Synthesis of new 6-alkylvinyl/arylalkylvinyl substituted 1,2,4-trioxanes active against multidrug-resistant malaria in mice

Article abstract of DOI:10.1016/j.bmc.2004.08.005

3-Alkyl/arylalkyl substituted 2-butenols 9, 10, 23a-d undergo regiospecific photooxygenation to furnish β-hydroxyhydroperoxides 11, 12, 24a-d, respectively, in reasonable yields. Acid catalyzed condensation of 11, 12, 24a-d with various ketones furnish ne

Full text of DOI:10.1016/j.bmc.2004.08.005

Bioorganic & Medicinal Chemistry 12 (2004) 5553–5562
Synthesis of new 6-alkylvinyl/arylalkylvinyl substituted
1,2,4-trioxanes active against multidrug-resistant
malaria in miceq
a
b
Chandan Singh,a, Nitin Gupta and Sunil K. Puri
*
aDivision of Medicinal & Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
bDivision of Parasitology, Central Drug Research Institute, Lucknow 226001, India
Received 7 July 2004;revised 5 August 2004;accepted 6 August 2004
Available online 8 September 2004
Abstract—3-Alkyl/arylalkyl substituted 2-butenols 9, 10, 23a–d undergo regiospecific photooxygenation to furnish b-hydroxyhydro-
peroxides 11, 12, 24a–d, respectively, in reasonable yields. Acid catalyzed condensation of 11, 12, 24a–d with various ketones furnish
new 1,2,4-trioxanes 13–18, 25a–d, 26a–d, 27a–d in good yields. Several of these trioxanes show promising antimalarial activity
against multidrug-resistant Plasmodium yoelii in mice by oral and intramuscular routes.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
structurally simple 1,2,4-trioxanes have been reported,
several of which have shown activity both in vitro and
in vivo.2,3
Artemisinin 1 the active principle of the Chinese tradi-
tional drug against malaria, Artemisia annua is active
against both chloroquine sensitive and chloroquine
resistant malaria.1 Preparation of a large number of
semisynthetic derivatives of artemisinin have been re-
ported some of which, for example, artemether 2, arte-
ether 3, and artesunic acid 4, are several times more
potent than the parent compound.1 These compounds
are rapidly acting and are currently the drugs of choice
for the treatment of malaria caused by multidrug-resist-
ant Plasmodium falciparum.1c The peroxide group pre-
sent in the form of 1,2,4-trioxane is essential for the
antimalarial activity. Preparation of a large number of
Using b-hydroxyhydroperoxides derived from photo-
oxygenation of 3-aryl-2-butenols, we have earlier
reported the preparation of several 6-arylvinyl substi-
tuted 1,2,4-trioxanes. Some of these trioxanes were
active against chloroquine sensitive P. berghei by i.p.
route but show poor activity against chloroquine resist-
ant P. yoelii in mice by i.m. route.4 In the present study
we have prepared a new series of 3-alkyl and 3-arylalkyl
substituted 2-butenols 9, 10, 23a–d, which undergo reg-
iospecific photooxygenation to furnish b-hydroxyhydro-
peroxides 11, 12, 24a–d in acceptable yields. Acid
catalyzed condensation of 11, 12, 24a–d with various
ketones furnish trioxanes 13–18, 25a–d, 26a–d, 27a–d
in good yields. Several of these trioxanes have shown
very promising antimalarial activity against multidrug-
resistant P. yoelii in mice by both i.m. and oral routes.
Also most of these trioxanes are hydroxyl-functionalized
and are amenable for preparation of new derivatives
such as water soluble hemisuccinates. Herein we report
the details of this study.5
H
H
H
O
O
O
O
O
O
O
O
O
H
H
H
O
O
O
O
O
O
OR
OH
2; R=Me
3; R=Et
O
1
4
Keywords: Artemisinin;Antimalarial;1,2,4-Trioxane;Photooxygen-
ation; Plasmodium yoelii.
2. Chemistry
q CDRI Communication no: 6559.
*
4-Hydroxybutyl and n-undecyl substituted allylic alco-
hols 9 and 10 were prepared in good yields from
Corresponding author. Tel.: +91 0522 2224273;fax: +91 0522
2223405;e-mail: chandancdri@yahoo.com
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.08.005

5554
C. Singh et al. / Bioorg. Med. Chem. 12 (2004) 5553–5562
(a)
CO2Et
R
O
R
OH
(b)
(a)
OAc
OH
7 R=CH2(CH2)2CO2Et
8 R=n-undecyl
5 R=CH2(CH2)2CO2Et
6 R=n-undecyl
CHO
22
Ar
23a-d
O
O
O
(c)
R1
R2
O
(b)
R
OH
O
R
OH
OH
OH
(c)
HO
OH
HO
9 R=CH2(CH2)3OH
10 R=n-undecyl
11 R=CH2(CH2)3OH
12 R=n-undecyl
Ar
Ar
25a-d, 26a-d, 27a-d
24a-d
(d)
O
O
O
R1
R2
Scheme 2. Reagents and reaction conditions: (a) (i) ArMgBr, dry
Et2O, 0ꢁC to rt, 3h, (ii) H2O, 0ꢁC;(b) hm, O2, methylene blue, MeCN,
<0ꢁC, 4–6h;(c) ketone, TsOH, CH 2Cl2, rt, 1h.
R
13-18
Scheme 1. Reagents and reaction conditions: (a) (OEt)2P(O)CH2-
CO2Et, NaH, DME, rt, 24h;(b) LiAlH 4, Et2O, 0ꢁC, 6h;(c) hm, O2,
C6H13
O
methylene blue, MeCN, <0ꢁC, 7h;(d) ketone, TsOH, CH Cl2, rt, 1h.
2
(a)
OMgBr
OMgBr
31
OAc
CHO
OH
X
commercially available ethyl-4-acetylbutyrate 5 and 2-
tridecanone 6, respectively, by means of Wadsworth–
Emmons olefination followed by reduction with LiAlH4
(Scheme 1). Methylene blue sensitized photooxygena-
tion of allylic alcohols 9 and 10 in MeCN furnished b-
hydroxyhydroperoxides 11 and 12 in 37% and 43%
yields, respectively. Acid catalyzed condensation of b-
hydroxyhydroperoxide 11 with cyclopentanone, cyclo-
hexanone, and 2-adamantanone, furnished trioxanes
13, 14, and 15 in 46%, 59%, and 50% yields, respectively.
Similar condensation of b-hydroxyhydroperoxide 12
with cyclopentanone, cyclohexanone, 2-adamantanone,
gave trioxanes 16, 17, and 18 in 65%, 76%, and 72%
yields, respectively (Scheme 1, Fig. 1). Trioxanes 13–15
on treatment with succinic anhydride, triethyl amine,
and DMAP (cat.) in CH2Cl2 furnished hemisuccinate
derivatives 19–21 in 75–96% yields (Fig. 1).
C6H13
22
OH
C6H13
32
Scheme 3. Reagents and reaction conditions: (a) (i) n-hexylMgBr, dry
Et2O, 0ꢁC to rt, 4h, (ii) H2O, 0ꢁC.
hyde 22 with 6-equiv of n-hexylmagnesiumbromide fur-
nished tetrahydrofuran derivative 31 instead of the
desired allylic alcohol 32 (Scheme 3).7 Methylene blue
sensitized photooxygenation of allylic alcohols 23a–d
in MeCN furnished b-hydroxyhydroperoxides 24a–d in
30–45% yield, as inseparable mixture of diastereomers
1
(analyzed by H NMR). Acid catalyzed condensation
of b-hydroxyhydroperoxides 24a–d with cyclopenta-
none, cyclohexanone, and 2-adamantanone furnished
hydroxy-functionalized 1,2,4-trioxanes 25a–d, 26a–d,
27a–d in 50–74% yields (Scheme 2, Fig. 2), also as insep-
Geranyl acetate was converted to aldehyde acetate 22
using a literature procedure.6 Reaction of 22 with 6-
equiv of Grignard reagents, prepared from bromobenz-
ene, 4-bromochlorobenzene, 1-bromonaphthalene, and
4-bromobiphenyl furnished allylic alcohols 23a–d in
60–75% yields (Scheme 2). Surprisingly, reaction of alde-
1
arable mixture of diastereomers (analyzed by H and
13C NMR). Oxidation of trioxanes 26a and 27a with
chromiumtrioxide–pyridine complex8 in CH2Cl2 fur-
nished keto-functionalized trioxanes 28 and 29 in 92%
and 89% yields, respectively (Fig. 2). 6-Phenylvinyl
O
O
O
O
O
O
O O
O
O O
O
R
R
n
13 n=1, R=4-hydroxybutyl
14 n=2, R=4-hydroxybutyl
16 n=1, R=n-undecyl
15 R=4-hydroxybutyl
18 R=n-undecyl
n
HO
HO
17 n=2, R=n-undecyl
Ar
Ar
n=1; 25a-d
27a-d
O
O
O
n=2; 26a-d
O
O
O
(a, Ar = Ph; b, Ar = 4-ClC6H4; c, Ar = 1-naphthyl; d, Ar = 4-PhC6H4)
O
O
4
n
4
O O
O
O O
O
O
O
O O
O
O
HO
Ph
O
HO
O
O
19 n=1
20 n=2
21
Ph
Ph
28
30
29
Figure 1.
Figure 2.

C. Singh et al. / Bioorg. Med. Chem. 12 (2004) 5553–5562
5555
trioxane 30 (Fig. 2) was prepared by published
procedure.4a
5. Conclusion
In conclusion, we have shown that like 3-aryl substi-
tuted 2-butenols, 3-alkyl substituted butenols also
undergo regiospecific photooxygenation to give b-
hydroxyhydroperoxides in acceptable yields. These
hydroperoxides undergo facile acid-catalyzed condensa-
tion with various ketones to give 1,2,4-trioxanes in good
yields and that some of these trioxanes show very prom-
ising activity both by oral and i.m. route. Most of these
trioxanes carry hydroxy-functionalized side chains and
that this hydroxyl group can be further manipulated
to give new series of 1,2,4-trioxanes.
3. Antimalarial activity
Trioxanes 13–21, 25a–d, 26a–d, 27a–d, 28, and 29 were
initially screened for their antimalarial activity against
multidrug-resistant P. yoelii in Swiss mice at 96mg/kg
by intramuscular (i.m.) and oral routes. The trioxanes
showing activity at 96mg/kg by either routes (100% sup-
pression of parasitaemia on day 4) were further evalu-
ated at 48 and 24mg/kg (if active at 48mg/kg). The
detailed activity results are shown in Table 1.
6. Experimental
4. Results and discussion
All glass apparatus were oven dried prior to use. Melt-
ing points were determined on complab melting point
apparatus and were uncorrected. IR spectra were
recorded on a Perkin–Elmer FT-IR RXI spectrophoto-
As can be seen from Table 1, 6-arylalkylvinyl substi-
tuted trioxanes (25a–d, 26a–d, 27a–d, and 29) are the
more active than the 6-alkylvinyl substituted trioxanes
(13–21). These trioxanes are also more active than the
6-phenylvinyl substituted trioxane 30. Among the active
trioxanes, 27b is the best compound of the series. At
96mg/kg it shows 100% clearance of parasitaemia on
day 4 by both i.m. and oral routes, and all the treated
mice survive beyond day 28. Even at 48mg/kg it shows
more than 90% suppression of parasitaemia by oral
route. Trioxane 27a is more active than 27b by i.m. route
as it shows 100% clearance of parasitaemia at 96 as well
as 48mg/kg and provides 100% and 40% protection,
respectively, in the 28-day observation period. It also
shows 100% clearance of parasitaemia on day 4 at
96mg/kg by oral route but only 40% of the mice are pro-
tected. Both the trioxanes are adamantane based. Triox-
anes 27c and 27d, the other adamantane based trioxanes
show 100% clearance of parasitaemia at 96mg/kg by
oral route but provide only partial protection. Trioxane
29 the keto analog of trioxane 27a is less active than the
parent compound. All the 3-spiropentano trioxanes
(25a–d) show 100% or near 100% clearance of parasitae-
mia both at 96 and 48mg/kg by i.m. route, but with the
exception of 26d, which shows 100% clearance of para-
sitaemia at 96mg/kg, all these trioxanes show poor
activity by oral route. Among the 3-spirohexano trioxa-
nes (26a–d) two trioxanes 26b and 26c show 100% clear-
ance of parasitaemia at 96mg/kg by i.m. route and
provide 100% and 80% protection, respectively. Even
at 48mg/kg by i.m. route they show more than 90% sup-
pression of parasitaemia on day 4, though none of the
treated mice survive beyond day 28. Trioxane 26d, on
the other hand show 96% and 100% clearance of parasit-
aemia at 96mg/kg by i.m. and oral routes, respectively,
but only 80% of the mice treated by i.m. route survive
beyond day 28.
1
meter. H NMR and 13C NMR spectra were recorded
on Bruker DPX-200 spectrometer (operating at
200MHz) using CDCl3 as solvent. Tetramethylsilane
(d 0.00ppm) served as an internal standard in 1H
NMR and CDCl3 (d 77.0ppm) in 13C NMR. Fast Atom
Bombardment Mass Spectra (FAB-MS) were obtained
on JEOL SX 102 spectrometer using argon/xenon
(6kV, 10mA) as the FAB gas. Glycerol or m-nitrobenzyl
alcohol was used as matrix. Elemental analyses were
done on Vario EL-III analyzer (Germany). 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 spray-
ing with an aq solution of vanillin in 10% sulfuric acid
followed by heating at 150ꢁC. Column chromatography
was performed over silica gel (60–120 mesh) procured
from QualigensTM (India). All chemicals and reagents
were obtained from Aldrich (USA), Lancaster (Eng-
land), or Spectrochem (India) and were used without
further purification. Anhydrous diethyl ether (ether)
used in Grignard reactions was obtained from Spectro-
chem and was kept over sodium overnight prior to use.
6.1. 3-Methyl-hept-2-enedioic acid diethyl ester (7)10
This was prepared in 90% yield by the literature proce-
dure, with a stereoisomeric composition of E:Z =
3:1,10 as a colorless oil: IR (neat, cmÀ1) 1649.2, 1725.1;
1H NMR (200MHz, CDCl3) d 1.25 (t, 3H, J = 7.2Hz),
1.27 (t, 3H, J = 7.2Hz), 1.81 (m, 2H), 2.15 (s, 3H),
2.11–2.66 (m, 4H), 4.12 (q, 2H, J = 7.2Hz), 4.16 (q,
2H, J = 7.2Hz), 5.66 (s, 1H);FAB-MS ( m/z) 229
[M+H]+.
Ester 8 was also prepared by the same procedure.
Both in 3-spiropentane and 3-spirohexane series intro-
duction of biphenyl, a highly hydrophobic moiety, leads
to improvement in activity by oral route. On the other
hand in 3-spiroadamantane series the compounds hav-
ing phenyl or chlorophenyl show good activity and
introduction of the more hydrophobic groups like naph-
thyl and biphenyl leads to decrease in activity.
6.2. 3-Methyl-tetradec-2-enoic acid ethyl ester (8)11
This was obtained in 85% yield as a 3:1 mixture of E and
Z isomers, respectively, as a colorless oil: IR (neat,
1
cmÀ1) 1648.3, 1713.3; H NMR (200MHz, CDCl3) d
0.88 (t, 3H, J = 5.8Hz), 1.26 (m, 21H), 1.87 and 2.14

5556
C. Singh et al. / Bioorg. Med. Chem. 12 (2004) 5553–5562
Table 1. In vivo antimalarial activity of trioxanes against P. yoelii in Swiss mice
Compound
Dose (mg/kg/day)
Route
% Suppression on day-4a
Mice alive on day-28
MSTb SE
13
96
96
96
96
96
96
96
96
96
96
96
96
96
96
96
96
96
96
96
48
96
96
48
96
96
48
96
96
48
24
96
48
96
96
96
48
96
96
48
96
96
96
48
96
48
96
48
96
48
96
48
96
96
48
24
96
96
48
24
96
96
96
96
96
96
i.m.
Oral
i.m.
Oral
i.m.
Oral
i.m.
Oral
i.m.
Oral
i.m.
Oral
i.m.
Oral
i.m.
Oral
i.m.
Oral
i.m.
i.m.
Oral
i.m.
i.m.
Oral
i.m.
i.m.
Oral
i.m.
i.m.
i.m.
Oral
Oral
i.m.
Oral
i.m.
i.m.
Oral
i.m.
i.m.
Oral
i.m.
Oral
Oral
i.m.
i.m.
Oral
Oral
i.m.
i.m.
Oral
Oral
i.m.
Oral
Oral
Oral
i.m.
Oral
Oral
Oral
i.m.
Oral
i.m.
Oral
i.m.
Oral
42.5
63.1
64.5
31.5
84.0
26.3
21.2
94.4
36.9
80.1
10.3
51.3
25.7
95.1
37.3
36.3
46.0
12.5
100.0
97.0
30.0
100.0
98.4
29.6
100.0
93.4
81.3
100.0
100.0
85.2
100.0
94.3
94.5
65.0
100.0
97.1
88.8
100.0
93.4
68.4
96.4
100.0
77.5
100.0
100.0
100.0
62.4
100.0
78.9
100.0
90.8
72.1
100.0
100.0
87.1
79.0
100.0
100.0
90.4
93.7
51.7
89.5
99.6
97.1
83.9
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
2/5
0/5
0/5
1/5
0/5
0/5
2/5
0/5
0/5
0/5
0/5
0/5
0/5
5/5
0/5
0/5
4/5
0/5
0/5
4/5
0/5
0/5
5/5
2/5
2/5
0/5
5/5
0/5
5/5
0/5
2/5
3/5
2/5
0/5
3/5
2/5
2/5
0/5
0/5
0/5
4/5
0/5
0/5
0/5
07.20 0.37
09.20 0.37
08.60 0.60
07.20 0.37
10.80 0.92
07.40 0.24
07.80 0.37
11.25 0.55
07.60 0.24
09.2 0.80
07.00 0.55
08.20 0.53
06.60 0.24
11.80 0.97
07.40 0.24
07.40 0.57
10.80 0.92
07.40 0.24
14.80 1.06
12.60 1.12
08.20 0.53
14.57 0.83
14.75 0.75
07.40 0.51
14.75 1.48
15.75 2.37
10.40 0.93
17.33 1.75
16.75 1.23
11.80 1.53
16.00 1.22
12.00 1.14
14.40 1.21
11.60 1.12
>28
14
15
16
17
18
19
20
21
25a
25b
25c
25d
26a
26b
16.00 1.93
10.20 0.53
16.00 0.00
14.20 1.33
13.00 1.67
14.00 0.00
13.80 0.53
11.20 1.36
>28
26c
26d
27a
15.57 0.33
16.57 1.21
09.00 0.71
>28
27b
27c
27d
15.00 0.95
>28
10.20 0.85
15.33 2.31
17.00 3.00
15.57 1.75
10.40 1.24
14.50 0.50
17.33 1.45
17.57 2.02
08.80 0.53
15.57 1.45
07.60 0.40
14.00 0.00
13.80 1.45
15.40 1.20
10.50 1.14
28
29
30

C. Singh et al. / Bioorg. Med. Chem. 12 (2004) 5553–5562
5557
Table 1 (continued)
Compound
Dose (mg/kg/day)
Route
% Suppression on day-4a
Mice alive on day-28
MSTb SE
Artemisinin
48
24
96
48
—
i.m.
i.m.
Oral
Oral
—
100.0
100.0
100.0
100.0
—
5/5
4/5
4/5
2/5
0/15
>28
16.00 0.00
20.00 0.00
17.60 1.33
07.00 0.14
Chloroquine
Vehicle control
a Percent suppression = [(CÀT)/C] · 100;where C = parasitaemia in control group, and T = parasitaemia in treated group.
b Mean survival time (MST) calculated (in days) only for the mice, which died during 28-day observation period.
(2 · s, 3H), 2.12 and 2.61 (2 · t, 2H, J = 8.0Hz each),
4.14 (q, 2H, J = 7.2Hz), 5.65 (s, 1H);FAB-MS ( m/z)
269 [M+H]+.
such a rate to maintain a gentle reflux. After the addi-
tion was complete the warm water bath was again
placed under the flask and stirring and refluxing contin-
ued for 30min followed by cooling to 0ꢁC (ice bath). To
the cold solution of phenyl magnesium bromide in ether
was added dropwise a solution of aldehyde acetate 22
(3.0g, 17.6mmol) in anhydrous ether (50mL), over
20min. After the addition was complete Grignard reac-
tion mixture was stirred for 3h at rt followed by again
cooling to 0ꢁC. Cold water was added to decompose
the Grignard complex. Ether was decanted off and the
residual inorganic matter rinsed with ether (3 · 70mL).
Standard work-up gave crude diol 23a that was sub-
jected to silica gel column chromatography, using
AcOEt–hexane (1:3) as eluent, to furnish pure 23a
6.3. 3-Methyl-hept-2-ene-1,7-diol (9)12
To a precooled (0ꢁC) magnetically stirred slurry of
LiAlH4 (9.7g, 0.255mol) in anhydrous ether (75mL)
was added a solution of di-ester 7 (9.2g, 0.064mol) in
anhydrous ether (75mL), under nitrogen and stirred at
0ꢁC for 8h. Excess LiAlH4 was quenched by careful
addition of cold water followed by 10% aq NaOH, dur-
ing which the gray color changed to snow-white. The
ether was decanted off and the white precipitate rinsed
with ether (4 · 50mL). Combined ether layers were con-
centrated to give crude diol as a colorless oil that was
chromatographed over a silica gel column, using
AcOEt–hexane (2:3) as eluent, to furnish 4.6g (79%)
of pure 9 as a colorless oil: IR (neat, cmÀ1) 1664.5,
(2.60g, 72%) as a colorless oil: IR (neat, cmÀ1
)
1
1596.4, 3262.7; H NMR (200MHz, CDCl3) d 1.65 (s,
3H), 1.81–2.12 (m, 4H), 4.11 (d, 2H, J = 7.0Hz), 4.63
(dd, 1H, J = 7.2, 5.6Hz), 5.39 (t, 1H, J = 7.0Hz), 7.25–
7.42 (m, 5H);FAB-MS ( m/z) 207 [M+H]+;Anal. Calcd
for C13H18O2: C, 75.69;H, 8.80. Found: C, 75.51;H,
8.66.
1
3340.3; H NMR (200MHz, CDCl3) d 1.50 (m, 4H),
1.66 and 1.73 (2 · s, 3H), 2.05 (m, 2H), 3.63 (t, 2H,
J = 6.0Hz), 4.10 and 4.13 (2 · d, 2H, J = 6.8Hz each),
5.40 (t, 1H, J = 6.8Hz);FAB-MS ( m/z) 145 [M+H]+.
6.6. 6-(4-Chloro-phenyl)-3-methyl-hex-2-ene-1,6-diol
(23b)
Allylic alcohol 10 was also prepared by the same
procedure.
This was prepared in 75% yield by the same procedure
as for compound 23a as a colorless oil: IR (neat,
6.4. 3-Methyl-tetradec-2-en-1-ol (10)
1
cmÀ1) 1596.3, 3384.8; H NMR (200MHz, CDCl3) d
This was obtained in 77% yield as a colorless oil: IR
(neat, cmÀ1) 1668.4, 3330.5; 1H NMR (200MHz,
CDCl3) d 0.88 (t, 3H, J = 6.8Hz), 1.26 (m, 18H), 1.66
and 1.73 (2 · s, 3H), 2.00 (t, 2H, J = 7.5Hz), 4.13 (d,
2H, J = 6.8Hz), 5.40 (t, 1H, J = 6.8Hz);FAB-MS ( m/
z) 227 [M+H]+;Anal. Calcd for C 15H30O: C, 79.58;H,
13.36. Found: C, 79.71;H, 13.12.
1.66 (s, 3H), 1.71–2.11 (m, 4H), 4.14 (d, 2H, J =
6.8Hz), 4.65 (dd, 1H, J = 6.6, 5.8Hz), 5.42 (t, 1H,
J = 6.8Hz), 7.30 (m, 4H);FAB-MS ( m/z) 241 and 243
[M+H]+;Anal. Calcd for C 13H17ClO2: C, 64.86;H,
7.12. Found: C, 65.08;H, 7.31.
6.7. 3-Methyl-6-naphthalen-1-yl-hex-2-ene-1,6-diol (23c)
6.5. 3-Methyl-6-phenyl-hex-2-ene-1,6-diol (23a)
The procedure for this compound was otherwise same as
for 23a except that the Grignard reagent was prepared as
Into an oven dried 1L three-necked round-bottomed
flask, equipped with a magnetic stirring unit, a double
surfaced reflux condenser, and a pressure equalizing
dropping funnel, was placed Mg-turnings (2.55g,
0.105g atom), under a static nitrogen atmosphere. The
Mg was covered with anhydrous ether (100mL) and a
small aliquot of a solution of bromobenzene (16.63g,
0.105mol) in anhydrous ether (75mL) together with a
small crystal of iodine were added with stirring and
moderated heating (warm water bath ꢀ45–50ꢁC). As
the reaction started the water bath was removed and
the solution of bromobenzene in ether was added at
per the literature procedure.13 This was obtained in 74%
À1
yield as a white solid: mp 81–83ꢁC;IR (KBr, cm
)
1
1597.3, 3264.9; H NMR (200MHz, CDCl3): d 1.63 (s,
3H), 1.92–2.05 (m, 2H), 2.15–2.24 (m, 2H), 4.08 (d, 2H,
J = 6.8Hz), 5.37–5.43 (m, 2H), 7.42–8.06 (m, 7H);
FAB-MS (m/z) 257 [M+H]+;Anal. Calcd for
C17H20O2: C, 79.65;H, 7.86. Found: C, 79.49;H, 7.92.
6.8. 6-Biphenyl-4-yl-3-methyl-hex-2-ene-1,6-diol (23d)
The experimental procedure for this compound was oth-
erwise same as for 23a except that the Grignard reagent

5558
C. Singh et al. / Bioorg. Med. Chem. 12 (2004) 5553–5562
was prepared by ꢀentrainment methodꢁ as follows. Into
an oven dried 1L three-necked round-bottomed flask,
equipped with a magnetic stirring unit, a double
surfaced reflux condenser, and a pressure equalizing
dropping funnel, was placed Mg-turnings (5.14g,
0.211g atom), under a static nitrogen atmosphere. The
Mg was covered with anhydrous ether (100mL) and a
6.12. 5-Hydroperoxy-4-methylene-1-phenyl-hexane-1,6-
diol (24a)
This was obtained in 35% yield as colorless oil: IR (neat,
cmÀ1) 1597.1, 1641.2, 3360.9; 1H NMR (200MHz,
CDCl3) d 1.86–2.01 (m, 2H), 2.08–2.36 (m, 2H), 3.30
(br s, 2H, 2 · OH), 3.67 (m, 2H), 4.50 (m, 1H), 4.70
(m, 1H), 5.03 and 5.04 (2 · s, 1H), 5.11 and 5.13
(2 · s, 1H), 7.27 (m, 5H), 10.12 (br s, 1H, OOH);
FAB-MS (m/z) 239 [M+H]+.
small aliquot of
a solution of 4-bromobiphenyl
(24.67g, 0.105mol) and 1,2-dibromoethane (9.9g,
52.6mmol) in anhydrous ether (250mL) was added with
stirring and moderated heating (warm water bath ꢀ45–
50ꢁC). As the reaction initiated the water bath was
removed and the solution of 4-bromobiphenyl and 1,2-
dibromoethane in ether was added at such a rate to
maintain a gentle reflux. After the addition was com-
plete the warm water bath was again placed under the
flask and stirring and refluxing continued for 1h, to
drive the reaction to completion. The Grignard reagent
that settled as heavy oil was dissolved by the addition of
80mL of dry benzene, prior to cooling. Diol 23d was
obtained in 60% yield as a white solid: mp 120–122ꢁC;
6.13. 1-(4-Chloro-phenyl)-5-hydroperoxy-4-methylene-
hexane-1,6-diol (24b)
This was obtained in 35% yield as a colorless oil: IR
)
(neat, cmÀ1
1596.1, 1647.5, 3376.2; 1H NMR
(200MHz, CDCl3) d 1.82–1.94 (m, 2H), 2.15–2.42 (m,
2H), 3.01 (br s, 2H, 2 · OH), 3.68 (m, 2H), 4.51 (m,
1H), 4.69 (m, 1H), 5.04 (s, 1H), 5.11 and 5.14 (2 · s,
1H), 7.26 (m, 4H), 9.99 (br s, 1H, OOH);FAB-MS
(m/z) 273 and 275 [M+H]+.
1
IR (KBr, cmÀ1) 1594.5, 3360.6; H NMR (200MHz,
CDCl3) d 1.68 (s, 3H), 1.78–2.20 (m, 4H), 4.14 (d, 2H,
J = 6.8Hz), 4.70 (dd, 1H, J = 7.0, 5.4Hz), 5.44 (t, 1H,
J = 6.8Hz), 7.29–7.59 (m, 9H);FAB-MS ( m/z) 283
[M+H]+;Anal. Calcd for C 19H22O2: C, 80.82;H, 7.85.
Found: C, 80.62;H, 8.03.
6.14. 5-Hydroperoxy-4-methylene-1-naphthalen-1-yl-hex-
ane-1,6-diol (24c)
This was obtained in 40% yield as a colorless oil:
IR (neat, cmÀ1) 1595.4, 1648.3, 3370.1; 1H NMR
(200MHz, CDCl3) d 1.94–2.22 (m, 4H), 3.72 (m,
2H), 4.52 (m, 1H), 5.10, 5.16, and 5.22 (3 · s, 2H),
5.54 (m, 1H), 7.46–8.07 (m, 7H);FAB-MS ( m/z) 289
[M+H]+.
6.9. General method for photooxygenation of allylic
alcohols (photooxygenation of 23a representative)
A slow stream of oxygen was bubbled into a solution of
23a (1.0g, 4.8mmol), and methylene blue (10mg) in
MeCN (50mL) in a 100mL jacketed round-bottomed
flask, maintained below 0ꢁC by circulating coolant eth-
anol through an ultra cryostat. The mixture was irradi-
ated with visible light by means of a tungsten–halogen
lamp (500W) kept at a distance of 6-in. from the flask.
Reaction was complete in about 6h as shown by silica
gel TLC monitoring. MeCN was evaporated on the
rotavapor (bath temp <40ꢁC) and the crude hydroper-
oxide 24a subjected to column chromatography over sil-
ica gel (deactivated with 12% v/w of water), using
AcOEt–hexane (2:3) as eluent to furnish reasonably
pure 24a (0.41g, 35%).
6.15. 1-Biphenyl-4-yl-5-hydroperoxy-4-methylene-hexane-
1,6-diol (24d)
This was obtained in 45% yield as colorless oil.
6.16. General procedure for condensation of hydroperox-
ides with ketones (preparation of trioxane 27a
representative)
A solution of hydroperoxy diol 24a (300mg, 1.26mmol),
2-adamantanone (750mg, 5.0mmol), and TsOHÆH2O
(50mg, 0.26mmol) in CH2Cl2 (25mL) was stirred at rt
for 1h. Reaction mixture was washed with saturated
aqueous NaHCO3 solution (20mL) and the aqueous
layer extracted with CH2Cl2 (2 · 15mL). Standard
work-up gave crude trioxane that was chromatographed
over a silica gel column, using AcOEt–hexane (1:9) as
eluent, to furnish pure 27a (0.34g, 73%).
6.10. 2-Hydroperoxy-3-methylene-heptane-1,7-diol (11)
This was obtained in 37% yield as a colorless oil: IR
(neat, cmÀ1) 1565.1, 3382.6; 1H NMR (200MHz,
CDCl3) d 1.50 (m, 4H), 2.13 (m, 2H), 3.67–3.75 (m,
4H), 4.53 (t, 1H, J = 6.0Hz), 5.08 and 5.14 (2 · s, 2H),
8.78 (s, 1H, OOH);FAB-MS ( m/z) 177 [M+H]+.
6.17. 5-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-hex-5-en-1-ol
(13)
6.11. 2-Hydroperoxy-3-undecyl-but-3-en-1-ol (12)
This was obtained in 46% yield as a colorless oil: IR (neat,
cmÀ1) 1646.2, 3393.2; 1H NMR(200MHz, CDCl3) d 1.52–
1.90 (m, 11H), 2.08 (t, 2H, J = 6.8Hz), 2.46 (m, 1H), 3.65
(t, 2H, J = 5.8Hz), 3.82 (d, 2H, J = 6.6Hz), 4.74 (t,
1H, J = 6.6Hz), 5.02 (s, 2H); 13C NMR (50MHz, CDCl3)
d 23.68 (t), 24.39 (t), 25.06 (t), 32.56 (t), 33.06 (t), 33.99
(t), 37.37 (t), 62.89 (t), 65.01 (t), 81.44 (d), 114.38 (t),
114.78 (s), 143.94 (s);FAB-MS ( m/z) 243 [M+H]+.
This was obtained in 43% yield as a colorless oil: IR
(neat, cmÀ1) 1647.7, 3375.0; 1H NMR (200MHz,
CDCl3) d 0.88 (t, 3H, J = 6.8Hz), 1.26 (m, 18H), 2.03
(m, 2H), 3.74 (d, 2H, J = 6.0Hz), 4.52 (t, 1H,
J = 6.0Hz), 5.06 and 5.11 (2 · s, 2H), 8.53 (br s, 1H,
OOH);FAB-MS ( m/z) 259 [M+H]+.

C. Singh et al. / Bioorg. Med. Chem. 12 (2004) 5553–5562
5559
6.18. 5-(1,2,5-Trioxa-spiro[5.5]undec-3-yl)-hex-5-en-1-ol
(14)
stirred for 1h. CH2Cl2 was removed under vacuum
and the residue taken up in Et2O (30mL) washed succes-
sively with 10% aq HCl (20mL) and water (20mL).
Standard work-up of the ether layer gave crude hemi-
succinate that was purified by column chromatography
over silica gel using MeOH–CHCl3 (1:99) as eluent to
furnish pure 19 (0.30g, 75%) as a colorless oil: IR (neat,
This was prepared in 59% yield as a colorless oil: IR
(neat, cmÀ1) 1645.6, 3409.6; 1H NMR (200MHz,
CDCl3) d 1.59 (m, 12H), 1.93–2.22 (m, 4H), 3.64 (t,
2H, J = 6.0Hz),3.72 (dd, 1H, J = 11.8, 3.0Hz), 3.96
(dd, 1H, J = 11.8, 10.4Hz), 4.70 (dd, 1H, J = 10.4,
3.0Hz), 5.03 (s, 2H);FAB-MS ( m/z) 257 [M+H]+;Anal.
Calcd for C14H24O4ÆH2O: C, 61.28;H, 9.55. Found: C,
61.24;H, 9.18.
1
cmÀ1) 1729.8, 3185.6; H NMR (200MHz, CDCl3) d
1.51–1.81 (m, 11H), 2.07 (t, 2H, J = 6.2Hz), 2.40–2.52
(m, 1H), 2.65 (m, 4H), 3.83 (d, 2H, J = 6.8Hz), 4.11
(t, 2H, J = 6.0Hz), 4.75 (t, 1H, J = 6.8Hz), 5.024 (s,
2H);FAB-MS ( m/z): 343 [M+H]+;Anal. Calcd for
C17H26O7Æ1.7H2O: C, 54.73;H, 7.94. Found: C, 54.48;
H, 7.67.
6.19. Trioxane 15
This was prepared in 50% yield as a colorless oil: IR
(neat, cmÀ1) 1648.7, 3404.8; 1H NMR (200MHz,
CDCl3) d 1.54–2.09 (m, 19H), 2.90 (br s, 1H), 3.65 (t,
2H, J = 5.8Hz), 3.72 (dd, 1H, J = 12.0, 2.8Hz), 3.94
(dd, 1H, J = 12.0, 10.6Hz), 4.70 (dd, 1H, J = 10.6,
2.8Hz), 5.03 (s, 2H);FAB-MS ( m/z) 309 [M+H]+;Anal.
Calcd for C18H28O4Æ0.3H2O: C, 68.89;H, 9.18. Found:
C, 68.57;H, 8.98.
Hemisuccinates 20 and 21 were also prepared by the
same procedure.
6.24. Succinic acid mono-[5-(1,2,5-trioxa-spiro[5.5]undec-
3-yl)-hex-5-enyl] ester (20)
This was obtained in 96% yield as a colorless oil: IR
(neat, cmÀ1) 1731.9, 3194.4; 1H NMR (200MHz,
CDCl3) d 1.59 (m, 12H), 1.90–2.12 (m, 4H), 2.64 (m,
4H), 3.74 (dd, 1H, J = 11.8, 3.0Hz), 3.95 (dd, 1H,
J = 11.8, 10.4Hz), 4.11 (t, 2H, J = 5.8Hz), 4.69 (dd,
1H, J = 10.4, 3.0Hz), 5.03 (s, 2H);FAB-MS ( m/z) 357
[M+H]+;Anal. Calcd for C 18H28O7Æ0.4H2O: C, 59.45;
H, 7.98. Found: C, 59.90;H, 8.00.
6.20. 8-(1-Undecyl-vinyl)-6,7,10-trioxa-spiro[4.5]decane
(16)
This was prepared in 65% yield as a colorless oil: IR
(neat, cmÀ1) 1646.3; 1H NMR (200MHz, CDCl3) d
0.88 (t, 3H, J = 6.8Hz), 1.26 (m, 18H), 1.66–1.87 (m,
7H), 2.04 (m, 2H), 2.46 (m, 1H), 3.80 (d, 2H,
J = 6.6Hz), 4.74 (t, 1H, J = 6.6Hz), 4.99 (s, 2H);FAB-
MS (m/z) 325 [M+H]+;Anal. Calcd for C 20H36O3: C,
74.03;H, 11.18. Found: C, 74.27;H, 11.09.
6.25. Trioxane 21
This was obtained in 87% yield as colorless oil: IR (neat,
1
cmÀ1) 1722.7, 3190.1; H NMR (200MHz, CDCl3) d
6.21. 3-(1-Undecyl-vinyl)-1,2,5-trioxa-spiro[5.5]undecane
(17)
1.42–2.08 (m, 19H), 2.64 (m, 4H), 2.90 (br s, 1H), 3.75
(dd, 1H, J = 11.6, 3.0Hz), 3.93 (dd, 1H, J = 11.6,
10.2Hz), 4.11 (t, 2H, J = 5.6Hz), 4.72 (dd, 1H,
J = 10.2, 3.0Hz), 5.02 (s, 2H);FAB-MS ( m/z) 409
[M+H]+;Anal. Calcd for C 22H32O7Æ1.2H2O: C, 61.43;
H, 8.06. Found: C, 61.42;H, 7.98.
This was prepared in 76% yield as a colorless oil: IR
(neat, cmÀ1) 1645.1; 1H NMR (200MHz, CDCl3) d
0.88 (t, 3H, J = 6.8Hz), 1.26 (m, 18H), 1.43–1.60 (m,
9H), 1.94–2.22 (m, 3H), 3.71 (dd, 1H, J = 11.8,
3.2Hz), 3.95 (dd, 1H, J = 11.8, 10.4Hz), 4.68 (dd, 1H,
J = 10.4, 3.2Hz), 5.00 (s, 2H);FAB-MS ( m/z) 339
[M+H]+ Anal. Calcd for C21H38O3: C, 74.51;H, 11.31.
Found: C, 74.36;H, 11.23.
6.26. 1-Phenyl-4-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-pent-
4-en-1-ol (25a)
This was prepared in 58% yield as a colorless oil: IR
)
(neat, cmÀ1
1598.5, 1645.5, 3421.1; 1H NMR
6.22. Trioxane 18
(200MHz, CDCl3) d 1.63–2.20 (m, 11H), 2.40–2.48 (m,
1H), 3.77–3.81 (m, 2H), 4.65–4.77 (m, 2H), 5.04 (s,
2H), 7.32 (m, 5H); 13C NMR (50MHz, CDCl3) d
23.70 (t), 25.08 (t), 30.35 (t), 33.08 (t), 37.36 (t), 37.54
(t), 64.93 (t), 74.11 (d), 81.56 (d), 81.60 (d), 114.59 (t),
114.80 (s), 126.24 (2 · d), 128.02 (d), 128.90 (2 · d),
143.67 (s), 144.89 (s);FAB-MS ( m/z): 305 [M+H]+;
Anal. Calcd for C18H24O4: C, 71.03;H, 7.95. Found:
C, 70.18;H, 7.31.
This was prepared in 76% yield as a colorless oil: IR
(neat, cmÀ1) 1646.0; 1H NMR (200MHz, CDCl3) d
0.88 (t, 3H, J = 6.8Hz), 1.26 (m, 18H), 1.60–2.08 (m,
15H), 2.91 (br m, 1H), 3.71 (dd, 1H, J = 11.8, 3.2Hz),
3.93 (dd, 1H, J = 11.8, 10.4Hz), 4.69 (dd, 1H,
J = 10.4, 3.2Hz), 5.00 (s, 2H);FAB-MS ( m/z) 391
[M+H]+;Anal. Calcd for C 25H42O3: C, 76.87;H,
10.84. Found: C, 77.00;H, 11.08.
6.27. 1-(4-Chloro-phenyl)-4-(6,7,10-trioxa-spiro[4.5]dec-
8-yl)-pent-4-en-1-ol (25b)
6.23. Succinic acid mono-[5-(6,7,10-trioxa-spiro[4.5]dec-
8-yl)-hex-5-enyl] ester (19)
This was prepared in 70% yield as a colorless oil: IR
)
(200MHz, CDCl3) d 1.70–2.16 (m, 11H), 2.38–2.44 (m,
1H), 3.78–3.82 (m, 2H), 4.64–4.76 (m, 2H), 5.05 (s,
To a solution of trioxane 13 (0.28g, 1.16mmol), Et3N
(0.35g, 3.46mmol), and DMAP (5mg) in CH2Cl2 was
added succinic anhydride (0.29g, 2.9mmol) at rt and
(neat, cmÀ1
1597.4, 1646.8, 3435.1; 1H NMR

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C. Singh et al. / Bioorg. Med. Chem. 12 (2004) 5553–5562
2H), 7.29 (m, 4H);FAB-MS ( m/z) 339 and 341 [M+H]+;
Anal. Calcd for C18H23ClO4: C, 63.81;H, 6.84. Found:
C, 63.58;H, 7.02.
6.33. 1-Biphenyl-4-yl-4-(1,2,5-trioxa-spiro[5.5]undec-3-
yl)-pent-4-en-1-ol (26d)
This was prepared in 71% yield as a colorless oil: IR
)
6.28. 1-Naphthalen-1-yl-4-(6,7,10-trioxa-spiro[4.5]dec-8-
yl)-pent-4-en-1-ol (25c)
(neat, cmÀ1
1602.0, 1648.1, 3423.9; 1H NMR
(200MHz, CDCl3) d 1.45–1.59 (m, 10H), 1.83–2.04 (m,
2H), 2.10–2.26 (m, 2H), 3.71 (dd, 1H, J = 11.8,
3.0Hz), 3.96 (dd, 1H, J = 11.8, 10.4Hz), 4.67–4.76 (m,
2H), 5.07 (s, 2H), 7.33–7.61 (m, 9H);FAB-MS ( m/z)
395 [M+H]+;Anal. Calcd for C 25H30O4: C, 76.11;H,
7.66. Found: C, 76.48;H, 8.04.
This was prepared in 54% yield as a colorless oil: IR
)
(neat, cmÀ1
1598.3, 1646.2, 3448.5; 1H NMR
(200MHz, CDCl3) d 1.68–1.81 (m, 7H), 2.01–2.10 (m,
2H), 2.20–2.35 (m, 3H), 3.78–3.83 (m, 2H), 4.76 (dd,
1H, J = 7.6, 5.8Hz), 5.05 and 5.08 (2 · s, 2H), 5.48
(dd, 1H, J = 7.4, 5.0Hz), 7.43–8.11 (m, 7H);FAB-MS
(m/z) 355 [M+H]+;Anal. Calcd for C 22H26O4: C,
74.55;H, 7.39. Found: C, 74.54;H, 7.36.
6.34. Trioxane 27a
This was prepared in 73% yield as a colorless oil: IR
)
(neat, cmÀ1
1596.1, 1646.1, 3422.5; 1H NMR
6.29. 1-Biphenyl-4-yl-4-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-
pent-4-en-1-ol (25d)
(200MHz, CDCl3) d 1.62–2.17 (m, 17H), 2.87 (br s,
1H), 3.65 (dd, 1H, J = 11.8, 3.2Hz), 3.91 (dd, 1H,
J = 11.8, 10.4Hz), 4.62–4.73 (m, 2H), 5.05 (s, 2H),
7.30 (m, 5H);FAB-MS ( m/z) 371 [M+H]+;Anal. Calcd
for C23H30O4: C, 74.56;H, 8.16. Found: C, 74.25;H,
8.43.
This was prepared in 73% yield as a colorless oil: IR
)
(neat, cmÀ1
1602.6, 1646.0, 3428.8; 1H NMR
(200MHz, CDCl3) d 1.66–2.31 (m, 11H), 2.40–2.49 (m,
1H), 3.79–3.83 (m, 2H), 4.70–7.79 (m, 2H), 5.06 (s,
2H), 7.34–7.60 (m, 9H). FAB-MS (m/z) 381 [M+H]+;
Anal. Calcd for C24H28O4: C, 75.76;H, 7.42. Found:
C, 76.06;H, 7.81.
6.35. Trioxane 27b
This was prepared in 59% yield as a colorless oil: IR
1599.4, 1646.5, 3427.6; 1H NMR
(neat, cmÀ1
)
6.30. 1-Phenyl-4-(1,2,5-trioxa-spiro[5.5]undec-3-yl)-pent-
4-en-1-ol (26a)
(200MHz, CDCl3) d 1.60–2.17 (m, 17H), 2.85 (br m,
1H), 3.70 (dd, 1H, J = 11.8, 3.0Hz), 3.91 (dd, 1H,
J = 11.8, 10.4Hz), 4.64–4.73 (m, 2H), 5.06 (s, 2H),
7.30 (m, 4H);FAB-MS ( m/z) 405 and 407 [M+H]+;
Anal. Calcd for C23H29ClO4: C, 68.22;H, 7.22. Found:
C, 68.45;H, 7.34.
This was prepared in 62% yield as a colorless oil: IR
)
(neat, cmÀ1
1598.2, 1646.3, 3424.4; 1H NMR
(200MHz, CDCl3) d 1.47–1.87 (m, 10H), 1.88–1.96 (m,
2H), 2.09–2.16 (m, 2H), 3.69 (dd, 1H, J = 11.8,
3.0Hz), 3.93 (dd, 1H, J = 11.8, 10.4Hz), 4.65–4.71 (m,
2H), 5.05 (s, 2H), 7.23–7.35 (m, 5H);FAB-MS ( m/z)
319 [M+H]+;Anal. Calcd for C 19H26O4Æ0.1H2O: C,
71.26;H, 8.24. Found: C, 70.79;H, 7.86.
6.36. Trioxane 27c
This was prepared in 50% yield as a colorless oil: IR
)
(neat, cmÀ1
1597.1, 1647.2, 3447.5; 1H NMR
(200MHz, CDCl3) d 1.57–2.36 (m, 17H), 2.86 (br m,
1H), 3.71 (dd, 1H, J = 11.8, 3.0Hz), 3.92 and 3.94
(2 · dd, 1H, J = 11.8, 10.4Hz each), 4.73 (dd, 1H,
J = 10.4, 3.0Hz), 5.06 and 5.09 (2 · s, 2H), 5.48 (dd,
1H, J = 7.0, 5.2Hz), 7.43–8.11 (m, 7H); 13C NMR
(50MHz, CDCl3) 27.59 (2 · d), 29.82 (d), 30.78 (t),
33.40 (t), 33.69 (t), 33.95 (2 · t), 36.57 (d), 36.84 (t),
37.64 (t), 62.06 (t), 70.67 (d), 70.83 (d), 81.59 (d),
81.62 (d), 104.92 (s), 114.64 (t), 114.94 (t), 123.22 (d),
123.34 (d), 123.54 (d), 125.84 (d), 125.97 (d), 126.50
(d), 128.40 (d), 129.32 (d), 130.75 (s), 134.26 (s),
140.69 (s), 143.98 (s);FAB-MS ( m/z) 421 [M+H]+;Anal.
Calcd for C27H32O4: C, 74.55;H, 7.39. Found: C, 73.71;
H, 7.06.
6.31. 1-(4-Chloro-phenyl)-4-(1,2,5-trioxa-spiro[5.5]undec-
3-yl)-pent-4-en-1-ol (26b)
This was prepared in 50% yield as a colorless oil: IR
)
(neat, cmÀ1
1596.2, 1645.1, 3419.0; 1H NMR
(200MHz, CDCl3) d 1.47–1.60 (m, 10H), 1.82–1.97 (m,
2H), 2.09–2.19 (m, 2H), 3.70 (dd, 1H, J = 11.8,
3.0Hz), 3.93 (dd, 1H, J = 11.8, 10.4Hz), 4.64–4.70 (m,
2H), 5.06 (s, 2H), 7.29 (m, 4H);FAB-MS ( m/z) 353
and 355 [M+H]+;Anal. Calcd for C 19H25ClO4: C,
64.67;H, 7.14. Found: C, 64.79;H, 7.25.
6.32. 1-Naphthalen-1-yl-4-(1,2,5-trioxa-spiro[5.5]undec-
3-yl)-pent-4-en-1-ol (26c)
6.37. Trioxane 27d
This was prepared in 74% yield as a colorless oil: IR
)
(neat, cmÀ1
1597.5, 1645.4, 3443.8; 1H NMR
This was prepared in 70% yield as a colorless oil: IR
)
(200MHz, CDCl3) d 1.42–1.58 (m, 9H), 1.84–2.15 (m,
3H), 2.20–2.31 (m, 2H), 3.68 (dd, 1H, J = 11.8,
3.0Hz), 3.91 and 3.93 (2 · dd, 1H, J = 11.8, 10.2Hz
each), 4.69 (dd, 1H, J = 10.2, 3.0Hz), 5.04 and 5.06
(2 · s, 2H), 5.44 (dd, 1H, J = 7.2, 5.0Hz), 7.45–8.08
(m, 7H);FAB-MS ( m/z) 369 [M+H]+;Anal. Calcd for
C23H28O4: C, 74.97;H, 7.66. Found: C, 75.20;H, 7.49.
(neat, cmÀ1
1600.8, 1646.5, 3407.3; 1H NMR
(200MHz, CDCl3) d 1.56–2.18 (m, 17H), 2.88 (br s,
1H), 3.72 (dd, 1H, J = 11.6, 3.0Hz), 3.93 (dd, 1H,
J = 11.6, 10.4Hz), 4.69–4.78 (m, 2H), 5.07 (s, 2H),
7.33–7.60 (m, 9H);FAB-MS ( m/z) 447 [M+H]+;Anal.
Calcd for C29H34O4: C, 78.00;H, 7.67. Found: C,
77.69;H, 8.01.

C. Singh et al. / Bioorg. Med. Chem. 12 (2004) 5553–5562
5561
6.38. 1-Phenyl-4-(1,2,5-trioxa-spiro[5.5]undec-3-yl)-pent-
4-en-1-one (28)
(t), 79.40 (d), 79.92 (d), 82.69 (s), 111.36 (t), 111.56 (t),
144.63 (d), 145.48 (d);FAB-MS ( m/z) 197 [M+H]+.
A 100mL round-bottomed flask, equipped with a mag-
netic stirrer and a CaCl2 guard tube was, charged with
dry pyridine (1.04g, 13.2mmol) and CH2Cl2 (20mL).
The solution was cooled to 0–5ꢁC (ice bath) and CrO3
(0.66g, 6.6mmol;stored in a vacuum desiccator over-
night over P2O5 prior to use) was added in one portion.
The deep burgundy solution was stirred in the cold for
an additional 5min and then allowed to warm to 20ꢁC
over a period of 30min. A solution of trioxane 26a
(0.35g, 1.10mmol) in CH2Cl2 (20mL) was added rapidly
with immediate separation of a tarry black deposit. The
reaction mixture was stirred for an additional 30min
and then decanted from the tarry residue. The organic
layer was washed successively with 5% aq NaOH
(40mL), 5% aq HCl (40mL), and saturated aq NaHCO3
solution (40mL). The organic layer was dried over an-
hyd Na2SO4 and evaporated under vacuum to afford
crude keto trioxane 28 that was purified by column
chromatography over silica gel using AcOEt–hexane
(1:19) as eluent to furnish pure 28 as a white solid
(0.32g;92%): mp 59–61 ꢁC;IR (KBr, cm À1) 1595.0,
6.41. Antimalarial activity
The in vivo efficacy of compounds was evaluated against
P. yoelii (MDR) in Swiss mice model. The colony bred
Swiss mice (25 1g) were inoculated with 1 · 106
parasitized RBC on day zero and treatment was admin-
istered to a group of five mice at each dose, from day 0
to 3, in two divided doses daily. The drug dilutions were
prepared in groundnut oil so as to contain the required
amount of the drug (1.2mg for a dose of 96mg/kg,
0.6mg for a dose of 48mg/kg and 0.3mg for a dose of
24mg/kg) in 0.1mL and administered either intramuscu-
larly or orally for each dose. Parasitaemia level were
recorded from thin blood smears between day 4 and
28.9 Mice treated with artemisinin and chloroquine
served as positive controls.
Acknowledgements
Nitin Gupta is thankful to the Council of Scientific and
Industrial Research (CSIR), New Delhi for award of
Senior Research Fellowship. Technical help by Mrs.
Shashi Rastogi is gratefully acknowledged.
1
1689.7; H NMR (200MHz, CDCl3) d 1.45–1.61 (m,
8H), 1.92–2.05 (m, 1H), 2.11–2.20 (m, 1H), 2.52 (t,
2H, J = 7.4Hz), 3.16 (m, 2H), 3.76 (dd, 1H, J = 11.8,
3.2Hz), 4.00 (dd, 1H, J = 11.8, 10.4Hz), 4.76 (dd, 1H,
J = 10.4, 3.0Hz), 5.07 and 5.09 (2 · s, 2H), 7.46 (t, 2H,
J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 7.97 (d,
2H, J = 7.5Hz); 13C NMR (50MHz, CDCl3) d 22.2
(t), 22.3 (t), 25.5 (t), 27.8 (t), 29.0 (t), 34.5 (t), 36.9 (t),
62.0 (t), 81.4 (d), 102.5 (s), 114.5 (t), 128.0 (2 · d),
128.6 (2 · d), 133.1 (d), 136.7 (s), 142.9 (s), 198.9 (s);
FAB-MS (m/z) 317 [M+H]+;Anal. Calcd for
C19H24O4: C, 72.13;H, 7.65. Found: C, 72.22;H, 7.39.
References and notes
1. (a) Klayman, D. L. Science 1985, 228, 1049;(b) Bhatta-
charya, A. K.;Sharma, R. P. Heterocycles 1999, 51, 1681;
(c) Borstnik, K.;Paik, I.;Shapiro, T. A.;Posner, G. H.
Int. J. Parasitol. 2002, 32, 1661;(d) Ploypradith, P. Acta
Trop. 2004, 89, 329;(e) O ꢁNeill, P. M.;Posner, G. H. J.
Med. Chem. 2004, 47, 2945.
2. (a) OꢁNeill, P. M.;Pugh, M.;Davies, J.;Ward, S. A.;Park,
B. K. Tetrahedron Lett. 2001, 42, 4569;(b) Bloodworth, A.
J.;Johnson, K. A. Tetrahedron Lett. 1994, 35, 8057;(c)
Bloodworth, A. J.;Shah, A. J. Chem. Soc., Chem.
Commun. 1991, 947;(d) Posner, G. H.;Oh, C. H.;
Milhous, W. K. Tetrahedron Lett. 1991, 32, 4235;(e)
Bunnelle, W. H.;Isbell, T. A.;Barnes, C. L.;Qualls, S. J.
Am. Chem. Soc. 1991, 113, 8168;(f) Avery, M. A.;
Jennings-White, C.;Chong, W. K. M. J. Org. Chem. 1989,
54, 1792;(g) Singh, C. Tetrahedron Lett. 1990, 31, 6901;
(h) Kepler, J. A.;Philip, A.;Lee, Y. W.;Morey, M. C.;
Caroll, F. I. J. Med. Chem. 1988, 31, 713;(i) Jefford, C.
W.;Jaggi, D.;Boukouvalas, J.;Kohmoto, S. J. Am. Chem.
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3. (a) Peters, W.;Robinson, B. L.;Rossier, J. C.;Jefford, C.
W. Ann. Trop. Med. Parasitol. 1993, 87, 1;(b) Posner, G.
H.;Jeon, H. B.;Parker, M. H.;Krasavin, M.;Paik, I.-H.;
Shapiro, T. A. J. Med. Chem. 2001, 44, 3054;(c) Posner,
G. H.;Jeon, H. B.;Polypradith, P.;Paik, I.-H.;Borstnik,
K.;Xie, S.;Shapiro, T. A. J. Med. Chem. 2002, 45, 3824.
4. (a) Singh, C.;Misra, D.;Saxena, G.;Chandra, S. Bioorg.
Med. Chem. Lett. 1992, 2, 497;(b) Singh, C.;Misra, D.;
Saxena, G.;Chandra, S. Bioorg. Med. Chem. Lett. 1995, 5,
1913.
6.39. Trioxane 29
This compound was also prepared by the same proce-
dure described for compound 28 in 89% yield as a white
solid: mp 66–68ꢁC;IR (KBr, cm À1): 1682.0; H NMR
1
(200MHz, CDCl3) d 1.59–2.08 (m, 13H), 2.52 (t, 2H,
J = 7.4Hz), 2.90 (br s, 1H), 3.16 (m, 2H), 3.76 (dd,
1H, J = 11.8, 3.0Hz), 3.98 (dd, 1H, J = 11.8, 10.2Hz),
4.78 (dd, 1H, J = 10.2, 3.0Hz), 5.07 and 5.09 (2 · s,
2H), 7.46 (t, 2H, J = 7.0Hz), 7.57 (t, 1H, J = 7.0Hz),
7.97 (d, 2H, J = 7.0Hz);FAB-MS ( m/z) 369 [M+H]+;
Anal. Calcd for C23H28O4: C, 74.97;H, 7.66. Found:
C, 74.84;H, 7.79.
6.40. 5-Hexyl-2-methyl-2-vinyl-tetrahydro-furan (31)
This was prepared by the same procedure as diol 23a in
62% yield as a colorless oil: IR (neat, cmÀ1) 1641.7; H
1
NMR (200MHz, CDCl3) d 0.80 (t, 3H, J = 6.2Hz), 1.23
(m, 13H), 1.49–1.84 (m, 4H), 3.93–4.01 (m, 1H), 4.96
(dd, 1H, J = 10.6, 1.4Hz), 5.09 and 5.13 (2 · dd, 1H,
J = 17.4, 1.4Hz each), 5.79 and 5.84 (2 · dd, 1H,
J = 17.4, 10.6Hz each); 13C NMR (50MHz, CDCl3): d
14.38 (q), 21.11 (q), 22.96 (t), 26.36 (t), 26.57 (t), 26.96
(q), 27.77 (q), 29.81 (t), 30.29 (t), 31.58 (t), 31.80 (t),
31.92 (t), 32.19 (t), 36.67 (t), 36.85 (t), 37.39 (t), 38.51
5. For preliminary results of this study see: Singh, C.;Gupta,
N.;Puri, S. K. Bioorg. Med. Chem. Lett. 2003, 13, 3447.
6. Dodd, D. S.;Oehlschlager,; A. C.;Georgopapadakou, N.
H.;Polok, A.-M.;Hartman, P. G. J. Org. Chem. 1992, 57,
7226.

5562
C. Singh et al. / Bioorg. Med. Chem. 12 (2004) 5553–5562
11. Jarolim, V.;Sorm, F. Collect. Czech. Chem. Commun.
7. Acid catalyzed cyclization of 2-hexene-1,6-diols to 2-vinyl
tetrahydrofurans is well documented see, for example:
Ohloff, G.;Schulte-Elte, K.-H.;Willhalm, B. Helv. Chim.
Acta 1964, 47, 602.
1976, 41, 1066.
12. For an alternative preparation from aldehyde acetate 22
see: Nakata, T.;Nomura, S.;Matsukara, H. Tetrahedron
Lett. 1996, 37, 213.
13. Gilman, H.;St. John, N. B.;Schulze, F. Org. Synth. Coll.
1943, 2, 425.
8. Ratcliffe, R. W. Org. Synth. 1976, 55, 84–86.
9. Puri, S. K.;Singh, N. Expl. Parasitol. 2000, 94, 8.
10. Bunce, R. A.;Harris, C. R. J. Org. Chem. 1992, 57, 6981.