Preparation of quinoline hexose analogs as novel chloroquine-resistant malaria treatments (1). Synthesis of 4-hydroxyquinoline-β-glucosides

Article abstract of DOI:10.1248/cpb.55.821

Quinoline hexose analogs are expected to be useful as novel agents for treatment of chloroquine-resistant malaria. Here, we report preparation of 4-hydroxy quinoline-β-glucosides from anilines in 4 steps.

Full text of DOI:10.1248/cpb.55.821

May 2007
Notes
Chem. Pharm. Bull. 55(5) 821—824 (2007)
821
Preparation of Quinoline Hexose Analogs as Novel Chloroquine-Resistant
b
Malaria Treatments (1). Synthesis of 4-Hydroxyquinoline- -glucosides
Hiroshi SUZUKI,*,a Nagwa S. M. ALY,b Yusuke WATAYA,b Hye-Sook KIM,b Ikumi TAMAI,c
e
Masaki KITA,d and Daisuke UEMURA
a National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine; Inada-cho,
Obihiro, Hokkaido 080–0555, Japan: b Faculty of Pharmaceutical Sciences, Okayama University; 1–1–1 Tsushima Naka,
Okayama, Okayama 700–8530, Japan: c Faculty of Pharmaceutical Sciences, Tokyo University of Science; 2641 Yamasaki,
Noda, Chiba 278–8510, Japan: d Research Center for Materials Science, Nagoya University; and eDepartment of
Chemistry, Graduate School of Sciences, Nagoya University; Chikusa-ku, Nagoya, Aichi 464–8602, Japan.
Received December 23, 2006; accepted February 19, 2007; published online February 22, 2007
Quinoline hexose analogs are expected to be useful as novel agents for treatment of chloroquine-resistant
malaria. Here, we report preparation of 4-hydroxy quinoline-b-glucosides from anilines in 4 steps.
Key words malaria; chloroquine-resistant malaria treatment; quinoline-glucosides
Malaria is one of the most serious infectious diseases in cordingly, quinoline hexose analogs can be expected to con-
the developing world, with mortality estimated at ca. 2.5 mil- centrate quinolines into the cytoplasm of the malaria parasite
lion deaths annually, mainly caused by the erythrocytic-stage by the above DDS and serve as novel chemotherapeutic can-
cells of Plasmodium falciparum.1) For four decades, malaria didates for treatment of CQ-resistant malaria. Here, we re-
has been treated effectively with the 4-aminoquinoline ana- port the synthesis of quinoline-b-glucosides in a systematic
log chloroquine (CQ). However, CQ-resistant strains of Plas- preparation of quinoline hexose analogs.
modium spp. have spread and continue to evolve.1) Therefore,
the development of new chemotherapeutic agents that are ef- Results and Discussion
fective against CQ-resistant malaria is required.
The target compounds 5a—f were prepared from the cor-
Malaria parasites are known to take up hemoglobin in their responding anilines (1a—f) in 4 steps shown in Charts 1, 2,
food vacuole as a source of amino acids and release ferripro- 3, and 4.
toporphyrin IX (FP IX) into the food vacuole and cytoplasm
As shown in Chart 1, 4-hydroxyquinoline-3-ethylesters
in the erythrocytic stage.2) FP IX is very toxic to Plasmodium 2a—f were prepared from the corresponding anilines 1a—f
spp., which explains why they have detoxification systems to by a modification of the method of Price and co-workers7) in
deal with this complex.2) The parasite’s food vacuole is the yields shown.
acidic, and so CQ accumulates in the vacuole due to its basic
Hydrolysis of 2a—f with 2 N-sodium hydroxide at room
quinoline moiety.2) CQ is thought to inhibit detoxification of temperature for 2 h afforded the corresponding crude quino-
FP IX in the food vacuole by forming a complex between the line carbonic acids, which were then heated in diphenylether
quinolinic nitrogen of CQ and Fe(II) of FP IX.2) Various under reflux. The decarboxylation described above gave
mechanisms have been proposed to explain CQ resistance, compounds 3a—f in the yields shown in Chart 2.
but none have been proven conclusively.3) All of the pro-
The quinoline ring is generally sensitive to reductive con-
posed mechanisms of CQ resistance have several points in ditions. The benzyl group is considered unsuitable as a pro-
common: (1) the concentration of CQ in the food vacuole of tecting group in quinoline glucosides, because the deprotec-
CQ-resistant strains is lower than that in CQ-sensitive strains, tion reaction requires reductive conditions. Therefore, the
and (2) CQ-resistance is reversible because CQ-resistant acetyl group was adopted for protection of the hydroxyl
strains can recover CQ sensitivity under some conditions.3) In group of D-glucose. 1-Bromo-tetraacetyl-a-D-glucose was
this context, quinoline analogs that can be concentrated in prepared from pentaacetyl-D-glucose and 30%-hydrobromic
the cytoplasm of malaria parasites may be suitable as novel acid in acetic acid solution.8) The reaction conditions were
chemotherapeutic candidates against CQ-resistant malaria determined by using 4-hydroxyquinoline (3g) and 7-chloro-
because they would facilitate maintenance of a high concen- 4-hydoxyquinoline (3h), both of which were commercial
tration of quinoline in the food vacuole by osmosis, and the
detoxification of FP IX in the cytoplasm can be inhibited.
Metabolism and transport of carbohydrates are essential
for cell viability. Carbohydrates are transported into the cell
through hexose transporters (HTPs), which are membrane
proteins expressed on the cell surface.4) Furthermore, HTPs
transport hexose analogs, such as glycosides.5) These mole-
cules can be utilized as novel drug delivery systems (DDS)
that can act as carriers and import medicines efficiently into
the cell through HTPs.
Malaria parasites have a high demand for carbohydrates in
the erythrocytic stage and often cause hypoglycemia.6) Ac-
Chart 1
∗ To whom correspondence should be addressed. e-mail: hiroshis@obihiro.ac.jp
© 2007 Pharmaceutical Society of Japan

822
Vol. 55, No. 5
Chart 4
Chart 2
Anti-malarial assays of other 4 and 5 are currently underway
and the results will be reported in a subsequent paper.
Experimental
The NMR spectra were obtained using a JEOL JNM-ECA 500 spectrome-
ter with tetramethylsilane (TMS) as an internal standard. Mass spectra were
recorded with a PE Biosystems QSTAR spectrometer. IR spectra were per-
formed with a JASCO FT/IR-420 spectrometer.
Preparation of 2 Typical Procedure: A mixture of 1 (10.7 g, 100 mmol)
and ethyl ethoxymethylenediethylmalonate (23.3 g, 110 mmol) in toluene
(100 ml) was heated under reflux for 1 h and then evaporated in vacuo.
Diphenylether (150 ml) was added to the residue and the mixture was heated
under reflux for 1 h or heated at 130 °C, as shown in Chart 1. After the reac-
tion mixture was cooled to room temperature, n-hexane was added and the
precipitates thus produced were filtered. The filtrate was washed with ethyl
acetate, which yielded 2a (10.5 g, 45%). Compounds 2 were not subjected to
further purification.
Preparation of 3 Typical Procedure: A mixture of 2a (10.5 g) and 2 N-
sodium hydroxide (100 ml) was heated under reflux for 1 h. The reaction
mixture was cooled to room temperature and 2 N-hydrochloride was added
until precipitates were produced. The precipitates were filtered, washed with
water, and dried. The obtained quinoline carbonic acid was not purified fur-
ther. Diphenylether (50 ml) was added to the colorless powder, and the mix-
ture was heated under reflux for 1 h. The reaction mixture was cooled to
Chart 3
products. A mixture of 3, 1-bromo-tetraacetyl-a-D-glucose,
and 2-fold equiv. silver carbonate in toluene previously dehy-
drated by passage through molecular sieve 4A was heated
under reflux for 1 h under a stream of argon gas. The reaction
mixture was subjected to silica gel column chromatography
with ethyl acetate as the eluent and afforded quinoline-b-glu-
coside tetraacetates 4. Although unreacted 3 was recovered,
the formation of a-anomers and glucoside-orthoesters was room temperature and n-hexane was added. Compound 3a (2.3 g, 32%) was
obtained by filtration and washing with ethyl acetate.
Preparation of 4 Typical Procedure: A suspension of 3a (548 mg,
3.44 mmol), 1-bromo-tetraacetyl-a-D-glucose (1.56 g, 3.79 mmol) and silver
carbonate (1.24 g, 3.79 mmol) in toluene previously dehydrated by passage
not confirmed in all cases, as shown in Chart 3. The low
yield of 4e was considered due to insolubility of 3e in boiling
toluene.
Deprotection of acetylated saccharides is generally per-
formed with a strong base, such as sodium methoxide,
sodium hydroxide, or potassium hydroxide. Deacetylation of
4 with sodium methoxide was carried out and the reaction
mixture was neutralized with sulfuric acid. The workup had
some problems: (1) large amounts of mineral salts were pro-
duced, and so it was not easy to isolate glucosides 5, and (2)
the reaction showed poor reproducibility. When an acidic
ion-exchange resin was employed in the neutralization step,
quinolinium salts were obtained. Therefore, deacetylation of
4 with a mineral base, such as sodium methoxide, was not
useful. With the use of ammonia gas for deacetylation of 4,
acetamide is produced, which makes it difficult to separate to
5. Therefore, deprotection of 4 with a basic ion-exchange
resin was carried out. A mixture of 4 and a 2- or 3-fold ex-
through molecular sieve 4A (25 ml) was heated under reflux for 1 h in a
stream of argon gas and cooled to room temperature. The insoluble products
were filtered off and the filtrate was evaporated in vacuo. Ethyl acetate was
added to the residue. Compound 4a (1.48 g, 86%) was obtained by silica gel
column chromatography of the solution with ethyl acetate as the eluent.
4-(b-O-Tetraacetyl-D-glucosyloxy)-6-methylquinoline (4a) as Colorless
Needles (Diisopropylether) (86%): mp 175—177 °C. 1H-NMR (CDCl3) d:
2.05 (3H, s), 2.06 (3H, s), 2.08 (3H, s), 2.09 (3H, s), 2.57 (3H, s), 4.07 (1H,
ddd, Jꢀ9.8, 5.3, 2.4 Hz), 4.22 (1H, dd, Jꢀ12.4, 2.4 Hz), 4.33 (1H, dd,
Jꢀ12.4, 5.3 Hz), 5.25 (1H, dd, Jꢀ9.8, 9.4 Hz), 5.41 (1H, dd, Jꢀ9.4, 9.2 Hz),
5.44 (1H, d, Jꢀ7.6 Hz), 5.52 (1H, dd, Jꢀ9.2, 7.6 Hz), 7.00 (1H, d,
Jꢀ5.2 Hz), 7.64 (1H, dd, Jꢀ8.6, 2.0 Hz), 7.88 (1H, d, Jꢀ2.0 Hz), 8.13 (1H,
d, Jꢀ8.6 Hz), 8.75 (1H, d, Jꢀ5.2 Hz). IR (KBr) cmꢁ1: 1749. ESI-MS m/z:
512.1551 (Calcd for C24H27NNaO10 (MꢂNa)ꢂ: 512.1533).
4-(b-O-Tetraacetyl-D-glucosyloxy)-6-methoxyquinoline (4b) as Colorless
1
Needles (Diisopropylether) (56%): mp 171—173 °C. H-NMR (CD3OD) d:
2.02 (3H, s), 2.04 (3H, s), 2.05 (3H, s), 3.95 (s, 3H), 4.21 (1H, dd, Jꢀ12.2,
2.3 Hz), 4.25 (1H, ddd, Jꢀ10.0, 4.9, 2.3 Hz), 4,35 (1H, dd, Jꢀ12.2, 4.9 Hz),
cess of Amberlyst® A-26 (OH) by weight in methanol was 5.19 (1H, dd, Jꢀ10.0, 9.4 Hz), 5.41 (1H, dd, Jꢀ9.5, 7.7 Hz), 5.49 (1H, dd,
Jꢀ9.5, 9.4 Hz), 5.70 (1H, d, Jꢀ7.7 Hz), 7.04 (1H, d, Jꢀ5.5 Hz), 7.23 (1H,
stirred at RT. After 1—2 h, the disappearance of acetates 4
was determined by TLC. Use of an ion-exchange resin al-
dd, Jꢀ9.2, 2.5 Hz), 7.32 (1H, d, Jꢀ2.5 Hz), 7.98 (1H, d, Jꢀ9.2 Hz), 8.64
(1H, d, Jꢀ5.5 Hz). IR (KBr) cmꢁ1: 1742. ESI-MS m/z: 528.1484 (Calcd for
lowed separation without difficulty using only filtration. The
precipitates thus produced were dissolved in methanol and
the filtrates were combined. Evaporation of methanol af-
forded 5 in high yield, as shown in Chart 4.
With regard to anti-malarial activity, 5g showed an EC50
value of 0.15 mg/ml in an in vitro Plasmodium falciparum
culture system, which was almost the same value obtained
with quinine used in commercial anti-malarial preparations.
C24H27NNaO11 (MꢂNa)ꢂ: 528.1482).
4-(b-O-Tetraacetyl-D-glucosyloxy)-7-methoxyquinoline (4c) as Colorless
Needles (Diisopropylether) (62%): mp 170—172 °C. 1H-NMR (CDCl3) d:
2.06 (3H, s), 2.07 (3H, s), 2.08 (6H, s), 3.96 (s, 3H), 4.08 (1H, ddd, Jꢀ10.1,
5.3, 2.3 Hz), 4,23 (1H, dd, Jꢀ12.5, 2.3 Hz), 4.36 (1H, dd, Jꢀ12.5, 5.3 Hz),
5.24 (1H, dd, Jꢀ10.1, 9.5 Hz), 5.43 (1H, d, Jꢀ7.6 Hz), 5.43 (1H, dd, Jꢀ9.5,
9.5 Hz), 5.54 (1H, dd, Jꢀ9.5, 7.6 Hz), 7.03 (1H, d, Jꢀ5.3 Hz), 7.39 (1H, d,
Jꢀ2.8 Hz), 7.47 (1H, dd, Jꢀ9.1, 2.8 Hz), 8.22 (1H, d, Jꢀ9.1 Hz), 8.68 (1H,
d, Jꢀ5.3 Hz). IR (KBr) cmꢁ1: 1742. ESI-MS m/z: 528.1485 (Calcd for

May 2007
823
C24H27NNaO11 (MꢂNa)ꢂ: 528.1482).
7.15 (1H, d, Jꢀ5.3 Hz), 7.61 (1H, dd, Jꢀ8.6, 1.9 Hz), 7.85 (1H, d,
4-(b-O-Tetraacetyl-D-glucosyloxy)-6-phenoxyquinoline (4d) as Colorless
Jꢀ8.6 Hz), 8.16 (1H, d, Jꢀ1.9 Hz), 8.61 (1H, d, Jꢀ5.3 Hz). IR (KBr) cmꢁ1
:
Needles (Diisopropylether) (85%): mp 136—138 °C. H-NMR (CD3OD) d: 3357 (br). ESI-MS m/z: 322.1268 (Calcd for C16H20NO6 (MꢂH)ꢂ:
1
1.90 (3H, s), 2.00 (3H, s), 2.03 (3H, s), 2.04 (3H, s), 4.22 (1H, dd, Jꢀ12.4,
2.3 Hz), 4.22 (1H, ddd, Jꢀ10.0, 4.9, 2.3 Hz), 4.32 (1H, dd, Jꢀ12.4, 4.9 Hz),
322.1291).
4-(b-D-Glucosyloxy)-6-methoxyquinoline (5b) as Colorless Needles
5.16 (1H, dd, Jꢀ10.0, 9.4 Hz), 5.28 (1H, dd, Jꢀ9.6, 7.8 Hz), 5.43 (1H, dd, (Ethanol) (74%): mp 175—177 °C (decomp.). 1H-NMR (CD3OD) d: 3.46
Jꢀ9.6, 9.4 Hz), 5.65 (1H, d, Jꢀ7.8 Hz), 7.08 (2H, ddd, Jꢀ6.7, 2.0, 1.0 Hz), (1H, dd, Jꢀ9.2, 9.2 Hz), 3.56 (1H, dd, Jꢀ9.2, 9.2 Hz), 3.59 (1H, ddd, Jꢀ9.2,
7.14 (1H, d, Jꢀ5.3 Hz), 7.22 (1H, tt, Jꢀ7.4, 1.0 Hz), 7.43 (2H, ddd, Jꢀ7.4, 5.7, 2.3 Hz), 3.69 (1H, dd, Jꢀ9.2, 7.4 Hz), 3.73 (1H, dd, Jꢀ12.6, 5.7 Hz),
6.7, 2.0 Hz), 7.45 (1H, d, Jꢀ2.6 Hz), 7.53 (1H, dd, Jꢀ9.1, 2.6 Hz), 7.98 (1H,
d, Jꢀ9.1 Hz), 8.64 (1H, d, Jꢀ5.3 Hz). IR (KBr) cmꢁ1: 1749. ESI-MS m/z:
590.1663 (Calcd for C29H29NNaO11 (MꢂNa)ꢂ: 590.1638).
3.93 (1H, dd, Jꢀ12.6, 2.3 Hz), 3.96 (3H, s), 5.29 (1H, d, Jꢀ7.4 Hz), 7.17
(1H, d, Jꢀ5.2 Hz), 7.39 (1H, dd, Jꢀ9.2, 2.9 Hz), 7.65 (1H, d, Jꢀ2.9 Hz),
7.85 (1H, d, Jꢀ9.2 Hz), 8.54 (1H, d, Jꢀ5.2 Hz). (KBr) cmꢁ1: 3356 (br). ESI-
MS m/z: 360.1065 (Calcd for C16H19NNaO7 (MꢂNa)ꢂ: 360.1059).
4-(b-O-Tetraacetyl-D-glucosyloxy)-6-N,N-dimethylaminoquinoline (4e) as
Ochre Needles (Diisopropylether) (11%): mp 167—169 °C. 1H-NMR
4-(b-D-Glucosyloxy)-7-methoxyquinoline (5c) as Colorless Needles
(CD3OD) d: 2.03 (3H, s), 2.04 (3H, s), 2.05 (3H, s), 2.06 (3H, s), 3.09 (6H, (Ethanol) (q.): mp 177—181 °C (decomp.). 1H-NMR (CD3OD) d: 3.45 (1H,
s), 4.25 (1H, dd, Jꢀ12.6, 2.3 Hz), 4.25 (1H, ddd, Jꢀ9.7, 5.2, 2.3 Hz), 4.36 dd, Jꢀ9.5, 9.1 Hz), 3.54 (1H, dd, Jꢀ9.1, 9.1 Hz), 3.57 (1H, ddd, Jꢀ9.5, 5.7,
(1H, dd, Jꢀ12.6, 5.2 Hz), 5.20 (1H, dd, Jꢀ9.7, 9.2 Hz), 5.43 (1H, dd, Jꢀ9.7,
2.1 Hz), 3.65 (1H, dd, Jꢀ9.1, 7.8 Hz), 3.72 (1H, dd, Jꢀ12.1, 5.7 Hz), 3.92
7.4 Hz), 5.51 (1H, dd, Jꢀ9.7, 9.2 Hz), 5.61 (1H, d, Jꢀ7.4 Hz), 7.06 (1H, d, (1H, dd, Jꢀ12.1, 2.1 Hz), 3.95 (3H, s), 5.29 (1H, d, Jꢀ7.8 Hz), 7.07 (1H, d,
Jꢀ5.2 Hz), 7.04 (1H, d, Jꢀ2.9 Hz), 7.45 (1H, dd, Jꢀ9.7, 2.9 Hz), 7.81 (1H,
d, Jꢀ9.7 Hz), 8.39 (1H, d, Jꢀ5.2 Hz). IR (KBr) cmꢁ1: 1743. ESI-MS m/z:
541.1812 (Calcd for C25H30N2NaO10 (MꢂNa)ꢂ: 541.1798).
Jꢀ5.4 Hz), 7.20 (1H, dd, Jꢀ9.2, 2.4 Hz), 7.29 (1H, d, Jꢀ2.4 Hz), 8.25 (1H,
d, Jꢀ9.2 Hz), 8.60 (1H, d, Jꢀ5.4 Hz). (KBr) cmꢁ1: 3376 (br). ESI-MS m/z:
360.1066 (Calcd for C16H19NNaO7 (MꢂNa)ꢂ: 360.1059).
4-(b-O-Tetraacetyl-D-glucosyloxy)-6-N-phenylaminoquinoline (4f) as
4-(b-D-Glucosyloxy)-6-phenoxyquinoline (5d) as Colorless Needles
1
1
Pale Brown Needles (Diisopropylether) (53%): mp 167—169 °C. H-NMR (Ethyl Acetate) (74%): mp 170—173 °C (decomp.). H-NMR (CD3OD) d:
(CD3OD) d: 1.93 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 4.22 (1H, 3.43 (1H, dd, Jꢀ9.6, 9.0 Hz), 3.52 (1H, dd, Jꢀ9.1, 9.0 Hz), 3.57 (1H, ddd,
dd, Jꢀ12.4, 2.3 Hz), 4.22 (1H, ddd, Jꢀ9.8, 4.9, 2.3 Hz), 4.32 (1H, dd, Jꢀ9.6, 5.7, 2.2 Hz), 3.58 (1H, dd, Jꢀ9.1, 7.7 Hz), 3.71 (1H, dd, Jꢀ12.1,
Jꢀ12.4, 4.9 Hz), 5.16 (1H, dd, Jꢀ9.8, 9.6 Hz), 5.29 (1H, dd, Jꢀ9.5, 7.7 Hz),
5.7 Hz), 3.91 (1H, dd, Jꢀ12.1, 2.2 Hz), 5.29 (1H, d, Jꢀ7.7 Hz), 7.06 (2H,
5.44 (1H, dd, Jꢀ9.6, 9.5 Hz), 5.65 (1H, d, Jꢀ7.7 Hz), 6.98 (1H, tt, Jꢀ7.4, ddd, Jꢀ8.7, 2.1, 1.1 Hz), 7.16 (1H, tt, Jꢀ7.4, 2.1 Hz), 7.19 (1H, d,
1.1 Hz), 7.05 (1H, d, Jꢀ5.3 Hz), 7.24 (2H, ddd, Jꢀ7.7, 2.0, 1.1 Hz), 7.43 Jꢀ5.4 Hz), 7.39 (2H, ddd, Jꢀ8.7, 7.4, 1.1 Hz), 7.48 (1H, dd, Jꢀ9.2, 2.8 Hz),
(2H, ddd, Jꢀ7.7, 7.4, 2.0 Hz), 7.48 (1H, dd, Jꢀ9.1, 2.5 Hz), 7.64 (1H, d, 7.87 (1H, d, Jꢀ2.8 Hz), 7.97 (1H, d, Jꢀ9.2 Hz), 8.63 (1H, d, Jꢀ5.4 Hz).
Jꢀ2.5 Hz), 7.81 (1H, d, Jꢀ9.1 Hz), 8.44 (1H, d, Jꢀ5.3 Hz). IR (KBr) cmꢁ1
1748. ESI-MS m/z: 567.1995 (Calcd for C29H31N2O10 (MꢂH)ꢂ: 567.1979).
:
(KBr) cmꢁ1: 3255 (br). ESI-MS m/z: 422.1217 (Calcd for C21H21NNaO7
(MꢂNa)ꢂ: 422.1216).
4-(b-O-Tetraacetyl-D-glucosyloxy)-quinoline (4g) as Colorless Needles
4-(b-D-Glucosyloxy)-6-N,N-dimethylaminoquinoline (5e) as an Ochre
1
(Diisopropylether) (81%): mp 175—176 °C. 1H-NMR (CD3OD) d: 2.02 Crystalline Powder (Ethyl Acetate) (85%): mp 179—184 °C (decomp.). H-
(3H, s), 2.04 (3H, s), 2.05 (3H, s), 2.06 (3H, s), 4.22 (1H, dd, Jꢀ12.3, NMR (CD3OD) d: 3.09 (6H, s), 3.46 (1H, dd, Jꢀ9.7, 9.0 Hz), 3.55 (1H, dd,
2.3 Hz), 4.27 (1H, ddd, Jꢀ10.0, 4.9, 2.3 Hz), 4.36 (1H, dd, Jꢀ12.3, 4.9 Hz),
Jꢀ9.1, 9.0 Hz), 3.56 (1H, ddd, Jꢀ9.7, 5.6, 2.3 Hz), 3.68 (1H, dd, Jꢀ9.1,
5.21 (1H, dd, Jꢀ10.0, 9.2 Hz), 5.44 (1H, dd, Jꢀ9.6, 7.7 Hz), 5.51 (1H, d, 7.8 Hz), 3.73 (1H, dd, Jꢀ12.1, 5.6 Hz), 3.92 (1H, dd, Jꢀ12.1, 2.3 Hz), 5.27
Jꢀ9.6, 9.2 Hz), 5.73 (1H, d, Jꢀ7.7 Hz), 7.17 (1H, d, Jꢀ5.3 Hz), 7.60 (1H,
ddd, Jꢀ8.4, 7.0, 1.2 Hz), 7.79 (1H, ddd, Jꢀ8.5, 7.0, 1.4 Hz), 7.98 (1H,
dd, Jꢀ8.5, 1.2 Hz), 8.10 (1H, dd, Jꢀ8.4, 1.4 Hz), 8.73 (1H, d, Jꢀ5.3 Hz).
(1H, d, Jꢀ7.8 Hz), 7.06 (1H, d, Jꢀ5.3 Hz), 7.31 (1H, d, Jꢀ2.9 Hz), 7.44
(1H, dd, Jꢀ9.4, 2.9 Hz), 7.79 (1H, d, Jꢀ9.4 Hz), 8.38 (1H, d, Jꢀ5.3 Hz).
(KBr) cmꢁ1: 3357 (br). ESI-MS m/z: 351.1561 (Calcd for C17H23N2O6
IR (KBr) cmꢁ1: 1752. ESI-MS m/z: 476.1559 (C23H26NO10 (MꢂH)ꢂ: (MꢂH)ꢂ: 351.1556).
476.1551).
4-(b-D-Glucosyloxy)-6-N-phenylaminoquinoline (5f) as Brown Needles
1
4-(b-O-Tetraacetyl-D-glucosyloxy)-7-chloroquinoline (4h) as Colorless
Prisms and Colorless Needles (Diisopropylether) (58%): mp 136—138 °C
(Ethyl Acetate) (74%): mp 168—175 °C (decomp.). H-NMR (CD3OD) d:
3.45 (1H, dd, Jꢀ9.6, 9.0 Hz), 3.52 (1H, dd, Jꢀ9.0, 9.0 Hz) 3.58 (1H, ddd,
(prisms) and 144—145 °C (needles). 1H-NMR (CD3OD) (prisms and nee- Jꢀ9.6, 5.6, 2.3 Hz), 3.62 (1H, dd, Jꢀ9.0, 7.7 Hz), 3.72 (1H, dd, Jꢀ12.2,
dles) d: 2.02 (3H, s), 2.04 (3H, s), 2.05 (3H, s), 2.06 (3H, s), 4.22 (1H, dd, 5.6 Hz), 3.91 (1H, dd, Jꢀ12.2, 2.3 Hz), 5.29 (1H, d, Jꢀ7.7 Hz), 6.93 (1H, tt,
Jꢀ12.3, 2.3 Hz), 4.26 (1H, ddd, Jꢀ10.0, 4.9, 2.3 Hz), 4.35 (1H, dd, Jꢀ12.3,
4.9 Hz), 5.21 (1H, dd, Jꢀ10.0, 9.2 Hz), 5.43 (1H, dd, Jꢀ9.6, 7.7 Hz), 5.50
(1H, dd, Jꢀ9.6, 9.2 Hz), 5.73 (1H, d, Jꢀ7.7 Hz), 7.18 (1H, d, Jꢀ5.3 Hz),
Jꢀ7.3, 1.2 Hz), 7.08 (1H, d, Jꢀ5.3 Hz), 7.23 (2H, ddd, Jꢀ8.7, 2.0, 1.2 Hz),
7.29 (2H, ddd, Jꢀ8.7, 7.3, 2.0 Hz), 7.51 (1H, dd, Jꢀ9.1, 2.6 Hz), 7.80 (1H,
d, Jꢀ9.1 Hz), 7.87 (1H, d, Jꢀ2.6 Hz), 8.44 (1H, d, Jꢀ5.3 Hz). (KBr) cmꢁ1
:
7.57 (1H, dd, Jꢀ9.0, 2.1 Hz), 7.97 (1H, d, Jꢀ2.1 Hz), 8.07 (1H, d, 3323 (br). ESI-MS m/z: 421.1356 (Calcd for C21H22N2NaO6 (MꢂNa)ꢂ:
Jꢀ9.0 Hz), 8.75 (1H, d, Jꢀ5.3 Hz). (CDCl3) (prisms) d: 2.06 (3H, s), 2.08 421.1376).
(3H, s), 2.09 (3H, s), 2.10 (3H, s), 4.15 (1H, ddd, Jꢀ10.0, 5.2, 2.3 Hz), 4.24
(1H, dd, Jꢀ12.6, 2.3 Hz), 4.35 (1H, dd, Jꢀ12.6, 5.2 Hz), 5.24 (1H, dd, (Ethanol) (99%): mp 178—179 °C (decomp.). 1H-NMR (CD3OD) d: 3.46
Jꢀ10.0, 9.5 Hz), 5.45 (1H, dd, Jꢀ9.5, 9.2 Hz), 5.54 (1H, dd, Jꢀ9.2, 7.6 Hz), (1H, dd, Jꢀ9.7, 9.1 Hz), 3.56 (1H, dd, Jꢀ9.2, 9.1 Hz), 3.60 (1H, ddd, Jꢀ9.7,
4-(b-D-Glucosyloxy)-quinoline (5g) as a Colorless Crystalline Powder
5.62 (1H, d, Jꢀ7.6 Hz), 7.32 (1H, d, Jꢀ6.2 Hz), 7.73 (1H, dd, Jꢀ9.0, 5.7, 2.2 Hz), 3.69 (1H, dd, Jꢀ9.2, 7.8 Hz), 3.73 (1H, dd, Jꢀ12.2, 5.7 Hz),
1.9 Hz), 8.17 (1H, d, Jꢀ9.0 Hz), 8.65 (1H, d, Jꢀ1.9 Hz), 8.94 (1H, d, 3.93 (1H, dd, Jꢀ12.2, 2.2 Hz), 5.31 (1H, d, Jꢀ7.8 Hz), 7.20 (1H, d,
Jꢀ6.2 Hz). (CDCl3) (needles) d: 2.06 (3H, s), 2.08 (3H, s), 2.09 (3H, s), Jꢀ5.4 Hz), 7.58 (1H, ddd, Jꢀ8.4, 7.0 1.3 Hz), 7.76 (1H, ddd, Jꢀ8.6, 7.0,
2.10 (3H, s), 4.13 (1H, ddd, Jꢀ10.0, 5.2, 2.2 Hz), 4.23 (1H, dd, Jꢀ12.6,
2.2 Hz), 4.34 (1H, dd, Jꢀ12.6, 5.2 Hz), 5.24 (1H, dd, Jꢀ10.0, 9.5 Hz), 5.44
1.5 Hz), 7.96 (1H, dd, Jꢀ8.6, 1.3 Hz), 8.38 (1H, dd, Jꢀ8.4, 1.5 Hz)), 8.70
(1H, d, Jꢀ5.4 Hz). (KBr) cmꢁ1: 3348 (br). ESI-MS m/z: 308.1129 (Calcd for
(1H, dd, Jꢀ9.5, 8.9 Hz), 5.54 (1H, dd, Jꢀ8.9, 7.7 Hz), 5.58 (1H, d, C15H18NO6 (MꢂH)ꢂ: 308.1129).
Jꢀ7.7 Hz), 7.24 (1H, d, Jꢀ6.1 Hz), 7.69 (1H, dd, Jꢀ9.0, 1.6 Hz), 8.14 (1H,
d, Jꢀ9.0 Hz), 8.55 (1H, d, Jꢀ1.6 Hz), 8.92 (1H, d, Jꢀ6.1 Hz). IR (KBr)
4-(b-D-Glucosyloxy)-7-chloroquinoline (5h) as a Colorless Crystalline
Powder (Ethyl Acetate) (58%): mp 167—172 °C (decomp.). 1H-NMR
cmꢁ1: 1746 (prisms), 1752 (needles). ESI-MS m/z: 510.1144 (C23H25ClNO10 (CD3OD) d: 3.45 (1H, dd, Jꢀ9.7, 9.0 Hz), 3.55 (1H, dd, Jꢀ9.2, 9.0 Hz),
(MꢂH)ꢂ: 510.1162).
3.60 (1H, ddd, Jꢀ9.7, 5.7, 2.2 Hz), 3.67 (1H, dd, Jꢀ9.2, 7.7 Hz), 3.72 (1H,
dd, Jꢀ12.2, 5.7 Hz), 3.93 (1H, dd, Jꢀ12.2, 2.2 Hz), 5.30 (1H, d, Jꢀ7.7 Hz),
7.21 (1H, d, Jꢀ5.5 Hz), 7.56 (1H, dd, Jꢀ9.0, 2.1 Hz), 7.95 (1H, d,
Preparation of 5 Typical Procedure: A suspension of 4a (500 mg,
1.02 mmol) and Amberlyst® A-26 (OH) (1.50 g) in methanol (50 ml) was
stirred for 1 h at room temperature. Insoluble materials were filtered and the Jꢀ2.1 Hz), 8.36 (1H, d, Jꢀ9.0 Hz), 8.72 (1H, d, Jꢀ5.5 Hz). (KBr) cmꢁ1
:
colorless powder was extracted with a large excess of methanol. The extract 3347 (br). ESI-MS m/z: 342.0715 (Calcd for C15H17ClNO6 (MꢂH)ꢂ:
was combined with the filtrate and evaporated in vacuo yielding compound
5a (337 mg, q.).
342.0739).
4-(b-D-Glucosyloxy)-6-methylquinoline (5a) as a Colorless Crystalline
Powder (Ethanol) (q.): mp 180—182 °C (decomp.). 1H-NMR (CD3OD) d:
2.55 (3H, s), 3.46 (1H, dd, Jꢀ9.5, 9.2 Hz), 3.55 (1H, dd, Jꢀ9.2, 9.2 Hz),
3.59 (1H, ddd, Jꢀ9.5, 5.7, 2.1 Hz), 3.68 (1H, dd, Jꢀ9.2, 7.7 Hz), 3.72 (1H,
dd, 12.2, 5.7 Hz), 3.93 (1H, dd, Jꢀ12.2, 2.1 Hz), 5.28 (1H, d, Jꢀ7.7 Hz),
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