m, 4 H, CH2); 13C NMR (75 MHz, CDCl3): l
146.20, 146.07 (Im C-2), 144.73, 144.62 (Im
C-4), 137.23 (Ph C-1), 129.22 (Ph C-4), 128.26
(Ph C-3,5), 126.04 (Ph C-2,6), 120.13, 119.79
mg, 6.0 mmol), the pure
D
-glucoside bis-
methylimidazole (4b, 296 mg, 52.9%) was ob-
tained as a syrup; [h]2D4 +37.63° (c 16.0,
CDCl3); 1H NMR (300 MHz, CDCl3): l
7.34–7.30 (m, 2 H, Ph H-2,6), 7.22–7.20 (m, 3
H, Ph H-3,4,5), 6.75 (bs, 1 H, Im H-4), 6.70
(d, J 6.00 Hz, 2 H, Im H-4,5), 6.55 (bs, 1 H,
Im H-5), 5.38 (s, 1 H, PhꢀCH), 4.68 (d, 1 H,
J1,2 3.5 Hz, H-1), 4.13 (dd, 1 H, J6eq,6ax 10,
J5,6eq 3.9 Hz, H-6eq), 3.71 (t, 7 Hz, 2 H,
NCH2), 3.68–3.53 (m, 7 H, H-3, H-5, H-6ax,
OCH2, NCH2), 3.49 (t, 6 Hz, 2 H, OCH2),
3.36 (t, 1 H, J3,4=J4,5 9 Hz, H-4), 3.29 (s, 3 H,
OCH3), 3.21 (dd, 1 H, J2,3 9 Hz, H-2), 2.23 (s,

320
C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
4a. Starting from NaH (100 mg 60%, 2.5
mmol), 2,3-O-bis(4-brombutyl) -glucoside
(Im C-5), 101.70 (PhꢀCH), 98.35 (C-1), 81.55
(C-4), 80.36 (C-2), 78.31 (C-3), 72.08 (OCH2),
70.10 (OCH2), 68.97 (C-6), 62.33 (C-5), 55.22
(OCH3), 46.79, 46.64 (NCH2), 27.35, 27.03,
26.67, 26.49 (CH2), 13.02, 12.89 (Im 2ꢀCH3);
CIHRMS m/z 645.2864 [M+H]+ ([C30H40-
N6O10+H] requires 645.2884). Anal. Calcd
for C30H40N6O10: C, 55.89; H, 6.25; N, 13.04.
Found: C, 55.98; H, 6.23; N, 12.99.
D
(3a, 100 mg, 0.18 mmol) and 5,6-dimethyl
benzimidazole (200 mg, 1.3 mmol), the pure
D
-glucoside bis-(5,6-dimethyl)benzimidazole
(4e, 82 mg, 66.7%) was obtained as a syrup;
1
[h]3D0 +34.76° (c 4.2, CHCl3); H NMR (300
MHz, CDCl3): l 7.88 (s, 1 H, Bim H-2), 7.70
(s, 1 H, Bim H-2), 7.54 (s, 1 H, Bim H-4), 7.53
(s, 1 H, Bim H-4), 7.43–7.40 (m, 2 H, Ph
H-2,6), 7.31–7.29 (m, 3 H, Ph H-3,4,5), 7.14
(s, 1 H, Bim H-7), 7.06 (s, 1 H, Bim H-7), 5.48
(s, 1 H, PhꢀCH), 4.76 (d, 1 H, J1,2 3.6 Hz,
H-1), 4.25 (dd, 1 H, J6eq,6ax 9, J5,6eq 3.8 Hz,
H-6eq), 4.09 (t, J 7 Hz, 2 H, NCH2), 3.98–3.87
(m, 2 H, NCH2), 3.82–3.63 (m, 5 H, OCH2,
H-3, H-5 and H-6ax), 3.58 (m, t, 6 Hz, 2 H,
OCH2), 3.45 (t, 1 H, J3,4=J4,5 9 Hz, H-4),
3.39 (s, 3 H, OCH3), 3.29 (dd, 1 H, J2,3 9 Hz,
H-2), 2.36 (s, 3 H, Bim 5-CH3), 2.34 (s, 3 H,
Bim 5-CH3), 2.33 (s, 6 H, Bim 6-CH3), 1.93–
1.79 (m, 4 H, CH2), 1.57–1.40 (m, 4 H, CH2);
13C NMR (75 MHz, CDCl3): l 142.10, 141.93
(Bim C-2), 141.70 (Bim C-9), 141.58 (Bim
C-8), 137.30 (Ph C-1), 132.21, 132.11 (Bim
C-5), 131.28, 131.22 (Bim C-6), 129.11 (Ph
C-4), 128.28 (Ph C-3,5), 126.03 (Ph C-2,6),
120.04, 119.94 (Bim C-4), 109.96 (Bim C-7),
101.53 (PhꢀCH), 98.58 (C-1), 81.92 (C-4),
80.29 (C-2), 78.28 (C-3), 72.32 (OCH2), 71.03
(OCH2), 69.05 (C-6), 62.35 (C-5), 55.26
(OCH3), 44.77, 44.69 (NCH2), 27.19, 27.08,
26.76, 26.60 (CH2), 20.61, 20.23 (Bim 5,6-
CH3); CIHRMS m/z 682.3730 [M]+
(C40H50N4O6 requires 682.3730). Anal. Calcd
for C40H50N4O6: C, 70.36; H, 7.38; N, 8.20.
Found: C, 70.49; H, 7.34; N, 8.16.
Methyl
2,3-O-bis[4-(N-benzimidazolyl)-
-glucopyranoside
butyl]-4,6-O-benzylidene-h-
D
(4d).—Prepared according to the procedure
reported for the synthesis of 4a. Starting from
NaH (100 mg 60%, 2.5 mmol), the 2,3-O-
bis(4-bromobutyl) sugar (3a, 351 mg, 0.63
mmol) and benzimidazole (200 mg, 1.6 mmol),
the pure
D
-glucoside bis-benzimidazole (4d,
269 mg, 67.7%) was obtained as a syrup; [h]D23
+30.79° (c 15.2, CHCl3); 1H NMR (300
MHz, CDCl3): l 7.83 (s, 1 H, Bim H-2),
7.76–7.73 (m, 2 H, Bim H-2,4), 7.65 (bs, 1 H,
Bim H-4), 7.39–7.37 (m, 2 H, Bim H-7),
7.27–7.24 (m, 4 H, 2Bim H-5, Ph H-2,6),
7.21–7.18 (m, 5 H, 2Bim H-6, Ph H-3,4,5),
5.43 (s, 1 H, PhꢀCH), 4.71 (d, 1 H, J1,2 3.0
Hz, H-1), 4.20 (dd, 1 H, J6eq,6ax 10, J5,6eq 3.9
Hz, H-6eq), 4.02 (t, J 7 Hz, 2 H, NCH2), 3.88
(t, J 7 Hz, 2 H, NCH2), 3.74–3.58 (m, 5 H,
OCH2, H-3, H-5 and H-6ax), 3.51 (t, J 6 Hz, 2
H, OCH2), 3.42 (t, 1 H, J3,4=J4,5 9 Hz, H-4),
3.34 (s, 3 H, OCH3), 3.26 (dd, 1 H, J2,3 9 Hz,
H-2), 1.83–1.79 (m, 4 H, CH2), 1.48–1.37 (m,
4 H, CH2); 13C NMR (75 MHz, CDCl3): l
143.69, 143.64 (Bim C-2), 143.09, 143.06 (Bim
C-9), 142.93, 142.90 (Bim C-8), 137.33 (Ph
C-1), 129.08 (Ph C-4), 128.25 (Ph C-3,5),
126.05 (Ph C-2,6), 122.82, 122.73 (Bim C-5),
122.06, 121.98 (Bim C-6), 120.20, 120.12 (Bim
C-4), 109.78 (Bim C-7), 101.47 (PhꢀCH),
98.49 (C-1), 81.85 (C-4), 80.23 (C-2), 78.22
(C-3), 72.24 (OCH2), 70.89 (OCH2), 68.98 (C-
6), 62.32 (C-5), 55.24 (OCH3), 44.63, 44.57
(NCH2), 27.16, 27.02, 26.75, 26.60 (CH2);
CIHRMS m/z 627.3177 [M+H]+ ([C36H42-
N4O6+H] requires: 627.3182). Anal. Calcd
for C36H42N4O6: C, 68.99; H, 6.75; N, 8.94.
Found: C, 68.91; H, 6.69; N, 8.99.
Methyl 2,3-O-bis[4-(N-(2-methyl-5-nitro)-
benzimidazolyl)butyl]-4,6-O-benzylidene-h- -
D
glucopyranoside (4f).—Compound 4f was pre-
pared according to the synthesis of 4c. Start-
ing from dried potassium carbonate (669 mg,
4.8 mmol), the
mg, 0.54 mmol) and 2-methyl-5-nitrobenzimi-
dazole (201 mg, 1.1 mmol), the pure -glu-
D
-glucoside dibromide (3a, 300
D
coside bis-nitrobenzimidazole (4f, 209 mg,
51.8%) was obtained as a syrup; [h]2D4 +28.46°
1
Methyl 2,3-O-bis[4-(N-(5,6-dimethyl)ben-
(c 1.3, CHCl3); H NMR (300 MHz, CDCl3):
zimidazolyl)butyl] - 4,6 - O - benzylidene - h -
D
-
l 8.44–8.42 (m, 1 H, Bim H-4), 8.21–8.14 (m,
1 H, Bim H-4), 8.07 (d, J 8.35 Hz, 1 H, Bim
H-6), 8.01–7.97 (m, 1 H, Bim H-6), 7.75–7.59
glucopyranoside (4e).—Prepared according to
the procedure reported for the preparation of

C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
321
C-3,5), 126.07 (Ph C-2,6), 118.76 (Im C-5),
101.43 (PhꢀCH), 98.77 (C-1), 81.73 (C-4),
80.44 (C-2), 78.18 (C-3), 72.57 (OCH2), 71.42
(OCH2), 69.03 (C-6), 62.36 (C-5), 55.27
(OCH3), 46.90, 46.83 (NCH2), 30.79, 30.65,
29.51, 29.45, 23.07, 23.03 (CH2); CIHRMS
m/z 555.3186 [M+H]+ ([C30H42N4O6+H] re-
quires 555.3183). Anal. Calcd for C30H42N4O6:
C, 64.96; H, 7.63; N, 10.10. Found: C, 65.13;
H, 7.64; N, 10.06.
(m, 1 H, Bim H-7), 7.36–7.29 (m, 2 H, Ph
H-2,6), 7.26–7.21 (m, 3 H, Ph H-3,4,5), 7.13–
7.11 (m, 1 H, Bim H-7), 5.44 (s, 1 H, PhꢀCH),
4.78 (d, 1 H, J1,2 3.3 Hz, H-1), 4.23 (dd, 1 H,
J6eq,6ax 9, J5,6eq 3.5 Hz, H-6eq), 4.19–4.11 (m, 2
H, NCH2), 3.97–3.90 (m, 2 H, NCH2), 3.73–
3.58 (m, 7 H, 2OCH2, H-3, H-5 and H-6ax),
3.48 (dd, 1 H, J3,4=J4,5 9 Hz, H-4), 3.40–3.34
(m, 4 H, H-2, OCH3), 2.61 (d, J 7 Hz, 3 H,
Bim 2-CH3), 2.45 (d, J 7 Hz, 3 H, Bim 2-
CH3),1.90–1.73 (m, 4 H, CH2), 1.61–1.46 (m,
4 H, CH2); 13C NMR (75 MHz, CDCl3): l
156.79, 155.44 (Bim C-8), 147.08, 143.28 (Bim
C-5), 143.18, 139.28 (Bim C-2), 137.20 (Ph
C-1), 129.16 (Ph C-4), 129.08, 128.14 (Bim
C-9), 128.21 (Ph C-3,5), 125.99 (Ph C-2,6),
118.86, 117.90 (Bim C-6), 115.44, 115.32 (Bim
C-7), 109.09, 106.11 (Bim C-4), 101.62
(PhꢀCH), 98.41 (C-1), 81.57 (C-4), 80.46 (C-
2), 78.37 (C-3), 72.21 (OCH2), 70.61 (OCH2),
68.97 (C-6), 62.33 (C-5), 55.23 (OCH3), 44.06,
43.91 (NCH2), 27.18, 27.04, 26.66, 26.61
(CH2), 14.18, 13.99 (Bim 2-CH3); CIHRMS
m/z 745.3188 [M+H]+ ([C38H44N6O10 +H]
Methyl
2,3-O-bis[4-(N-imidazolyl)hexyl]-
-glucopyranoside (4h).
4,6-O-benzylidene-h-
D
—Prepared according to the procedure for the
synthesis of 4a. Starting from NaH (880 mg
60%, 22 mmol), the 2,3-O-bis(bromohexyl)
glycoside (3c, 100 mg, 0.16 mmol) and imida-
zole (584 mg, 8.5 mmol), the pure -glucoside
D
-
D
bis-imidazole (4h, 80 mg, 83.6%) was obtained
1
as a syrup; [h]2D7 +21.36° (c 6.6, CHCl3); H
NMR (300 MHz, CDCl3): l 7.45–7.39 (m, 4
H, Ph H-2,6 and 2 Im H-2), 7.31–7.29 (m, 3
H, Ph H-3,4,5), 7.01 (d, J 6 Hz, 2 H, Im H-4),
6.86 (d, J 19 Hz, 2 H, Im H-5), 5.48 (s, 1 H,
PhꢀCH), 4.75 (d, 1 H, J1,2 3.6 Hz, H-1), 4.23
(dd, 1 H, J6eq,6ax 9, J5,6eq 3.9 Hz, H-6eq), 3.88 (t,
J 7 Hz, 2 H, NCH2), 3.77–3.62 (m, 7 H,
NCH2, OCH2, H-3, H-5 and H-6ax), 3.57 (t, J
requires
745.3197).
Anal.
Calcd
for
C38H44N6O10: C, 61.28; H, 5.95; N, 11.28.
Found: C, 61.19; H, 5.93; N, 11.32.
Methyl 2,3-O-bis[5-(N-imidazolyl)pentyl]-
6 Hz, 2 H, OCH2), 3.44 (t, 1 H, J3,4 =J4,5 9
4,6-O-benzylidene-h-
D
-glucopyranoside (4g).
Hz, H-4), 3.39 (s, 3 H, OCH3), 3.29 (dd, 1 H,
J2,3 9 Hz, H-2), 1.75–1.68 (m, 2 H, CH2),
1.63–1.44 (m, 6 H, CH2), 1.34–1.25 (m, 6 H,
—Compound 4g was prepared according to
the procedure for 4a. Starting from NaH (1.2
g 60%, 30 mmol), the 2,3-O-bis(bromopentyl)
sugar (3b, 450 mg, 0.77 mmol) and imidazole
13
CH2), 1.24–1.17 (m, 2 H, CH2); C NMR (75
MHz, CDCl3): l 137.48 (Ph C-1), 136.95 (Im
C-2), 129.16 (Ph C-4), 129.03, 128.94 (Im C-
4), 128.17 (Ph C-3,5), 126.06 (Ph C-2,6),
118.78 (Im C-5), 101.35 (PhꢀCH), 98.87 (C-1),
81.85 (C-4), 80.45 (C-2), 78.15 (C-3), 72.87
(OCH2), 71.66 (OCH2), 69.06 (C-6), 62.38 (C-
5), 55.27 (OCH3), 46.96, 46.90 (NCH2), 30.99,
30.94, 29.95, 29.81, 26.32, 26.25, 25.47, 25.47
(CH2); CIHRMS m/z 583.3491 [M+H]+
([C32H46N4O6+H] requires 583.3496). Anal.
Calcd for C32H46N4O6: C, 65.96; H, 7.96; N,
9.61. Found: C, 65.79; H, 7.91; N, 9.70.
(544 mg, 8.0 mmol), the pure
D
-glucoside
bis-imidazole (4g, 290 mg, 68.6%) was ob-
tained as a syrup; [h]2D5 +26.69° (c 16.3,
CHCl3); 1H NMR (300 MHz, CDCl3): l
7.44–7.41 (m, 3 H, Ph H-2,6, Im H-2), 7.33–
7.27 (m, 4 H, Ph H-3,4,5 and Im H-2), 7.00 (d,
J 10 Hz, 2 H, Im H-4), 6.86 (d, J 32 Hz, 2 H,
Im H-5), 5.47 (s, 1 H, PhꢀCH), 4.73 (d, 1 H,
J1,2 3.3 Hz, H-1), 4.21 (dd, 1 H, J6eq,6ax 9, J5,6eq
3.5 Hz, H-6eq), 3.88 (t, J 7 Hz, 2 H, NCH2),
3.75–3.63 (m, 7 H, NCH2, OCH2, H-3, H-5
and H-6ax), 3.56 (t, J 6 Hz, 2 H, OCH2), 3.42
(t, 1 H, J3,4=J4,5 9 Hz, H-4), 3.37 (s, 3 H,
OCH3), 3.27 (dd, 1 H, J2,3 9 Hz, H-2), 1.77–
1.72 (m, 2 H, CH2), 1.66–1.47 (m, 6 H, CH2),
Methyl 2,3-O-bis[4-(N-imidazolyl)butyl]-h-
-glucopyranoside dihydrochloride (5a).—A
D
mixture of analytic grade concentrated hydro-
chloric acid (1 mL), distilled water (3 mL) and
13
1.36–1.19 (m, 4 H, CH2); C NMR (75 MHz,
methyl 4,6-O-benzylidene a- -glucopyran-
D
CDCl3): l 137.43 (Ph C-1), 136.92 (Im C-2),
oside bis-imidazole (4a, 40 mg, 0.076 mmol)
was stirred at 50 °C for 2 h. The solvents were
129.17 (Ph C-4), 129.02 (Im C-4), 128.16 (Ph

322
C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
Methyl 2,3-O-bis[4-(N-(2-methyl-4-nitro)-
imidazolyl)butyl]-h- -glucopyranoside dihy-
drochloride (5c).—Prepared according to the
procedure reported for 5a. Starting from the
evaporated under reduced pressure. The
residue was washed with petroleum ether (30–
60 °C) to remove benzaldehyde and dried to
D
afford corresponding a- -glucopyranoside
D
D
-glucoside bis(2-methyl-4-nitro) imidazole
-glu-
bis-imidazole hydrochloric acid salt (5a) as a
syrup (38 mg, 98.2%); [h]2D7 +42.78° (c 1.8,
(4c, 140 mg, 0.217 mmol), the pure
coside bis-nitroimidazole hydrochloric acid
D
1
water); H NMR (300 MHz, D2O): l 8.76–
salt (5c, 136 mg, ꢀ100%) was obtained as a
8.75 (m, 2 H, Im H-2), 7.54–7.52 (m, 2 H, Im
H-4), 7.49–7.47 (m, 2 H, Im H-5), 4.96 (d, 1
H, J1,2 3.3 Hz, H-1), 4.28 (t, 7 Hz, 4 H,
NCH2), 3.88–3.60 (m, 8 H, H-3, H-5, H-6eq,
H-6ax, 2 OCH2), 3.47 (dd, 1 H, J3,4 =J4,5 10
Hz, H-4), 3.41 (s, 3 H, OCH3), 3.38 (dd, 1 H,
J2,3 10 Hz, H-2), 2.00–1.94 (m, 4 H, CH2),
1
syrup; [h]3D1 +22.12° (c 3.3, water); H NMR
(300 MHz, D2O): l 8.14 (s, 1 H, Im H-5), 8.12
(s, 1 H, Im H-5), 4.93 (d, 1 H, J1,2 3.2 Hz,
H-1), 4.05–4.00 (m, 4 H, NCH2), 3.83 (dd, 1
H, J6eq,6ax 12, J5,6eq 2.3 Hz, H-6eq), 3.80–3.68
(m, 4 H, H-5, H-6ax, OCH2), 3.60–3.56 (m, 2
H, OCH2), 3.54–3.40 (m, 2 H, H-3, H-4), 3.39
(s, 3 H, OCH3), 3.32 (m, 1 H, H-2), 2.42 (s, 6
H, Im 2ꢀCH3), 1.84–1.80 (m, 4 H, CH2),
13
1.64–1.59 (m, 4 H, CH2); C NMR (75 MHz,
D2O): l 134.43 (Im C-2), 121.79 (Im C-4),
119.81 (Im C-5), 97.28 (C-1), 81.14 (C-4),
79.32 (C-2), 72.51 (OCH2), 71.64(C-3), 70.25
(OCH2), 69.14 (C-5), 60.46 (C-6), 54.88
(OCH3), 49.10, 49.06 (NCH2), 26.36, 26.30,
26.11, 26.03 (CH2); CIHRMS m/z 439.2565
13
1.58–1.56 (m, 4 H, CH2); C NMR (75 MHz,
D2O): l 146.77 (Im C-2), 143.33, 143.31 (Im
C-4), 122.06 (Im C-5), 97.15 (C-1), 81.07 (C-
4), 79.17 (C-2), 72.64 (OCH2), 71.60 (C-3),
70.06 (OCH2), 69.31 (C-5), 60.49 (C-6), 54.85
(OCH3), 47.16, 47.10 (NCH2), 26.22, 26.10,
26.06 (CH2), 11.72 (ImꢀCH3); CIHRMS m/z
557.2550 [M−2 HCl+H]+ ([C23H38Cl2-
N6O10−2 HCl+H] requires 557.2571). Anal.
Calcd for C23H38Cl2N6O10: C, 43.88; H, 6.08;
N, 13.35. Found: C, 43.58; H, 6.21; N, 13.47.
[M−2
HCl+H]+
([C21H36Cl2N4O6 −2
HCl+H] requires 439.2557). Anal. Calcd for
C21H36Cl2N4O6: C, 49.32; H, 7.09; N, 10.95.
Found: C, 49.59; H, 7.20; N, 10.64.
Methyl
dazolyl)butyl]-h-
2,3-O-bis[4-(N-(2-methyl)imi-
-glucopyranoside dihydro-
D
chloride (5b).—Compound 5b was prepared
according to the procedure for 5a. Starting
from the sugar bis-methylimidazole (4b, 150
Methyl
butyl]-h-
2,3-O-bis[4-(N-benzimidazolyl)-
-glucopyranoside dihydrochloride
D
mg, 0.27 mmol), the pure
D
-glucoside bis-imi-
(5d).—Prepared according to the procedure
for 5a. Starting from the bis-benzimidazole
dazole hydrochloric acid salt (5b, 145 mg,
ꢀ100%) was obtained as a syrup; [h]D31
+
D
-glucoside (4d, 80 mg, 0.127 mmol), the pure
1
38.75° (c 4.0, water); H NMR (300 MHz,
D2O): l 7.37 (bs, 2 H, Im H-4), 7.31 (bs, 2 H,
Im H-5), 4.95 (d, 1 H, J1,2 3.3 Hz, H-1), 4.13
(bs, 7 Hz, 4 H, NCH2), 3.82–3.62 (m, 8 H,
H-3, H-5, H-6eq, H-6ax, 2OCH2), 3.50–3.39
(m, 5 H, H-2, H-4, OCH3), 2.61 (bs, 6 H, Im
2ꢀCH3), 1.90 (bs, 4 H, CH2), 1.61 (bs, 4 H,
CH2); 13C NMR (75 MHz, D2O): l 144.05 (Im
C-2), 121.52 (Im C-4), 117.78 (Im C-5), 97.28
(C-1), 81.10 (C-4), 79.32 (C-2), 72.57 (OCH2),
71.64 (C-3), 70.32 (OCH2), 69.16 (C-5), 60.51
(C-6), 54.90 (OCH3), 47.17 (NCH2), 26.25,
26.17, 25.91 (CH2), 10.02 (ImꢀCH3);
CIHRMS m/z 467.2807 [M−2 HCl+H]+
deprotected -glucoside bis-benzimidazole hy-
D
drochloric acid salt (5d, 77 mg, 99.2%) was
obtained. mp 74–76 °C; [h]2D9 +34.50° (c 2.0,
1
water); H NMR (300 MHz, D2O): l 9.18 (s,
1 H, Bim H-2), 9.16 (s, 1 H, Bim H-2),
7.81–7.74 (m, 4 H, Bim H-4,7), 7.59–7.55 (m,
4 H, Bim H-5,6), 4.92 (d, 1 H, J1,2 3.6 Hz,
H-1), 4.43 (t, J 7 Hz, 2 H, NCH2), 4.39 (t, J 7
Hz, 2 H, NCH2), 3.84 (dd, 1 H, J6eq,6ax 12,
J5,6eq 2.4 Hz, H-6eq), 3.75–3.67 (m, 4 H,
OCH2, H-5 and H-6ax), 3.62–3.57 (m, 2 H,
OCH2), 3.54–3.40 (m, 2 H, H-3, H-4), 3.37 (s,
3 H, OCH3), 3.32 (dd, 1 H, J2,3 9 Hz, H-2),
1.97–1.89 (m, 4 H, CH2), 1.59–1.53 (m, 4 H,
CH2); 13C NMR (75 MHz, D2O): l 139.80,
139.73 (Bim C-2), 130.82, 130.48 (Bim C-9),
127.03, 126.61 (Bim C-8), 114.67 (Bim C-5,6),
112.84 (Bim C-4,7), 97.12 (C-1), 81.03 (C-4),
([C23H40Cl2N4O6−2
HCl+H]
requires
467.2870). Anal. Calcd for C23H40Cl2N4O6: C,
51.20; H, 7.47; N, 10.39. Found: C, 51.38; H,
7.54; N, 10.14.

C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
323
acid salt (5f, 95 mg, 97.2%) was obtained. mp
79.16 (C-2), 72.46 (OCH2), 71.59 (C-3), 69.93
(OCH2), 69.23 (C-5), 60.44 (C-6), 54.84
(OCH3), 46.77 (NCH2), 26.27, 26.18, 25.62,
25.48 (CH2); CIHRMS m/z 539.2856 [M−2
HCl+H]+ ([C29H40Cl2N4O6 −2 HCl+H] re-
1
146–148 °C; [h]2D9 +20.85° (c 10.6, water); H
NMR (300 MHz, D2O): l 8.65 (d, J 10 Hz, 1
H, Bim H-4), 8.49 (d, J 2 Hz, 1 H, Bim H-4),
8.24–8.21 (m, 2 H, Bim H-6), 7.95–7.79 (m, 2
H, Bim H-7), 4.87 (d, 1 H, J1,2 3.3 Hz, H-1),
4.45 (bs, 4 H, NCH2), 3.74–3.44 (m, 8 H, 2
OCH2, H-3, H-5, H-6eq and H-6ax), 3.40 (t, 1
H, J3,4=J4,5 9 Hz, H-4), 3.30 (s, 3 H, OCH3),
3.26 (dd, 1 H, J2,3 10 Hz, H-2), 2.91 (m, 12 H,
Bim 2-CH3), 1.91 (bs, 4 H, CH2), 1.63 (bs, 4
quires
539.2870).
Anal.
Calcd
for
C29H40Cl2N4O6: C, 56.95; H, 6.59; N, 9.16.
Found: C, 57.13; H, 6.69; N, 9.01.
Methyl 2,3-O-bis[4-(N-(5,6-dimethyl)ben-
zimidazolyl)butyl]-h- -glucopyranoside dihy-
D
drochloride (5e).—Compound 5e was pre-
pared according to the procedure reported for
the preparation of 5a. Starting from the pro-
13
H, CH2); C NMR (75 MHz, D2O): l 155.62,
155.55 (Bim C-8), 145.34, 145.16 (Bim C-5),
135.65, 133.89 (Bim C-2), 131.50, 129.40 (Bim
C-9), 121.64, 121.14 (Bim C-6), 114.92, 114.49
(Bim C-4), 110.83, 109.49 (Bim C-7), 97.21
(C-1), 81.01 (C-4), 79.30 (C-2), 72.38 (OCH2),
71.59 (C-3), 70.14 (OCH2), 69.10 (C-5), 60.49
(C-6), 54.84 (OCH3), 45.47, 45.40 (NCH2),
26.50, 26.41, 25.34, 25.25 (CH2), 11.68 (Bim
2-CH3); CIHRMS m/z 657.2830 [M−2
HCl+H]+ ([C31H42Cl2N6O10−2 HCl+H] re-
tected
dazole (4e, 90 mg, 0.132 mmol), the pure free
-glucoside bis-benzimidazole hydrochloric
D
-glucoside bis-(5,6-dimethyl)benzimi-
D
acid salt (5e, 86 mg, 98.0%) was obtained. mp
1
102–104 °C; [h]2D9 +27.25° (c 4.0, water); H
NMR (300 MHz, D2O): l 8.99 (s, 1 H, Bim
H-2), 8.96 (s, 1 H, Bim H-2), 7.32 (t, 20 Hz, 4
H, Bim H-4,7), 4.93 (d, 1 H, J1,2 3.3 Hz, H-1),
4.24 (t, J 7 Hz, 2 H, NCH2), 4.18 (t, J 7 Hz,
2 H, NCH2), 3.83 (dd, 1 H, J6eq,6ax 12, J5,6eq
2.1 Hz, H-6eq), 3.79–3.65 (m, 4 H, OCH2, H-5
and H-6ax), 3.60–3.55 (m, 2 H, OCH2), 3.53–
3.40 (m, 2 H, H-3, H-4), 3.37 (s, 3 H, OCH3),
3.31 (dd, 1 H, J2,3 10 Hz, H-2), 2.24 (s, 3 H,
Bim 5-CH3), 2.22 (s, 3 H, Bim 5-CH3), 2.21 (s,
3 H, Bim 6-CH3), 2.16 (s, 3 H, Bim 6-CH3),
1.91–1.80 (m, 4 H, CH2), 1.58–1.50 (m, 4 H,
CH2); 13C NMR (75 MHz, D2O): l 138.27,
138.17 (Bim C-2), 137.34, 137.29 (Bim C-9),
136.91 (Bim C-8), 129.01 (Bim C-5), 128.69
(Bim C-6), 113.82, 113.76 (Bim C-4), 111.95,
111.89 (Bim C-7), 97.02 (C-1), 80.95 (C-4),
79.02 (C-2), 72.32 (OCH2), 71.58 (C-3), 69.61
(OCH2), 69.36 (C-5), 60.45 (C-6), 54.83
(OCH3), 46.60 (NCH2), 26.29, 26.18, 25.69,
25.53 (CH2), 19.64, 19.61 (Bim 5-CH3), 19.44,
19.41 (Bim 6-CH3); CIHRMS m/z 594.3401
[M−2 HCl]+ ([C33H48Cl2N4O6 −2 HCl] re-
quires
657.2884).
Anal.
Calcd
for
C31H42Cl2N6O10: C, 51.03; H, 5.80; N, 11.52.
Found: C, 51.39; H, 5.88; N, 11.30.
Methyl 2,3-O-bis[5-(N-imidazolyl)pentyl]-h-
-glucopyranoside dihydrochloride (5g).—Pre-
D
pared as described for 5a. Starting from the
-glucoside bis-imidazole (4g, 80 mg, 0.144
mmol), the pure -glucoside bis-imidazole hy-
D
D
drochloric acid salt (5g, 75 mg, 96.7%) was
obtained as a syrup; [h]2D9 +51.11° (c 5.4,
1
water); H NMR (300 MHz, D2O): l 8.76–
8.75 (m, 2 H, Im H-2), 7.55–7.52 (m, 2 H, Im
H-4), 7.49–7.47 (m, 2 H, Im H-5), 4.92 (d, 1
H, J1,2 3.6 Hz, H-1), 4.28–4.23 (m, 4 H,
NCH2), 3.85 (dd, 1 H, J6eq,6ax 12, J5,6eq 2.1 Hz,
H-6eq), 3.76–3.57 (m, 7 H, H-3, H-5, H-6ax,
2OCH2), 3.42 (dd, 1 H, J3,4=J4,5 9 Hz, H-4),
3.39 (s, 3 H, OCH3), 3.34 (dd, 1 H, J2,3 9 Hz,
H-2), 1.97–1.87 (m, 4 H, CH2), 1.65–1.58 (m,
4 H, CH2), 1.41–1.33 (m, 4 H, CH2); 13C
NMR (75 MHz, D2O): l 134.38 (Im C-2),
121.87 (Im C-4), 119.75 (Im C-5), 97.44 (C-1),
81.05 (C-4), 79.30 (C-2), 73.07 (OCH2), 71.64
(C-3), 70.89 (OCH2), 69.22 (C-5), 60.56 (C-6),
54.96 (OCH3), 49.33 (NCH2), 29.14, 29.11,
28.74, 28.61 22.18, 22.16 (CH2); CIHRMS
m/z 467.2870 [M−2 HCl+H]+ ([C23H40Cl2-
N4O6−2 HCl+H] requires 467.2870). Anal.
Calcd for C23H40Cl2N4O6: C, 51.20; H, 7.47;
N, 10.39. Found: C, 51.37; H, 7.53; N, 10.11.
quires
594.3417).
Anal.
Calcd
for
C33H48Cl2N4O6: C, 59.36; H, 7.25; N, 8.39.
Found: C, 59.61; H, 7.31; N, 8.23.
Methyl 2,3-O-bis[4-(N-(2-methyl-5-nitro)-
benzimidazolyl)butyl]-h- -glucopyranoside di-
D
hydrochloride (5f).—Prepared according to
the procedure reported for 5a. Starting from
the protected sugar bis(2-methyl-5-nitro) imi-
dazole (4f, 100 mg, 0.134 mmol), the pure
D
-glucoside bis-benzimidazole hydrochloric

324
C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
4(a)), 75.84 (C-3(b)), 72.59 (OCH2), 71.48
Methyl 2,3-O-bis[4-(N-imidazolyl)hexyl]-h-
-glucopyranoside dihydrochloride (5h).—Pre-
pared according to the procedure described
for 5a. Starting from the -glucoside bis-imi-
dazole (4h, 55 mg, 0.094 mmol), the pure
-glucoside bis-imidazole hydrochloric acid
(C-3(a)),70.03 (OCH2), 69.36 (C-5(b)), 69.24
(C-5(a)), 60.69 (C-6(b)), 60.57 (C-6(a)), 49.14
(NCH2), 26.37, 26.25, 26.17, 26.02 (CH2);
CIHRMS m/z 425.2314 [M−2 HCl+H]+
D
D
([C20H34Cl2N4O6−2
HCl+H]
requires
D
425.2400). Anal. Calcd for C20H34Cl2N4O6·
H2O: C, 48.29; H, 6.89; N, 11.26. Found: C,
48.41; H, 6.99; N, 10.95.
salt (5h, 51 mg, 95.5%) was obtained as a
1
syrup; [h]2D9 +44.75° (c 4.0, water); H NMR
(300 MHz, D2O): l 8.75 (bs, 2 H, Im H-2),
7.53–7.48 (m, 4 H, Im H-4,5), 4.94 (d, 1 H,
J1,2 3.3 Hz, H-1), 4.27–4.23 (m, 4 H, NCH2),
3.86 (dd, 1 H, J6eq,6ax 12, J5,6eq 2.1 Hz, H-6eq),
3.76–3.60 (m, 7 H, H-3, H-5, H-6ax, 2OCH2),
3.49 (dd, 1 H, J3,4=J4,5 9 Hz, H-4), 3.41 (s, 3
H, OCH3), 3.36 (dd, 1 H, J2,3 9 Hz, H-2), 1.90
(bs, 4 H, CH2), 1.57 (bs, 4 H, CH2), 1.36 (bs,
8 H, CH2); 13C NMR (75 MHz, D2O): l
134.32 (Im C-2), 121.84 (Im C-4), 119.71 (Im
C-5), 97.47 (C-1), 81.03 (C-4), 79.29 (C-2),
73.40 (OCH2), 71.63 (C-3), 71.10 (OCH2),
69.27 (C-5), 60.55 (C-6), 54.98 (OCH3), 49.38
(NCH2), 29.32, 29.28, 29.11, 28.92, 25.25,
25.20, 24.72 (CH2); CIHRMS m/z 495.3196
[M−2 HCl+H]+ ([C25H42N4O6 −2 HCl+
H] requires 495.3183). Anal. Calcd for
C25H44Cl2N4O6: C, 52.91; H, 7.81; N, 9.87.
Found: C, 53.09; H, 7.89; N, 9.66.
Methyl 2,3-O-bis[4-(N-imidazolyl)butyl]-h-
D
-glucopyranoside (7a).—The deprotected
D
-
glucoside bis-imidazole hydrochloride (5a, 50
mg, 0.098 mmol) was dissolved in water (5
mL). The resulting solution was neutralized
with 28% analytic grade ammonium hydrox-
ide under stirring, and then the mixture was
evaporated to dryness. The solid residue was
washed with CHCl3 (3×20 mL). The com-
bined CHCl3 solution was evaporated to af-
ford the pure compound 7a as a syrup (41 mg,
1
96.3%); [h]2D5 +50.06° (c 8.0, CHCl3); H
NMR (300 MHz, CDCl3): l 7.41 (d, J 8 Hz, 2
H, Im H-2), 6.93 (d, J 12 Hz, 2 H, Im H-4),
6.83 (d, J 8 Hz, 2 H, Im H-5), 4.71 (d, J1,2 3.3
Hz, 1 H, H-1), 4.29 (bs, 2 H, OH), 3.90–3.82
(m, 4 H, NCH2, H-6eq, H-5), 3.75 (bs, 2 H,
H-4, H-6ax), 3.69 (t, J 6 Hz, NCH2), 3.53–3.44
(m, 5 H, 2 OCH2, H-2), 3.32 (s, 3 H, OCH3),
3.18 (m, J2,3 9 Hz, 1 H, H-3), 1.79–1.68 (m, 4
2,3-O-bis[4-(N-imidazolyl)butyl]- -glucose
D
dihydrochloride (6a).—A mixture of analytic
13
grade conc HCl (4 mL), distilled water (2 mL)
H, CH2), 1.50–1.40 (m, 4 H, CH2); C NMR
and the methyl 4,6-O-benzylidene a-
D
-
(75 MHz, CDCl3): l 136.99 (Im C-2), 128.91,
128.54 (Im C-4), 118.98, 118.86 (Im C-5),
97.66 (C-1), 81.31 (C-4), 80.31 (C-2), 72.39
(OCH2), 71.56 (C-3), 70.46 (C-5), 70.14
(OCH2), 61.81 (C-6), 55.01 (OCH3), 46.78,
46.73 (NCH2), 27.92, 27.88, 27.06, 26.87
(CH2); CIHRMS m/z 439.2553 ([C21H34-
N4O6+H] requires 439.2557). Anal. Calcd for
C21H34N4O6: C, 57.52; H, 7.81; N, 12.78.
Found: C, 57.46; H, 7.78; N, 12.96.
glucopyranoside bis-imidazole (4a, 60 mg,
0.114 mmol) was stirred at 60 °C for 24 h. The
solvents were evaporated to dryness under
reduced pressure. The resulting solid residue
was washed with petroleum ether (30–60 °C)
and dried to afford the corresponding totally
deprotected
D
-glucopyranoside bis-imidazole
hydrochloric acid salt (6a) as a syrup (53 mg,
93.9%); [h]2D5 +37.14° (c 7.3, watre); 1H NMR
(300 MHz, D2O): l 8.77 (s, 2 H, Im H-2), 7.54
(bs, 2 H, Im H-4), 7.48 (bs, 1 H, Im H-5), 5.36
(d, J1,2 2.6 Hz, 0.5 H, H-1(a)), 4.65 (d, J1,2 8.1
Hz, 0.5 H, H-1(b)), 4.28 (t, 7 Hz, 4 H, NCH2),
3.84–3.42 (m, 9 H, H-3, H-4, H-5, H-6eq, 6ax
and 2 OCH2), 3.35 (m, 0.5 H, H-2(a)), 3.08 (t,
0.5 H, H-2(b)), 1.97 (bs, 4 H, CH2), 1.61 (bs,
4 H, CH2); 13C NMR (75 MHz, D2O): l
134.46 (Im C-2), 121.85 (Im C-4), 119.82 (Im
C-5), 95.88 (C-1(b)), 90.08 (C-1(a)), 84.00 (C-
4(a)), 82.37 (C-4(b)), 80.83 (C-2(b)), 79.49 (C-
2,3-O-bis[4-(N-imidazolyl)butyl]- -glucose
D
(8a).—Compound 8a was prepared according
to the procedure reported for the preparation
of 7a. Starting from the totally deprotected
D
-glucoside bis-imidazole hydrochloride (6a,
40 mg, 0.08 mmol), the pure free -glucoside
D
bis-imidazole (8a, 32 mg, 94.1%) was obtained
as a syrup; [h]2D5 +33.68° (c 4.2, CHCl3); H
1
NMR (300 MHz, CDCl3): l 7.42 (s, 2 H, Im
H-2), 6.95 (bs, 2 H, Im H-4), 6.86 (bs, 1 H, Im
H-5), 5.19 (d, J1,2 2.7 Hz, 0.5 H, H-1(a)), 4.62

C. Zhou, A. Hassner / Carbohydrate Research 333 (2001) 313–326
325
(d, J1,2 7.9 Hz, 0.5 H, H-1(b)), 3.91–3.83 (m, 4
H, NCH2, H-5, H-6eq), 3.76–3.39 (m, 9 H,
H-3, H-4, H-6ax and 2 OCH2), 3.16 (m, 0.5 H,
H-2(a)), 3.02 (t, 0.5 H, H-1(b), 1.80–1.69 (bs,
4 H, CH2), 1.58–1.47 (bs, 4 H, CH2); 13C
NMR (75 MHz, CDCl3): l 136.95, 136.89 (Im
C-2), 128.99,128.60 (Im C-4), 118.86, 118.76
(Im C-5), 96.11 (C-1(b)), 91.01 (C-1(a)), 84.14
(C-4 (a)), 82.58 (C-4(b)), 81.34 (C-2 (b)), 80.18
(C-2(a)), 74.69 (C-3(b)), 72.40 (OCH2), 70.99
(C-3(a)), 70.74 (C-5(b)), 70.57 (C-5(a)), 70.01
(OCH2), 61.86 (C-6(b)), 61.69 (C-6(a)), 46.59,
46.54 (NCH2), 27.91, 27.80, 26.99, 26.85
(CH2); CIHRMS m/z 425.2399 [M+H]+
([C20H32N4O6+H] requires 425.2400). Anal.
Calcd for C20H32N4O6: C, 56.59; H, 7.60; N,
13.20. Found: C, 56.48; H, 7.55; N, 13.31.
Methyl 2,3-O-butylene-4,6-O-benzylidene-h-
—Method A: Compound 10 (576 mg, 75%)
was obtained as a syrup according to the
procedure for 9 (method A) from 1,2-bis(bro-
momethyl) benzene (1.32 g, 5 mmol), the bis-
hydroxy sugar (2, 565 mg, 2 mmol), NaH (400
mg 60%, 10 mmol) and DMF (10 mL).
Method B: the
D
-Glucoside (10, 115 mg,
-glucoside 2)
98.5%, based on the reacted
D
was obtained as a syrup according to the
procedure for 9 (method B) from 1,2-bis(bro-
momethyl) benzene (1.056 g, 4 mmol), the
bis-hydroxy sugar (2, 508 mg, 1.8 mmol),
dibenzo-18-crown-6 (50 mg, 0.138 mmol), tet-
rabutylammonium bromide (50 mg, 0.155
mmol), NaOH (400 mg, 10 mmol) and DMF
1
(20 mL); [h]2D5 +138.75° (c 2.4, CHCl3); H
NMR (300 MHz, CDCl3): l 7.58 (d, J 6 Hz, 2
H, PhꢀH), 7.43–7.39 (m, 3 H, PhꢀH), 7.29–
7.26 (m, 2 H, PhꢀH), 7.18–7.15 (m, 2 H,
PhꢀH), 5.55 (s, 1 H, PhꢀCH), 5.24–4.99 (m, 4
H, PhꢀCH2O), 4.90 (d, 1 H, J1,2 3.7 Hz, H-1),
4.31 (dd, 1 H, J6eq,6ax 9, J5,6eq 5 Hz, H-6eq),
4.06 (t, J 9 Hz, 1 H, H-3), 3.89 (ddd, 1 H,
H-5), 3.73 (t, J5,6ax 10 Hz, H-6ax), 3.67 (dd, 1
H, H-2), 3.56 (t, J3,4 =J4,5 9 Hz, 1 H, H-4),
3.46 (s, 3 H, OCH3); 13C NMR (75 MHz,
CDCl3): l 137.42, 137.04, 136.26, 130.05,
129.69, 129.14, 128.31, 128.03, 127.89, 126.47
(PhꢀC), 101.90 (PhꢀCH), 99.14 (C-1), 80.51
(C-4), 80.31 (C-2), 78.18 (C-3), 73.64 (OCH2),
73.11 (OCH2), 69.09 (C-6), 62.21 (C-5), 55.28
(OCH3); CIHRMS m/z 384.1561 [M]+
(C22H24O6 requires 384.1573).
D
-glucopyranoside (9).—Method A: Com-
pound 9 (456 mg, 58.1%) was obtained as a
syrup according to the procedure for 3a from
1,4-dibromo butane (3 mL), the bis-hydroxy
sugar (2, 660 mg, 2.34 mmol), NaH (400 mg
60%, 10 mmol) and DMF (10 mL). 1,4-Di-
bromo butane was added at 60 °C. Method B:
A mixture of the bis-hydroxy sugar (2, 400
mg, 1.4 mmol), dibenzo-18-crown-6 (40 mg,
0.11 mmol), tetrabutylammonium bromide (40
mg, 0.12 mmol), NaOH (500 mg, 12.5 mmol)
and 1,4-dibromo butane (10 mL) in DMF (5
mL) was stirred at 100 °C for 2 days. Water
(50 ml) was added. The workup was the same
as method A. The cyclic
D
-glucoside (9, 67
mg, 97.6%, based on the reacted
D
-glucoside
2) was obtained as a syrup; [h]2D5 +42.67° (c
1
3.1, CHCl3); H NMR (300 MHz, CDCl3): l
Acknowledgements
7.48–7.45 (m, 2 H, Ph H-2,6), 7.34–7.27 (m, 3
H, Ph H-3,4,5), 5.48 (s, 1 H, PhꢀCH), 4.74 (d,
1 H, J1,2 3.6 Hz, H-1), 4.29 (dd, 1 H, J6eq,6ax 9,
J5,6eq 3.9 Hz, H-6eq), 4.14–4.00 (m, 2 H,
OCH2), 3.85–3.65 (m, 5 H, OCH2, H-3, H-5
and H-6ax), 3.58–3.36 (m, 5 H, H-2, H-4 and
OCH3), 1.87–1.64 (m, 4 H, CH2); 13C NMR
(75 MHz, CDCl3): l 137.37 (Ph C-1), 128.92
(Ph C-4), 128.11 (Ph C-3,5), 126.32 (Ph C-2,6),
101.63 (PhꢀCH), 99.79 (C-1), 81.75 (C-4),
80.05 (C-2), 78.97 (C-3), 73.18 (OCH2), 72.20
(OCH2), 68.99 (C-6), 62.78 (C-5), 55.16
(OCH3), 27.20 (CH2); CIHRMS m/z 337.1639
[M+H]+ ([C18H24O6+H] requires 337.1651).
Methyl 2,3-O-(1,2-phenylenedimethylene)-
Support of this research from the Fred and
Barbara Kort Sino-Israel Postdoctoral Fel-
lowship Program as well as from the Marcus
Center of Medicinal Chemistry is gratefully
acknowledged. The authors thank Dr Hugo
E. Gottlieb for valuable help with the NMR
spectra.
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