Potent antimalarial febrifugine analogues against the Plasmodium malaria parasite

Article abstract of DOI:10.1021/jm010448q

Although febrifugine (1) and isofebrifugine (2), alkaloids isolated from roots of the Dichroa febrifuga plant, show powerful antimalarial activity against Plasmodium falciparum, strong side effects such as the emetic effect have precluded their clinical u

Full text of DOI:10.1021/jm010448q

J . Med. Chem. 2002, 45, 2563-2570
2563
P oten t An tim a la r ia l F ebr ifu gin e An a logu es a ga in st th e P la sm od iu m Ma la r ia
P a r a site
Haruhisa Kikuchi,† Hidehisa Tasaka,† Shingo Hirai,† Yoshiaki Takaya,† Yoshiharu Iwabuchi,‡ Hidenori Ooi,‡
Susumi Hatakeyama,‡ Hye-Sook Kim,§ Yusuke Wataya,§ and Yoshiteru Oshima*,†
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai 980-8578, J apan, Faculty of
Pharmaceutical Sciences, Nagasaki University, Bunkyo-machi, Nagasaki 852-8521, J apan, and Faculty of Pharmaceutical
Sciences, Okayama University, Tsushima, Okayama 700-8530, J apan
Received September 24, 2001
Although febrifugine (1) and isofebrifugine (2), alkaloids isolated from roots of the Dichroa
febrifuga plant, show powerful antimalarial activity against Plasmodium falciparum, strong
side effects such as the emetic effect have precluded their clinical use against malaria. However,
their antimalarial potency makes them attractive substances as leads for developing new types
of chemotherapeutic antimalarial drugs. Thus, we have evaluated the in vitro antimalarial
activity of the analogues of febrifugine (1) and isofebrifugine (2). The activities of the analogues
derived from Df-1 (3) and Df-2 (4), condensation products of 1 and 2 with acetone, respectively,
were also obtained. The 3′′-keto derivative (7, EC50 ) 2.0 × 10-8 M) of 1 was found to exhibit
potential antimalarial activity with high selectivity against P. falciparum in vitro. The in vitro
activities of the reduction product (8, EC50 ) 2.0 × 10-8 M) of 1 at C-2′ and its cyclic derivatives
9 and 10 (EC50 ) 3.7 × 10-9 and 8.6 × 10-9 M, respectively) were found to be strongly active
and selective. Additionally, the Dess-Martin oxidation product of 3 was found to be strongly
active with high selectivity against P. falciparum. A structure-activity relationship study (SAR)
demonstrates that the essential role played by the 4-quinazolinone ring in the appearance of
activity and the presence of a 1′′-amino group and C-2′, C-3′′ O-functionalities are crucial in
the activity of 1. For 7, 8, and 9, prepared as racemic forms, an in vivo study has also been
conducted.
In tr od u ction
is unable to come into equilibrium with 2, which exhibits
in vivo activity approximately 1/211of that of 1 (Table
3). Thus, there is difficulty in handling compound 1.7
Many reports have shown that the powerful emetic
property associated with 1 has limited its potential
usefulness as a chemotherapeutic drug against ma-
laria.8,9 It is also reported that 1 is precluded as an
clinical drug due to liver toxicity.1 However, the chemi-
cal and pharmacological characteristics of 1 encouraged
medicinal chemists to pursue suitable lead compounds
based on 1 for the development of novel antimalarial
drugs. Antimalarial screening demonstrated that feb-
rifugine analogues bearing a modified or unmodified
4-quinazolinone ring are active, while analogues pro-
duced through the modification of the side chain at-
tached to the N-3 position of the 4-quinazolinone ring
are ineffective.8-10 Additionally, an enantiomer of 1
prepared synthetically was found to have dramatically
decreased activity.3b,10 We recently proposed new types
of febrifugine and isofebrifugine analogues, Df-1 (3) and
Df-2 (4), which exhibit excellent antimalarial activities
with high selectivity against the malaria parasite.7 A
detailed study of the structure-activity relationship of
compounds 1-4 is required in order to develop potent
chemotherapeutic drugs from the analogues of 1.
Malaria is one of the major parasitic infections in
many tropical and subtropical regions. After the intro-
duction of synthetic antimalarial drugs such as chloro-
quine and mefloquine, use of the Cinchona alkaloid
quinine declined. However, because of the widespread
emergence of chloroquine-resistant and multiple-drug-
resistant strains of malarial parasites, its use has
become firmly reestablished. Quinine is considered to
be the drug of choice for severe, chloroquine-resistant
malaria from Plasmodium falciparum. In many clinics
in the tropics, quinine is the only effective treatment
for severe malaria; unfortunately, decreasing sensitivity
of P. falciparum to quinine has already been reported.
This development indicates the increasing importance
for discovering new and effective antimalarial drugs.1
In China, the roots of Dichroa febrifuga, a saxifrag-
aceous plant, have been employed in the treatment of
malaria fevers for centuries with no reported parasitic
resistance. Febrifugine (1) and its stereoisomer, iso-
febrifugine (2), were isolated as the active components
against malaria.2 They have attracted the attention of
synthetic organic chemists for their potentially powerful
activities, and were recently synthesized independently
by the research groups of Kobayashi, Ogasawara,
Takeuchi, and Hatakeyama.3-6 Under protic solvent, 1
Ch em istr y
F ebr ifu gin e a n d Isofebr ifu gin e An a logu es. Feb-
rifugine (1) was acetylated with Ac2O and pyridine
resulting in 1′′,3′′-di-N,O-acetate (5). Additionally, 1 was
reacted with ethyl chloroformate and K2CO3 in acetone
* To whom correspondence should be addressed. Tel: +81-22-217-
6822. Fax: +81-22-217-6821. E-mail: oshima@mail.pharm.tohoku.ac.jp.
† Tohoku University.
‡ Nagasaki Univeristy.
§ Okayama University.
10.1021/jm010448q CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/11/2002

2564 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12
Kikuchi et al.
Sch em e 1a
a
Reagent and condition: (a) Ac2O, pyridine, rt, 10 h (100%); (b) ethyl chloroformate, K2CO3, acetone, reflux, 2 h (46%); (c) Boc2O, Et3N,
CH2Cl2, 0 °C, 2.5 h; (d) Dess-Martin periodinane, CH2Cl2, 0 °C, 2.5 h; (e) HCl, MeOH, rt, 2 h (86% from 1); (f) NaBH4, MeOH, 0 °C, 0.5
h (86%); (g) dimethoxymethane, TsOH, CH2Cl2, rt, 12 h (9, 33%; 10, 10%); (h) NaBH4, MeOH, 0 °C, 0.5 h; (i) dimethoxymethane, TsOH,
CH2Cl2, rt, 12 h (40% from 2).
Ch a r t 1. Structures of Febrifugine (1), Isofebrifugine
(2), Df-1 (3), and Df-2 (4)
Ch a r t 2. NOEs of 9 and 11
to yield methyl carbamate (6) (Scheme 1). Dess-Martin
oxidation of 1 afforded the 3′′-keto derivative (7). Sodium
borohydride reduction of the 2′-carbonyl group of 1
formed the sole product 8. The product 8 was converted
to 9 following cyclization between the C-2′ oxygen and
N-1′′ atoms by a reaction with dimethoxymethane/TsOH
in CH2Cl2. Compound 10 was obtained as a byproduct
on the 1,3-dipolar cycloaddition of nitrone to allyl alcohol
(Scheme 2).6 1,4-Butanediol was reacted with p-meth-
oxybenzyl chloride/KOH in DMSO to afford mono-p-
methoxybenzyl ether 16. Swern oxidation of 16 followed
by a Grignard reaction (vinylmagnesium bromide in
THF) and tert-butyldiphenyl silylation (TBDPS-Cl)
yielded 17. The p-methoxybenzyl group was removed
from 17 with DDQ in CH2Cl2/H2O prior to the mesyl-
ation of the resulting product with MsCl and Et3N in
CH2Cl2, generating mesylate 18. After ozonolysis of 18,
the resulting aldehyde 19 was directly reacted with
hydroxylamine hydrochloride in the presence of Et3N
at room temperature. Therefore, nitrone 21 was gener-
ated in situ via oxime 20 which underwent a simulta-
neous 1,3-dipolar cycloaddition to allyl alcohol to give
the diastereomeric mixture of 22, 23, and 24. This
mixture was subjected to hydrogenolytic N-O bond
fission and tert-butoxycarbonylation without separation
to give diol 25. Reaction of 25 with N-tosylimidazole in
the presence of NaH afforded epoxide 26; compound 26
was reacted with the potassium salt generated from
pyrimidone to produce alcohol 27. Dess-Martin oxida-
tion of 27 afforded an epimeric mixture of 28. The
epimeric mixture was then subjected to acid hydrolysis
in boiling HCl to furnish racemic 12 and 13. Identical
1
in the transformation of 8 to 9. The H-NMR spectrum
of 9 displayed signals for the methylene hydrogens
newly formed between the C-2′ oxygen and N-1′′ atoms
at δ 3.51 and 4.39, respectively (each 1H, d, J ) 8.4 Hz).
The C-3′′ carbinyl hydrogen at δ 3.84 exhibited a NOE
with the C-1′′ axial hydrogen on the methylene carbon
at δ 3.51. A NOE was also detected between the C-4′′
and C-5′′ axial hydrogens (δ 1.42 and 3.42, respectively)
(Chart 2). These NMR spectral data unambiguously
imply the absolute configuration of 9 at C-3′′ is S, which
fixes the C-2′ stereochemistry of 8 to be S. Isofebrifugine
(2) was also converted to 11 using the same reactions
as those performed on 1 (Scheme 1 and Chart 2).
Compounds 12-15, bearing a pyrimidone or iso-
quinolone ring instead of the quinazolinone ring in 1
and 2, clearly explain the role of the benzene moiety
and nitrogen atom of the quinazolinone ring in the
appearance of activity. Racemic 12-15 were synthesized
employing the synthetic strategy of 1 and 2 which relies

Potent Antimalarial Febrifugine Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12 2565
Sch em e 2a
a
Reagent and condition: (a) p-methoxybenzyl chloride, KOH, DMSO, 0 °C, 1 h (90%); (b) Swern oxidation, 2 h; (c) vinylmagnesium
bromide, THF, -60 °C (60% from 16); (d) TBDPS-Cl, imidazole, DMF, rt, 12 h (81%); (e) DDQ, CH2Cl2‚H2O (10:1), 0 °C, 1.5 h (87%); (f)
MsCl, Et3N, CH2Cl2, rt, 1 h (99%); (g) O3 then Me2S, NaHCO3, CH2Cl2, -78 °C; (h) HONH2‚HCl, allyl alcohol, Et3N, rt, 11 h (22+23+24,
74% from 18); (i) H2, PdCl2, MeOH, rt, 12 h; (j) Boc2O, Et3N, CH2Cl2, rt, 10 h (94% from 22+23+24); (k) tosylimidazole, NaH, THF, rt,
12 h (92%); (l) 4(3H)-pyrimidone, KH, DMF, 70 °C, 12 h (63%); (m) Dess-Martin periodinane, CH2Cl2, rt, 3 h (98%); (n) 6 M HCl, reflux,
4 h (12, 58%; 13, 27%); (o) isocarbostyril, NaH, DMF, 70 °C, 12 h; (p) Dess-Martin periodinane, CH2Cl2, rt, 3 h; (q) 6 M HCl, reflux, 4
h (14, 18%; 15, 12% from 26).
to the synthesis of 12 and 13, racemic 14 and 15 were
obtained by the reaction of 26 with the potassium salt
of isocarbostyril followed by oxidation and acid hydroly-
sis (Scheme 2).
Compounds 7, 8, and 9 were also prepared as racemic
mixtures from the racemic 1 which was synthesized by
the same reactions as in 12 and 14.
place of the expected transformation in which a methyl
group was induced to the C-2′ carbonyl group of 3. The
lithium aluminum hydride reduction of 30 afforded two
products, 38 and 39. m-Chloroperbenzoic acid oxidation
of 3 afforded N-oxide 40.
As in the case of compound 3, Df-2 (4), the active
analogue of 2, was reduced with NaBH4 to yield two
epimeric alcohols, 41 and 42, bearing axial and equato-
rial hydroxyl groups at C-2′, respectively. Compound 41
was acetylated to give 9′-O-monoacetate (43) and 2′,9′-
di-O-acetate (44). Acetylation of 4 afforded monoacetate
45.
Biological Evalu ation . Antimalarial activity against
P. falciparum (FCR-3 strain) and the cytotoxicity against
mouse mammary FM3A cells in vitro11 were investi-
gated by examining analogues of 1-4 whose activities
are summarized in Tables 1 and 2. Acetate and ethyl
carbamate (5 and 6), as analogues of 1 at the N-1′′
position, show antimalarial activities of EC50 ) 9.1 ×
10-7 and 4.8 × 10-6 M, respectively, with low thera-
peutic selectivity against P. falciparum. Their potencies
decrease considerably compared to that of 1 (EC50 ) 7.0
× 10-10 M), indicating that the substitution of an
electron-withdrawing group with an amino group de-
creases antimalarial activity. 3′′-Keto and 2′-hydroxy
Df-1 a n d Df-2 An a logu es. Dess-Martin oxidation
of Df-1 (3), the potentially active analogue of 1, gave
the 9′-keto derivative 29 (Scheme 3). Upon the reduction
of Df-1 (3) with NaBH4 in MeOH, two epimeric alcohols,
30 and 31, were afforded in a ratio of ca. 5:1. The
conversion of the carbonyl group at C-2′ to a methylene
group was then performed. Compound 3 was acetylated
to give monoacetate 32 which was then treated with
K-selectride in THF to generate alcohol 33 as the sole
reduction product bearing an axial hydroxyl group at
C-2′. A xanthate salt was prepared by treating 33 with
CS2/NaH, and then methylated with CH3I to form
methyl xanthate, 34. Treatment of 34 with Bu3SnH/
AIBN in toluene followed by alkali hydrolysis with
K2CO3 in MeOH yielded compound 35. The Chugaev
reaction of 34 followed by alkali hydrolysis afforded 36.
The sodium salt of 3, prepared with NaH/THF, was
treated with CH3I to generate 37 which occurred in

2566 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12
Kikuchi et al.
Sch em e 3a
a
Reagent and condition: (a) Dess-Martin periodinane, CH2Cl2, rt, 3 h (90%); (b) NaBH4, MeOH, 0 °C, 0.5 h (30, 66%; 31, 14%); (c)
LiAlH4, THF, reflux, 6 h (38, 24%; 39, 20%); (d) Ac2O, pyridine, 0 °C, 10 h (93%); (e) K-selectride, THF, 0 °C, 2 h (69%); (f) CS2, NaH,
THF, 0 °C, 1 h; (g) CH3I, THF, rt, 12 h; (h) Bu3SnH, AIBN, toluene, reflux, 2 h (81% from 33); (i) K2CO3, MeOH, 0 °C, 2 h (79%); (j)
o-dichlorobenzene, reflux, 16 h (47% from 33); (k) K2CO3, MeOH, 0 °C, 3 h (43%); (l) CH3I, NaH, THF, rt, 2 h (100%); (m) m-CPBA,
K2CO3, CH2Cl2, -78 °C, 4 h (76%).
Ta ble 1. Antimalarial Activities of Febrifugine (1) and
Isofebrifugine (2) Derivatives in Vitro
Ta ble 2. Antimalarial Activities of Df-1 (3) and Df-2 (4)
Derivatives in Vitro
EC50 (M)
EC50 (M)
antimalarial
antimalarial
compound
activitya
cytotoxicityb
selectivityc
compound
activitya
cytotoxicityb
selectivityc
1
2
5
6
7
8
9
10
11
12
13
14
7.0 × 10-10
3.4 × 10-9
9.1 × 10-7
4.8 × 10-6
2.0 × 10-8
2.0 × 10-8
3.7 × 10-9
8.6 × 10-9
8.4 × 10-7
6.0 × 10-7
4.0 × 10-8
5.0 × 10-7
2.1 × 10-6
1.8 × 10-8
1.0 × 10-8
1.7 × 10-7
1.8 × 10-7
>2.9 × 10-5
>1.7 × 10-5
1.0 × 10-5
1.5 × 10-5
3.8 × 10-6
2.5 × 10-6
>2.5 × 10-5
>1.9 × 10-5
7.0 × 10-6
>1.6 × 10-5
>6.3 × 10-6
3.2 × 10-5
1.0 × 10-5
243
53
>32
>3.5
500
750
1027
291
3
4
1.6 × 10-9
2.8 × 10-9
1.9 × 10-9
4.0 × 10-7
3.0 × 10-7
3.6 × 10-9
8.3 × 10-7
4.8 × 10-6
1.3 × 10-6
4.2 × 10-7
6.0 × 10-7
1.0 × 10-7
8.0 × 10-7
3.4 × 10-6
4.0 × 10-7
7.0 × 10-6
1.9 × 10-8
3.8 × 10-7
238
857
2.4 × 10-6
29
30
31
32
35
36
37
38
39
40
41
42
43
44
45
5.9 × 10-6
>3105
2.8 × 10-6
70
8.5 × 10-5
283
361
>27
>7
1.3 × 10-6
>2.2 × 10-5
>3.2 × 10-5
>6.6 × 10-5
>1.6 × 10-5
>1.7 × 10-5
>2.9 × 10-5
>2.4 × 10-5
>1.0 × 10-4
>1.1 × 10-5
>2.1 × 10-5
7.0 × 10-6
>30
>32
175
>32
>3
>51
>38
>28
>290
>30
>28
>28
>3
15
chloroquine
artemisinin
1778
1000
a
b
Against P. falciparum FCR-3. Against FM3A mouse mam-
368
mary cells. c Cytotoxicity/antimalarial activity.
a
b
Against P. falciparum FCR-3. Against FM3A mouse mam-
mary cells. c Cytotoxicity/antimalarial activity.
analogues (7 and 8) of 1 have the same EC50 value (2.0
× 10-8 M) for their antimalarial activities with high
selectivity. Cyclic compounds 9 and 10 also show power-
ful antimalarial activities (EC50 ) 3.7 × 10-9 and 8.6 ×
10-9 M, respectively). These results suggest that O-
functionality at C-2′ and C-3′′ in 1 is crucial to activity;
thus, these types of derivatives would make suitable
lead compounds for the development of new anti-
malarial drugs. In contrast, 11, which was derived from
2, is found to be less active than 9. While compounds 3
and 4 derive their stereochemistry from being conden-
sation products of compounds 1 and 2 with acetone,
respectively, compounds 9 and 11 are also enantiomers,
provided that the stereochemistry of the hydroxyl group
is disregarded. The enantiomer of 1 was reported to
exhibit reduced antimalarial activity when compared to
1.3b,10 Moreover, 3 differs from 4 in the potency of in
vivo activity, even though both 3 and 4 exhibited
excellent activities with high selectivity in vitro.7 Data
obtained for 9 and 11, along with reported antimalarial

Potent Antimalarial Febrifugine Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12 2567
Ta ble 3. In Vivo Antimalarial Activities of Febrifugine (1)
Derivatives against Mice Infected with P. bergheia
and 29 might be metabolites of 1 and 3 in the body, a
metabolic study of these compounds will be prudent.
compound
17
2
7
8
9
ED50 (µmol/kg)
ED90 (µmol/kg)
Exp er im en ta l Section
1.0
211
1.3
2.9
82
5.0
>267
6.2
Analytical TLC was performed on silica gel 60 F254 (Merck)
and aluminum oxide 60 F254 (Merck). Column chromatography
was carried out on silica gel 60 (70-230 mesh, Merck),
Cosmosil 75C18-OPN (Nacalai Tesque Inc., Kyoto, J apan), and
activated alumina (300 mesh, Wako Pure Chemicals Co., Ltd.,
Osaka, J apan). Chloroquine diphosphate (Sigma) was used as
a positive control in the antimalarial assay in vitro and in vivo.
Optical rotation were measured using a J ASCO DIP-370
22
>180
chloroquine
artemisinin
4.7
17.7
9.4
46.0
a
The detail of the experimenal procedure was described in ref
11.
1
digital polarimeter. H- and 13C-NMR spectra were recorded
on a J EOL J NM GX-500 spectrometer (1H, 500 MHz; 13C, 125
MHz) and a Varian Gemini 2000 spectrometer (1H, 300 MHz).
Chemical shifts for 1H- and 13C-NMR are given in parts per
million (δ) relative to tetramethylsilane (δH 0.00) and CDCl3
(δC 77.1) as internal standards, respectively, and coupling
constants were reported in hertz. High-resolution EI mass
spectra were measured on J EOL J MS DX-303 and J MS AX-
500 mass spectrometers.
Where appropriate, reactions were performed in flame-dried
glassware under an argon atmosphere. The extracts were dried
over Na2SO4 unless otherwise noted and concentrated by
rotary evaporation below 30 °C.
activities,3b,7,10 imply that analogues of 1 have greater
potential than those of 2 in use as powerful antimalarial
drugs.
The roles played by the benzene moiety and the N-1
atom of the 4-quinazolinone ring in determining activity
were evaluated using synthetic racemates 12-15. They
exhibited moderate antimalarial activity (EC50 ) 6.0 ×
10-7, 9.0 × 10-8, 5.0 × 10-7, and 2.1 × 10-6 M,
respectively) and were not selective against P. falci-
parum (>32, >175, >38, and >3, respectively). This
points out the importance of the 4-quinazolinone ring
in antimalarial activity and selectivity.
Isola tion of F ebr ifu gin e (1) a n d Isofebr ifu gin e (2)
fr om D. febr ifu ga Roots a n d P r ep a r a tion of Df-1 (3) a n d
Df-2 (4). Compounds 1 and 2 were isolated from a dried root
of D. febrifuga, and 3 and 4 were synthesized from 1 and 2,
respectively, following the procedure previously reported.7
3-{3-[(2R,3S)-3-Acet oxy-1-a cet yl-2-p ip er id in yl]-2-oxo-
p r op yl}-4(3H)-qu in a zolin on e (5). To an ice-cooled solution
of 1 (9.9 mg, 0.033 mmol) in pyridine (0.5 mL) was added Ac2O
(0.25 mL), and the mixture was stirred at room temperature
for 10 h. The mixture was extracted with EtOAc, and the
organic layer was washed with brine, dried, and concentrated.
The crude residue was chromatographed over silica gel (CHCl3:
MeOH ) 98:2) to give 5 (12.7 mg, 100%) as colorless needles.
3-{3-[(2R,3S)-1-Eth oxyca r bon yl-3-h yd r oxy-2-p ip er id in -
yl]-2-oxop r op yl}-4(3H)-qu in a zolin on e (6). A mixture of 1
(11.0 mg, 0.040 mmol), K2CO3 (100 mg, 0.724 mmol), and ethyl
chloroformate (0.10 mL, 1.05 mmol) in acetone (1.0 mL) was
refluxed for 2 h. The reaction mixture was cooled to room
temperature, and the resulting precipitate was filtered. The
filtrate was extracted with EtOAc, and the organic layer was
washed with brine, dried, and concentrated. Silica gel column
chromatography of the crude residue (CHCl3:MeOH ) 98:2)
afforded 6 (6.3 mg, 46%) as colorless needles.
3-{3-[(2R,3S)-3-Oxo-2-p ip er id in yl]-2-oxop r op yl}-4(3H)-
qu in a zolin on e (7). To an ice-cooled solution of 1 (152 mg,
0.506 mmol) in CH2Cl2 (6.0 mL) were added triethylamine (78
mL) and di-tert-bicarbonate (123 mg, 0.557 mmol), and the
mixture was stirred for 2.5 h at 0 °C. The reaction mixture
was quenched with aqueous 0.1 M HCl (6.0 mL), and the
mixture was extracted with EtOAc. The organic layer was
washed with a saturated aqueous NaHCO3 solution and brine,
dried, and concentrated. The crude residue was chromato-
graphed over silica gel (CHCl3:MeOH ) 98:2) to give N-Boc
derivative (189 mg, 93%) as a colorless oil. N-Boc derivative
(20.9 mg, 0.052 mmol) in CH2Cl2 (2.0 mL) was treated with
Dess-Martin periodinane (88.3 mg, 0.156 mmol) and stirred
for 2.5 h at 0 °C. The reaction mixture was quenched with an
aqueous Na2S2O3 solution, and the mixture was extracted with
EtOAc. The organic layer was washed with a saturated
aqueous NaHCO3 solution and brine, dried, and concentrated.
The crude residue was chromatographed over silica gel (CHCl3)
to give the 3′′-keto compound (20.4 mg, 98%) as a colorless
oil. The 3′′-keto compound (20.4 mg, 0.051 mmol) was dissolved
in 1.25% HCl-MeOH (4.0 mL) at room temperature. After the
reaction mixture was stirred for 2 h, it was concentrated and
chromatographed over ODS (H2O:MeOH ) 9:1) to yield 7 (16.1
mg, 94%) as colorless needles.
In regards to the analogues of 3 and 4, the powerful
activities of C-9′-keto analogue 29 and acetate 32 (EC50
) 1.9 × 10-9 and 3.6 × 10-9 M, respectively) are
noteworthy. It should be mentioned that 29 exhibits a
surprisingly high selectivity (>3105), especially when
compared with those of chloroquine and artemisinin
(1778 and 1000, respectively). While other analogues of
3 and 4 showed antimalarial activities, EC50 ) 3.0 ×
10-7 to 4.8 × 10-6 M, they were found to be unselective.
The compounds 7-9 chemically transformed from
natural 1 were found to be highly effective in vitro
(Table 1), and we examined their in vivo antimalarial
activity against mice infected with Plasmodium berghei.11
Because a sufficient supply of natural 1 for transforma-
tion to 7-9 necessary for the test was thought to be
difficult to obtain from D. febrifuga roots, the racemic
7-9 obtained from synthetic 1 were used in the test.
The results compiled in Table 3 indicated that febri-
fugine derivatives 7 and 8 exhibited potent antimalarial
activities (ED50 ) 1.3 and 2.9 mmol/kg, respectively)
rather than chloroquine and artemisinin (ED50 ) 4.7
and 17.7 mmol/kg, respectively). Compound 9 (ED50
)
80 mmol/kg) was less effective than 7 and 8. Further-
more, during administration of 7 and 8 to infected mice
by intraperitoneal injection (8.9 mmol/kg/day, 4 days),
the survival rate was increased 2 times.
In conclusion, we have described the syntheses and
SAR of a new series of febrifugine analogues. We
discovered strong antimalarial activities in vitro with
high therapeutic selectivity against P. falciparum for
compounds 7-10 which were derived from 1. In addi-
tion, the 4-quinazolinone moiety and C-2′ and C-3′′
O-functionalities are found to play an important role
in the activity. Compound 29, the C-9′-keto analogue
of 3, also exhibited good antimalarial activity and very
high selectivity. Most importantly, the fact that racemic
mixtures of 7 and 8 also exhibited extremely strong in
vivo activity against P. berghei suggests that they are
the leads of a new type of antimalarial agent. As 7, 8,
3-{(2S)-3-[(2R,3S)-3-Hyd r oxy-2-p ip er id in yl]-2-h yd r oxy-
p r op yl}-4(3H)-qu in a zolin on e (8). To an ice-cooled solution

2568 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12
Kikuchi et al.
of 1 (10.6 mg, 0.035 mmol) in MeOH (2.0 mL) was added
NaBH4 (1.0 mg, 0.026 mmol), and the mixture was stirred at
the same temperature for 10 min. The reaction mixture was
diluted with MeOH, concentrated, and chromatographed over
silica gel (CHCl3:MeOH ) 80:20) to yield 8 (9.1 mg, 86%) as
colorless needles.
3-{(3S,4a R,5S)-5-Hyd r oxyh exa h yd r op yr id o[1,2-c][1,3]-
oxa zin -3-ylm eth yl}-4(3H)-qu in a zolin on e (9) a n d 3-{(3S,
4a R,5S)-5-Met h oxym et h yloxy-h exa h yd r op yr id o[1,2-c]-
[1,3]oxa zin -3-ylm eth yl}-4(3H)-qu in a zolin on e (10). To a
solution of 8 (18.0 mg, 0.059 mmol) in CH2Cl2 (1.0 mL) were
added dimethoxymethane (10 mL, 0.118 mmol) and pTsOH‚
H2O (15.0 mg, 0.189 mmol), and the mixture was stirred at
room temperature for 12 h. The reaction mixture was quenched
with a saturated aqueous NaHCO3 solution and extracted with
EtOAc. The organic layer was washed with brine, dried, and
concentrated. The crude residue was chromatographed over
aluminum oxide (n-hexane:CHCl3 ) 50:50) to give 9 and 10
(4.4 and 1.4 mg, 33 and 10%, respectively) as colorless needles.
3-{(3S,4a R,5S)-5-Hyd r oxyh exa h yd r op yr id o[1,2-c][1,3]-
oxa zin -3-yl-m eth yl}-4(3H)-qu in a zolin on e (11). Compound
11 was synthesized from 2 following the representative
procedure described for 9 and 10, and was obtained as colorless
needles in 40% yield.
4-(4-Meth oxyben zyloxy)-bu ta n -1-ol (16). To a solution
(50 mL) of 1,4-butanediol (25 g, 227 mmol) in DMSO (50 mL)
was added KOH (15.5 g, 277 mmol). The mixture was cooled
to 0 °C, and p-methoxybenzyl chloride (17.5 mL, 0.129 mmol)
was added dropwise for 1 h. The reaction mixture was poured
into ice-water and extracted with Et2O. The organic layer was
washed with brine, dried, concentrated, and chromatographed
over silica gel (n-hexanes:EtOAc ) 70:30) to yield 16 (24.4 g,
90%) as a colorless oil.
4-(ter t-Bu tyld ip h en ylsila n yloxy)-1-(4-m eth oxyben zyl-
oxy)-5-h exen e (17). To a solution of oxalylchloride (20.3 mL,
232 mmol) in CH2Cl2 (450 mL) was added dropwise DMSO
(33 mL, 465 mmol) at -78 °C, and the mixture was stirred at
the same temperature for 30 min. To this solution was added
dropwise a solution of 16 (24.4 g, 116 mmol) in CH2Cl2 (50
mL) at a rate which was sufficient to keep the temperature at
-78 °C. After the reaction mixture had been stirred at this
temperature for 2 h, Et3N (81 mL, 581 mmol) was added, and
the solution was warmed to room temperature. A saturated
aqueous NH4Cl solution was added, and the organic layer was
washed with water and brine, dried, and concentrated to give
a crude aldehyde which was used in the following reaction
without purification. To a solution of the crude aldehyde in
THF (500 mL) was added dropwise a 0.232 M solution of
vinylmagnesium bromide in THF (200 mL) at -60 °C, and the
mixture was stirred at the same temperature for 18 h. The
reaction mixture was quenched with a saturated aqueous
NH4Cl solution and extracted with Et2O. The organic layer
was washed with brine, dried, and concentrated. The crude
residue was chromatographed over silica gel (n-hexanes:EtOAc
) 70:30) to give allyl alcohol (16.5 g, 60%) as a colorless oil:
1H-NMR (300 MHz, CDCl3, δ) 1.56-1.77 (4H, m), 2.46 (1H, d,
J ) 3.9 Hz), 3.49 (2H, t, J ) 5.7 Hz), 3.80 (3H, s), 4.07-4.16
(1H, m), 4.45 (2H, s), 5.09 (1H, dt, J ) 10.5, 1.5 Hz), 5.22 (1H,
dt, J ) 17.4, 1.5 Hz), 5.86 (1H, ddd, J ) 17.4, 10.5, 6.0 Hz),
6.88 (2H, d, J ) 8.4 Hz), 7.26 (2H, d, J ) 8.4 Hz); 13C-NMR
(75 MHz, CDCl3, δ) 25.9, 34.5, 55.4, 70.1, 72.8, 113.9, 114.5,
129.4, 130.4, 141.2.
saturated aqueous NaHCO3 solution was added, and the
mixture was extracted with Et2O. The organic layer was
washed with brine, dried, and concentrated. NaBH4 (189 mg,
5.00 mmol) was added to a solution of the crude residue in
MeOH (40 mL) at 0 °C and stirred for 15 min. A saturated
aqueous NH4Cl solution was added, and the mixture was
extracted with Et2O. The organic layer was washed with brine,
dried, and concentrated to yield a residue which was chro-
matographed over silica gel (n-hexanes:EtOAc ) 80:20) to give
alcohol (3.07 g, 87%) as a colorless oil: 1H-NMR (300 MHz,
CDCl3, δ) 1.07 (9H, s), 1.47-1.56 (5H, m), 3.50 (2H, br t, J )
6.0 Hz), 4.21 (1H, m), 4.97 (1H, ddd, J ) 10.5, 2.1, 0.9 Hz),
5.01 (1H, ddd, J ) 17.1, 2.1, 1.8 Hz), 5.80 (1H, ddd, J ) 17.1,
10.5, 6.6 Hz), 7.32-7.43 (6H, m), 7.64-7.70 (4H, m); 13C-NMR
(75 MHz, CDCl3, δ) 19.4, 27.1, 27.6, 33.8, 62.9, 74.3, 114.7,
127.4, 127.6, 129.6, 129.7, 134.0, 134.3, 135.9, 136.0, 140.4.
To an ice-cooled solution of alcohol (1.80 g, 5.08 mmol) in
CH2Cl2 (36 mL) were added Et3N (0.92 mL, 6.60 mmol) and
methanesulfonyl chloride (0.43 mL, 5.60 mmol) at 0 °C. After
the mixture was stirred at room temperature for 1 h, a
saturated aqueous NaHCO3 solution was added. The mixture
was extracted with Et2O, and the organic layer was washed
with water and brine, dried, and concentrated. The residue
was purified by silica gel column chromatography (n-hexane:
EtOAc ) 80:20) to give 18 (2.17 g, 99%) as a colorless oil.
(2R*,3a R*,4S*)-, (2S*,3a R*,4S*)-, a n d (2S*,3a S*,4S*)-4-
(ter t-Bu tyldiph en ylsilyl)oxy-2-[(h ydr oxy)m eth yl]h exah y-
d r oisoxa zolo[2,3-a ]p yr id in e (22, 23, a n d 24, r esp ec-
tively). A mixture of 18 (1.87 g, 4.31 mmol) and NaHCO3 (1.87
g, 21.6 mmol) in CH2Cl2 (30 mL) was reacted with O3 at -78
°C for 20 min. After an excess of the O3 was removed by
flushing with argon, Me2S (0.48 mL, 6.47 mmol) was added,
and the mixture was allowed to warm to room temperature.
The mixture was diluted with CH2Cl2, and the organic layer
was washed with brine, dried, and concentrated. To an allyl
alcohol solution (20 mL) of the crude aldehyde 19 (1.91 g)
obtained were added NH2OH‚HCl (330 mg, 4.75 mmol) and
Et3N (1.32 mL, 9.49 mmol) at room temperature. After the
mixture was stirred for 11 h, it was concentrated and chro-
matographed (n-hexane:EtOAc ) 65:35) to give a 64:10:26
mixture of 22, 23, and 24 (1.31 g, 74%) as a colorless
amorphous solid.
N-(ter t-Bu t oxyca r b on yl)-3-(ter t-b u t yld ip h en ylsilyl)-
oxy-2-(2,3-d ih yd r oxyp r op yl)p ip er id in e (25). The mixture
of 22, 23, and 24 (350 mg, 0.85 mmol) was dissolved in MeOH
(10 mL) and stirred in the presence of PdCl2 (35 mg, 0.20
mmol) under H2 at room temperature for 12 h. The mixture
was diluted with CH2Cl2, filtered through Celite, and concen-
trated to give crude amino diol (360 mg) as a yellow viscous
oil. To a solution of crude amino diol (360 mg) in CH2Cl2 (10
mL) were added Et3N (0.21 mL, 1.53 mmol) and Boc2O (278
mg, 1.28 mmol) at room temperature. After the mixture was
stirred at the same temperature for 10 h, it was diluted with
Et2O, washed with brine, dried, and concentrated. The residue
was chromatographed over silica gel (n-hexane:EtOAc ) 65:
35) to give 25 (410 mg, 94%) as a colorless amorphous solid.
N-(ter t-Bu t oxyca r b on yl)-3-(ter t-b u t yld ip h en ylsilyl)-
oxy-2-[(oxir a n yl)m eth yl]p ip er id in e (26). To an ice-cooled
solution of 25 (400 mg, 0.78 mmol) in THF (10 mL) was added
NaH (60% in dispersion oil, 169 mg, 0.86 mmol), and the
mixture was stirred at 0 °C for 20 min. Tosylimidazole (190
mg, 0.86 mmol) was added, and the cooling bath was removed.
After the mixture was stirred at room temperature for 12 h,
it was quenched with water and extracted with Et2O. The
organic layer was washed with brine, dried, concentrated, and
chromatographed over silica gel (n-hexane:EtOAc ) 90:10) to
give 26 (355 mg, 92%) as a colorless amorphous solid.
To a solution of allyl alcohol (3.0 g, 12.7 mmol) in DMF (30
mL) were added imidazole (1.73 g, 25.4 mmol) and tert-
butyldiphenylsilane chloride (5.23 g, 19.0 mmol) at 0 °C. The
reaction mixture was warmed to room temperature and stirred
for 12 h. A saturated aqueous NaHCO3 solution was added,
and the mixture was extracted with n-hexane. The organic
layer was washed with brine, dried, and concentrated. Silica
gel column chromatography of the crude residue gave 17 (4.9
g, 81%) as a colorless oil.
3-[3-(3-H yd r oxy-p ip er id in -2-yl)-2-oxop r op yl]-3H -p yr -
im idin -4-on e (12), 3-(2-Hydr oxy-octah ydr o-fu r o[3,2-b]pyr -
idin -2-ylm eth yl)-3H-pyr im idin -4-on e (13), 2-[3-(3-Hydr oxy-
p ip er id in -2-yl)-2-oxop r op yl]-2H -isoq u in olin -1-on e (14),
4-(ter t-Bu tyld ip h en ylsilyl)oxy-5-h exen yl Meth a n esu lf-
on a te (18). A solution of 17 (4.9 g, 10.3 mmol) and DDQ in
CH2Cl2‚H2O (10:1, 60 mL) was stirred at 0 °C for 1.5 h. A
a n d
2-(2-H yd r oxy-oct a h yd r o-fu r o[3,2-b]p yr id in -2-yl-
m eth yl)-2H-isoqu in olin -1-on e (15). To an ice-cooled suspen-
sion of KH (24.3 mg, 0.606 mmol) in DMF (1.5 mL) was added

Potent Antimalarial Febrifugine Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12 2569
Sch em e 4a
4(3H)-pyrimidone (64 mg, 0.667 mmol), and the mixture was
stirred at 0 °C for 30 min. A solution of 26 (100 mg, 0.202
mmol) in DMF (1.0 mL) was added, and the mixture was
heated at 80 °C for 16 h. The mixture was cooled to room
temperature, quenched with a saturated aqueous NH4Cl
solution, and extracted with Et2O. The organic layer was
washed with brine, dried, concentrated, and chromatographed
over silica gel (n-hexane:EtOAc ) 65:35) to give 27 (82 mg,
69%) as an amorphous solid and unreacted 26 (14.4 mg, 14%).
To a solution of 27 in CH2Cl2 (10 mL) was added Dess-Martin
periodinane (533 mg, 1.26 mmol), and the mixture was stirred
at room temperature for 17 h. The mixture was diluted with
Et2O, filtered through Celite, and concentrated. The residue
was purified by silica gel column chromatography (n-hexane:
EtOAc ) 65:35) to give a mixture of 28 as an 80:20 epimeric
mixture (81 mg, 98%). A solution of the mixture in 6 M HCl
(10 mL) was refluxed for 12 h. The mixture was cooled in an
ice bath, and K2CO3 was added and extracted with CHCl3. The
organic layer was dried over K2CO3, concentrated, and chro-
matographed over silica gel (CHCl3:MeOH ) 90:10) to give 12
and 13 as colorless needles (13 and 9 mg, 38 and 26%,
respectively).
Compounds 14 and 15 were synthesized from isocarbostyril
and 26 with a 20 and 9% overall yield, respectively, following
the representative procedure described for 12 and 13.
3-[(3R,9a R)-Octa h yd r o-2,9-d ioxo-4,4-d im eth yl-2H-qu i-
n olizin -3-yl]-4(3H)-qu in a zolin on e (29). Compound 3 (5.0
mg, 0.014 mmol) in CH2Cl2 (1.0 mL) was treated with Dess-
Martin periodinane (15.8 mg, 0.028 mmol) and stirred for 2.5
h at 0 °C. The reaction mixture was quenched with an aqueous
Na2S2O3 solution and extracted with EtOAc. The organic layer
was washed with a saturated aqueous NaHCO3 solution and
brine, dried, and concentrated. The crude residue was chro-
matographed over silica gel (CHCl3) to give 29 (3.7 mg, 79%)
as a colorless oil.
3-[(2S,3R,9S,9aR)-Octah ydr o-2,9-dih ydr oxy-4,4-dim eth -
yl-2H-qu in olizin -3-yl]-4(3H)-qu in azolin on e (30) an d 3-[(2R,
3R,9S,9a R)-Oct a h yd r o-2,9-d ih yd r oxy-4,4-d im et h yl-2H -
qu in olizin -3-yl]-4(3H)-qu in a zolin on e (31). Compounds 30
and 31 were synthesized from 3 following the representative
procedure described for 8, and were obtained as colorless
needles (20.8 and 4.4 mg, 66 and 14%, respectively).
3-[(2S,3R,9S,9aR)-Octah ydr o-2,9-dih ydr oxy-4,4-dim eth -
yl-2H-qu in olizin -3-yl]-2,3-dih ydr oxy-4(1H)-qu in azolin on e
(38) a n d N-[(2S,3R,9S,9a R)-Octa h yd r o-2,9-d ih yd r oxy-
4,4-d im et h yl-2H -q u in olizin -3-yl]-2-m et h yla m in ob en z-
a m id e (39). To a solution of 30 (6.1 mg, 0.018 mmol) in THF
(2.0 mL) was added LiAlH4 (1.4 mg, 0.037 mmol), and the
mixture was refluxed for 6 h. After the mixture was cooled to
room temperature, Et2O (4.0 mL) and 1 N NaOH (1.3 mL) were
added, and an excess of LiAlH4 was precipitated. After
filtration of the precipitate, the mixture was extracted with
EtOAc, washed with brine, dried, and concentrated. Silica gel
chromatography of the residue gave 38 and 39 (24 and 20%,
respectively) as colorless needles.
a
Reagent and condition: (a) NaBH4, MeOH, 0 °C, 0.5 h (41,
61%; 42, 14%); (b) Ac2O, pyridine, rt, 12 h (43, 41%; 44, 28%); (c)
Ac2O, pyridine, rt, 12 h (62%).
added a THF solution (1.5 mL) of 33 (9.9 mg, 0.026 mmol) at
0 °C. The mixture was allowed to warm to room temperature
and stirred for 1 h. After the mixture was cooled to 0 °C, CS2
(16 mL, 0.26 mmol) was added. The mixture was warmed to
room temperature and stirred for 12 h. The mixture was
diluted with EtOAc, washed with brine, dried, and concen-
trated to give crude 34 (15.1 mg). Without purification, 34 (8.3
mg) in toluene (3 mL) was refluxed with Bu3SnH (20 mL, 0.075
mmol) and AIBN (1.2 mg, 7.5 mmol) at room temperature for
2 h. After the mixture was cooled to room temperature, it was
diluted with n-hexane and chromatographed over silica gel (n-
hexane:CHCl3 ) 70:30) to give an acetate of 35 (4.2 mg, 81%).
The acetate of 35 in MeOH (1.0 mL) was hydrolyzed with
K2CO3 (2.4 mg, 0.018 mmol) at 0 °C for 2 h, and then at room
temperature for 3 h. The mixture was diluted with EtOAc,
washed with brine, dried, concentrated, and chromatographed
over aluminum oxide (n-hexane:CHCl3 ) 70:30) to give 35 (2.3
mg, 79%) as colorless needles.
3-[(3S,9S,9a R)-3,6,7,8,9,9a -H exa h yd r o-9-h yd r oxy-4,4-
d im eth yl-4H-qu in olizin -3-yl]-4(3H)-qu in a zolin on e (36).
The crude 34 (6.8 mg) was refluxed in o-dichlorobenzene (3.0
mL) for 16 h. After the mixture was allowed to cool to room
temperature, it was diluted with n-hexane and chromato-
graphed over silica gel (n-hexane:CHCl3 ) 50:50) to give an
acetate of 36 (2.0 mg, 47%). The acetate of 36 (26.1 mg, 0.071
mmol) in MeOH (2.0 mL) and K2CO3 (25.0 mg, 0.178 mmol)
was stirred at room temperature for 3 h. The mixture was
diluted with EtOAc, washed with brine, dried, concentrated,
and chromatographed over aluminum oxide (n-hexane:CHCl3
) 70:30) to give 36 (10.0 mg, 43%) as colorless needles.
3-[(3R,9S,9aR)-3,6,7,8,9,9a-Hexah ydr o-9-h ydr oxy-2-m eth -
oxy-4,4-d im et h yl-4H -q u in olizin -3-yl]-4(3H )-q u in a zoli-
n on e (37). To a solution of NaH (60% in oil, 1.0 mg, 0.025
mmol) in THF (1.0 mL) was added dropwise a THF solution
(2.0 mL) of 3 (4.1 mg, 0.012 mmol) at 0 °C. The mixture was
allowed to warm to room temperature and stirred for 1 h. After
the mixture was cooled to 0 °C, MeI (23 mL, 0.369 mmol) was
added, and the mixture was warmed to room temperature and
stirred for 2 h. The mixture was diluted with EtOAc, washed
with brine, dried, and concentrated. Chromatography of the
residue over aluminum oxide (n-hexane:CHCl3 ) 70:30) af-
forded 37 (4.4 mg, 100%) as colorless needles.
3-[(3R,9S,9a R)-Oct a h yd r o-9-a cet oxy-4,4-d im et h yl-2-
oxo-2H-qu in olizin -3-yl]-4-(3H)-qu in a zolin on e (32). Com-
pound 32 was synthesized from 3 following the representative
procedure described for 5, and was obtained as colorless
needles (93%).
3-[(2S,3R,9S,9a R)-Octa h yd r o-9-a cetoxy-2-h yd r oxy-4,4-
d im eth yl-2H-qu in olizin -3-yl]-4(3H)-qu in a zolin on e (33).
To an ice-cooled solution of 32 (14.3 mg, 0.037 mmol) in THF
(1.0 mL) was added K-selectride (1.0 M solution in THF, 0.15
mL), and the mixture was stirred at 0 °C for 2 h. A saturated
aqueous NH4Cl solution (0.4 mL) was added and stirred for 5
min, and the resulting precipitate was filtered. The filtrate
was extracted with Et2O, and the organic layer was washed
with brine, dried, concentrated, and chromatographed over
aluminum oxide (n-hexane:CHCl3 ) 80:20) to give 33 (9.9 mg,
69%) as colorless needles.
3-[(3R,9S,9a R)-Oct a h yd r o-9-h yd r oxy-4,4-d im et h yl-2-
oxo-5-oxy-2H-qu in olizin -3-yl]-4(3H)-qu in a zolin on e (40).
A mixture of 3 (5.0 mg, 0.014 mmol), m-CPBA (3.5 mg, 0.020
mmol), and K2CO3 (2.0 mg) in CH2Cl2 (200 mL) was stirred at
-78 °C for 4 h. The mixture was warmed to room temperature
and stirred for 2 h. The mixture was diluted with EtOAc,
washed with brine, dried, concentrated, and chromatographed
over aluminum oxide (n-hexane:CHCl3 ) 60:40) to give 40 (3.8
mg, 76%) as colorless needles.
3-[(3S,9S,9a R)-Octa h yd r o-9-h yd r oxy-4,4-d im eth yl-2H-
qu in olizin -3-yl]-4(3H)-qu in a zolin on e (35). To a THF solu-
tion (1.0 mL) of NaH (60% in oil, 2.1 mg, 0.053 mmol) was

2570 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12
Kikuchi et al.
(3) (a) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H. Catalytic
Asymmetric Synthesis of Febrifugine and Isofebrifugine. Tet-
rahedron Lett. 1999, 40, 2175-2178. (b) Kobayashi, S.; Ueno,
M.; Suzuki, R.; Ishitani, H.; Kim, H.-S.; Wataya, Y. Catalytic
Asymmetric Synthesis of Antimalarial Alkaloids Febrifugine and
Isofebrifugine and Their Biological Activity. J . Org. Chem. 1999,
64, 6833-6841. (c) Okitsu, O.; Suzuki, R.; Kobayashi, S. Efficient
Synthesis of Piperidine Derivatives: Development of Metal
Triflate-Catalyzed Diastereoselective Nucleophilic Substitution
Reactions of 2-Methoxy- and 2-Acyloxypiperidines. J . Org. Chem.
2001, 66, 809-823.
3-[(2R,3S,9S,9aS)-Octah ydr o-2,9-dih ydr oxy-4,4-dim eth -
yl-2H-qu in olizin -3-yl]-4(3H)-qu in azolin on e (41) an d 3-[(2S,
3S,9S,9a S)-Oct a h yd r o-2,9-d ih yd r oxy-4,4-d im et h yl-2H -
qu in olizin -3-yl]-4(3H)-qu in a zolin on e (42). Compounds 41
and 42 were synthesized from 3 following the representative
procedure described for 8, and were obtained as colorless
needles (61 and 14%, respectively).
3-[(2R,3S,9S,9a S)-Oct a h yd r o-9-a cet oxy-4,4-d im et h yl-
2H-qu in olizin -3-yl]-4(3H)-qu in azolin on e (43)an d 3-[(2R,3S,
9S,9a S)-Octa h yd r o-2,9-d ia cetoxy-4,4-d im eth yl-2H-qu in o-
lizin -3-yl]-4(3H)-qu in a zolin on e (44). Compounds 43 and 44
were synthesized from 41 following the representative proce-
dure described for 5, and were obtained as colorless needles
(41 and 28%, respectively).
3-[(3S,9S,9aS)-Octah ydr o-9-acetoxy-4,4-dim eth yl-2-oxo-
2H-qu in olizin -3-yl]-4(3H)-qu in a zolin on e (45). Compound
45 was synthesized from 4 following the representative
procedure described for 5, and was obtained as colorless
needles (62%).
An t im a la r ia l a ssa ys in Vit r o a n d in Vivo. The anti-
malarial activities in vitro and in vivo against P. falciparum
and P. berghei, respectively, were investigated as described
in ref 11.
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of (+)-Febrifugine: A Potent Antimalarial Piperidine Alkaloid.
Org. Lett. 2000, 2, 3193-3195.
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DL-Febrifugine. Chem. Pharm. Bull. 1999, 47, 905-906. (b)
Takeuchi, Y.; Hattori, M.; Abe, H.; Harayama, T. Synthesis of
D/L-Febrifugine and D/L-Isofebrifugine. Synthesis 1999, 1814-
1818. (c) Takeuchi, Y.; Azuma, K.; Takakura, K.; Abe, H.;
Harayama, T. Asymmetric Synthesis of Febrifugine and Isofeb-
rifugine Using Yeast Reduction. Chem. Commun. 2000, 1643-
1644.
(6) Ooi, H.; Urushibara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama,
S. A Concise Enantioselective Synthesis of Antimalarial Febri-
fugine Alkaloids. Org. Lett. 2001, 3, 953-955.
(7) Takaya, Y.; Tasaka, H.; Chiba, T.; Uwai, K.; Tanitsu, M.; Kim,
H.-S.; Wataya, Y.; Miura, M.; Takeshita, M.; Oshima, Y. New
Type of Febrifugine Analogues, Bearing a Quinolizidine Moiety,
Show Potent Antimalarial Activity against Plasmodium Malaria
Parasite. J . Med. Chem. 1999, 42, 3163-3166.
Ack n ow led gm en t. This work was supported in part
by Grants-in-Aid for Scientific Research (12307007,
12557197, and 13226079) from the Ministry of Educa-
tion, Science, Sports and Culture of J apan.
(8) Fishman, M.; Cruickshank, P. A. Febrifugine Antimalarial
Agents. I. Pyridine Analogs of Febrifugine. J . Med. Chem. 1970,
13, 155-156.
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Su p p or tin g In for m a tion Ava ila ble: Analytical data and
purity criteria for new febrifugine analogues. This material is
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