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 multi-drug-resistant Plasmodium yoelii nigeriensis in mice

Article abstract of DOI:10.1021/jm051130r

Using easily accessible keto-trioxanes 7a-g as the starting materials, a series of new variously functionalized 1,2,4-trioxanes 10-36 have been prepared and evaluated for antimalarial activity against multi-drug-resistant Plasmodium yoelii nigeriensis in

Full text of DOI:10.1021/jm051130r

2794
J. Med. Chem. 2006, 49, 2794-2803
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 Multi-Drug-Resistant
Plasmodium yoelii nigeriensis in Mice1
Chandan Singh,*,† Heetika Malik,† and Sunil K. Puri‡
DiVision of Medicinal & Process Chemistry and DiVision of Parasitology, Central Drug Research Institute, Lucknow-226001, India
ReceiVed NoVember 10, 2005
Using easily accessible keto-trioxanes 7a-g as the starting materials, a series of new variously functionalized
1,2,4-trioxanes 10-36 have been prepared and evaluated for antimalarial activity against multi-drug-resistant
Plasmodium yoelii nigeriensis in mice in the dose range of 24 mg/kg × 4 days to 96 mg/kg × 4 days by
oral route. Trioxanes 10, 12, 14, 16, 18, 20, and 22 have shown promising antimalarial activity. Trioxanes
14 and 18, the two most active compounds of the series, provide 100% and 60% protection at 48 mg/kg ×
4 days and 24 mg/kg × 4 days, respectively. In this model â-arteether provides 100% and 20% protection
at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively.
Malaria is a major parasitic disease affecting over 100 coun-
tries of the tropical and subtropical regions of the world includ-
ing India. Around 300-500 million clinical cases of malaria
are reported every year of which around 2-3 million die due to
complicated cases of malaria.2 Situation is getting worse with
the emergence of multi-drug-resistant parasites. Against this back-
ground, isolation of artemisinin 1 by the Chinese as the antima-
larial principle of Artemisia annua has been a major break-
Figure 1. Artemisinin and its derivatives.
through in malaria chemotherapy. Artemisinin is active against
both chloroquine-sensitive and chloroquine-resistant malaria.3
Scheme 1a
Artemisinin derivatives such as artemether 2, arteether 3, and
artesunic acid 4 (Figure 1) have better solubility and activity
profile than the parent compound and are increasingly finding
use either alone or in combination with other drugs for the
treatment of malaria caused by multi-drug-resistant P. falci-
parum.4 The peroxide group present in the form of 1,2,4-trioxane
is essential for the antimalarial activity of artemisinin and its
derivatives. Several synthetic trioxanes originating from different
laboratories including our group have shown promising anti-
malarial activity both in vitro and in vivo.5,6
a Reagents and reaction conditions: (a) hν, O2, methylene blue, MeCN,
-10 to 0 °C; (b) 1,4-cyclohexanedione, concd HCl, 5 °C.
Earlier we have shown that â-hydroxyhydroperoxides pre-
pared by photooxygenation of allylic alcohols6a,7 react with 1,4-
cyclohexanedione to give keto-functionalized 1,2,4-trioxanes
(Scheme 1), and that these trioxanes undergo facile reductive
amination with various amines to give amino-functionalized
1,2,4-trioxanes (prototype 8 and 9) (Figure 2).8,9 Some of these
amino-functionalized 1,2,4-trioxanes have shown high order of
activity against multi-drug-resistant Plasmodium yoelii nigerien-
sis in mice.9
Figure 2. Prototypes of amino-functionalized 1,2,4-trioxanes.
Scheme 2a
We have further explored the chemistry of the carbonyl group
of these keto-trioxanes with the twin objectives (i) to assess
the stability of the trioxane moiety under conditions of variety
of organic reactions and (ii) to generate a library of new
trioxanes with different functional groups. In the event these
keto-trioxanes were found to be stable under conditions of
reduction with NaBH4, Wadsworth-Emmons reaction with
triethylphosphonacetate and triethylphosphon-2-propionate, Re-
formatsky reaction with BrCH2COOEt/Zn, and Grignard reac-
tion with MeMgBr and PhMgBr. In the process, we have
a Reagents and reaction conditions: (a) (OEt)2P(O)CH2CO2Et/(OEt)2-
P(O)CH(CH3)CO2Et, NaH, DME/ THF, 0 °C to room temperature, 2-3 h.
prepared series of variously functionalized 1,2,4-trioxanes 10-
36 and assessed their antimalarial activity against multi-drug-
resistant P. yoelii nigeriensis in mice. Some of these trioxanes
have shown high order of antimalarial activity comparable with
that of the â-arteether, by oral route. In this paper we describe
the details of the study.10
Chemistry. â-Hydroxyhydroperoxides 6a-g prepared by
photooxygenation of allylic alcohols 5a-g were condensed with
1,4-cyclohexanedione in the presence of concd HCl to furnish
keto-trioxanes 7a-g in 28-51% yields (based on allylic
* Corresponding author. Tel.: +91 0522 2624273; fax: +91 0522
2623405, e-mail: chandancdri@yahoo.com.
† Division of Medicinal & Process Chemistry.
‡ Division of Parasitology.
10.1021/jm051130r CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/05/2006

Orally ActiVe 1,2,4-Trioxanes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9 2795
Table 1. Yields of Functionalized 1,2,4-Trioxanes 10-36
a Yield in each case refers to the single preparation of the target compound.
alcohol). Reaction of keto-trioxanes 7a-g with triethylphos-
phonacetate in the presence of NaH in dimethoxyethane
furnished R,â-unsaturated esters 10, 12, 14, 16, 18, 20, and 22
as inseparable mixtures of geometrical isomers in 90-93%
J ) 11.8, 10.0 Hz), and 6-H around δ 5.26 (dd, J ) 10.0, 3.0
1
Hz). The isomeric pairs show identical H NMR except the
signal for 5-He appears at different places. Similar reaction of
keto-trioxanes 7a-g with triethylphosphon-2-propionate under
similar conditions furnished R,â-unsaturated esters 11, 13, 15,
17, 19, 21, and 23 as inseparable mixtures of geometrical
1
yields (Scheme 2, Table 1). H NMR of these trioxanes show
characteristics signals of 1,2,4-trioxane moiety: 5-He appears
around δ 3.80 (dd, J ) 11.8, 3.0 Hz), 5-Ha around δ 3.98 (dd,
1
isomers in 82-86% yields (Scheme 2, Table 1). H NMR of

2796 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9
Singh et al.
Scheme 3a
Scheme 5a
a Reagents and reaction conditions: (a) CH3MgI/C6H5MgBr, 0 °C, 1 h.
a Reagents and conditions: (a) Zn/BrCH2CO2Et, benzene, 50 °C, 4 h.
protection, respectively at 96 mg/kg × 4 days, were also
evaluated at 48 mg/kg × 4 days. Results are summarized in
Table 2.
the isomeric pairs differ only for the signals for OCH2CH3; they
have identical δ values for 5-He, 5-Ha, and 6-H.
Reformatsky reaction of 7a with BrCH2COOEt/Zn in dry
benzene furnished â-hydroxyesters 24a and 24b as a mixture
of diastereomers in 83% yield, which were separated by column
chromatography. 5He in both these isomers show similar δ
values; (δ 3.67 for 24a and δ 3.77 for 24b) whereas 5Ha of
24b appears downfield as compared to that of 24a; (δ 3.78 for
24a and δ 4.03 for 24b). Keto-trioxanes 7b and 7c under similar
reaction conditions furnished esters 25a and 25b, and 26a and
26b as a diastereomeric mixture in 88% and 84% yields,
respectively. Pure isomers 25a and 25b, and 26a and 26b, were
obtained by column chromatography (Scheme 3, Table 1). A
similar difference in δ values of 5Ha in 25a and 25b, and 26a
and 26b, was observed.
Reduction of 7a-c and 7e with NaBH4 in MeOH furnished
alcohols 27-30 in 93-96% yields as inseparable mixtures of
diastereomers, which on reaction with succinic anhydride and
triethylamine in CH2Cl2 at room temperature gave hemisucci-
nates 31-34 in 91-94% yields, again as inseparable mixtures
of diastereomers (Scheme 4, Table 1).
Reaction of keto-trioxane 7a with MeMgBr in dry diethyl
ether furnished a diastereomeric mixture of alcohols 35a and
35b in 54% yield. These two isomers were separated by column
chromatography. Similar reaction of 7a with PhMgBr furnished
trioxanes 36a and 36b as a mixture of diastereomers in 57%
yield. These isomers were separated by column chromatography
and characterized separately, while they were screened as
mixture for biological activity (Scheme 5, Table 1).11 Here also
isomeric pairs show similar δ for 5He but downfield shift in
the δ value of 5Ha.
Antimalarial Activity. Parent trioxanes 7a-g and their
derivatives 10-36 were assessed for antimalarial activity against
multi-drug-resistant P. yoelii nigeriensis in mice by oral route
using Peters’s procedure.13a In this model â-arteether shows
100% clearance of parasitemia at 48 mg/kg × 4 days and all
the treated mice survive beyond day 28. At 24 mg/kg × 4 days
â-arteether provides only 20% protection to the treated mice.
Therefore all the trioxanes were initially tested at 96 mg/kg ×
4 days orally, double the effective dose of â-arteether. Trioxanes
10, 12, 14, 18, and 22 which provided 100% protection at this
dose were further tested at 48 mg/kg × 4 days and 24 mg/kg ×
4 days.13b Trioxanes 16 and 20 which provided 80% and 60%
Results and Discussion
As can be seen from Table 2, except for trioxane 7f, which
protects 60% of the treated mice, none of the parent keto-
trioxanes 7a-g provides significant protection. Similarly, none
of their NaBH4-reduced products 27-30 and their hemisucci-
nates 31-34 show significant activity. Wadsworth-Emmons
reaction products 10, 12, 14, 16, 18, 20, and 22 show very
promising activity. The most active compounds of the series
are 14 and 18, both of which show 100% protection at 48 mg/
kg. Even at 24 mg/kg, these trioxanes provide 60% protection
to the treated mice. These two compounds have an edge over
â-arteether which shows only 20% protection at 24 mg/kg.
Trioxanes 10 and 22 also provide 100% protection at 48 mg/
kg. At 24 mg/kg both 10 and 22, however, show complete
clearance of parasitemia on day 4 but none of the treated mice
survive till day 28. Trioxane 12 provides 100% protection at
96 mg/kg only. At 48 mg/kg it shows more than 90%
suppression of parasitemia on day 4 but none of the treated
mice is protected. Trioxanes 16 and 20 provide 80% and 60%
protection, respectively, at 96 mg/kg. Even at 48 mg/kg both
these compound show 100% clearance of parasitemia on day 4
and 40% of the treated mice survive beyond day 28. Surpris-
ingly, none of the Wadsworth-Emmons products 11, 13, 15,
17, 19, 21, and 23, which have only an extra methyl group at
the double bond, show significant protection, indicating that the
spatial requirement in this part of the molecule is very stringent
and even an extra methyl group is not tolerated. This is further
reflected in the Reformatsky reaction products 24-26 and
Grignard reaction products 35 and 36, none of which show any
activity. Among the active trioxanes 10, 12, 14, 16, 18, 20, and
22, there is clear correlation between antimalarial activity and
hydrophobicity. Trioxanes 10, 14, 18, and 22 which have log p
values between 3.79 and 4.79 show a better activity profile than
those which have either lower log p values (trioxane 16, log p
) 3.66) or higher log p values (trioxane 12, log p ) 5.46,
trioxane 20, log p ) 5.78). The log p value of â-arteether also
lies within this range (log p ) 3.84). Comparatively poor
antimalarial activity of trioxanes 12 and 20 are in conformity
with Lipinski’s rule of five.14 However, in the rest of the series,
there are several trioxanes having log p values which range
Scheme 4a
a Reagents and reaction conditions: (a) NaBH4, MeOH, 0°, 0.5 h; (b) succinic anhydride, triethylamine, CH2Cl2, rt, 1 h.

Orally ActiVe 1,2,4-Trioxanes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9 2797
Table 2. In Vivo Antimalarial Activity of 1,2,4-Trioxanes 10-36 against P. yoelii in Swiss Mice

2798 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9
Table 2. (Continued)
Singh et al.
a Percent suppression ) [(C - T)/C] × 100; where C ) Parasitemia in control group, and T ) Parasitemia in treated group. b 100% suppression of
parasitemia means, number of parasites if at all present, are below the detection limit.13
spectrometer using argon/xenon (6 kV, 10 mA) as the FAB gas.
Glycerol or m-nitrobenzyl alcohol was used as matrix. Elemental
analyses were done on Vario EL-III C H N S analyzer (Germany).
High-resolution electron impact mass spectra (HR-EIMS) were
obtained on a JEOL MS route 600H instrument. Reactions were
monitored on silica gel TLC plates (coated with TLC grade silica
gel, obtained from Merck). Detecting agents used (for TLC) were
iodine vapors and/or spraying with an aqueous solution of vanillin
in 10% sulfuric acid followed by heating at 150 °C. Column
chromatography was performed over silica gel (60-120 Mesh)
procured from Qualigens (India) using freshly distilled solvents.
All chemicals and reagents were obtained from Aldrich (Milwaukee,
WI), Lancaster (England), or Spectrochem (India) and were used
without further purification. Anhydrous diethyl ether (ether) used
in Grignard reactions was obtained from Spectrochem and was kept
over sodium wires overnight prior to use. Log p values of the
compounds were calculated using Chem Draw Ultra 6.0.
between 3.79 and 4.79 but none of them show significant
activity, indicating therefore that minor structural differences
can override the hydrophobicity criterion.
Conclusions
In conclusion, in our efforts to assess the behavior of 1,2,4-
trioxane moiety toward variety of reaction conditions we have
prepared a new series of functionalized trioxanes using the
chemistry of carbonyl group of trioxanes 7a-g. Several of these
trioxanes show a better activity profile than the parent trioxanes
7a-g. The activity profiles of trioxanes 14 and 18, the most
active compounds of the series, are better than that of the
clinically used drug, â-arteether. Trioxanes 10 and 22 also show
high order of antimalarial activity, which is very close to that
of â-arteether.
Experimental Section
3-(1-Phenyl-vinyl)-1,2,5-trioxaspiro[5.5]undec-9-one (7a). A
solution of allylic alcohol 5a (1 g, 6.75 mmol) and methylene blue
(30 mg) in acetonitrile (100 mL) was irradiated with a 500 W
tungsten-halogen lamp at -10 to 0 °C while oxygen was bubbled
slowly into the reaction mixture for 4 h. 1,4-Cyclohexanedione (1.15
g, 10.13 mmol) and concd HCl (0.2 mL) were added, and the
reaction mixture was left at 5 °C for 18 h. Usual workup followed
by chromatography over silica gel furnished trioxane 7a (0.94 g,
51% yield, based on allylic alcohol 5a); mp 70-71 °C; IR (KBr,
All glass apparatus were oven dried prior to use. Melting points
were determined on COMPLAB melting point apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR
RXI spectrophotometer. 1H NMR and 13C NMR spectra were
recorded on Bruker DPX-200 (operating at 200 MHz for 1H and at
50 MHz for 13C) or DRX-300 (operating at 300 MHz for H and
1
at 75 MHz for 13C) spectrometers using CDCl3 as solvent.
Tetramethylsilane (0.00 ppm) served as an internal standard in 1H
NMR and CDCl3 (77.0 ppm) in 13C NMR. Fast atom bombardment
mass spectra (FAB-MS) were obtained on a JEOL SX 102
1
cm-1) 1717; H NMR (200 MHz, CDCl3) δ 2.05 (t, 2H, J ) 7.06
Hz), 2.32-2.67 (m, 6H), 3.85 (dd, 1H, J ) 11.8, 2.9 Hz), 3.96

Orally ActiVe 1,2,4-Trioxanes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9 2799
(dd, 1H, J ) 11.8, 10.1 Hz), 5.31 (dd, 1H, J ) 10.1, 2.9 Hz), 5.36
and 5.53 (2 × s, 2H), 7.32-7.40 (m, 5H); 13C NMR (50 MHz,
CDCl3) δ 27.79 (t), 33.57 (t), 36.79 (t), 36.95 (t), 63.72 (t), 80.83
(d), 101.50 (s), 117.10 (t), 126.81 (d, integrating for two carbons),
128.72 (d), 129.05 (d, integrating for two carbons), 138.84 (s),
143.59 (s), 210.00 (s); FAB-MS (m/z) 275 [M + H]+; Anal. Calcd
for C16H18O4: C 70.06%, H 6.61%; found: C 69.77%, H 6.86%.
Compounds 7b-g were prepared by the above procedure.
3-(1-Biphenyl-4yl-vinyl)-1,2,5-trioxaspiro[5.5]undec-9-one (7b).
Yield 42%; mp 104-105 °C; IR (KBr, cm-1) 1711; 1H NMR (200
MHz, CDCl3) δ 2.07 (t, 2H, J ) 7.06 Hz), 2.33-2.69 (m, 6H),
3.91 (dd, 1H, J ) 12.0, 3.5 Hz), 4.02 (dd, 1H, J ) 12.0, 9.7 Hz),
5.38 (dd, 1H, J ) 9.7, 3.5 Hz), 5.41 and 5.59 (2 × s, 2H), 7.31-
7.62 (m, 9H); 13C NMR (50 MHz, CDCl3) δ 27.85 (t), 33.61 (t),
36.83 (t), 36.99 (t), 63.76 (t), 80.77 (d), 101.56 (s), 117.01 (t),
127.20 (d, integrating for two carbons), 127.42 (d, integrating for
two carbons), 127.53 (d, integrating for two carbons), 127.98 (d),
129.26 (d, integrating for two carbons), 137.65 (s), 140.76 (s),
141.62 (s), 143.11 (s), 210.08 (s); FAB-MS (m/z) 351 [M + H]+;
Anal. Calcd for C22H22O4: C 75.41%, H 6.33%; found: C 75.41%,
H 6.68%.
cooled to 0 °C, and a solution of triethylphosphonoacetate (1.35 g,
6.04 mmol) in dry DME (10 mL) was added dropwise with stirring.
After the addition was complete, the resulting solution was stirred
for an additional 1 h. To the yellow solution thus obtained was
added dropwise a solution of trioxane 7a (1 g, 3.64 mmol) in dry
DME (15 mL), while maintaining the temperature of the flask at 0
°C. After the addition was complete the resulting solution was
stirred for additional 0.5 h at 0 °C. Reaction mixture was diluted
with water (40 mL) and extracted with diethyl ether (2 × 75 mL).
The combined organic layer was washed successively with water
(2 × 15 mL) and brine (10 mL), dried over anhyd Na2SO4, and
concentrated to obtain crude product which was purified by column
chromatography over silica gel using AcOEt-hexane (1:49) as
eluant to furnish spiro trioxane 10 (viscous oil, 1.16 g, 93% yield)
as an inseparable mixture of geometrical isomers. IR (neat, cm-1
)
1
1711; H NMR (200 MHz, CDCl3) δ 1.26 (t, 3H, J ) 7.1 Hz),
1.77-1.84 (m, 2H), 2.08-2.19 (m, 1H), 2.27-2.45 (m, 3H), 2.84-
3.13 (m, 2H), 3.79 (dd, 1H, J ) 12.1, 2.9 Hz), 3.94 and 3.96 (2 ×
dd, 1H, J ) 12.1, 10.0 Hz, together integrating for 1H), 4.14 (q,
2H, J ) 7.1 Hz), 5.28 (dd, 1H, J ) 10.0, 2.9 Hz), 5.33 and 5.50 (2
× s, 2H), 5.68 (s, 1H), 7.30-7.38 (m, 5H); 13C NMR (50 MHz,
CDCl3) δ 14.69 (q), 24.82 and 24.97 (t), 29.18 and 29.90 (t), 33.06
and 33.28 (t), 34.82 and 35.46 (t), 60.04 (t), 63.41 (t), 80.77 (d),
102.14 (s), 115.08 (d), 116.85 and 117.00 (t), 126.80 (d, integrating
for two carbons), 128.62 (d), 128.99 (d, integrating for two carbons),
138.96 (s), 143.78 (s), 159.97 (s), 166.78 (s); FAB-MS (m/z) 345
[M + H]+; HR-EIMS calc for C20H24O5 344.1624 found 344.1625.
Compounds 11-23 were also prepared by the same procedure.
2-[3-(1-Phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-
propionic Acid Ethyl Ester (11). Yield 83%, viscous oil: IR (neat,
cm-1) 1709; 1H NMR (300 MHz, CDCl3) δ 1.29 and 1.30 (2 × t,
3H, J ) 7.2 Hz, together integrating for 3H), 1.72-1.78 (m, 2H),
1.89 (s, 3H), 2.00-2.16 (m, 1H), 2.28-2.43 (m, 3H), 2.51-2.71
(m, 2H), 3.79 (dd, 1H, J ) 11.7, 3.1 Hz), 3.96 (dd, 1H, J ) 11.7,
10.8 Hz), 4.19 and 4.20 (2 × q, 2H, J ) 7.2 Hz, together integrating
for 2H), 5.28 (dd, 1H, J ) 10.8, 3.1 Hz), 5.33 and 5.50 (2 × s,
2H), 7.28-7.37 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 14.64 (q),
15.72 (q), 26.40 and 26.58 (t), 27.18 and 27.37 (t), 29.16 and 29.70
(t), 34.78 and 35.29 (t), 60.66 (t), 61.43 (t), 80.80 (d), 102.59 (s),
116.88 and 116.96 (t), 122.05 (s), 126.82 (d, integrating for two
carbons), 128.58 (d), 128.97 (d, integrating for two carbons), 138.99
(s), 143.82 (s), 145.04 and 145.15 (s), 170.38 (s); FAB-MS (m/z)
359 [M + H]+; HR-EIMS calc for C21H26O5 358.1780 found
358.1780.
3-[1-(4-Chloro-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undecan-
1
9-one (7c). Yield 38%; mp 72-74 °C; IR (KBr, cm-1) 1715; H
NMR (200 MHz, CDCl3) δ 2.05 (t, 2H, J ) 7.1 Hz), 2.35-2.69
(m, 6H), 3.86 (dd, 1H, J ) 11.9, 3.2 Hz), 3.97 (dd, 1H, J ) 11.9,
10.0 Hz), 5.26 (dd, 1H, J ) 10.0, 3.2 Hz), 5.36 and 5.52 (2 × s,
2H), 7.27-7.32 (m, 4H); FAB-MS (m/z) 309 and 311 [M + H]+;
Anal. Calcd for C16H17ClO4: C 62.24%, H 5.55%; found: C
62.51%, H 5.46%.
3-[1-(4-Methoxy-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undecan-
9-one (7d). Yield 28%; viscous oil; IR (neat, cm-1) 1716; 1H NMR
(CDCl3, 200 MHz) δ 2.05 (t, 2H, J ) 7.0 Hz), 2.32-2.70 (m, 6H),
3.75-3.89 (m, 1H), 3.81 (s, 3H, OCH3), 3.97 (dd,,1H, J ) 11.9,
10.0 Hz), 5.30 (dd, 1H, J ) 10.0, 2.9 Hz), 5.24 and 5.45 (2 × s,
2H), 6.88 (d, 2H, J ) 8.0 Hz), 7.33 (d, 2H, J ) 8.0 Hz); FAB-MS
(m/z) 305 [M + H]+; Anal. Calcd for C17H20O5: C 67.09%, H
6.62%; found: C 66.92%, H 6.72%.
3-(1-p-Tolyl-vinyl)-1,2,5-trioxa-spiro[5.5]undecan-9-one (7e).
1
Yield 32%; mp 66-68 °C; IR (KBr, cm-1) 1718; H NMR (200
MHz, CDCl3) δ 2.04 (t, 2H, J ) 7.0 Hz), 2.31-2.66 (m, 6H), 2.34
(s, 3H), 3.86 (dd, 1H, J ) 12.1, 3.7 Hz), 3.95 (dd, 1H, J ) 12.1,
10.2 Hz), 5.31 (dd, 1H, J ) 10.2, 3.7 Hz), 5.28 and 5.49 (2 × s,
2H), 7.15 (d, 2H, J ) 8.0 Hz), 7.28 (d, 2H, J ) 8.0 Hz); FAB-MS
(m/z) 289 [M + H]+; Anal. Calcd for C17H20O4: C 70.81%, H
6.99%; found: C 70.54%, H 6.77%.
[3-(1-Biphenyl-4-yl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-yli-
dene]-acetic Acid Ethyl Ester (12). Yield 93%, mp 143-145 °C;
IR (KBr, cm-1) 1707; 1H NMR (200 MHz, CDCl3) δ 1.27 (t, 3H,
J ) 7.1 Hz), 1.79-1.86 (m, 2H), 2.08-2.45 (m, 4H), 2.81-3.14
(m, 2H), 3.84 (dd, 1H, J ) 11.7, 3.3 Hz), 3.97 and 3.99 (2 × dd,
1H, J ) 11.7, 10.2 Hz, together integrating for 1H), 4.15 (q, 2H,
J ) 7.1 Hz), 5.32 (dd, 1H, J ) 10.2, 3.3 Hz), 5.35 and 5.57 (2 ×
s, 2H), 5.69 (s, 1H), 7.34-7.60 (m, 9H); 13C NMR (50 MHz,
CDCl3) δ 14.74 (q), 25.01 (t), 29.94 and 30.15 (t), 33.12 and 33.33
(t), 34.86 and 35.50 (t), 60.13 (t), 63.48 (t), 80.72 (d), 102.26 (s),
115.07 (d), 116.94 (t), 127.21 (d, integrating for two carbons),
127.43 (d, integrating for two carbons), 127.72 (d, integrating for
two carbons), 127.95 (d), 129.27 (d, integrating for two carbons),
137.78 (s), 140.80 (s), 141.49 (s), 143.19 (s), 160.10 (s), 166.87
(s); FAB-MS (m/z) 421 [M + H]+; Anal. Calcd for C26H28O5: C
74.26%, H 6.71%; found: C 74.37%, H 6.82%.
3-[1-(4-Cyclohexyl-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]un-
decan-9-one (7f). Yield 32%; mp 62-64 °C; IR (KBr, cm-1) 1719;
1H NMR (300 MHz, CDCl3) δ 1.30-1.47 (m, 5H), 1.73-1.85 (m,
5H), 2.05 (t, 2H, J ) 7.2 Hz), 2.35-2.67 (m, 7H), 3.87 (dd, 1H,
J ) 12.0, 3.3 Hz), 3.97 (dd, 1H, J ) 12.0, 10.2 Hz), 5.28 (s, 1H),
5.40 (dd, 1H, J ) 10.2, 3.3 Hz), 5.51 (s, 1H), 7.20 (d, 2H, J ) 8.2
Hz), 7.32 (d, 2H, J ) 8.2 Hz); 13C NMR (50 MHz, CDCl3) δ 26.51
(t), 27.24 (t, integrating for two carbons), 27.79 (t), 33.66 (t), 34.75
(t, integrating for two carbons), 36.85 (t), 37.02 (t), 44.64 (d), 63.91
(t), 80.81 (d), 101.46 (s), 116.19 (t), 126.63 (d, integrating for two
carbons), 127.51 (d, integrating for two carbons), 136.18 (s), 143.34
(s), 148.81 (s), 210.18 (s); FAB-MS (m/z) 357 [M + H]+; HR-
EIMS calc for C22H28O4 356.1988 found 356.2008.
3-(1-Naphthalen-2-yl-vinyl)-1,2,5-trioxa-spiro[5.5]undecan-9-
1
one (7 g). Yield 33%; mp 58-60 °C; IR (KBr, cm-1) 1714; H
NMR (200 MHz, CDCl3) δ 2.06 (t, 2H, J ) 7.0 Hz), 2.32-2.70
(m, 6H), 3.93 (dd, 1H, J ) 11.9, 3.0 Hz), 4.00 (dd, 1H, J ) 11.9,
9.9 Hz), 5.46 (dd, 1H, J ) 9.9, 3.0 Hz), 5.42 and 5.65 (2 × s, 2H),
7.45-7.53 (m, 3H), 7.79-7.83 (m, 4H); FAB-MS (m/z) 325 [M
+ H]+; Anal. Calcd for C20H20O4: C 74.06%, H 6.21%; found: C
74.12%, H 6.28%.
[3-(1-Phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-
acetic Acid Ethyl Ester (10). In an oven dried three-necked flask
(100 mL), equipped with a magnetic stirrer, was placed NaH (50%
suspension in mineral oil; 0.20 g, 8.39 mmol) and washed with
dry hexane (20 mL). Dry DME (20 mL) was added, the slurry was
2-[3-(1-Biphenyl-4-yl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-yli-
dene]-propionic Acid Ethyl Ester (13). Yield 84%, mp 68-70
°C; IR (KBr, cm-1) 1705; 1H NMR (200 MHz, CDCl3) δ 1.29 and
1.30 (2 × t, 3H, J ) 7.0 Hz, together integrating for 3H), 1.75-
1.82 (m, 2H), 1.89 (s, 3H), 2.06-2.13 (m, 1H), 2.33-2.46 (m,
3H), 2.56-2.68 (m, 2H), 3.83 (dd, 1H, J ) 11.7, 3.1 Hz), 4.00
(dd, 1H, J ) 11.7, 10.3 Hz), 4.19 and 4.20 (2 × q, 2H, J ) 7.0
Hz, together integrating for 2H), 5.30 (dd, 1H, J ) 10.3, 3.1 Hz),
5.35 and 5.57 (2 × s, 2H), 7.30-7.60 (m, 9H); 13C NMR (50 MHz,
CDCl3) δ 14.71 (q), 15.80 (q), 26.46 and 26.64 (t), 27.23 and 27.43
(t), 29.22 and 29.76 (t), 34.83 and 35.34 (t), 60.72 (t), 63.46 (t),

2800 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9
Singh et al.
80.69 and 80.73 (d), 102.65 (s), 116.82 and 116.90 (t), 122.09 (s),
127.22 (d, integrating for two carbons), 127.43 (d, integrating for
two carbons), 127.70 (d, integrating for two carbons), 127.95 (d),
129.27 (d, integrating for two carbons), 137.81 (s), 140.81 (s),
141.47 (s), 143.31 (s), 145.11 and 145.24 (s), 170.40 (s); FAB-MS
(m/z) 435 [M + H]+; Anal. Calcd for C27H30O5: C 74.63%, H
6.96%; found: C 74.84%, H 6.82%.
for 1H), 4.15 (q, 2H, J ) 7.1 Hz), 5.26 (dd, 1H, J ) 10.3, 2.9 Hz),
5.28 and 5.48 (2 × s, 2H), 5.68 (s, 1H), 7.15 (d, 2H, J ) 8.2 Hz),
7.28 (d, 2H, J ) 8.2 Hz); 13C NMR (50 MHz, CDCl3) δ 14.71 (q),
21.51 (q), 24.83 and 24.98 (t), 29.18 and 29.89 (t), 33.09 and 33.30
(t), 34.87 and 35.51 (t), 60.07 (t), 63.51 (t), 80.82 (d), 102.13 (s),
115.03 (d), 116.01 and 116.17 (t), 126.65 (d, integrating for two
carbons), 129.69 (d, integrating for two carbons), 136.02 (s), 138.49
(s), 143.54 (s), 160.05 (s), 166.81 (s); FAB-MS (m/z) 359 [M +
H]+; Anal. Calcd for C21H26O5: C 70.37%, H 7.31%; found: C
70.46%, H 7.45%.
{3-[1-(4-Chloro-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undec-
9-ylidene}-acetic Acid Ethyl Ester (14). Yield 91%; mp 78-80
1
°C; IR (KBr, cm-1) 1710; H NMR (200 MHz, CDCl3) δ 1.27 (t,
3H, J ) 7.1 Hz), 1.78-1.84 (m, 2H), 2.08-2.18 (m, 1H), 2.28-
2.43 (m, 3H), 2.83-3.09 (m, 2H), 3.79 (dd, 1H, J ) 11.9, 2.7 Hz),
3.95 and 3.97 (2 × dd, 1H, J ) 11.9, 10.0 Hz, together integrating
for 1H), 4.15 (q, 2H, J ) 7.1 Hz), 5.22 (dd, 1H, J ) 10.0, 2.7 Hz),
5.34 and 5.36 (2 × s, 1H), 5.50 and 5.51 (2 × s, 1H), 5.68 (s, 1H),
7.32 (s, 4H); 13C NMR (50 MHz, CDCl3) δ 14.67 (q), 24.79 and
24.93 (t), 29.20 and 29.93 (t), 33.02 and 33.22 (t), 34.71 and 35.36
(t), 60.06 (t), 63.11 (t), 80.61 (d), 102.23 (s), 115.13 (d), 117.56
and 117.65 (t), 128.18 (d, integrating for two carbons), 129.17 (d,
integrating for two carbons), 134.61 (s), 137.40 (s), 142.66 (s),
159.81 (s), 166.70 (s); FAB-MS (m/z) 379 and 381 [M + H]+;
Anal. Calcd for C20H23ClO5: C 63.41%, H 6.12%; found: C
63.56%, H 6.17%.
2-{3-[1-(4-Chloro-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undec-
9-ylidene}-propionic Acid Ethyl Ester (15). Yield 85%; viscous
oil; IR (neat, cm-1) 1707; 1H NMR (300 MHz, CDCl3) δ 1.29 and
1.30 (2 × t, 1H, J ) 6.6 Hz each), 1.77-1.78 (m, 2H), 1.88 (s,
3H), 2.06-2.09 (m, 1H), 2.36 (m, 3H), 2.50-2.68 (m, 2H), 3.78
(dd, 1H, J ) 11.7, 2.8 Hz), 3.96 (dd, 1H, J ) 11.7, 10.8 Hz), 4.19
and 4.20 (2 × q, 2H, J ) 6.6 Hz, together integrating for 2H),
5.21 (dd, 1H, J ) 10.8, 2.8 Hz), 5.35 and 5.51 (2 × s, 2H), 7.32
(s, 4H); 13C NMR (50 MHz, CDCl3) δ 14.66 (q), 15.74 (q), 26.39
and 26.56 (t), 27.15 and 27.34 (t), 29.20 and 29.73 (t), 34.70 and
35.20 (t), 60.67 (t), 63.10 (t), 80.56 (d), 102.65 (s), 117.62 (t),
122.10 (s), 128.19 (d, integrating for two carbons), 129.16 (d,
integrating for two carbons), 134.56 (s), 137.42 (s), 142.71 (s),
145.09 (s), 170.34 (s); FAB-MS (m/z) 393 and 395 [M + H]+;
Anal. Calcd for C21H25ClO5: C 64.20%, H 6.41%; found: C
64.34%, H 6.37%.
2-[3-(1-p-Tolyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-
propionic Acid Ethyl Ester (19). Yield 86%; viscous oil: IR (neat,
cm-1) 1711; 1H NMR (200 MHz, CDCl3) δ 1.29 and 1.30 (2 × t,
3H, J ) 7.0 Hz each), 1.66-1.80 (m, 2H), 1.88 (s, 3H), 2.04-
2.11 (m, 1H), 2.34 (s, 3H), 2.37-2.41 (m, 2H), 2.55-2.66 (m,
2H), 3.78 (dd, 1H, J ) 11.5, 2.6 Hz), 3.95 (dd, 1H, J ) 11.5, 10.4
Hz), 4.18 and 4.19 (2 × q, 2H, J ) 7.0 Hz, together integrating
for 2H), 5.25 (dd, 1H, J ) 10.4, 2.6 Hz), 5.27 and 5.47 (2 × s,
2H), 7.15 (d, 2H, J ) 8.0 Hz), 7.28 (d, 2H, J ) 8.0 Hz); 13C NMR
(50 MHz, CDCl3) δ 14.66 (q), 15.75 (q), 21.53 (q), 26.41 and 26.58
(t), 27.19 and 27.39 (t), 29.14 and 29.68 (t), 34.82 and 35.32 (t),
60.69 (t), 63.52 (t), 80.81 (d), 102.56 (s), 116.14 (t), 122.03 (s),
126.65 (d, integrating for two carbons), 129.68 (d, integrating for
two carbons), 136.03 (s), 138.50 (s), 143.58 (s), 145.06 and 145.18
(s), 170.47 (s); FAB-MS (m/z) 373 [M + H]+; Anal. Calcd for
C22H28O5: C 70.94%; H 7.58%; found: C 71.04%, H 7.66%.
{3-[1-(4-Cyclohexyl-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undec-
9-ylidene}-acetic Acid Ethyl Ester (20). Yield 90%; viscous oil:
1
IR (neat, cm-1) 1713; H NMR (200 MHz, CDCl3) δ 1.27 (t, 3H,
J ) 7.1 Hz), 1.34-1.45 (m, 4H), 1.71-1.84 (m, 8H), 2.09-2.17
(m, 1H), 2.28-2.45 (m, 4H), 2.83-3.09 (m, 2H), 3.81 (dd, 1H, J
) 12.1, 2.9 Hz), 3.95 and 3.97 (2 × dd, 1H, J ) 12.1, 10.8 Hz,
together integrating for 1H), 4.15 (q, 2H, J ) 7.1 Hz), 5.27 (dd,
1H, J ) 10.8, 2.9 Hz), 5.30 and 5.49 (2 × s, 2H), 5.68 (s, 1H),
7.18 (d, 2H, J ) 8.1 Hz), 7.31 (d, 2H, J ) 8.1 Hz); FAB-MS (m/z)
427 [M + H]+; Anal. Calcd for C26H34O5: C 73.21%; H 8.03%;
found: C 73.38%, H 8.14%.
2-{3-[1-(4-Cyclohexyl-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]-
undec-9-ylidene}-propionic Acid Ethyl Ester (21). This was
1
{3-[1-(4-Methoxy-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undec-
9-ylidene}-acetic Acid Ethyl Ester (16). Yield 91%; viscous oil;
obtained in 82% yield as an oil: IR (neat, cm-1) 1712; H NMR
(200 MHz, CDCl3) δ 1.30 (t, 3H, J ) 7.2 Hz), 1.39-1.50 (m, 4H),
1.73-1.95 (m, 8H), 2.02-2.14 (m, 1H), 2.32-2.76 (m, 6H), 3.79
(dd, 1H, J ) 11.8, 2.8 Hz), 3.96 (dd, 1H, J ) 11.8, 10.5 Hz), 4.19
and 4.20 (2 × q, 2H, J ) 7.2 Hz, together integrating for 2H),
5.27 (dd, 1H, J ) 10.5, 2.8 Hz), 5.30 and 5.49 (2 × s, 2H), 7.18
(d, 2H, J ) 8.0 Hz), 7.32 (d, 2H, J ) 8.0 Hz); FAB-MS (m/z) 441
[M + H]+; Anal. Calcd for C27H36O5: C 73.61%; H 8.24%;
found: C 73.72%, H 8.37%.
[3-(1-Naphthalen-2-yl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-
ylidene]-acetic Acid Ethyl Ester (22). Yield 92%; mp 54-56 °C;
IR (KBr, cm-1) 1706; 1H NMR (200 MHz, CDCl3) δ 1.27 (t, 3H,
J ) 7.1 Hz), 1.65-1.87 (m, 2H), 2.08-2.20 (m, 1H), 2.29-2.49
(m, 3H), 2.86-3.14 (m, 2H), 3.86 (dd, 1H, J ) 11.8, 2.4 Hz), 4.00
and 4.02 (2 × dd, 1H, J ) 11.8, 10.3 Hz, together integrating for
1H), 4.15 (q, 2H, J ) 7.1 Hz), 5.42 (dd, 1H, J ) 11.8, 2.4 Hz),
5.44 and 5.65 (2 × s, 2H), 5.69 (s, 1H), 7.45-7.54 (m, 3H), 7.79-
7.84 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 14.75 (q), 24.86 and
25.01 (t), 29.25 and 29.95 (t), 33.10 and 33.31 (t), 34.87 and 35.51
(t), 60.10 (t), 63.53 (t), 80.79 (d), 102.24 (s), 115.14 (d), 117.30
and 117.45 (t), 124.80 (d), 125.75 (d), 126.79 (d), 126.89 (d), 128.02
(d), 128.67 (d), 128.75 (d), 133.48 and 133.69 (s), 136.19 (s), 143.65
(s), 159.99 (s), 166.81 (s); FAB-MS (m/z) 395 [M + H]+; HR-
EIMS calc for C24H26O5 394.1780 found 394.1763.
1
IR (neat, cm-1) 1712; H NMR (200 MHz, CDCl3) δ 1.27 (t, 3H,
J ) 7.1 Hz), 1.66-1.85 (m, 2H), 2.10-2.17 (m, 1H), 2.28-2.44
(m, 3H), 2.87-3.10 (m, 2H), 3.79 (dd, 1H, J ) 11.8, 3.1 Hz), 3.81
(s, 3H), 3.95 and 3.97 (2 × dd, 1H, J ) 11.8, 10.4 Hz, together
integrating for 1H), 4.15 (q, 2H, J ) 7.1 Hz), 5.23-5.28 (m, 2H),
5.44 (s, 1H), 5.68 (s, 1H), 6.87 (d, 2H, J ) 8.6 Hz), 7.33 (d, 2H,
J ) 8.6 Hz); 13C NMR (50 MHz, CDCl3) δ 14.68 (q), 24.82 and
24.97 (t), 29.16 and 29.87 (t), 33.08 and 33.29 (t), 34.86 and 35.50
(t), 55.69 (q), 60.08 (t), 63.50 (t), 80.91 (d), 102.16 (s), 114.37 (d,
integrating for two carbons), 115.01 (d), 115.29 and 115.47 (t),
127.97 (d, integrating for two carbons), 131.33 (s), 143.03 (s),
160.06 (s), 166.85 (s); FAB-MS (m/z) 375 [M + H]+; HR-EIMS
calc for C21H26O6 374.1721 found 374.1701.
2-{3-[1-(4-Methoxy-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undec-
9-ylidene}-propionic Acid Ethyl Ester (17). Yield 84%; viscous
oil; IR (neat, cm-1) 1710; 1H NMR (200 MHz, CDCl3) δ 1.29 and
1.30 (2 × t, 3H, J ) 7.0 Hz, together integrating for 3H), 1.76-
1.80 (m, 2H), 1.88 (s, 3H), 2.04-2.11 (m, 1H), 2.32-2.45 (m,
3H), 2.51-2.66 (m, 2H), 3.78 (dd, 1H, J ) 11.8, 2.8 Hz), 3.81 (s,
3H), 3.95 (dd, 1H, J ) 11.8, 10.3 Hz), 4.19 and 4.20 (2 × q, 2H,
J ) 7.0 Hz, together integrating for 2H), 5.23 (s, 1H), 5.26 (dd,
1H, J ) 10.3, 2.8 Hz), 5.43 (s, 1H), 6.87 (d, 2H, J ) 8.6 Hz), 7.33
(d, 2H, J ) 8.6 Hz); FAB-MS (m/z) 389 [M + H]+; HR-EIMS
calc for C22H28O6 388.1886 found 388.1914.
2-[3-(1-Naphthalen-2-yl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-
ylidene]-propionic Acid Ethyl Ester (23). Yield 82%; viscous
1
[3-(1-p-Tolyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-
acetic Acid Ethyl Ester (18). Yield 91%; mp 64-66 °C; IR (KBr,
oil: IR (neat, cm-1) 1700; H NMR (200 MHz, CDCl3) δ 1.29
and 1.30 (2 × t, 3H, J ) 7.0 Hz, together integrating for 3H),
1.63-1.83 (m, 2H), 1.89 (s, 3H), 2.04-2.16 (m, 1H), 2.33-2.48
(m, 3H), 2.57-2.71 (m, 2H), 3.85 (dd, 1H, J ) 11.9, 2.8 Hz), 4.01
(dd, 1H, J ) 11.9, 10.3 Hz), 4.19 and 4.20 (2 × q, 2H, J ) 7.0
Hz, together integrating for 2H), 5.42 (dd, 1H, J ) 10.3, 2.8 Hz),
1
cm-1) 1711; H NMR (200 MHz, CDCl3) δ 1.27 (t, 3H, J ) 7.1
Hz), 1.75-1.84 (m, 2H), 2.12-2.16 (m, 1H), 2.29-2.44 (m, 3H),
2.34 (s, 3H), 2.90-3.05 (m, 2H), 3.79 (dd, 1H, J ) 11.8, 2.9 Hz),
3.94 and 3.95 (2 × dd, 1H, J ) 11.8, 10.3 Hz, together integrating

Orally ActiVe 1,2,4-Trioxanes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9 2801
5.43 and 5.65 (2 × s, 2H), 7.46-7.55 (m, 3H), 7.80-7.84 (m, 4H);
13C NMR (50 MHz, CDCl3) δ 14.69 (q), 15.78 (q), 26.44 and 26.61
(t), 27.22 and 27.41 (t), 29.20 and 29.74 (t), 34.82 and 35.33 (t),
60.72 (t), 63.56 (t), 80.81 (d), 102.67 (s), 117.34 and 117.42 (t),
122.09 (s), 124.82 (d), 125.75 (d), 126.76 (d), 126.87 (d), 128.01
(d), 128.65 (d), 128.72 (d), 133.45 and 133.67 (s), 136.21 (s), 143.68
(s), 145.05 and 145.17 (s), 170.42 (s); FAB-MS (m/z) 409 [M +
H]+; HR-EIMS calc for C25H28O5 408.1937 found 408.1961.
9-Hydroxy-3-(1-phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-
yl]-acetic Acid Ethyl Ester (24). To a refluxing mixture of Zn
dust (0.57 g, 8.75 mmol) and I2 (3-4 crystals) in benzene (50 mL)
was added ethyl bromoacetate (1.4 g, 8.75 mmol) dissolved in
benzene (20 mL) over 30 min. Reaction mixture was refluxed for
3 h and then cooled to 50 °C. A solution of trioxane 7a (0.60 g,
2.18 mmol) in benzene (15 mL) was added dropwise, and the
reaction mixture was stirred at the same temperature for 4 h, when
it was cooled to 0 °C and treated with 5% aq H2SO4 (20 mL). The
organic layer was separated, washed successively with 5% aq
NaHCO3 (20 mL) and brine (10 mL), and dried over anhyd Na2-
SO4, solvent was removed, and the crude product, consisting of a
mixture of diastereomers, was purified by column chromatography
over silica gel using AcOEt-hexane (1:9) as eluant to furnish 24a
(higher Rf) and 24b (lower Rf) in combined yield of 83% as viscous
oil.
9-Hydroxy-3-(1-phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-
yl]-acetic Acid Ethyl Ester (24a, higher Rf). viscous oil; IR (neat,
cm-1) 1730, 3515; 1H NMR (200 MHz, CDCl3) δ 1.19 (t, 3H, J )
7.1 Hz), 1.47-2.01 (m, 7H), 2.39 (s, 2H), 2.45-2.48 (m, 1H), 3.41
(s, 1H, OH), 3.67 (dd, 1H. J ) 11.9, 3.4 Hz), 3.78 (dd, 1H, J )
11.9, 9.8 Hz), 4.11 (q, 2H, J ) 7.1 Hz), 5.17 (dd, 1H, J ) 9.8, 3.4
Hz), 5.24 and 5.41 (2 × s, 2H), 7.21-7.33 (m, 5H); 13C NMR (50
MHz, CDCl3) δ 14.57 (q), 29.93 (t), 30.10 (t), 33.36 (t), 33.62 (t),
45.55 (t), 61.14 (t), 63.35 (t), 69.46 (s), 80.76 (d), 102.61 (s), 116.86
(t), 126.82 (d, integrating for two carbons), 128.57 (d), 128.96 (d,
integrating for two carbons), 138.99 (s), 143.85 (s), 173.22 (s); FAB-
MS (m/z) 363 [M + H]+; Anal. Calcd for C20H26O6: C 66.28%, H
7.23%; found: C 66.34%, H 7.25%.
[3-(1-Biphenyl-4-yl-vinyl)-9-hydroxy-1,2,5-trioxa-spiro[5.5]-
undec-9-yl]-acetic Acid Ethyl Ester (25b, lower Rf). mp 124-
125 °C; IR (KBr, cm-1) 1700, 3515; 1H NMR (200 MHz, CDCl3)
δ 1.27 (t, 3H, J ) 7.1 Hz), 1.54-2.09 (m, 7H), 2.46 (s, 2H), 2.67
(dd, 1H, J ) 13.4, 2.4 Hz), 3.51 (s, 1H, OH), 3.82 (dd, 1H, J )
11.9, 2.9 Hz), 4.06 (dd, 1H, J ) 11.9, 10.2 Hz), 4.17 (q, 2H, J )
7.1 Hz), 5.28 (dd, 1H, J ) 10.2, 2.9 Hz), 5.33 and 5.56 (2 × s,
2H), 7.34-7.61 (m, 9H); 13C NMR (50 MHz, CDCl3) δ 14.57 (q),
24.50 (t), 30.57 (t), 33.50 (t), 33.73 (t), 45.69 (t), 61.16 (t), 63.29
(t), 69.37 (s), 80.63 (d), 102.64 (s), 116.69 (t), 127.15 (d, integrating
for two carbons), 127.43 (d, integrating for two carbons), 127.69
(d, integrating for two carbons), 127.91 (d), 129.23 (d, integrating
for two carbons), 137.85 (s), 140.83 (s), 141.47 (s), 143.31 (s),
173.40 (s); FAB-MS (m/z) 439 [M + H]+; Anal. Calcd for
C26H30O6: C 71.21%, H 6.90%; found: C 70.89%, H 6.97%.
{3-[1-(4-Chloro-phenyl)-vinyl]-9-hydroxy-1,2,5-trioxa-spiro-
[5.5]undec-9-yl}-acetic Acid Ethyl Ester (26). This was obtained
as a white solid in 84% yield as a mixture of diastereomers 26a
and 26b which were separated by column chromatography.
{3-[1-(4-Chloro-phenyl)-vinyl]-9-hydroxy-1,2,5-trioxa-spiro-
[5.5]undec-9-yl}-acetic-Acid Ethyl Ester (26a, higher Rf). mp
1
104-105 °C; IR (KBr, cm-1) 1712, 3445; H NMR (200 MHz,
CDCl3) δ 1.27 (t, 3H, J ) 7.1 Hz), 1.42-1.78 (m, 5H), 1.88-2.12
(m, 2H), 2.47 (s, 2H), 2.51-2.57 (m, 1H), 3.47 (s, 1H, OH), 3.74
(dd, 1H, J ) 11.8, 3.2 Hz), 3.85 (dd, 1H, J ) 11.8, 9.8 Hz), 4.17
(q, 2H, J ) 7.1 Hz), 5.18 (dd, 1H, J ) 9.8, 3.2 Hz), 5.34 and 5.48
(2 × s, 2H), 7.29-7.31 (m, 4H); 13C NMR (50 MHz, CDCl3) δ
14.56 (q), 24.29 (t), 29.83 (t), 33.35 (t), 33.61 (t), 45.57 (t), 61.13
(t), 63.02 (t), 69.42 (s), 80.59 (d), 102.68 (s), 117.56 (t), 128.20
(d, integrating for two carbons), 129.13 (d, integrating for two
carbons), 134.53 (s), 137.45 (s), 142.79 (s), 173.15 (s); FAB-MS
(m/z) 397 and 399 [M + H]+; Anal. Calcd for C20H25ClO6: C
60.53%, H 6.35%; found: C 60.64%, H 6.42%.
{3-[1-(4-Chloro-phenyl)-vinyl]-9-hydroxy-1,2,5-trioxa-spiro-
[5.5]undec-9-yl}-acetic Acid Ethyl Ester (26b, lower Rf). This
was obtained as a white solid: mp 96-97 °C; IR (KBr, cm-1) 1703,
1
3497; H NMR (200 MHz, CDCl3) δ 1.27 (t, 3H, J ) 7.2 Hz),
1.52-1.71 (m, 5H), 1.89-2.12 (m, 2H), 2.46 (s, 2H), 2.62 (dd,
1H, J ) 13.4, 2.5 Hz), 3.53 (bs, 1H, OH), 3.77 (dd, 1H, J ) 11.8,
2.9 Hz), 4.02 (dd, 1H, J ) 11.8, 10.3 Hz), 4.17 (q, 2H, J ) 7.2
Hz), 5.18 (dd, 1H, J ) 10.3, 2.9 Hz), 5.33 and 5.49 (2 × s, 2H),
7.30-7.31 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 14.55 (q), 24.52
(t), 30.47 (t), 33.48 (t), 33.70 (t), 45.68 (t), 61.12 (t), 62.98 (t),
69.32 (s), 80.55 (d), 102.67 (s), 117.44 (t), 128.14 (d, integrating
for two carbons), 129.16 (d, integrating for two carbons), 134.57
(s), 137.48 (s), 142.74 (s), 173.33 (s); FAB-MS (m/z) 397 and 399
[M + H]+; Anal. Calcd for C20H25ClO6: C 60.53%, H 6.35%;
found: C 60.68%, H 6.39%.
9-Hydroxy-3-(1-phenl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-
yl]-acetic Acid Ethyl Ester (24b, lower Rf). viscous oil: IR (neat,
cm-1) 1714, 3512; 1H NMR (200 MHz, CDCl3) δ 1.27 (t, 3H, J )
7.1 Hz), 1.53-2.12 (m, 7H), 2.46 (s, 2H), 2.62-2.70 (m, 1H), 3.53
(s, 1H, OH), 3.77 (dd, 1H, J ) 11.9, 2.9 Hz), 4.03 (dd, 1H, J )
11.9, 10.3 Hz), 4.17 (q, 2H, J ) 7.1 Hz), 5.25 (dd, 1H, J ) 10.3,
2.9 Hz), 5.31 and 5.50 (2 × s, 2H), 7.31-7.38 (m, 5H); 13C NMR
(50 MHz, CDCl3) δ 14.56 (q), 30.10 (t), 30.56 (t), 33.48 (t), 33.71
(t), 45.67 (t), 61.14 (t), 63.29 (t), 69.37 (s), 80.74 (d), 102.58 (s),
116.79 (t), 126.77 (d, integrating for two carbons), 128.59 (d),
128.98 (d, integrating for two carbons), 139.01 (s), 143.80 (s),
173.39 (s); FAB-MS (m/z) 363 [M + H]+; Anal. Calcd for
C20H26O6: C 66.28%, H 7.23%; found: C 66.41%, H 7.33%.
3-(1-Phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undecan-9-ol (27). To
a magnetically stirred ice cooled solution of 7a (0.50 g, 1.82 mmol)
in MeOH (20 mL) was added powdered NaBH4 (0.07 g, 1.82 mmol)
over 10 min. The reaction mixture was stirred at 0 °C for 0.5 h.
The mixture was neutralized with glacial acetic acid, diluted with
water, and extracted with diethyl ether (2 × 30 mL). The combined
organic layer was washed with brine (10 mL), dried over anhyd
Na2SO4, and concentrated in vacuo. The crude product was purified
by column chromatography over silica gel using AcOEt-hexane
(3:7) as eluant to furnish 27 as an inseparable mixture of
diastereomers (0.48 g, 96%) as a white solid. mp 68-70 °C; IR
Compounds 25 and 26 were also prepared by the same procedure.
[3-(1-Biphenyl-4-yl-vinyl)-9-hydroxy-1,2,5-trioxa-spiro[5.5]-
undec-9-yl]-acetic Acid Ethyl Ester (25). This was obtained as a
white solid in 88% yield as a mixture of diastereomers 25a and
25b which were separated by column chromatography.
[3-(1-Biphenyl-4-yl-vinyl)-9-hydroxy-1,2,5-trioxa-spiro[5.5]-
undec-9-yl]-acetic Acid Ethyl Ester (25a, higher Rf). mp 140-
141 °C; IR (KBr, cm-1) 1713, 3510; 1H NMR (200 MHz, CDCl3)
δ 1.27 (t, 3H, J ) 7.1 Hz), 1.49-2.15 (m, 7H), 2.45 (s, 2H), 2.49-
2.57 (m, 1H), 3.44 (s, 1H, OH), 3.80 (dd, 1H, J ) 11.9, 3.5 Hz),
3.90 (dd, 1H, J ) 11.9, 9.7 Hz), 4.17 (q, 2H, J ) 7.1 Hz), 5.29
(dd, 1H, J ) 9.7, 3.5 Hz), 5.35 and 5.56 (2 × s, 2H), 7.34-7.60
(m, 9H); 13C NMR (50 MHz, CDCl3) δ 14.60 (q), 24.31 (t), 29.96
(t), 33.40 (t), 33.67 (t), 45.60 (t), 61.15 (t), 63.35 (t), 69.49 (s),
80.69 (d), 102.67 (s), 116.79 (t), 127.22 (d, integrating for two
carbons), 127.41 (d, integrating for two carbons), 127.66 (d,
integrating for two carbons), 127.92 (d), 129.24 (d, integrating for
two carbons), 137.84 (s), 140.82 (s), 141.43 (s), 143.40 (s), 173.20
(s); FAB-MS (m/z) 439 [M + H]+; Anal. Calcd for C26H30O6: C
71.21%, H 6.90%; found: C 71.43%, H 6.94%.
1
(KBr, cm-1) 3394; H NMR (200 MHz, CDCl3) δ 1.57-2.12 (m,
7H), 2.36-2.45 and 2.54-2.64 (m, 1H), 3.77-4.03 (m, 3H), 5.25
(dd, 1H, J ) 10.1, 3.3 Hz), 5.32 and 5.50 (2 × s, 2H), 7.31-7.39
(m, 5H); 13C NMR (50 MHz, CDCl3) δ 25.32 and 25.80 (t), 30.41
and 30.58 (t), 30.83 and 30.95 (t), 31.17 and 31.85 (t), 63.17 and
63.53 (t), 68.28 and 68.79 (d), 80.72 and 80.77 (d), 102.26 and
102.37 (s), 116.84 and 116.88 (t), 126.79 (d, integrating for two
carbons), 128.60 (d), 128.99 (d, integrating for two carbons), 139.00
(s), 143.79 (s); FAB-MS (m/z) 277 [M + H]+; Anal. Calcd for
C16H20O4: C 69.54%, H 7.30%; found: C 69.47%, H 7.36%.
Compounds 28-30 were also prepared by the same procedure.
Biphenyl-4-yl-vinyl)-1,2,5-trioxa-spiro[5.5]undecan-9-ol (28).

2802 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9
Singh et al.
Yield 94%; mp 106-108 °C; IR (KBr, cm-1) 3426; 1H NMR (200
MHz, CDCl3) δ 1.43-2.11 (m, 7H), 2.37-2.48 and 2.57-2.65 (2
× bm, 1H), 3.77-4.03 (m, 3H), 5.30 (dd, 1H, J ) 10.7, 3.2 Hz),
5.34 and 5.57 (2 × s, 2H), 7.31-7.66 (m, 9H); FAB-MS (m/z)
353 [M + H]+; Anal. Calcd for C22H24O4: C 74.98%, H 6.86%;
found: C 74.82%, H 6.72%.
3.96 (2 × dd, 1H, J ) 11.8, 10.4 Hz, together integrating for 1H),
4.90-4.93 (bm, 1H), 5.23 (dd, 1H, J ) 11.8, 3.1 Hz), 5.26 and
5.47 (2 × s, 2H), 7.14 (d, 2H, J ) 7.9 Hz), 7.27 (d, 2H, J ) 7.9
Hz); FAB-MS (m/z) 391[M + H]+; Anal. Calcd for C21H26O7: C
64.60%, H 6.71%; found: C 64.46%, H 6.37%.
9-Methyl-3-(1-phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undecan-
9-ol (35). To an ice cold solution of MeMgBr (prepared from 0.18
g of Mg and 1.8 g of MeI) in ether was added a solution of 7a
(0.70 g, 2.55 mmol) in anhydrous ether, and the reaction mixture
was stirred at 0 °C for 1 h. The reaction mixture was cooled and
quenched with water (7 mL). Usual workup followed by chroma-
tography furnished 35a (higher Rf) and 35b (lower Rf) in combined
yield of 54%.
9-Methyl-3-(1-phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undecan-
9-ol (35a, higher Rf). viscous oil: IR (neat, cm-1) 3419; 1H NMR
(200 MHz, CDCl3) δ 1.26 (s, 3H), 1.63-1.93 (m, 6H), 2.03-2.18
(m, 1H), 2.37-2.44 (m, 1H), 3.76 (dd, 1H, J ) 11.6, 3.1 Hz), 3.88
(dd, 1H, J ) 11.6, 10.1 Hz), 5.25 (dd, 1H, J ) 10.1, 3.1 Hz), 5.33
and 5.50 (2 × s, 2H), 7.31-7.36 (m, 5H); 13C NMR (50 MHz,
CDCl3) δ 24.94 (t), 30.08 (q), 30.68 (t), 35.31 (t), 35.60 (t), 63.36
(t), 69.56 (s), 80.76 (d), 102.73 (s), 116.83 (t), 126.43 (d, integrating
for two carbons), 127.65 (d), 128.57 (d, integrating for two carbons),
139.02 (s), 143.87 (s); ES-MS (ES++Na) 313; Anal. Calcd for
C17H22O4: C 70.32%, H 7.64%; found: C 70.37%, H 7.24%.
9-Methyl-3-(1-phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undecan-
9-ol (35b, lower Rf). viscous oil: IR (neat, cm-1) 3381; 1H NMR
(200 MHz, CDCl3) δ 1.25 (s, 3H), 1.58-2.03 (m, 7H), 2.58 (dd,
1H, J ) 6.2, 2.2 Hz), 3.77 (dd, 1H, J ) 11.9, 2.9 Hz), 4.01 (dd,
1H, J ) 11.9, 10.3 Hz), 5.25 (dd, 1H, J ) 10.3, 2.9 Hz), 5.31 and
5.50 (2 × s, 2H), 7.29-7.48 (m, 5H); 13C NMR (50 MHz, CDCl3)
δ 25.04 (t), 30.48 (q), 31.13 (t), 35.35 (t), 35.51 (t), 63.27 (t), 69.44
(s), 80.72 (d), 102.71 (s), 116.79 (t), 126.78 (d, integrating for two
carbons), 128.58 (d), 128.98 (d, integrating for two carbons), 139.04
(s), 143.82 (s); ES-MS (ES++Na) 313; Anal. Calcd for C17H22O4:
C 70.32%, H 7.64%; found: C 70.66%, H 7.36%.
3-[1-(4-Chloro-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undecan-
1
9-ol (29). Yield 93%; mp 108-110 °C; IR (KBr, cm-1) 3387; H
NMR (200 MHz, CDCl3) δ 1.50-2.01 (m, 7H), 2.26-2.32 and
2.48-2.54 (2 × bm, 1H), 3.72-3.95 (m, 3H), 5.18 (dd, 1H, J )
10.1, 3.1 Hz), 5.33 and 5.49 (2 × s, 2H), 7.28-7.31 (m, 4H); FAB-
MS (m/z) 311 and 313 [M + H]+; Anal. Calcd for C16H19ClO4: C
61.84%, H 6.16%; found: C 61.76%, H 6.22%.
3-(1-p-Tolyl-vinyl)-1,2,5-trioxa-spiro[5.5]undecan-9-ol (30).
1
Yield 95%; mp 70-72 °C; IR (KBr, cm-1) 3426; H NMR (200
MHz, CDCl3) δ 1.51-2.09 (m, 7H), 2.34 (s, 3H), 2.55-2.65 (bm,
1H), 3.72-4.00 (m, 3H), 5.25 (dd, 1H, J ) 11.9, 3.2 Hz), 5.30
and 5.47 (2 × s, 2H), 7.15 (d, 2H, J ) 8.0 Hz), 7.28 (d, 2H, J )
8.0 Hz); FAB-MS (m/z) 291 [M + H]+; Anal. Calcd for C17H22O4:
C 70.32%, H 7.64%; found: C 70.46%, H 7.69%.
SuccinicAcidMono-[3-(1-phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]-
undec-9-yl] Ester (31). To a solution of alcohol 27 (0.40 g, 1.44
mmol), triethylamine (0.22 g, 2.18 mmol), and DMAP (5 mg) in
CH2Cl2 (20 mL) was added succinic anhydride (0.29 g, 2.89 mmol)
at room temperature. After 1h the solvent was removed under
vacuum, and the residue was taken up in water and was extracted
with diethyl ether (2 × 25 mL). The combined organic layer was
washed with brine (10 mL), dried over anhyd Na2SO4, and
evaporated to dryness. The crude product was purified by column
chromatography over silica gel using AcOEt-hexane (5:5) as eluant
to furnish 31 as an inseparable mixture of diastereomers, (0.58 g,
1
91% yield), mp 60-62 °C; IR (KBr, cm-1) 1729; H NMR (300
MHz, CDCl3) δ 1.63-1.86 (m, 6H), 2.02-2.15 (m, 1H), 2.30-
2.39 (m, 1H), 2.62-2.67 (m, 4H), 3.77 and 3.79 (2 × dd, 1H, J )
11.7, 3.6 Hz, together integrating for 1H), 3.91 and 3.97 (2 × dd,
1H, J ) 11.7, 10.2 Hz, together integrating for 1H), 4.92-4.94
(bm, 1H), 5.26 (dd, 1H, J ) 10.2, 3.6 Hz), 5.32 and 5.50 (2 × s,
2H), 7.28-7.37 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 25.08 and
25.34 (t), 26.99 and 27.11 (t, integrating for two carbons), 29.38
and 29.70 (t, integrating for two carbons), 30.64 and 30.86 (t), 63.14
and 63.40 (t), 70.84 and 71.20 (d), 80.71 (d), 102.04 and 102.11
(s), 116.91 (t), 126.77 (d, integrating for two carbons), 128.61 (d),
128.99 (d, integrating for two carbons), 138.93 (s), 143.71 (s),
172.10 (s), 177.81 (s); FAB-MS (m/z) 377 [M + H]+; Anal. Calcd
for C20H24O7: C 63.82%, H 6.43%; found: C 64.12%, H 6.34%.
Compounds 32-34 were prepared by the same procedure.
Compound 36 was prepared by the same procedure.
9-Phenyl-3-(1-phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undecan-9-
ol (36). This was obtained as a white solid in 57% yield as a mixture
of diastereomers 36a and 36b which were separated by column
chromatography.
9-Phenyl-3-(1-phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undecan-9-
ol (36a, higher Rf). mp 96-98 °C; IR (KBr, cm-1) 3448; 1H NMR
(300 MHz, CDCl3) δ 1.70-1.78 (m, 4H), 1.95-2.26 (m, 3H), 2.71
(d, 1H, J ) 12.0 Hz), 3.80 (dd, 1H, J ) 12.0, 3.0 Hz), 3.91 (dd,
1H, J ) 12.0, 9.9 Hz), 5.28 (dd, 1H, J ) 9.9, 3.0 Hz), 5.34 and
5.50 (2 × s, 2H), 7.23-7.50 (m, 10H); 13C NMR (75 MHz, CDCl3)
δ 24.3 (t), 29.9 (t), 34.5 (t), 35.0 (t), 62.9 (t), 72.5 (s), 80.3 (d),
102.1 (s), 116.4 (t), 124.5 (d, integrating for two carbons), 126.4
(d, integrating for two carbons), 127.0 (d), 128.1 (d), 128.3 (d,
integrating for two carbons), 128.5 (d, integrating for two carbons),
138.5 (s), 143.3 (s), 148.0 (s); FAB-MS (m/z) 353 [M + H]+; Anal.
Calcd for C22H24O4: C 74.98%, H 6.86%; found: C 74.66%, H
6.71%.
Succinic Acid Mono-[3-(1-biphenyl-4-yl-vinyl)-1,2,5-trioxa-
spiro[5.5]undec-9-yl] Ester (32). Yield 95%; mp 104-106 °C;
1
IR (KBr, cm-1) 1727; H NMR (200 MHz, CDCl3) δ 1.67-1.83
(m, 6H), 2.04-2.16 (m, 1H), 2.32-2.38 (m, 1H), 2.59-2.70 (m,
4H), 3.81 and 3.83 (2 × dd, 1H, J ) 11.9, 3.3 Hz, together
integrating for 1H), 3.95 and 4.01 (2 × dd, 1H, J ) 11.9, 10.2 Hz,
together integrating for 1H), 4.92-4.94 (bm, 1H), 5.29 (dd, 1H, J
) 10.2, 3.3 Hz), 5.34 and 5.57 (2 × s, 2H), 7.34-7.60 (m, 9H);
FAB-MS (m/z) 453 [M + H]+; Anal. Calcd for C26H28O7: C
69.01%, H 6.24%; found: C 69.14%, H 6.27%.
9-Phenyl-3-(1-phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undecan-9-
1
ol (36b, lower Rf). mp 104-106 °C; IR (KBr, cm-1) 3449; H
NMR (200 MHz, CDCl3) δ 1.69-2.21 (m, 7H), 2.84 (d, 1H, J )
12.5 Hz), 3.81 (dd, 1H, J ) 11.9, 2.8 Hz), 4.07 (dd, 1H, J ) 11.9,
10.4 Hz), 5.29 (dd, 1H, J ) 10.4, 2.8 Hz), 5.34 and 5.52 (2×s,
2H), 7.28-7.52 (m, 10H); 13C NMR (50 MHz, CDCl3) δ 25.11
(t), 31.25 (t), 35.49 (t, integrating for two carbons), 63.39 (t), 73.46
(s), 80.78 (d), 102.50 (s), 116.92 (t), 124.91 (d, integrating for two
carbons), 126.81 (d, integrating for two carbons), 127.46 (d), 128.67
(d), 128.76 (d, integrating for two carbons), 129.05 (d, integrating
for two carbons), 139.04 (s), 143.78 (s), 148.66 (s); FAB-MS (m/
z) 353 [M + H]+; Anal. Calcd for C22H24O4: C 74.98%, H 6.86%;
found: C 74.72%, H 6.53%.
Succinic Acid Mono-{3-[1-(4-chloro-phenyl)-vinyl]-1,2,5-tri-
oxa-spiro[5.5]undec-9-yl} Ester (33). Yield 91%; mp 72-74 °C;
1
IR (KBr, cm-1) 1725; H NMR (200 MHz, CDCl3) δ 1.65-1.87
(m, 6H), 2.04-2.11 (m, 1H), 2.28-2.34 (m, 1H), 2.59-2.70 (m,
4H), 3.76 and 3.78 (2 × dd, 1H, J ) 11.8, 3.2 Hz, together
integrating for 1H), 3.91 and 3.97 (2 × dd, 1H, J ) 11.8, 10.0 Hz,
together integrating for 1H), 4.91-4.93 (bm, 1H), 5.19 (dd, 1H, J
) 10.0, 3.2 Hz), 5.34 and 5.50 (2 × s, 2H), 7.31 (s, 4H); FAB-MS
(m/z) 411 and 413 [M + H]+; Anal. Calcd for C20H23ClO7: C
58.47%, H 5.64%; found: C 58.32%, H 5.46%.
Succinic Acid Mono-[3-(1-p-tolyl-vinyl)-1,2,5-trioxa-spiro[5.5]-
undec-9-yl] Ester (34). Yield 93%; mp 64-66 °C; IR (KBr, cm-1
)
1
Acknowledgment. H.M. is grateful to the Council of
Scientific and Industrial Research (CSIR), New Delhi for award
of Senior Research Fellowship.
1731; H NMR (200 MHz, CDCl3) δ 1.65-1.87 (m, 6H), 2.02-
2.19 (m, 2H), 2.34 (s, 3H), 2.62-2.72 (m, 4H), 3.76 and 3.77 (2
× dd, 1H, J ) 11.8, 3.1 Hz, together integrating for 1H), 3.90 and

Orally ActiVe 1,2,4-Trioxanes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9 2803
Supporting Information Available: 1H NMR and 13C NMR
spectra of compounds 10, 11, 12, 13, 14, 15, 16, 18, 19, 22, 23,
24a, 24b, 25a, 25b, 27, 31, 35a, 35b, 36a, and 36b. This material
is available free of charge via the Internet at http://pubs.acs.org.
10, 1625-1636. (k) Griesbeck, A. G.; El-Idreesy, T. T.; Ho¨inck, L.-
O, Lex, J.; Brun, R. Novel spiroanellated 1,2,4-trioxanes with high
in vitro antimalarial activities. Bioorg. Med. Chem. Lett. 2005, 15,
595-597.
(6) (a) Singh, C. Preparation of â -hydroxyhydroperoxides by photo-
oxygenation of allylic alcohols and their elaboration into 1,2,4-
trioxanes. Tetrahedron Lett. 1990, 31, 6901-6902. (b) 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. (c) 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-arylvinyl)-1,2,5-trioxaspiro-
[5,5]undecanes against Plasmodium berghei in mice. Bioorg. Med.
Chem. Lett. 1995, 5, 1913-1916. (d) 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.
(7) Singh, C.; Tiwari, P.; Puri, S. K. Substituted 1,2,4-trioxanes useful
as antimalarial agents and a process for the preparation thereof. US
Patent 6737438 B2, dated May 18, 2004. (b) 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 effective against rodent
and simian malaria. Bioorg. Med. Chem. Lett. 2006, 16, 584-586.
(8) Singh, C.; Malik, H.; Puri, S. K. Synthesis and antimalarial activity
of a new series of trioxaquines. Bioorg. Med. Chem. 2004, 12, 1177-
1182.
(9) Singh, C.; Malik, H.; Puri, S. K. Orally active amino functionalized
antimalarial 1,2,4-trioxanes. Bioorg. Med. Chem. Lett. 2004, 14, 459-
462.
(10) For preliminary communications of this study see: (a) 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. (b) Singh, C.; Malik, H. Protection of the carbonyl group as
1,2,4-trioxane and its regeneration under basic conditions. Org. Lett.
2005, 7, 5673-5676.
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(11) We have not been able to assign the relative stereochemistry to the
pairs of the diastereomers 24a and 24b, 25a and 25b, 26a and 26b,
35a and 35b, and 36a and 36b. For the sake of clarity these isomers
have been differentiated on the basis of their behaviour on TLC.;
faster moving (higher Rf) and slower moving (lower Rf).
(12) (a) Peters, W. Techniques for the study of drug response in
experimental malaria. In Chemotherapy and drug resistance in
malaria; Academic Press: London, 1970; pp 64-136. (b) In vivo
test procedure: The colony bred Swiss mice (25 ( 1 g) 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 3, in two divided doses daily. The drug dilutions of compounds
10-30, 35, and 36 were prepared in groundnut oil while hemisuc-
cinates 31-34 were dissolved in 5% NaHCO3 so as 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. Parasitemia levels were
recorded from thin blood smears between day 4-28.15 The treated
mice surviving beyond day 28 were recorded as the mice protected
by the drug. Mice treated with â-arteether served as positive controls.
(13) (a) 100% suppression of parasitemia means, number of parasites if
at all present, are below the detection limit. The parasites present
below the detection limit can multiply and eventually can be detected.
In such cases though the drug is providing near 100% suppression
of the parasitemia but will not provide full protection to the treated
mice. Multi-drug-resistant Plasmodium yoelii nigeriensis used in this
study is resistant to chloroquine, mefloquine and halofantrine. (b)
100% protection means all the treated mice survive till day 28.
Similarly 60% protection means only 60% of the treated survive till
day 28.
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