Novel bis- and tris-1,2,4-trioxanes: Synthesis and antimalarial activity against multidrug-resistant Plasmodium yoelii in swiss mice

Article abstract of DOI:10.1021/jm801006v

A new series of bis-1,2,4-trioxanes 12a-h, 13a-h, and 14a-h and tris-1,2,4-trioxanes 12i-14i were prepared and evaluated against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. Cyclopentane-based bis-trioxanes 12a, 12b, 12f-h and cycloh

Full text of DOI:10.1021/jm801006v

J. Med. Chem. 2008, 51, 7581–7592
7581
Novel Bis- and Tris-1,2,4-trioxanes: Synthesis and Antimalarial Activity against
Multidrug-Resistant Plasmodium yoelii in Swiss Mice1
Chandan Singh,*,† Ved Prakash Verma,† Niraj Krishna Naikade,† Ajit Shankar Singh, Mohammad Hassam,† and Sunil K. Puri‡
DiVision of Medicinal and Process Chemistry and DiVision of Parasitology, Central Drug Research Institute, Lucknow-226001, India
ReceiVed August 8, 2008
A new series of bis-1,2,4-trioxanes 12a-h, 13a-h, and 14a-h and tris-1,2,4-trioxanes 12i-14i were prepared
and evaluated against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. Cyclopentane-
based bis-trioxanes 12a, 12b, 12f-h and cyclohexane-based bis-trioxanes 13a, 13f, and 13g showed promising
activity. All the tris-1,2,4-trioxanes were found to be inactive. Bis-trioxane 12a, the most active compound
of the series, provided 100% and 80% protection to infected mice at 48 and 24 mg/kg × 4 days, respectively.
Clinically useful drug ꢀ-arteether provided 100% and 20% protection at similar doses.
Introduction
Despite comprehensive global efforts for eradication of
malaria, about 40% of world population still is at risk of the
disease. Of these 2.5 billion people at risk, more than 500 million
become ill and more than 1 million, mostly children, die of
malaria every year.2 The rapid emergence of multidrug-resistant
P. falciparum has further complicated the problem. Against this
background, the isolation of artemisinin 1 as the active principle
of the Chinese traditional drug against malaria, Artemisia annua,
is a major breakthrough in malaria chemotherapy. Artemisinin
Figure 1. Artemisinin and its derivatives.
and its derivatives, e.g., artemether 2, arteether 3, and artesunic
acid 4 (Figure 1), are effective against both chloroquine-sensitive
and chloroquine-resistant malaria.3 The peroxide group present
in the form of 1,2,4-trioxane is essential for the antimalarial
activity of these compounds, and currently the focus is on
structurally simple synthetic 1,2,4-trioxanes. We had earlier
reported a photooxygenation route for the preparation of 1,2,4-
trioxanes. The key steps of this method are (i) preparation of
ꢀ-hydroxyhydroperoxides by photooxygenation of allylic alco-
hols and (ii) elaboration of these hydroperoxides into 1,2,4-
trioxanes (Scheme 1).4,5 Several trioxanes prepared by this
method in our laboratory have shown promising antimalarial
activity.6 Inspired by the work of Posner et al. on artemisinin
derived dimers, e.g., 5 and 6 (Figure 2), which have shown
excellent antimalarial activitry,7 we have extended our photo-
oxygenation method for the preparation of bis-and tris-1,2,4-
trioxanes. In this communication we report the synthesis and
antimalarial assessment of 24 bis-trioxanes and 3 tris-trioxanes.
To the best of our knowledge, this is the first report on
antimalarial bis- and tris-trioxanes.
Scheme 1
62-78% yields, respectively (Table 1). Wittig reaction of
diketone 8a with triethylphosphonoacetate/sodium hydride
furnished R,ꢀ-unsaturated diester 9a (61% yield). A similar
reaction of diketones 8b-e furnished R,ꢀ-unsaturated diesters
9b-e in 40-94% yields, respectively (Table 2). Reduction of
R,ꢀ-unsaturated diester 9a with LiAlH4 furnished allylic alcohol
10a (83% yield). A similar reduction of R,ꢀ-unsaturated diesters
9b-e furnished allylic alcohols 10b-e in 67-80% yields,
respectively (Table 3). Photooxygenation of allylic alcohol 10a
furnished ꢀ-hydroxyhydroperoxide 11a. Similar photooxygen-
ation of allylic alcohols 10b-e furnished ꢀ-hydroxyhydroper-
oxides 11b-e. In situ acid-catalyzed condensation of ꢀ-hy-
droxyhydroperoxides 11a-e with cyclopentanone furnished bis-
1,2,4-trioxanes 12a-e in 20-31% yields. A similar acid-
catalyzed condensation of 11a-e with cyclohexanone and
Chemistry
Bis-1,2,4-trioxanes 12a-e, 13a-e, and 14a-e were prepared
by the procedure given in Scheme 2. Thus, the reaction of
p-fluoroacetophenone with p-hydroxyacetophenone 7a in re-
fluxing in dimethyl sulfoxide furnished diketone 8a (75% yield).
A similar reaction of p-fluoroacetophenone with m-hydroxyac-
etophenone 7b, quinol 7c, 2,7-dihydroxynaphthalene 7d, and
1,5-dihydroxynaphthalene 7e furnished diketones 8b-e in
* To whom correspondence should be addressed. Phone: +91 0522
2624273. Fax: +91 0522 2623405. E-mail: chandancdri@yahoo.com.
†
Division of Medicinal and Process Chemistry.
Division of Parasitology.
‡
Figure 2. Artemisinin derived dimers.
10.1021/jm801006v CCC: $40.75
2008 American Chemical Society
Published on Web 11/12/2008

7582 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23
Singh et al.
Scheme 2a
a Reagents and conditions: (i) K2CO3, dimethyl sulfoxide, reflux, 2 h; (ii) (OEt)2P(O)CH2CO2Et, sodium hydride, THF, room temp, 6-21 h; (iii) LiAlH4,
THF, 0 °C, 1 h; (iv) 1O2, organic solvent, -10 to 0 °C, 11-13 h; (v) cyclopentanone, CH3CN, HCl, room temp, 1 h.
2-adamantanone furnished bis-1,2,4-trioxanes 13a-e and
14a-e, respectively, in 19-42% yields (Table 4).
hexanone and 2-admantanone furnished tris-1,2,4-trioxanes 13i
and 14i in 15% and 11% yields, respectively (Table 4).
Bis-1,2,4-trioxanes 12f-h, 13f-h, and 14f-h were prepared
by the procedure given in Scheme 3. Thus, the reaction of
p-hydroxyacetophenone with epichlorohydrin 7f at 115-130 °C
furnished diketone 8f (91% yield). A similar reaction of
p-hydroxyacetophenone with 1,3-dibromopropane 7g and 1,2-
dibromoethane 7h furnished diketones 8g (98% yield) and 8h
(71% yield) (Table 1). Wittig reaction of diketone 8f with
triethylphosphonoacetate/sodium hydride furnished R,ꢀ-unsatur-
ated diester 9f (46% yield). A similar reaction of diketones 8g
and 8h furnished R,ꢀ-unsaturated diesters 9g (70% yield) and
9h (46% yield) (Table 2). Reduction of R,ꢀ-unsaturated diester
9f with LiAlH4 furnished allylic alcohol 10f (82% yield). A
similar reduction of R,ꢀ-unsaturated diesters 9g and 9h furnished
allylic alcohols 10g (81% yield) and 10h (73% yield), respec-
tively (Table 3). Photooxygenation of allylic alcohol 10f
furnished ꢀ-hydroxyhydroperoxide 11f. Similar photooxygen-
ation of allylic alcohols 10g and 10h furnished ꢀ-hydroxyhy-
droperoxides 11g and 11h, respectively. In situ acid-catalyzed
condensation of ꢀ-hydroxyhydroperoxides 11f-h with cyclo-
pentanone furnished bis-1,2,4-trioxanes 12f-h in 16-40%
yields. A similar acid-catalyzed condensation of 11f-h with
cyclohexanone and 2-adamantanone provided bis-1,2,4-trioxanes
13f-h and 14f-h, respectively, in 19-32% yields (Table 4).
Tris-1,2,4-trioxanes 12i-14i were prepared by the procedure
given in Scheme 4. Thus, the reaction of p-fluoroacetophenone
with phluroglucinol 7i in refluxing in dimethyl sulfoxide fur-
nished triketone 8i (27% yield). Wittig reaction of triketone 8i
with triethylphosphonoacetate/sodium hydride furnished R,ꢀ-
unsaturated triester 9i (61% yield). Reduction of R,ꢀ-unsaturated
triester 9i with LiAlH4 furnished allylic alcohol 10i (61% yield).
Photooxygenation of allylic alcohol 10i furnished ꢀ-hydroxy-
hydroperoxide 11i, which on in situ acid-catalyzed condensation
with cyclopentanone furnished tris-1,2,4-trioxane 12i in 12%
yield. Similar acid-catalyzed condensation of 11i with cyclo-
Antimalarial Activity
All the new bis-and tris-trioxanes were evaluated for anti-
malarial activity against multidrug-resistant P. yoelii in Swiss
mice by oral route.8 In this model ꢀ-arteether provides 100%
protection at 48 mg/kg × 4 days. Therefore, all the trioxanes
were initially screened at 96 mg/kg × 4 days, twice the effective
dose of ꢀ-arteether. Trioxanes 12a, 12b, 12f-h, 13a, 13f, and
13g, which provided 100% protection at this dose, were further
screened at 48 mg/kg × 4 days. Trioxane 12a, which showed
100% protection at 48 mg/kg × 4 days, was further tested at
24 mg/kg × 4 days. The results are summarized in Table 5.
Results and Discussion
Artemisinin derivatives artemether 2, arteether 3, and arte-
sunic acid 4 are currently the drugs of choice for the treatment
of malaria caused by multidrug-resistant P. falciparum. These
drugs, however, have short half-lives and poor bioavailability
when given by oral route. We have recently reported a series
of lipophilic derivatives of dihydroartemisinin with excellent
antimalarial activity by oral route.10 More recently, Posner et
al. have reported orally active artemisinin dimers with high order
of activity.7 Inspired by this work, we have prepared a series
of bis-1,2,4-trioxanes and evaluated them against multidrug-
resistant P. yoelii in mice by oral route. These bis-trioxanes
have been prepared by a minor modification of our photooxy-
genation method, which we have used in the past for the
synthesis of a large number of 6-arylvinyl substituted-1,2,4-
trioxanes. In fact, structurally these bis-trioxanes are two
6-aryvinyl-1,2,4-trioxane moieties joined by a variety of linkers
and their antimalarial activity shows a strong dependence on
the nature of the linker.
As can be seen from Table 5, bis-trioxane 12a, which has
two 6-arylvinyl-1,2,4-trioxane moieties joined by an oxygen

Bis- and Tris-1,2,4-trioxanes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23 7583
Table 2. R,ꢀ-Unsaturated Diesters 9a–h and Triester 9i
Table 1. Diketones 8a-h and Triketone 8i
of these tris-trioxanes showed significant activity, the reason
again could be their high lipophilicity.
Conclusion
We have successfully extended our photooxygenation method
for the preparation of 1,2,4-trioxanes to the corresponding bis-
and tris-trioxanes. While none of the tris-trioxanes showed
significant activity, several bis-trioxanes showed promising
activity. Bis-trioxane 12a, the most active compound of the
present series, showed 100% and 80% protection at 48 and 24
mg/kg × 4 days, respectively. Clinically used drug arteether
showed only 20% protection at 24 mg/kg × 4 days.
atom, is the most active compound of the series. It provided
100% and 80% protection at 48 and 24 mg/kg × 4 days,
respectively, and therefore is slightly more active than arteether
which provided only 20% protection at 24 mg/kg × 4 days.
Bis-trioxanes 12b and 12f-h, which are structurally very close
to trioxane 12a, provided 100% protection only at 96 mg/kg ×
4 days. Thus, not only the nature of the linker but also the point
of linkage is all important for antimalarial activity. Cyclohexane-
based bis-trioxanes 13a, 13f, and 13g are other compounds that
provided 100% protection at 96 mg/kg × 4 days. Surprisingly,
all the admantane-based bis-trioxanes 14a-h showed very poor
activity. This is in sharp contrast with our earlier observation
on 6-arylvinyl-1,2,4-trioxanes where only admantane-based
trioxanes have shown antimalarial activity comparable with that
of arteether;11 the corresponding cyclopentane-and cyclohexane-
based spiro trioxanes were comparatively less active.12 The very
high lipophilicity of admantane-based bis-trioxanes appears to
be the main reason for their poor antimalarial activity. Similarly,
the poor activity shown by cyclopentane-based bis-trioxanes
12c-e could be due to their high lipophilicity.
Experimental Section
General. All glass apparatus were oven-dried prior to use.
Melting points were taken in open capillaries on a Complab melting
point apparatus and are presented uncorrected. Infrared spectra were
recorded on a Perkin-Elmer FT-IR RXI spectrophotometer. 1H
NMR and 13C NMR spectra were recorded using a Bruker Supercon
Magnet DPX-200 or DRX-300 spectrometer (operating at 200 and
300 MHz, respectively, for 1H and at 50 and 75 MHz, respectively,
for 13C) using CDCl3 as solvent. Tetramethylsilane (δ 0.00 ppm)
served as an internal standard in 1H NMR, and CDCl3 (δ 77.0 ppm)
served as an internal standard in 13C NMR. Chemical shifts are
reported in parts per million. Splitting patterns are described as
singlet (s), doublet (d), triplet (t), and multiplet (m). In NMR,
numbering of atoms is presented according to the usual numbering
in artemisinin as indicated in the text. Fast atom bombardment mass
Encouraged by the high order of activity shown by bis-
trioxanes, we also prepared tris-trioxanes 12i-14i. But none

7584 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23
Table 3. Allylic Alcohols 10a-i
Singh et al.
(0.4% of the calculated values except where noted. Column
chromatography was performed over Merck silica gel (particle size,
60-120 mesh), procured from Qualigens (India), and flash silica
gel (particle size, 230-400 mesh). All chemicals and reagents were
obtained from Aldrich, Lancaster (England), or Spectrochem (India)
and were used without further purification. The log P values of the
compounds were calculated using Chem Draw Ultra 7.0 software.
General Procedure for Synthesis of Diketones 8a-e and
Triketone 8i. Preparation of 8a. To a stirred mixture of p-
hydroxyacetophenone 7a (15 g, 110 mmol) in dimethyl sulfoxide
(50 mL) were added p-fluoroacetophenone (15.22 g, 110 mmol, 1
equiv) and anhydrous K2CO3 (22.5 g, 160 mmol, 1.5 equiv), and
the reaction mixture was refluxed for 2 h with continuous stirring.
The reaction mixture was cooled to room temperature, diluted with
water (100 mL), and extracted with ether (3 × 200 mL). The organic
layer was dried over anhydrous Na2SO4 and concentrated to furnish
a crude product, which on crystallization in a mixture of benzene
and hexane (3:7) furnished diketone 8a (21 g, 75% yield) as a white
solid, mp 98-100 °C.
Compounds 8b-e were prepared by the above procedure by
condensing p-fluoroacetophenone with m-hydroxyacetophenone 7b,
quinol 7c, 2,7-dihydroxynaphthalene 7d, and 1,5-dihydroxynaph-
thalene 7e, respectively. Compound 8i was prepared by condensing
p-fluoroacetophenone with phluroglucinol 7i.
1-[4-(4-Acetylphenoxy)phenyl]ethanone (8a). Yield 75%, white
solid, mp 98-100 °C; IR (KBr, cm-1) 1678; 1H NMR (300 MHz,
CDCl3) δ 2.57 (s, 6H), 7.06 (d, 4H, Ar, J ) 8.8 Hz), 7.97 (d, 4H,
Ar, J ) 8.8 Hz); FAB-MS (m/z) 255 [M + H]+.
1-[4-(3-Acetylphenoxy)phenyl]ethanone (8b). Yield 78%, white
1
solid, mp 65-67 °C; IR (KBr, cm-1) 1675; H NMR (300 MHz,
CDCl3) δ 2.58 (s, 3H), 2.59 (s, 3H), 7.01 (d, 2H, Ar, J ) 8.9 Hz),
7.25-7.29 (m, 1H, Ar), 7.50 (t, 1H, Ar, J ) 8 Hz), 7.64 (t, 1H,
Ar, J ) 1.9 Hz), 7.77 (dd, 1H, Ar, J ) 6.6 and 1.2 Hz), 7.96 (d,
2H, Ar, J ) 8.9 Hz); FAB-MS (m/z) 255 [M + H]+.
1-{4-[4-(4-Acetylphenoxy)phenoxy]phenyl}ethanone (8c). Yield
60%, white solid, mp 157-159 °C; IR (KBr, cm-1) 1671; 1H NMR
(300 MHz, CDCl3) δ 2.58 (s, 6H), 7.03 (d, 4H, Ar, J ) 8.8 Hz),
7.11 (s, 4H, Ar), 7.97 (d, 4H, Ar, J ) 8.8 Hz); FAB-MS (m/z) 347
[M + H]+.
Table 4. Trioxanes 12a-i, 13a-i, and 14a-i
compd
mp (°C)
yield (%)
12a
12b
12c
12d
12e
12f
12g
12h
13a
13b
13c
13d
13e
13f
13g
13h
14a
14b
14c
14d
14e
14f
14g
14h
12i
78-80
oil
115-120
oil
148-150
100-103
120-122
158-160
98-100
oil
135-138
oil
158-160
oil
118-120
145-147
60-63
45-50
55-60
oil
31
28
20
23
30
21
40
16
39
29
20
32
42
23
32
22
19
20
26
38
34
19
19
19
12
15
11
1-{4-[7-(4-Acetylphenoxy)naphthalen-2-yloxy]phenyl}ethanone
(8d). Yield 77%, white solid, mp 135-137 °C; IR (KBr, cm-1
)
1
1673; H NMR (300 MHz, CDCl3) δ 2.59 (s, 6H,), 7.08 (d, 4H,
Ar, J ) 8.8 Hz), 7.23 (dd, 2H, J ) 8.9 and 2.3 Hz), 7.33 (d, 2H,
Ar, J ) 2.1 Hz), 7.89 (d, 2H, Ar, J ) 8.9 Hz), 7.97 (d, 4H, Ar, J
) 8.8 Hz); FAB-MS (m/z) 397 [M + H]+.
1-{4-[5-(4-Acetylphenoxy)naphthalen-1-yloxy]phenyl}ethanone
(8e). Yield 62%, yellow solid, mp 180-183 °C; IR (KBr, cm-1
)
1
1680; H NMR (300 MHz, CDCl3) δ 2.59 (s, 6H), 7.07 (d, 4H,
Ar, J ) 8.6 Hz), 7.16 (d, 2H, Ar, J ) 7.5 Hz), 7.44-7.49 (m, 2H,
Ar), 7.95 (d, 2H, Ar, J ) 8.8 Hz), 7.98 (d, 4H, Ar, J ) 8.7 Hz);
FAB-MS (m/z) 397 [M + H]+.
1-{4-[3,5-Bis(4-acetylphenoxy)phenoxy]phenyl}ethanone (8i).
Yield 27%, white solid, mp 145-147 °C; IR (KBr, cm-1) 1674;
1H NMR (200 MHz, CDCl3) δ 2.57 (s, 9H), 6.54 (s, 3H, Ar), 7.07
(d, 6H, Ar, J ) 8.6 Hz), 7.96 (d, 6H, Ar, J ) 8.6 Hz); FAB-MS
(m/z) 481 [M + H]+.
General Procedure for Preparation of Diketones 8f-h. Pre-
paration of 8f. To a stirred mixture of epichlorohydrin (15 g, 160
mmol) and p-hydroxyacetophenone (48.5 g, 360 mmol, 2.2 equiv)
was added anhydrous K2CO3 (49.21 g, 360 mmol, 2.2 equiv), and
the reaction mixture was heated at 115-130 °C for 2 h. The reaction
mixture was cooled to room temperature, diluted with water (100
mL), and extracted with ether (3 × 200 mL). The organic layer
was dried over anhydrous Na2SO4 and concentrated to furnish a
crude product, which on column chromatography over silica gel
(60-120 mesh) using EtOAc/hexane (10:90) as eluant furnished
diketone 8f (48.40 g, 91% yield) as a white solid, mp 102-104
°C.
155-157
oil
114-116
156-158
oil
13i
oil
14i
oil
spectra (FAB-MS) were obtained on JEOL SX-102/DA-6000 mass
spectrometer using argon/xenon (6 kV, 10 mA) as the FAB gas.
Glycerol or m-nitrobenzyl alcohol was used as matrix. Electrospray
mass spectrometry (ES-MS) were recorded on a MICROMASS
QUATTRO II triple quadruple mass spectrometer. High resolution
electron impact mass spectra (HR-EIMS) were obtained on JEOL
MS route 600H instrument. Elemental analyses were performed
on Vario EL-III CHNS analyzer (Germany), and values were within
Compounds 8g and 8h were prepared by the above procedure
by replacing epichlorohydrin 7f with 1,3-dibromopropane 7g and
1,2-dibromoethane 7h, respectively.

Bis- and Tris-1,2,4-trioxanes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23 7585
Scheme 3a
a Reagents and conditions: (i) K2CO3, 115-130 °C, 2 h; (ii) (OEt)2P(O)CH2CO2Et, sodium hydride, THF, room temp, 21-24 h; (iii) LiAlH4, THF, 0 °C,
1 h; (iv) 1O2, organic solvent, -10 to 0 °C, 10-11 h; (v) cyclopentanone, CH3CN, HCl, room temp, 1 h.
Scheme 4a
a Reagents and conditions: (i) K2CO3, dimethyl sulfoxide, reflux, 6 h; (ii) (OEt)2P(O)CH2CO2Et, sodium hydride, THF, room temp, 26 h; (iii) LiAlH4,
THF, 0 °C, 1 h; (iv) 1O2, organic solvent, -10 to 0 °C, 13 h; (v) cyclopentanone, CH3CN, HCl, room temp, 1 h.
1-{4-[3-(4-Acetylphenoxy)-2-hydroxypropoxy]phenyl}ethanone
1-{4-[3-(4-Acetylphenoxy)propoxy]phenyl}ethanone (8g). Yield
98%, white solid, mp 124-126 °C; IR (KBr, cm-1) 1667; 1H NMR
(300 MHz, CDCl3) δ 2.25-2.33 (m, 2H), 2.51 (s, 6H), 4.21 (t,
4H, J ) 6 Hz), 6.92 (d, 4H, Ar, J ) 8.8 Hz), 7.89 (d, 4H, Ar, J )
8.8 Hz); ESI 313 [M + H]+.
(8f). Yield 91%, white solid, mp 102-104 °C; IR (KBr, cm-1
)
1666, 3389; 1H NMR (300 MHz, CDCl3) δ 2.56 (s, 6H), 2.96 (bs,
1H), 4.20-4.29 (m, 4H), 4.43-4.48 (m, 1H), 6.97 (d, 4H, Ar, J )
9 Hz), 7.93 (d, 4H, Ar, J ) 8.9 Hz); ESI 329 [M + H]+.

7586 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23
Singh et al.
Table 5. Blood Schizontocidal Activity of Trioxanes 12a-i, 13a-i, and 14a-i against Multidrug-Resistant P.yoelii in Swiss Mice via Oral Routec

Bis- and Tris-1,2,4-trioxanes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23 7587
Table 5. Continued
a Percent suppression ) [(C - T)/C] × 100, where C is parasitaemia in control group and T is parasitaemia in treated group. b 100% suppression of
parasitaemia means no parasites were detected in 50 oil immersion fields during microscopic observation.9 c Asterisk symbols represent the following: (/)
observation was discontinued after day 28; (//) mice that did not develop patent infection till day 28 were recorded as cured.
1-{4-[2-(4-Acetylphenoxy)ethoxy]phenyl}ethanone (8h). Yield
71%, white solid, mp 161-162 °C; IR (KBr, cm-1) 1673; 1H NMR
(300 MHz, CDCl3) δ 2.55 (s, 6H), 4.41 (s, 4H), 6.98 (d, 4H, Ar,
J ) 8.9 Hz), 7.94 (d, 4H, Ar, J ) 8.9 Hz); ESI 299 [M + H]+.

7588 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23
Singh et al.
General Procedure for Preparation of Esters 9a-i. Prepara-
tion of 9a. To a stirred slurry of sodium hydride (60% dispersion
in mineral oil, 6.08 g, 250 mmol, 4 equiv), in dry THF (20 mL) at
0 °C under nitrogen atmosphere was added a solution of trieth-
ylphosphonoacetate (34.07 g, 152 mmol, 4 equiv) in dry THF (50
mL). The reaction mixture was stirred at room temperature for 1 h.
The diketone 8a (15 g, 3.81 mmol), dissolved in dry THF (100
mL), was added to the reaction mixture dropwise, and the reaction
mixture was further stirred at room temperature for 6 h. The reaction
mixture was diluted with water (100 mL) and extracted with ether
(3 × 200 mL). The organic layer was dried over anhydrous Na2SO4,
concentrated, and purified by column chromatography over silica
gel (60-120 mesh) using EtOAc/hexane (1:99) as eluant to furnish
diester 9a (14 g, 61% yield) as a white solid, mp 52-56 °C.
Compounds 9b-h were prepared by the above procedure from
diketones 8b-h, and 9i was prepared from triketone 8i.
(q, 4H, J ) 7.1 Hz), 4.38 (s, 4H), 6.14 (d, 2H, J ) 1.1 Hz), 6.97
(d, 4H, Ar, J ) 8.9 Hz), 7.49 (d, 4H, Ar, J ) 8.9 Hz); ESI 461 [M
+ Na]+.
3-(4-{3,5-Bis[4-(2-ethoxycarbonyl-1-methylvinyl)phenoxy]phe-
noxy}phenyl)but-2-enoic Acid Ethyl Ester (9i). Yield 61%, oil; IR
1
(neat, cm-1) 1711; H NMR (200 MHz, CDCl3) δ 1.31 (t, 9H, J
) 6 Hz), 2.56 (s, 9H), 4.22(q, 6H, J ) 9 Hz), 6.10 (s, 3H, Ar),
6.44 (s, 3H, Ar), 7.02 (d, 6H, Ar, J ) 9 Hz), 7.49 (d, 6H, Ar, J )
9 Hz); FAB-MS (m/z) 691 [M + H]+.
General Procedure for Preparation of Allylic Alcohols 10a-i.
Preparation of 10a. To a stirred slurry of LiAlH4 (2.9 g, 80 mmol,
2 equiv) in dry THF (100 mL) at 0 °C was added diester 9a (15 g,
3.81 mmol) in dry THF (100 mL) dropwise. The reaction mixture
was stirred for 2 h at 0 °C. The reaction was quenched with 5%
aqueous NaOH (5 mL) and water (10 mL). The organic layer was
decanted, dried over anhydrous Na2SO4, and concentrated to furnish
a crude product, which on crystallization in CHCl3 furnished
compound 10a (9.10 g, 83% yield) as white solid, mp 126-129
°C.
3-{4-[4-(2-Ethoxycarbonyl-1-methylvinyl)phenoxy]phenyl}but-
2-enoic Acid Ethyl Ester (9a). Yield 61%, white solid, mp 52-56
°C; IR (KBr, cm-1) 1711; 1H NMR (300 MHz, CDCl3) δ 1.33 (t,
6H, J ) 7.2 Hz), 2.58 (d, 6H, J ) 1 Hz), 4.23(q, 4H, J ) 7.1 Hz),
6.14 (d, 2H, J ) 1.2 Hz), 7.02 (d, 4H, Ar, J ) 8.7 Hz), 7.49 (d,
4H, Ar, J ) 8.7 Hz); FAB-MS (m/z) 395 [M + H]+.
Compounds 10b-h were prepared by the above procedure from
diesters 9b-h, and 10i was prepared from triester 9i.
3-{4-[4-(3-Hydroxy-1-methylpropenyl)phenoxy]phenyl}but-
2-ene-1-ol (10a). Yield 83%, white solid, mp 126-129 °C; IR (KBr,
3-{4-[3-(2-Ethoxycarbonyl-1-methylvinyl)phenoxy]phenyl}-
1
cm-1) 3457; H NMR (200 MHz, CDCl3) δ 2.05 (d, 6H, J ) 1
but-2-enoic Acid Ethyl Ester (9b). Yield 60%, oil; IR (neat,
1
cm-1) 1718; H NMR (300 MHz, CDCl3) δ 1.28-1.33 (m, 6H),
Hz), 3.5 (bs, 2H), 4.32 (d, 4H, J ) 6.6 Hz), 5.89-5.96 (m, 2H,),
6.95 (d, 4H, Ar, J ) 8.8 Hz), 7.38 (d, 4H, Ar, J ) 8.8 Hz); FAB-
MS (m/z) 311 [M + H]+.
2.54 (s, 3H), 2.57 (s, 3H), 4.17-4.24 (m, 4H), 6.12 (s, 1H), 6.13
(s, 1H), 6.98 (d, 2H, Ar, J ) 8.7 Hz), 7.02 (d, 1H, Ar, J ) 1.5
Hz), 7.16 (s, 1H, Ar), 7.25 (d, 1H, Ar, J ) 7.8 Hz), 7.34 (dd, 1H,
Ar, J ) 7.8 and 1.5 Hz), 7.47 (d, 2H, Ar, J ) 8.7 Hz); FAB-MS
(m/z) 395 [M + H]+.
3-{4-[3-(3-Hydroxy-1-methylpropenyl)phenoxy]phenyl}but-
2-ene-1-ol (10b). Yield 80%, oil; IR (neat, cm-1) 3450; 1H NMR
(300 MHz, CDCl3) δ 2.0 and 2.03 (2 × s, 6H), 4.04 (bs, 2H),
4.28-4.31 (m, 4H), 5.92-5.98 (m, 2H), 6.84-6.93 (m, 3H, Ar),
7.06 (s, 1H, Ar), 7.15 (d, 1H, Ar, J ) 7.8 Hz), 7.25 (d, 1H, Ar, J
) 7.8 Hz), 7.36 (d, 2H, Ar, J ) 8.7 Hz); FAB-MS (m/z) 311 [M
+ H]+.
3-(4-{4-[4-(3-Hydroxy-1-methylpropenyl)phenoxy]phenoxy}-
phenyl)but-2-en-1-ol (10c). Yield 67%, white solid, mp 140-143
°C; IR (KBr, cm-1) 3404; 1H NMR (300 MHz, CDCl3) δ 1.97 (s,
6H), 4.15 (bs, 4H), 4.71 (bs, 2H), 5.86 (t, 2H, J ) 5 Hz), 6.96 (d,
4H, Ar, J ) 8.6 Hz), 7.06 (s, 4H, Ar), 7.43 (d, 4H, Ar, J ) 8.6
Hz); FAB-MS (m/z) 403 [M + H]+.
3-(4-{7-[4-(3-Hydroxy-1-methylpropenyl)phenoxy]naphthalen-
2-yloxy}phenyl)but-2-en-1-ol (10d). Yield 77%, white solid, mp
120-122 °C; IR (KBr, cm-1) 3505; 1H NMR (300 MHz, CDCl3)
δ 2.10 (s, 6H), 4.38 (d, 4H, J ) 6.7 Hz), 5.96-6.01 (m, 2H), 7.03
(d, 4H, Ar, J ) 8.8 Hz), 7.15-7.21 (m, 4H, Ar), 7.42 (d, 4H, Ar,
J ) 8.7 Hz), 7.81 (d, 2H, Ar, J ) 8.8 Hz); FAB-MS (m/z) 453 [M
+ H]+.
3-(4-{4-[4-(2-Ethoxycarbonyl-1-methylvinyl)phenoxy]phenoxy}-
phenyl)but-2-enoic Acid Ethyl Ester (9c). Yield 94%, white solid,
mp 100-102 °C; IR (KBr, cm-1) 1704; 1H NMR (300 MHz,
CDCl3) δ 1.33 (t, 6H, J ) 7.1 Hz), 2.58 (d, 6H, J ) 1 Hz), 4.23
(q, 4H, J ) 7.1 Hz), 6.13 (d, 2H, J ) 1.1 Hz), 7.0 (d, 4H, Ar, J )
8.8 Hz), 7.06 (s, 4H, Ar), 7.48 (d, 4H, Ar, J ) 8.8 Hz); FAB-MS
(m/z) 487 [M + H]+.
3-(4-{7-[4-(2-Ethoxycarbonyl-1-methylvinyl)phenoxy]naph-
thalen-2-yloxy}phenyl)but-2-enoic Acid Ethyl Ester (9d). Yield
71%, white solid, mp 58-59 °C; IR (KBr, cm-1) 1704; 1H NMR
(300 MHz, CDCl3) δ 1.31 (t, 6H, J ) 7.1 Hz), 6.12 (d, 6H, J )
1.1 Hz), 4.21 (q, 4H, J ) 7.1 Hz), 6.12 (d, 2H, J ) 1.2 Hz), 7.04
(dd, 4H, Ar, J ) 6.8 and 2 Hz), 7.17-7.24 (m, 4H, Ar), 7.48 (dd,
4H, Ar, J ) 6.9 and 1.9 Hz), 7.83 (d, 2H, Ar, J ) 8.9 Hz); FAB-
MS (m/z) 537 [M + H]+.
3-(4-{7-[4-(2-Ethoxycarbonyl-1-methylvinyl)phenoxy]naph-
thalen-2-yloxy}phenyl)but-2-enoic Acid Ethyl Ester (9e). Yield
40%, yellow solid, mp 158-160 °C; IR (KBr, cm-1) 1720; 1H
NMR (300 MHz, CDCl3) δ 1.34 (t, 6H, J ) 7.1 Hz), 2.60 (d, 6H,
J ) 1 Hz), 4.24 (q, 4H, J ) 7.1 Hz), 6.15 (d, 2H, J ) 1 Hz),
7.04-7.09 (m, 6H, Ar), 7.41-7.52 (m, 6H, Ar), 7.98 (d, 2H, Ar,
J ) 8.4 Hz); FAB-MS (m/z) 537 [M + H]+
3-(4-{3-[4-(2-Ethoxycarbonyl-1-methylvinyl)phenoxy]-2-
hydroxypropoxy}phenyl)but-2-enoic Acid Ethyl Ester (9f). Yield
46%, oil; IR (neat, cm-1) 1704, 3435; 1H NMR (300 MHz, CDCl3)
δ 1.32 (t, 6H, J ) 7.1 Hz), 2.57 (d, 6H, J ) 1 Hz), 2.71 (bs, 1H),
4.18-4.26 (m, 8H), 4.41-4.47 (m, 1H), 6.12 (d, 2H, J ) 1.1 Hz),
6.94 (d, 4H, Ar, J ) 8.8 Hz), 7.46 (d, 4H, Ar, J ) 8.9 Hz); ESI
486 [M + NH4]+.
3-(4-{5-[4-(3-Hydroxy-1-methylpropenyl)phenoxy]naphthalen-
1-yloxy}phenyl)but-2-en-1-ol (10e). Yield 79%, yellow solid, mp
98-100 °C; IR (KBr, cm-1) 3640; 1H NMR (300 MHz, CDCl3) δ
1.59 (bs, 2H), 1.95 (s, 6H), 4.17 (d, 4H, J ) 6.6 Hz), 5.78-5.83
(m, 2H), 6.86 (d, 6H, Ar, J ) 8.5 Hz), 7.27-7.33 (m, 6H, Ar), 7.8
(d, 2H, Ar, J ) 8.6 Hz); FAB-MS (m/z) 453 [M + H]+.
3-(4-{2-Hydroxy-3-[4-(3-hydroxy-1-methylpropenyl)phenoxy]-
propoxy}phenyl)but-2-en-1-ol (10f). Yield 82%, oil; IR (neat, cm-1
)
3406, 3435; 1H NMR (300 MHz, MeOD) δ 2.02 (s, 6H), 4.06-4.16
(m, 5H), 4.28 (d, 4H J ) 6.6 Hz), 5.86-5.91 (m, 2H), 6.91 (d,
4H, Ar, J ) 8.8 Hz), 7.35 (d, 4H, Ar, J ) 12.3 Hz); FAB-MS
(m/z) 385 [M + H]+.
3-(4-{3-[4-(2-Ethoxycarbonyl-1-methylvinyl)phenoxy]propoxy}-
phenyl)but-2-enoic Acid Ethyl Ester (9g). Yield 70%, white solid,
mp 58-60 °C; IR (KBr, cm-1) 1719; 1H NMR (300 MHz, CDCl3)
δ 1.32 (t, 6H, J ) 7.1 Hz), 2.24-2.32 (m, 2H), 2.57 (d, 6H, J )
1.2 Hz), 4.17-4.25 (m, 8H), 6.12 (d, 2H J ) 1 Hz), 6.91 (d, 4H,
Ar, J ) 8.8 Hz), 7.45 (d, 4H, Ar, J ) 8.8 Hz); ESI 475 [M +
Na]+.
3-(4-{3-[4-(3-Hydroxy-1-methylpropenyl)phenoxy]propoxy}phe-
nyl)but-2-en-1-ol (10g). Yield 81%, white solid, mp 110-112 °C;
1
IR (KBr, cm-1) 3446; H NMR (300 MHz, CDCl3) δ 1.48 (bs,
2H), 2.07 (d, 6H, J ) 0.6 Hz), 2.23-2.31 (m, 2H), 4.18 (t, 4H, J
) 6.1 Hz), 4.36 (d, 4H J ) 6.8 Hz), 5.90-5.96 (m, 2H), 6.88 (d,
4H, Ar, J ) 8.8 Hz), 7.35 (d, 4H, Ar, J ) 8.8 Hz); ESI 369 [M +
NH4]+.
3-(4-{2-[4-(2-Ethoxycarbonyl-1-methylvinyl)phenoxy]ethoxy}-
phenyl)but-2-enoic Acid Ethyl Ester (9h). Yield 46%, white solid,
mp 115-117 °C; IR (KBr, cm-1) 1700; 1H NMR (300 MHz,
CDCl3) δ 1.34 (t, 6H, J ) 7.1 Hz), 2.59 (d, 6H, J ) 1 Hz), 4.23
3-(4-{2-[4-(3-Hydroxy-1-methylpropenyl)phenoxy]ethoxy}phe-
nyl)but-2-en-1-ol (10h). Yield 73%, white solid, mp 156-160 °C;
IR (KBr, cm-1) 3337; 1H NMR (300 MHz, DMSO) δ 1.95 (s,
6H), 4.13 (t, 4H, J ) 5.8 Hz), 4.30 (s, 4H), 4.68 (t, 2H, J ) 5.4

Bis- and Tris-1,2,4-trioxanes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23 7589
Hz), 5.80-5.85 (m, 2H), 6.94 (d, 4H, Ar, J )8.8 Hz), 7.36 (d, 4H,
Ar, J ) 8.8 Hz); ESI 355 [M + H]+.
× C), 157.27 (2 × C); FAB-MS (m/z) 649 [M + H]+. Anal. Calcd
for C40H40O8: C, 74.06; H, 6.21. Found: C, 74.20; H, 6.35.
Trioxane 12e. Yield 30%, white solid, mp 148-150 °C; IR
(KBr, cm-1) 1596; 1H NMR (300 MHz, CDCl3) δ 1.66-1.92 (m,
14H), 2.46-2.52 (m, 2H), 3.86 (d, 4H, J ) 6.4 Hz), 5.26-5.30
(m, 4H), 7.02 (dd, 6H, Ar, J ) 6.3 and 2.1 Hz), 7.36-7.42 (m,
6H), 7.96 (d, 2H, Ar, J ) 8.5 Hz); 13C NMR (75 MHz, CDCl3) δ
23.58 (2 × CH2), 24.99 (2 × CH2), 30.03 (2 × CH2), 37.25 (2 ×
CH2), 65.26 (2 × CH2), 80.53 (2 × CH), 114.89 (2 × C), 116.09
(2 × CH2), 118.05 (2 × CH), 118.59 (4 × CH), 126.22 (2 × CH),
128.19 (4 × CH), 133.80 (2 × C), 142.76 (2 × C), 152.95 (2 ×
C), 158.14 (2 × C); FAB-MS (m/z) 649 [M + H]+. Anal. Calcd
for C40H40O8: C, 74.06; H, 6.21. Found: C, 74.17; H, 6.38.
Trioxane 12f. Yield 21%, white solid, mp 100-103 °C; IR (KBr,
cm-1) 3460; 1H NMR (300 MHz, CDCl3) δ 1.71-1.93 (m, 14H),
2.49-2.57 (m, 2H), 2.63 (d, 1H, J ) 5.2 Hz), 3.85 (d, 4H, J ) 6.5
Hz), 4.14-4.23 (m, 4H), 4.38-4.46 (m, 1H), 5.26-5.32 (m, 4H),
5.45 (s, 2H), 6.93 (d, 4H, Ar, J ) 8.8 Hz), 7.37 (d, 4H, Ar, J )
8.8 Hz); 13C NMR (75 MHz, CDCl3) δ 23.56 (2 × CH2), 24.98 (2
× CH2), 32.25 (2 × CH2), 37.25 (2 × CH2), 65.30 (2 × CH2),
68.30 (2 × CH2), 80.53 (2 × CH), 114.75 (4 × CH), 115.41 (2 ×
CH2), 127.89 (4 × CH), 131.83 (2 × C), 142.67 (2 × C), 158.58
(2 × C); ESI 598 [M + NH4]+, 603 [M + Na]+. Anal. Calcd for
C33H40O9: C, 68.26; H, 6.94. Found: C, 68.49; H, 6.99.
3-(4-{3,5-Bis[4-(3-hydroxy-1-methylpropenyl)phenoxy]phenoxy}-
phenyl)but-2-en-1-ol (10i). Yield 61%, oil; IR (neat, cm-1) 3440;
1H NMR (300 MHz, CDCl3) δ 2.04 (s, 9H), 2.25 (bs, 3H), 4.34
(d, 6H, J) 6.6 Hz), 5.90-5.94 (m, 3H), 6.36 (s, 3H, Ar), 6.98 (dd,
6H, Ar, J ) 8.7 and 3 Hz), 7.38 (dd, 6H, Ar, J ) 8.8 and 2.3 Hz);
FAB-MS (m/z) 565 [M + H]+.
General Procedure for Preparation of 1,2,4-Trioxanes. Prepa-
ration of 12a. A solution of allylic alcohol 10a (1 g, 3.22 mmol)
and methylene blue (5 mg) in a mixture of acetonitrile (100 mL),
THF (100 mL), and CHCl3 (50 mL) was irradiated with a 500 W
tungsten-halogen lamp at -10 to 0 °C, while oxygen gas was
bubbled into the reaction mixture for 11 h. The reaction mixture
was concentrated on a rotatory evaporator at room temperature and
then dissolved in acetonitrile (100 mL). Cyclopentanone (1.62 mL,
19.3 mmol, 6 equiv) and HCl (0.5 mL) were added to the reaction
mixture, and it was stirred for 1 h at room temperature. The reaction
mixture was concentrated and the crude product was purified by
column chromatography over silica gel (60-120 mesh) using
EtOAc/hexane (1:99) as eluant to furnish compound 12a (500 mg,
31% yield) as white solid, mp 78-80 °C.
Trioxanes 12b-i, were prepared from allylic alcohols 10b-i
using the above procedure, and trioxanes 13a-i and 14a-i were
prepared from allylic alcohols 10a-i by replacing cyclopentanone
with cyclohexanone and 2-admantanone, respectively.
Trioxane 12g. Yield 40%, white sold, mp 120-122 °C; IR (KBr,
1
cm-1) 1609; H NMR (300 MHz, CDCl3) δ 168-1.96 (m, 14H),
2.24-2.32 (m, 2H), 2.49-2.57 (m, 2H), 3.84 (d, 4H, J ) 6.4 Hz),
4.18 (t, 4H, J ) 6.1 Hz), 5.23-5.31 (m, 4H), 5.43 (s, 2H), 6.89 (d,
4H, Ar, J ) 8.8 Hz), 7.34 (d, 4H, Ar, J ) 8.8 Hz); 13C NMR (75
MHz, CDCl3) δ 23.56 (2 × CH2), 24.98 (2 × CH2), 29.48 (CH2),
32.99 (2 × CH2), 37.27 (2 × CH2), 64.66 (2 × CH2), 66.37 (2 ×
CH2), 80.61 (2 × CH), 114.73 (2 × C), 114.75 (4 × CH), 115.08
(2 × CH2), 127.82 (4 × CH), 131.33 (2 × C), 142.88 (2 × C),
142.88 (2 × C), 159.10 (2 × C); EI+ 564, ESI 582 [M + NH4]+.
Anal. Calcd for C33H40O8 ·0.1H2O: C, 70.19; H, 7.14. Found: C,
69.97; H, 7.12.
Trioxane 12a. Yield 31%, white solid, mp 78-80 °C; IR (KBr,
cm-1) 1596; 1H NMR (300 MHz, CDCl3) δ 1.68-1.96 (m, 14H),
2.48-2.56 (m, 2H), 3.87 (d, 4H, J ) 6.5 Hz), 5.27-5.31 (m, 4H),
5.49 (s, 2H), 7.00 (d, 4H, Ar, J ) 8.7 Hz), 7.39 (d, 4H, Ar, J )
8.7 Hz); 13C NMR (75 MHz, CDCl3) δ 23.38 (2 × CH2), 24.79 (2
× CH2), 32.81 (2 × CH2), 37.04 (2 × CH2), 65.02 (2 × CH2),
80.27 (2 × CH), 114.60 (2 × C), 116.02 (2 × CH2), 118.88 (4 ×
CH), 127.92 (4 × CH), 133.78 (2 × C), 142.45 (2 × C), 156.96 (2
× C); FAB-MS (m/z) 507 [M + H]+. Anal. Calcd for C30H34O7:
C, 71.13; H, 6.76. Found: C, 71.25; H, 6.82.
Trioxane 12h. Yield 16%, white solid, mp 158-160 °C; IR
(KBr, cm-1) 1607; 1H NMR (300 MHz, CDCl3) δ 1.68-1.94 (m,
14H), 2.49-2.58 (m, 2H), 3.86 (d, 4H, J ) 6.4 Hz), 4.35 (s, 4H),
5.25-5.32 (m, 4H), 5.45 (s, 2H), 6.94 (d, 4H, Ar, J ) 8.8 Hz),
7.37 (d, 4H, Ar, J ) 8.8 Hz); 13C NMR (75 MHz, CDCl3) δ 23.55
(2 × CH2), 24.97 (2 × CH2), 32.96 (2 × CH2), 37.24 (2 × CH2),
65.32 (2 × CH2), 66.69 (2 × CH2), 80.53 (2 × CH), 114.76 (4 ×
CH), 115.25 (2 × CH2), 127.82 (4 × CH), 131.62 (2 × C), 158.79
(2 × C); ESI 568 [M + NH4]+. Anal. Calcd for C32H38O8: C, 69.80;
H, 6.96. Found: C, 69.93; H, 6.99. HRMS calcd for C32H38O8
550.2567; found, 550.2546.
Trioxane 13a. Yield 39%, white solid, mp 98-100 °C; IR (KBr,
cm-1) 1595; 1H NMR (300 MHz, CDCl3) δ 1.46-1.66 (m, 16H),
2.01-2.07 (m, 2H), 2.19-2.26 (m, 2H), 3.79 (dd, 2H, J ) 11.8
and 2.9 Hz), 4.0 (dd, 2H, J ) 11.7 and 10.7 Hz), 5.23 (dd, 2H, J
) 10.2 and 2.6 Hz), 5.39 and 5.49 (2 × s, 4H), 6.99 (d, 4H, Ar, J
) 8.6 Hz), 7.39 (d, 4H, Ar, J ) 8.6 Hz); 13C NMR (75 MHz,
CDCl3) δ 22.48 (2 × CH2), 22.52 (2 × CH2), 25.74 (2 × CH2),
29.23 (2 × CH2), 34.83 (2 × CH2), 62.80 (2 × CH2), 80.47 (2 ×
CH), 102.81 (2 × C), 116.07 (2 × CH2), 119.05 (4 × CH), 128.10
(4 × CH), 134.11 (2 × C), 142.92 (2 × C), 157.17 (2 × C); FAB-
MS (m/z) 535 [M + H]+. Anal. Calcd for C32H38O7: C, 71.89; H,
7.16. Found: C, 71.98; H, 7.22. HRMS calcd for C32H38O7
534.2618; found, 534.2614.
Trioxane 12b. Yield 28%, oil; IR (neat, cm-1) 1505; 1H NMR
(300 MHz, CDCl3) δ 1.69-1.95 (m, 14H), 2.48-2.56 (m, 2H),
3.86-3.90 (m, 4H), 5.26-5.36 (m, 4H), 5.50 and 5.53 (2 × s, 2H),
6.97-7.01 (m, 3H, Ar), 7.11-7.12 (m, 1H, Ar), 7.17-7.20 (m,1H,
Ar), 7.31-7.43 (m, 3H, Ar); 13C NMR (75 MHz, CDCl3) δ 23.51
(2 × CH2), 24.92 (2 × CH2), 32.94 (2 × CH2), 37.12 (CH2), 37.16
(CH2), 65.07 (CH2), 65.14 (CH2), 80.41 (CH), 80.44 (CH), 114.70
(2 × C), 116.03 (CH2), 116.05 (CH2), 117.32 (CH), 117.44 (CH),
118.75 (CH), 118.86 (CH), 121.81 (C), 128.06 (CH), 130.07 (CH),
133.78 (CH), 140.67 (C), 142.64 (C), 142.81 (C), 157.13 (C),
157.32 (C); FAB-MS (m/z) 507 [M + H]+. Anal. Calcd for
C30H34O7: C, 71.13; H, 6.76. Found: C, 71.23; H, 6.93. HRMS
calcd for C30H34O7 506.2305; found, 506.2317.
Trioxane 12c. Yield 20%, white solid, mp 115-120 °C; IR
1
(KBr, cm-1) 1509; H NMR (300 MHz, CDCl3) δ 173-1.96 (m,
14H), 2.50-2.59 (m, 2H), 3.89 (d, 4H J ) 6.3 Hz), 5.29-5.33 (m,
4H), 5.50 (s, 2H), 7.0 (d, 4H, Ar, J ) 8.8 Hz), 7.06 (s, 4H, Ar),
7.41 (d, 4H, Ar, J ) 8.8 Hz); 13C NMR (75 MHz, CDCl3) δ 23.56
(2 × CH2), 24.91 (2 × CH2), 32.99 (2 × CH2), 37.22 (2 × CH2),
65.22 (2 × CH2), 80.49 (2 × CH), 114.79 (2 × C), 116.01 (2 ×
CH2), 118.28 (4 × CH), 120.93 (4 × CH), 128.07 (4 × CH), 133.52
(2 × C), 142.69 (2 × C), 152.71 (2 × C), 158.03 (2 × C); FAB-
MS (m/z) 599 [M + H]+. Anal. Calcd for C36H38O8: C, 72.22; H,
6.40. Found: C, 72.34; H, 6.62.
Trioxane 13b. Yield 29%, oil; IR (neat, cm-1) 1505; 1H NMR
(300 MHz, CDCl3) δ 1.43-1.64 (m, 16H), 1.97-2.08 (m, 2H),
2.17-2.26 (m, 2H), 3.75-3.82 (m, 2H), 3.95-4.04 (m, 2H),
5.19-5.36 (m, 4H), 5.50 and 5.52 (2 × s, 2H), 6.95-7.06 (m, 3H,
Ar), 7.09-7.11 (m,1H, Ar), 7.18 (d, 1H, Ar, J ) 7.8 Hz), 7.30-7.41
(m, 3H, Ar); 13C NMR (75 MHz, CDCl3) δ 22.40 (2 × CH2), 22.44
(2 × CH2), 25.65 (2 × CH2), 29.13 (2 × CH2), 34.69 (2 × CH2),
34.74 (CH2), 62.66 (CH2), 66.72 (CH2), 80.25 (CH), 80.35 (CH),
102.70 (2 × C), 115.88 (CH2), 117.17 (CH), 117.38 (CH), 118.71
(CH), 118.76 (CH), 121.75 (CH2), 128.01 (CH), 130.05 (CH),
140.73 (C), 142.80 (C), 142.98 (C), 157.09 (C), 157.26 (C); FAB-
Trioxane 12d. Yield 23%, oil; IR (neat, cm-1) 1600; 1H NMR
(300 MHz, CDCl3) δ 1.68-1.91 (m, 14H), 2.48-2.56 (m, 2H),
3.88 (d, 4H, J ) 6.5 Hz), 5.28-5.32 (m, 4H), 5.50 (s, 2H),
7.02-7.07 (m, 4H, Ar), 7.19 (dd, 4H, Ar, J ) 7.1 and 2.4 Hz),
7.38-7.43 (m, 4H, Ar), 7.83 (dd, 2H, Ar, J ) 7 and 2.7 Hz); 13
C
NMR (75 MHz, CDCl3) δ 23.58 (2 × CH2), 24.99 (2 × CH2),
33.02 (2 × CH2), 37.24 (2 × CH2), 65.24 (2 × CH2), 80.48 (2 ×
CH), 113.77 (2 × CH), 114.83 (2 × C), 116.22 (2 × CH2), 118.15
(2 × CH), 119.28 (4 × CH), 127.21 (C), 128.15 (4 × CH), 130.04
(2 × CH), 134.06 (2 × C), 135.64 (C), 142.68 (2 × C), 155.77 (2

7590 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23
Singh et al.
MS (m/z) 535 [M + H]+. Anal. Calcd for C32H38O7 ·0.1H2O: C,
71.89; H, 7.16. Found: C, 71.65; H, 7.14. HRMS calcd for C32H38O7
534.2618; found, 534.2623.
Trioxane 13h. Yield 22%, white solid, mp 145-147 °C; IR
(KBr, cm-1) 1635; 1H NMR (300 MHz, CDCl3) δ 1.47-1.65 (m,
16H), 1.99-2.08 (m, 2H), 2.21-2.29 (m, 2H), 3.77 (dd, 2H, J )
11.9 and 2.9 Hz), 3.99 (dd, 2H, J ) 11.8 and 10.4 Hz), 5.23 (d,
2H, J ) 2.9 Hz), 5.27 and 5.46 (2 × s, 4H), 6.94 (d, 4H, Ar, J )
8.6 Hz), 7.37 (d, 4H, Ar, J ) 8.8 Hz); 13C NMR (75 MHz, CDCl3)
δ 22.50 (2 × CH2), 25.72 (2 × CH2), 29.15 (2 × CH2), 34.86 (2
× CH2), 62.91 (2 × CH2), 66.67 (2 × CH2), 80.47 (2 × CH),
102.77 (2 × C), 114.83 (4 × CH), 115.15 (2 × CH2), 127.79 (4 ×
CH), 131.70 (2 × C), 142.91 (2 × C), 158.76 (2 × C); ESI 596
[M + NH4]+. Anal. Calcd for C34H42O8: C, 70.57; H, 7.32. Found:
C, 70.67; H, 7.48.
Trioxane 14a. Yield 19%, white solid, mp 60-63 °C; IR (KBr,
cm-1) 1596; 1H NMR (300 MHz, CDCl3) δ 1.60-2.11 (m, 26H),
2.96 (s, 2H), 3.79 (dd, 2H, J ) 11.8 and 2.9 Hz), 3.99 (dd, 2H, J
) 11.7 and 10.5 Hz), 5.25 (dd, 2H, J ) 10.3 and 2.7 Hz), 5.31 and
5.49 (2 × s, 4H), 6.99 (d, 4H, Ar, J ) 8.6 Hz), 7.4 (d, 4H, Ar, J
) 8.6 Hz); 13C NMR (75 MHz, CDCl3) δ 27.38 (4 × CH), 29.64
(2 × CH), 33.22 (2 × CH2), 33.46 (2 × CH2), 33.69 (2 × CH2),
33.79 (2 × CH2), 36.44 (2 × CH), 37.42 (2 × CH2), 62.33 (2 ×
CH2), 80.33 (2 × CH), 104.89 (2 × C), 116.02 (2 × CH2), 119.07
(4 × CH), 128.09 (4 × CH), 134.20 (2 × C), 142.97 (2 × C),
157.18 (2 × C); FAB-MS (m/z) 639 [M + H]+. Anal. Calcd for
C40H46O7: C, 75.21; H, 7.26. Found: C, 75.30; H, 7.30.
Trioxane 14b. Yield 20%, white solid, mp 45-50 °C; IR (KBr,
cm-1) 1606; 1H NMR (300 MHz, CDCl3) δ 1.60-2.10 (m, 26H),
2.95 and 2.97 (2 × s, 2H), 3.77-3.83 (m, 2H), 3.94-4.03 (m, 2H),
5.22-5.36 (m, 4H), 5.51 and 5.53 (2 × s, 2H), 6.96-7.0 (m, 3H,
Ar), 7.09-7.11 (m, 1H, Ar), 7.18 (d, 1H, Ar, J ) 7.8 Hz),
7.31-7.42 (m, 3H, Ar); 13C NMR (75 MHz, CDCl3) δ 27.36 (4 ×
CH), 29.62 (2 × CH), 33.20 (2 × CH2), 33.44 (2 × CH2), 33.68
(2 × CH2), 37.77 (2 × CH2), 36.38 (CH), 36.44 (CH), 37.40 (2 ×
CH2), 62.30 (CH2), 62.39 (CH2), 80.22 (CH), 80.32 (CH), 104.87
(2 × C), 115.93 (CH2), 117.22 (CH2), 117.49 (CH), 118.80 (CH),
118.90 (CH), 121.84 (CH), 128.11(CH), 130.15 (CH), 134.06 (C),
140.90 (CH), 142.94 (CH), 143.14 (C), 157.19 (C), 157.37 (C);
FAB-MS (m/z) 639 [M + H]+. Anal. Calcd for C40H46O7 ·0.1H2O:
C, 75.21; H, 7.26. Found: C, 75.00; H, 7.08.
Trioxane 14c. Yield 26%, white solid, mp 55-60 °C; IR (KBr,
cm-1) 1490; 1H NMR (300 MHz, CDCl3) δ 1.60-2.11 (m, 26H),
2.96 (s, 2H), 3.8 (dd, 2H, J ) 11.9 and 2.9 Hz), 3.99 (dd, 2H, J )
11.7 and 10.5 Hz), 5.26 (dd, 2H, J ) 10.7 and 2.7 HZ), 5.30 and
5.49 (2 × s, 4H), 6.99 (d, 4H, Ar, J ) 8.7 Hz), 7.04 (s, 4H, Ar),
7.39 (d, 4H, Ar, J ) 8.7 Hz); 13C NMR (75 MHz, CDCl3) δ 27.36
(4 × CH), 29.60 (2 × CH), 33.20 (2 × CH2), 33.45 (2 × CH2),
33.68 (2 × CH2), 33.78 (2 × CH2), 36.44 (2 × CH), 37.40 (2 ×
CH2), 62.34 (2 × CH2), 80.31 (2 × CH), 104.89 (2 × C), 115.85
(2 × CH2), 118.32 (4 × CH), 120.91 (4 × CH), 128.03 (4 × CH),
133.71 (2 × C), 142.92 (2 × C), 152.73 (2 × C), 158.01 (2 × C);
FAB-MS (m/z) 731 [M + H]+. Anal. Calcd for C46H50O8: C, 75.59;
H, 6.90. Found: C, 75.74; H, 6.98.
Trioxane 13c. Yield 20%, white solid, mp 135-138 °C; IR
(KBr, cm-1) 1507; 1H NMR (200 MHz, CDCl3) δ 1.21-1.62 (m,
16H), 1.94-2.08 (m, 2H), 2.16-2.28 (m, 2H), 3.76 (dd, 2H, J )
11.8 and 3 Hz), 3.98 (dd, 2H, J ) 11.8 and 10.3 Hz), 5.22 (dd,
2H, J ) 10.4 and 2.8 Hz), 5.28 and 5.46 (2 × s, 4H), 6.96 (d, 4H,
Ar, J ) 8.7 Hz), 7.01 (s, 4H, Ar), 7.36 (d, 4H, J ) 8.7 Hz); 13C
NMR (50 MHz, CDCl3) δ 22.18 (2 × CH2), 22.70 (2 × CH2),
24.80 (2 × CH2), 29.43 (2 × CH2), 35.04 (2 × CH2), 63.03 (2 ×
CH2), 80.69 (2 × CH), 103.02 (2 × C), 116.09 (2 × CH2), 118.50
(4 × CH), 121.10 (4 × CH), 128.26 (4 × CH), 133.86 (2 × C),
143.14 (2 × C), 152.94 (2 × C), 158.22 (2 × C); FAB-MS (m/z)
627 [M + H]+. Anal. Calcd for C38H42O8: C, 72.82; H, 6.75. Found:
C, 72.40; H, 6.95.
Trioxane 13d. Yield 32%, oil; IR (neat, cm-1) 1603; 1H NMR
(300 MHz, CDCl3) δ 1.46-165 (m, 16H), 2.01-2.07 (m, 2H),
2.19-2.26 (m, 2H), 3.80 (dd, 2H, J ) 11.8 and 2.9 Hz), 4.01 (dd,
2H, J ) 11.8 and 10.4 Hz), 5.25 (dd, 2H, J ) 10.3 and 2.5 Hz),
5.32 and 5.51 (2 × s, 4H), 7.04 (dd, 4H, Ar, J ) 6.8 and 1.9 Hz),
7.18-7.22 (m, 4H, Ar), 7.38-7.42 (m, 4H, Ar), 7.81-7.84 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 21.01 (3 × CH2), 24.25 (2 ×
CH2), 27.73 (2 × CH2), 33.35 (2 × CH2), 61.34 (2 × CH2), 78.96
(2 × CH), 101.37 (2 × C), 112.22 (2 × CH), 114.62 (2 × CH2),
117.47 (2 × CH), 117.81 (4 × CH), 125.69 (C), 126.64 (4 × CH),
128.53 (2 × CH), 132.67 (2 × C), 134.14 (C), 141.38 (2 × C),
154.30 (2 × C), 155.74 (2 × C); FAB-MS (m/z) 677 [M + H]+.
Anal. Calcd for C42H44O8: C, 74.54; H, 6.55. Found: C, 74.66; H,
6.68.
Trioxane 13e. Yield 42%, white solid, mp 158-160 °C; IR
(KBr, cm-1) 1596; 1H NMR (300 MHz, CDCl3) δ 1.42-1.63 (m,
16H), 1.97-2.05 (m, 2H), 2.17-2.26 (m, 2H), 3.78 (dd, 2H, J )
12 and 3 Hz), 3.99 (dd, 2H, J ) 12 and 10.5 Hz), 5.22 (dd, 2H, J
) 10.6 and 3.1 Hz), 5.29 and 5.47 (2 × s, 4H), 7.01 (dd, 6H, Ar,
J ) 9.3 and 7.3 Hz), 7.36-7.42 (m, 6H, Ar), 7.96 (d, 2H, Ar, J )
8.4 Hz); 13C NMR (75 MHz, CDCl3) δ 22.52 (2 × CH2), 22.56 (2
× CH2), 25.77 (2 × CH2), 29.27 (2 × CH2), 34.87 (2 × CH2),
62.87 (2 × CH2), 80.52 (2 × CH), 102.85 (2 × C), 114.63 (2 ×
CH), 115.97 (2 × CH2), 118.03 (2 × CH), 118.61 (4 × CH), 126.20
(2 × CH), 128.17 (4 × CH), 128.72 (2 × C), 133.92 (2 × C),
142.99 (2 × C), 152.97 (2 × C), 158.11 (2 × C); FAB-MS (m/z)
677 [M + H]+. Anal. Calcd for C42H44O8: C, 74.54; H, 6.55. Found:
C, 74.62; H, 6.65.
1
Trioxane 13f. Yield 23%, oil; IR (neat, cm-1) 3455; H NMR
(300 MHz, CDCl3) δ 1.45-1.64 (m, 16H), 1.97-2.06 (m, 2H),
2.18-2.25 (m, 2H), 3.76 (dd, 2H, J ) 11.9 and 2.9 Hz), 3.97 (dd,
2H, J ) 11.8 and 10.4 Hz), 4.12-4.12 (m, 5H), 4.36-4.43 (m,
1H), 5.23 (dd, 2H, J ) 10.8 and 2.8 Hz), 5.26 and 5.44 (2 × s,
4H), 6.91 (d, 4H, Ar, J ) 8.8 Hz), 7.34 (d, 4H, Ar, J ) 8.7 Hz);
13C NMR (75 MHz, CDCl3) δ 22.45 (2 × CH2), 22.49 (2 × CH2),
25.70 (2 × CH2), 29.17 (2 × CH2), 34.82 (2 × CH2), 62.84 (2 ×
CH2), 68.89 (CH), 68.98 (2 × CH2), 80.50 (2 × CH), 102.77 (2 ×
C), 114.76 (4 × CH), 115.25 (2 × CH2), 127.83 (4 × CH), 131.90
(2 × C), 142.91 (2 × C), 158.59 (2 × C); ESI 626 [M + NH4]+.
Anal. Calcd for C35H44O9 ·0.1H2O: C, 69.06; H, 7.29. Found: C,
68.86; H, 7.26.
Trioxane 13g. Yield 32%, white solid, mp 118-120 °C; IR
(KBr, cm-1) 1608; 1H NMR (300 MHz, CDCl3) δ 1.46-1.65 (m,
16H), 1.98-2.07 (m, 2H), 2.19-2.32 (m, 4H), 3.76 (dd, 2H, J )
11.9 and 2.9 Hz), 3.97 (dd, 2H, J ) 11.8 and 10.4 Hz), 4.18 (t,
4H, J ) 6 Hz) 5.22 (d, 2H, J ) 2.9 Hz), 5.25 and 5.44 (2 × s,
4H), 6.89 (d, 4H, Ar, J ) 8.8 Hz), 7.34 (d, 4H, Ar, J ) 8.7 Hz);
13C NMR (75 MHz, CDCl3) δ 22.47 (2 × CH2), 22.51 (2 × CH2),
25.73 (2 × CH2), 29.18 (2 × CH2), 29.43 (CH2), 34.86 (2 × CH2),
62.94 (2 × CH2), 64.91 (2 × CH2), 80.54 (2 × CH), 102.74 (2 ×
C), 114.68 (4 × CH), 114.95 (2 × CH2), 127.75 (4 × CH), 131.36
(2 × C), 143.03 (2 × C), 159.04 (2 × C); ESI 610 [M + NH4]+.
Anal. Calcd for C35H44O8 ·0.1H2O: C, 70.92; H, 7.48. Found: C,
70.71; H, 7.46.
Trioxane 14d. Yield 38%, oil; IR (neat, cm-1) 1598; 1H NMR
(300 MHz, CDCl3) δ 1.68-2.08 (m, 26 H), 2.96 (s, 2H), 3.81 (dd,
2H, J ) 11.9 and 2.9 Hz), 4.0 (dd, 2H, J ) 11.8 and 10.6 Hz),
5.27 (dd, 2H, J ) 10.7 and 2.9 Hz), 5.31 and 5.51 (2 × s, 4H),
7.04 (dd, 4H, Ar, J ) 6.8 and 1.9 Hz), 7.18-7.22 (m, 4H, Ar),
7.39-7.43 (m, 4H, Ar), 7.80-7.84 (m, 2H, Ar); 13C NMR (75
MHz, CDCl3) δ 27.36 (4 × CH), 29.62 (2 × CH), 33.20 (2 ×
CH2), 33.44 (2 × CH2), 33.67 (2 × CH2), 33.77 (2 × CH2), 36.42
(2 × CH), 37.40 (2 × CH2), 62.31 (2 × CH2), 80.28 (2 × CH),
104.88 (2 × C), 113.71 (2 × CH), 115.99 (2 × CH2), 118.93 (2 ×
CH), 119.29 (4 × CH), 127.18 (C), 128.09 (4 × CH), 129.99 (2 ×
CH), 134.24 (2 × CH), 135.63 (C), 142.93 (2 × C), 155.80 (2 ×
C), 157 0.21 (2 × C); FAB-MS (m/z) 781 [M + H]+. Anal. Calcd
for C50H52O8: C, 76.90; H, 6.71. Found: C, 76.97; H, 6.98.
Trioxane 14e. Yield 34%, white solid, mp 155-157 °C; IR
(KBr, cm-1) 1598; 1H NMR (300 MHz, CDCl3) δ 1.57-2.09 (m,
26H), 2.94 (s, 2H), 3.78 (dd, 2H, J ) 11.8 and 2.9 Hz), 3.97 (dd,
2H, J ) 11.8 and 10.6 Hz), 5.24 (dd, 2H, J ) 10.9 and 2.9 Hz),
5.28 and 5.47 (2 × s, 4H), 7.01 (dd, 6H, Ar, J ) 6.9 and 2 Hz),
7.37-7.42 (m, 6H, Ar), 7.95 (d, 2H, Ar, J ) 8.4 Hz); 13C NMR

Bis- and Tris-1,2,4-trioxanes
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23 7591
1
(75 MHz, CDCl3) δ 27.40 (4 × CH), 29.67 (2 × CH), 33.24 (2 ×
CH2), 33.48 (2 × CH2), 33.71 (2 × CH2), 38.81 (2 × CH2), 36.46
(2 × CH), 37.44 (2 × CH2), 62.37 (2 × CH2), 80.34 (2 × CH),
104.90 (2 × C), 114.84 (2 × CH), 115.89 (2 × CH2), 118.03 (2 ×
CH), 118.62 (4 × CH), 126.20 (2 × CH), 128.14 (4 × CH), 128.72
(2 × C), 134 (2 × C), 143.01 (2 × C), 152.99 (2 × C), 158.10 (2
× C); FAB-MS (m/z) 781 [M + H]+. Anal. Calcd for C50H52O8:
C, 76.90; H, 6.71. Found: C, 76.87; H, 6.95.
Trioxane 14i. Yield 11%, oil; IR (KBr, cm-1) 1593; H NMR
(300 MHz, CDCl3) δ 1.60-2.10 (m, 39H), 2.94 (s, 3H), 3.77 (dd,
3H, J ) 11.8 and 2.9 Hz), 3.97 (dd, 3H, J ) 11.8 and 10.4 Hz),
5.26 (dd, 3H, J ) 10.3 and 2.7 Hz), 5.30 and 5.48 (2 × s, 6H),
6.99 (d, 4H, Ar, J ) 8.6 Hz), 7.4 (d, 4H, Ar, J ) 8.6 Hz); 13C
NMR (75 MHz, CDCl3) δ 27.38 (6 × CH), 29.64 (3 × CH), 33.22
(3 × CH2), 33.46 (3 × CH2), 33.69 (3 × CH2), 33.79 (3 × CH2),
36.44 (3 × CH), 37.42 (3 × CH2), 62.29 (3 × CH2), 80.28 (3 ×
CH), 104.29 (3 × C), 104.91 (3 × CH), 116.22 (3 × CH2), 119.40
(6 × CH), 128.16 (6 × CH), 134.66 (3 × C), 142.86 (3 × C),
156.44 (3 × C), 159.43 (3 × C); FAB-MS (m/z) 1058 [M + H]+.
Anal. Calcd for C66H72O12: C, 74.98; H, 6.86. Found: C, 74.90; H,
6.96.
1
Trioxane 14f. Yield 19%, oil; IR (neat, cm-1) 3450; H NMR
(300 MHz, CDCl3) δ 1.60-2.10 (m, 26H), 2.62 (bs, 1H), 2.96 (s,
2H), 3.77 (dd, 2H, J ) 11.9 and 2.9 Hz), 3.96 (dd, 2H, J ) 11.8
and 10.62 Hz), 4.13-4.22 (m, 4H), 4.39-4.42 (m, 1H), 5.23 (d,
2H, J ) 2.9 Hz), 5.26 and 5.45 (2 × s, 4H), 6.92 (d, 4H, Ar, J )
8.8 Hz), 7.35 (d, 4H, Ar, J ) 8.7 Hz); 13C NMR (75 MHz, CDCl3)
δ 27.37 (4 × CH), 29.60 (2 × CH), 33.21 (2 × CH2), 33.45 (2 ×
CH2), 33.69 (2 × CH2), 33.78 (2 × CH2), 36.47 (2 × CH), 37.42
(2 × CH2), 62.40 (2 × CH2), 68.99 (2 × CH2), 80.38 (2 × CH),
104.85 (2 × C), 114.80 (4 × CH), 115.26 (2 × CH2), 127.86 (4 ×
CH), 132.07 (2 × C), 143.00 (2 × C), 158.61 (2 × C); ESI 730
[M + NH4]+. Anal. Calcd for C43H52O9: C, 72.45; H, 7.35. Found:
C, 72.48; H, 7.50.
Trioxane 14g. Yield 19%, white solid, mp 114-116 °C; IR
(KBr, cm-1) 1606; 1H NMR (300 MHz, CDCl3) δ 1.59-2.11 (m,
26H), 2.23-2.32 (m, 2H), 2.97 (s, 2H), 3.76 (dd, 2H, J ) 11.9
and 2.8 Hz), 3.95 (dd, 2H, J ) 12.1 and 10.7 Hz), 4.17 (t, 4H, J
) 5.8 Hz), 5.22-5.26 (m, 4H), 5.43 (s, 2H) 6.88 (d, 4H, Ar, J )
8.9 Hz), 7.33 (d, 4H, Ar, J ) 8.7 Hz); 13C NMR (75 MHz, CDCl3)
δ 27.46 (4 × CH), 29.65 (2 × CH2), 29.76 (2 × CH), 33.39 (2 ×
CH2), 33.64 (2 × CH2), 33.89 (2 × CH2), 33.87 (2 × CH2), 36.67
(2 × CH), 37.61 (2 × CH2), 62.66 (2 × CH2), 64.82 (2 × CH2),
80.58 (2 × CH), 105.01 (2 × C), 114.89 (4 × CH), 115.11 (2 ×
CH2), 127.94 (4 × CH), 131.63 (2 × C), 143.25 (2 × C), 159.25
(2 × C); ESI 714 [M + NH4]+. Anal. Calcd for C43H52O8: C, 74.11;
H, 7.52. Found: C, 74.32; H, 7.64.
Acknowledgment. V.P.V., N.K.N., A.S.S, and M.H. are
thankful to the Council of Scientific and Industrial Research
(CSIR) and University of Grants Commission (UGC), New
Delhi, India, for the award of Senior Research Fellowship.
Supporting Information Available: 1H NMR spectra of
compounds 8a-i, 9a-i, and 10a-i; elemental analysis results; 1H
NMR and 13C NMR spectra of compounds 12a-i, 13a-i, and
14a-i. This material is available free of charge via the Internet at
http://pubs.acs.org.
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Trioxane 14h. Yield 19%, white solid, mp 156-158 °C; IR
(KBr, cm-1) 1607; 1H NMR (300 MHz, CDCl3) δ 1.61-2.09 (m,
26H), 2.98 (s, 2H), 3.78 (dd, 2H, J ) 11.8 and 2.9 Hz), 3.98 (dd,
2H, J ) 11.7 and 10.7 Hz), 4.35 (s, 4H), 5.25-5.29 (m, 4H), 5.46
(s, 2H), 6.94 (d, 4H, Ar, J ) 8.8 Hz), 7.37 (d, 4H, Ar, J ) 8.8
Hz); 13C NMR (75 MHz, CDCl3) δ 27.34 (4 × CH), 29.54 (2 ×
CH), 33.17 (2 × CH2), 33.43 (2 × CH2), 33.67 (2 × CH2), 33.76
(2 × CH2), 36.45 (2 × CH), 37.387 (2 × CH2), 62.41 (2 × CH2),
66.70 (2 × CH2), 80.35 (2 × CH), 104.83 (2 × C), 114.85 (4 ×
CH), 115.11 (2 × CH2), 127.77 (4 × CH), 131.79 (2 × C), 142.95
(2 × C), 158.77 (2 × C); ESI 700 [M + NH4]+, 705 [M + Na]+;.
Anal. Calcd for C42H50O8: C, 73.88; H, 7.38. Found: C, 73.96; H,
7.50.
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of cyclohexene in nonaqueous media. J. Org. Chem. 1957, 22, 1682–
1685. (b) Jefford, C. W.; Jaggi, D.; Boukouvalas, J.; Kohmoto, S.
Reaction of bicyclic endoperoxides with carbonyl compounds. A new
approach to 1,2,4-trioxanes. J. Am. Chem. Soc. 1983, 105, 6497–6498.
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antimalarial 1,2,4-trioxanes. Tetrahedron Lett. 1991, 32, 4235–4238.
(g) Bloodworth, A. J.; Shah, A. Synthesis of 1,2,4-trioxanes via
intramolecular oxymercuration. J. Chem. Soc., Chem. Commun. 1991,
947, 948. (h) Bloodwarth, A. J.; Johnson, K. A. 6-Hydroxymethyl-
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from ꢀ′γ′-unsaturated ꢀ-hydroxyhydroperoxides. Tetrahedron Lett.
1994, 35, 8057–8060. (i) O’Neill, P. M.; Pugh, M.; Davies, J.; Ward,
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Org. Lett. 2004, 6, 3035–3038.
1
Trioxane 12i. Yield 12%, oil; IR (neat, cm-1) 1602; H NMR
(200 MHz, CDCl3) δ 1.68-1.96 (m, 21H), 2.44-2.55 (m, 3H),
3.83 (d, 6H, J ) 6.5 Hz), 5.22-5.27 (m, 6H), 5.46 (s, 3H), 6.39
(s, 3H, Ar), 6.99 (d, 6H, Ar, J ) 8.8 Hz), 7.37 (d, 6H, Ar, J ) 8.7
Hz); 13C NMR (50 MHz, CDCl3) δ 23.74 (3 × CH2), 25.51 (3 ×
CH2), 33.18 (3 × CH2), 37.40 (3 × CH2), 65.34 (3 × CH2), 80.64
(3 × CH), 104.51 (3 × CH), 114.98 (3 × C), 116.56 (3 × CH2),
119.55 (6 × CH), 128.37 (6 × CH), 134.67 (3 × C), 142.81 (3 ×
C), 156.64 (3 × C), 159.64 (3 × C); FAB-MS (m/z) 859 [M +
H]+. Anal. Calcd for C51H54O12: C, 71.31; H, 6.34. Found: C, 71.30;
H, 6.39.
1
Trioxane 13i. Yield 15%, oil; IR (neat, cm-1) 1604; H NMR
(300 MHz, CDCl3) δ 1.43-1.67 (m, 24H), 1.97-2.06 (m, 3H),
2.17-2.26 (m, 3H), 3.79 (dd, 3H, J ) 12 and 3.1 Hz), 3.99 (dd,
3H, J ) 11.8 and 10.4 Hz), 5.22 (dd, 3H, J ) 10. and 2.9 Hz),
5.39 and 5.48 (2 × s, 6H), 6.42 (s, 3H, Ar), 7.01 (d, 6H, Ar, J )
9 Hz), 7.38 (d, 6H, Ar, J ) 9 Hz); 13C NMR (75 MHz, CDCl3) δ
22.46 (3 × CH2), 22.49 (3 × CH2), 25.71 (3 × CH2), 29.20 (3 ×
CH2), 34.78 (3 × CH2), 62.72 (3 × CH2), 80.38 (3 × CH), 102.79
(3 × C), 104.25 (3 × CH), 116.21 (3 × CH2), 119.33 (6 × CH),
128.13 (6 × CH), 134.54 (3 × C), 142.78 (3 × C), 156.40 (3 ×
C), 159.38 (3 × C); FAB-MS (m/z) 901 [M + H]+. Anal. Calcd
for C54H60O12: C, 71.98; H, 6.71. Found: C, 71.84; H, 6.92.

7592 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23
Singh et al.
(6) (a) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Synthesis of in
vivo potent antimalarial 1,2,4-trioxanes. Bioorg. Med. Chem. Lett.
1992, 2, 497–500. (b) Singh, C.; Misra, D.; Saxena, G.; Chandra,
S. In vivo potent antimalarial 1,2,4-trioxanes: synthesis and activity
of 8-(R-arylvinyl)-6,7,10-trioxaspiro[4,5]decanes and 3-(R-arylvi-
nyl)-1,2,5-trioxaspiro[5,5]undecanes against Plasmodium berghei
in mice. Bioorg. Med. Chem. Lett. 1995, 5, 1913–1916. (c) Singh,
C.; Gupta, N.; Puri, S. K. Geraniol-derived 1,2,4-trioxanes with
potent in vivo antimalarial activity. Bioorg. Med. Chem. Lett. 2003,
13, 3447–3450. (d) Singh, C.; Malik, H.; Puri, S. K. Synthesis and
antimalarial activity of a new series of trioxaquines. Bioorg. Med.
Chem. 2004, 12, 1177–1182. (e) Singh, C.; Gupta, N.; Puri, S. K.
Synthesis of new 6-alkylvinyl/arylalkylvinyl substituted 1,2,4-
trioxanes active against multidrug-resistant malaria in mice. Bioorg.
Med. Chem. 2004, 12, 5553–5562. (f) Singh, C.; Srivastav, N. C.;
Puri, S. K. Synthesis and antimalarial activity of 6-cycloalkylvinyl
substituted 1,2,4-trioxanes. Bioorg. Med. Chem. 2004, 12, 5745–5752.
(g) Singh, C.; Malik, H.; Puri, S. K. Orally active amino functionalized
antimalarial 1,2,4-trioxanes. Bioorg. Med. Chem. Lett. 2004, 14, 459–
462. (h) Singh, C.; Malik, H.; Puri, S. K. New orally active spiro
1,2,4-trioxanes with high antimalarial potency. Bioorg. Med. Chem.
Lett. 2005, 15, 4484–4487. (i) Singh, C.; Malik, H.; Puri, S. K. Orally
active 1,2,4-trioxanes: synthesis and antimalarial assessment of a new
series of 9-functionalized 3-(1-arylvinyl)-1,2,5-trioxaspiro[5,5]undecanes
against multidrug-resistant Plasmodium yoelii nigeriensis in mice.
J. Med. Chem. 2006, 49, 2794–2803.
Malaria; Academic Press: London, 1970; pp 64-136. (b) In vivo test
procedure is as follows: The colony bred Swiss mice (25 ( 1g) were
inoculated with 1 × 106 parasitized RBC on day zero, and treatment
was administered to a group of five mice at each dose, from day 0 to
day 3, in two divided doses daily. The drug dilutions of compounds
12a-i, 13a-i, and 14a-i were prepared in groundnut oil to contain
the required amount of the drug (1.2 mg for a dose of 96 mg/kg, 0.6
mg for a dose of 48 mg/kg, and 0.3 mg for a dose of 24 mg/kg) in 0.1
mL and administered orally for each dose. Parasitaemia level were
recorded from thin blood smears between day 4 and day 28. The
animals that did not develop patent infection till day 28 were recorded
as cured.13 Mice treated with ꢀ-arteether served as positive con-
trol.
(9) (a) 100% suppression of parasitaemia means no parasites were
detected in 50 oil immersion microscopic fields (parasites, if at all
present, are below the detection limit). The parasites present below
the detection limit can multiply and eventually can be detected
during observation on subsequent days. In such cases though the
drug is providing near 100% suppression of the parasitaemia on
day 4, it will not provide full protection to the treated mice in the
28 day survival assay. Multi-drug resistant Plasmodium yoelii
nigeriensis used in this study is resistant to chloroquine, mefloquine,
and halofantrine. (b) 100% protection means none of the treated
mice developed patent infection during the 28-day observation
period and hence recorded as cured. Similarly, 20% protection
means only 1 out of 5 mice was cured.
(7) (a) Paik, I.-H.; Xie, S.; Shapiro, T. A.; Labonte, T.; Narducci
Sarjeant, A. A.; Baege, A. C.; Posner, G. H. Second generation,
orally active, antimalarial, artemisinin-derived trioxane dimers with
high stability, efficacy, and anticancer activity. J. Med. Chem. 2006,
49, 2731–2734. (b) Posner, G. H.; Paik, I.-H.; Chang, W.; Borstnik,
K.; Sinishtaj, S.; Rosenthal, A. S.; Shapiro, T. A. Malaria infected
mice are cured by a single dose of novel artemisinin derivatives.
J. Med. Chem. 2007, 50, 2516–2519. (c) Posner, G. H.; Chang, W.;
Hess, L.; Woodard, L.; Sinishtaj, S.; Usera, A. R.; Maio, W.;
Rosenthal, A. S.; Kalinda, A. S.; D’; Angelo, J. G.; Petersen, K. S.;
Stohler, R.; Chollet, J.; Santo-Thomas, J.; Snyder, C.; Rottmann,
M.; Wittlin, S.; Brun, R.; Shapiro, T. A. Malaria-infected mice are
cured by oral administration of new artemisinin derivatives. J. Med.
Chem. 2008, 51, 1035–1042.
(10) Singh, C.; Chaudhary, S.; Puri, S. K. New orally active derivatives of
artemisinin with high efficacy against multidrug-resistant malaria in
mice. J. Med. Chem. 2006, 49, 7227–7233.
(11) Singh, C.; Kanchan, R.; Sharma, U.; Puri, S. K. New adamantane-
based spiro 1,2,4-trioxanes orally effective against rodent and simian
malaria. J. Med. Chem. 2007, 50, 521–527.
(12) Singh, C.; Kanchan, R.; Srivastava, D.; Puri, S. K. 8-(1-Naphthalen-
2-yl-vinyl)-6,7,10-trioxaspiro (4.5) decane, a new 1,2,4-trioxane ef-
fective against rodent and simian malaria. Bioorg. Med. Chem. Lett.
2006, 16, 584–586.
(13) Puri, S. K.; Singh, N. Azithromycin: antimalarial profile against blood
and sporozoite-induced infections in mice and monkeys. Exp. Para-
sitol. 2000, 94, 8–14.
(8) (a) Peters, W. Techniques for the Study of Drug Response in
Experimental Malaria. In Chemotherapy and Drug Resistance in
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