Photooxygenation of 3-aryl-2-cyclohexenols: Synthesis of a new series of antimalarial 1,2,4-trioxanes

Article abstract of DOI:10.1016/j.tetlet.2004.11.078

Using easily accessible 3-aryl-2-cyclohexenols, a photooxygenation route for the preparation of bicyclic 1,2,4-trioxanes is reported. Several of these trioxanes have shown significant antimalarial activity against multidrug resistant Plasmodium yoelii in

Full text of DOI:10.1016/j.tetlet.2004.11.078

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 205–207
Photooxygenation of 3-aryl-2-cyclohexenols: synthesis of a
new series of antimalarial 1,2,4-trioxanesq
Chandan Singh,a,* Nitin Guptaa and Sunil K. Purib
aDivision of Medicinal & Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
bDivision of Parasitology, Central Drug Research Institute, Lucknow 226001, India
Received 27 September 2004; revised 11 November 2004; accepted 16 November 2004
Available online 30 November 2004
Abstract—Using easily accessible 3-aryl-2-cyclohexenols, a photooxygenation route for the preparation of bicyclic 1,2,4-trioxanes is
reported. Several of these trioxanes have shown significant antimalarial activity against multidrug resistant Plasmodium yoelii in
mice by the oral route.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Artemisinin 1, since its isolation and characterization in
the early 1970s from Artemisia annua, has been a subject
of much investigation, not only due to its unique struc-
ture but also because of its potent antimalarial activity.1
With the establishment of 1,2,4-trioxane as the antima-
larial pharmacophore of artemisinin, various successful
attempts have been made to prepare derivatives1 as well
as simple 1,2,4-trioxanes with varying orders of antima-
larial activity.2,3
hydroperoxides with aldehydes or ketones are the key
steps of this method (Scheme 1). Several monocyclic
1,2,4-trioxanes prepared using this procedure have
shown promising antimalarial activity in vitro and in
vivo.4
Using easily accessible 3-aryl-2-cyclohexenols we have
explored the scope of this photooxygenation route for
the preparation of bicyclic 1,2,4-trioxanes and report
herein the synthesis of a new series of 1,2,4-trioxanes
some of which show significant antimalarial activity
against multidrug resistant Plasmodium yoelii in mice
by the oral route. There are only a few reports on pho-
tooxygenation of allylic cyclohexenols,5 and the hydro-
peroxides were isolated only in one study.5c This is the
first report on the synthesis of trioxanes using b-hydroxy-
hydroperoxides derived from photooxygenation of
cyclohexenols.
H
O
O
O
H
O
O
1
3-Aryl-2-cyclohexenones 5a–c, prepared by a literature
procedure,6 were reduced with NaBH4 in MeOH or
As a part of our endeavour to develop structurally sim-
ple synthetic substitutes of artemisinin, we earlier devel-
oped a new, convenient and high yielding method for
the preparation of 1,2,4-trioxanes.2h Preparation of b-
hydroxyhydroperoxides by photooxygenation of allylic
alcohols and the acid-catalyzed condensation of the
1O2
O
OH
OH
R
OH
R
R1
R1
2
3
R2
R3
H+
2'
1
2
O
O
O
R2
R3
3
6
Keywords:
Plasmodium yoelii.
q CDRI Communication No: 6658.
Antimalarial;
1,2,4-Trioxane;
Photooxygenation;
R
1'
R1
O
4
5
4
*
Corresponding author. Tel.: +91 522 2624273; fax: +91 522
2623405; e-mail: chandancdri@yahoo.com
Scheme 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.078

206
C. Singh et al. / Tetrahedron Letters 46 (2005) 205–207
CH2Cl2–MeOH (2:1) to yield 3-aryl-2-cyclohexenols 6a–
c in 95–98% yields. No double-bond reduction was
observed under these conditions.7 Methylene blue sensi-
tized photooxygenation of these 3-aryl-2-cyclohexenols
6a–c in MeCN gave 2-hydroperoxy-3-aryl-3-cyclohex-
enols 7a–c in 22–35% yields. Hydroperoxides 7a–c on
acid catalyzed condensation with acetone furnished tri-
oxanes 8a–c in 25–37% yields.8,9 Similar condensation
with benzaldehyde, cyclopentanone, cyclohexanone,
cycloheptanone and 2-adamantanone furnished triox-
anes 9a–c, 10a–c, 11a–c, 12a–c and 13a–c in 28–37%,
16–26%, 19–21%, 12–16% and 17–24% yields, respec-
tively9 (Scheme 2).
Ph
Ph
HO
HO
H
H
H
O
O
O
O
O
H
O
(a)
H
8a
14
2
1
O
6
PhOC
5
O
O
(b)
O
4
3
H
H
15
Scheme 3. Reagents and conditions: (a) OsO4 (cat.), 70% TBHP,
Et3BnNOAc, Me2CO, rt, 2d, 64%; (b) Pb(OAc)4, PhH, rt, stir, 1h,
84%.
Though formation of both cis and trans fused trioxanes
Table 1. In vivo antimalarial activity results of trioxanes against
Plasmodium yoelii in mice by the oral routea
is possible, all the trioxanes isolated appeared to be
1
13
single isomers by H and C NMR.9 Also based on
coupling constants it was not possible to assign
unambiguously the stereochemistry. So an indirect ap-
proach was adopted. Thus trioxane 8a was treated with
catalytic OsO4 and 70% t-butyl hydroperoxide (TBHP)
in the presence of triethylbenzylammonium acetate
(Et3BnNOAc) to give diol 14.10 This diol appeared as
a mixture of two isomers on TLC but homogeneous
Compound
Dose (mg/kg/day)
% Suppression on day 4b
10c
11c
96
96
96
96
48
96.2
98.5
12c
13b
100.0
96.3
100.0
b-Arteether
a See Ref. 11.
b Percent suppression = [(C À T)/C] · 100; where C = parasitaemia in
1
1
by H NMR. In the H NMR spectrum of 14 H-8a ap-
peared as a doublet at 4.19ppm with J = 9.4Hz, indicat-
ing that the stereochemistry at the ring junction is trans.
This was further confirmed by Pb(OAc)4 mediated
cleavage of trioxane 14 to monocyclic trioxane 15. In
the 1H NMR spectrum of 15 H-6 appeared as a doublet
at 5.20ppm with J = 9.6Hz, confirming the trans stereo-
chemistry. Since NMR spectra of all the trioxanes were
similar it is assumed that the stereochemistry at the ring
junction in all these trioxanes is trans. Also the 1H NMR
spectra of these trioxanes deserves further comments. In
the 1H NMR spectrum of 8a (as well as all the other tri-
oxanes), although signals for each proton were easily as-
signed, most of the signals appeared as multiplets and
H-8a in particular gave rise to a very complex pattern.
Thus H-8a which would be expected to be either a dou-
blet (coupling with only H-4a) or at the most a doublet
of doublets (direct coupling with H-4a and allylic cou-
pling with H-7) appeared as a seven-line pattern. The
2D NMR (1H–1H COSY) spectrum of 8a revealed that
H-8a was not only coupling with H-4a and H-7, but also
with the C-6 protons (Scheme 3).
the control group, and T = parasitaemia in the treated group.
These trioxanes were subjected to in vivo antimalarial
activity against multidrug-resistant P. yoelii in mice at
a dose of 96mg/kg by the oral route.11 Trioxanes 10c,
11c, 12c and 13b showed more than 95% suppression
of parasitaemia at this dose (Table 1). As can be seen
in Table 1, trioxane 12c was the most active of the series.
It shows complete suppression of parasitaemia on day 4.
In conclusion, we have developed a photooxygenation
route for the preparation of trans-fused bicyclic 1,2,4-
trioxanes. Stereoselective photooxygenation of 3-aryl-
2-cyclohexenols and acid catalyzed condensation of
trans-2-hydroperoxy-3-aryl-3-cyclohexenols with alde-
hydes and ketones are the key steps of this method. Sev-
eral new trioxanes prepared by this method have shown
significant antimalarial activity against multidrug resis-
tant P. yoelii in mice by the oral route.
Acknowledgements
Ar
Ar
Ar
O
(a)
(c)
(b)
OH
OH
Nitin Gupta is grateful to the Council of Scientific and
Industrial Research (CSIR), New Delhi for the award
of Senior Research Fellowship.
O
H
OH
Ar
7a-c
5a-c
6a-c
Ar
Ar
1
O
H
H
H
8
O2
3
R2
O
O
O
O
7
6
O
8a
R1
4aO
O
References and notes
5
H
H
4
n
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13a-c
a, Ar=Ph; b, Ar=4-ClC6H4; c, Ar=4-PhC6H4
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C. Singh et al. / Tetrahedron Letters 46 (2005) 205–207
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4.36 (m, 1H), 4.82 (m, 1H), 6.18 (t, 1H, J = 3.4Hz), 7.32
(m, 5H), 8.43 (br s, 1H, OOH); FAB-MS (m/z) 207
[M+H]+. Trioxane 8a: mp 88–89ꢁC; IR (KBr, cmÀ1) 1605;
1H NMR (200MHz, CDCl3): d 1.40 (s, 3H), 1.66 (s, 3H),
1.76–1.98 (m, 2H), 2.40 (m, 2H), 4.18 (m, 1H), 5.15 (m,
1H), 5.89 (m, 1H), 7.21–7.36 (m, 5H); 13C NMR (50MHz,
CDCl3): d 21.14 (q), 25.21 (t), 25.85 (t), 26.41 (q), 70.67
(d), 82.76 (d), 104.67 (s) 127.13 (2 · d), 127.76 (d), 128.52
(3 · d), 135.03 (s), 137.05 (s); FAB-MS (m/z) 247 [M+H]+;
HR EIMS (m/z) calcd for C22H26O3 246.1256 (M)+, found
246.1263. Trioxane 9a: mp 135–136ꢁC; IR (KBr, cmÀ1
)
1
1597; H NMR (200MHz, CDCl3): d 2.01–2.17 (m, 2H),
2.47 (m, 2H), 4.16 (m, 1H), 5.42 (m, 1H), 5.95 (m, 1H),
6.31 (s, 1H), 7.23–7.40 (m, 8H), 7.49–7.54 (m, 2H); 13C
NMR (50MHz, CDCl3): d 25.24 (t), 25.55 (t), 77.90 (d),
82.61 (d), 105.70 (d) 127.22 (2 · d), 127.46 (2 · d), 127.87
(d), 128.81 (2 · d), 128.87 (3 · d), 130.39 (d), 134.56 (s),
134.86 (s), 136.94 (s); FAB-MS (m/z) 295 [M+H]+.
Trioxane 11a: IR (neat, cmÀ1
)
1600; 1H NMR
(200MHz, CDCl3): d 1.46–1.65 (m, 9H), 1.75–1.99 (m,
2H), 2.24–2.45 (m, 3H), 4.22 (m, 1H), 5.17 (m, 1H), 5.88
(m, 1H), 7.30 (m, 5H); 13C NMR (50MHz, CDCl3): d
22.71 (t), 22.82 (t), 25.24 (t), 25.95 (t), 25.99 (t), 29.90 (t),
35.72 (t), 69.78 (d), 82.93 (d), 104.88 (s), 127.10 (2 · d),
127.71 (d), 128.54 (3 · d), 135.19 (s), 137.15 (s); FAB-MS
(m/z) 287 [M+H]+. Trioxane 13a: mp 138–140ꢁC;
IR (KBr, cmÀ1) 1604; 1H NMR (200MHz, CDCl3): d
1.55–2.19 (m, 15H), 2.40 (m, 2H), 2.97 (br s, 1H), 4.18 (m,
1H), 5.18 (m, 1H), 5.88 (m, 1H), 7.30 (m, 5H); 13C NMR
(50MHz, CDCl3) 25.30 (t), 26.03 (t), 27.65 (2 · d), 30.08
(d), 33.48 (t), 33.74 (t), 33.81 (t), 34.11 (t), 37.18 (d), 37.66
(t), 69.18 (d), 82.81 (d), 106.91 (s), 127.10 (2 · d), 127.67
(d), 128.56 (2d), 128.66 (d), 135.35 (s), 137.28 (s); FAB-MS
(m/z) 339 [M+H]+; HR EIMS (m/z) calcd for C22H26O3
338.1882 (M)+, found 338.1851. Trioxane 14: mp 146–
148ꢁC; 1H NMR (200MHz, CDCl3) d 1.32 (s, 3H), 1.67 (s,
3H), 1.69–2.10 (m, 4H), 2.68 (s, 1H, OH), 3.90 (dd, 1H,
J = 10.6, 4.8Hz), 4.19 (d, 1H, J = 9.4Hz), 4.47 (ddd, 1H,
J = 11.2, 9.4, 4.2Hz), 7.30–7.51 (m, 5H); 1H NMR
(200MHz, CDCl3/D2O): d 1.32 (s, 3H), 1.67 (s, 3H),
1.69–2.10 (m, 4H), 3.90 (dd, 1H, J = 10.6, 4.8Hz), 4.19 (d,
1H, J = 9.4Hz), 4.47 (ddd, 1H, J = 11.2, 9.4, 4.2Hz), 7.30–
7.51 (m, 5H); FAB-MS (m/z) 281 [M+H]+. Trioxane 15:
IR (neat, cmÀ1) 1688; 1H NMR (300MHz, CDCl3): d 1.40
(s, 3H), 1.64 (s, 3H), 1.69–1.96 (m, 2H), 2.61 (m, 2H), 4.40
(td, 1H, Jt = 9.6Hz, Jd = 3.0Hz), 5.20 (d, 1H, J = 9.6Hz),
7.50 (t, 2H, J = 7.2Hz), 7.63 (t, 1H, J = 7.2Hz), 8.05 (d,
2H, J = 7.2Hz), 9.76 (t, 1H, J = 1.2Hz); FAB-MS (m/z)
279 [M+H]+.
10. A slight modification of the SharplessÕ procedure was
used: Akashi, K.; Palermo, R. E.; Sharpless, K. B. J. Org.
Chem. 1978, 43, 2063–2066.
11. The in vivo efficacy of compounds was evaluated against
Plasmodium yoelii (MDR) in the Swiss mice model. The
colony of bred Swiss mice (25 1g) were inoculated with
1 · 106 parasitized RBC on day zero and treatment was
administered to a group of five mice at each dose, from
day 0 to 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) in 0.1mL and administered orally for each dose.
Parasitaemia level were recorded from thin blood smears
between days 4–28.12 Mice treated with b-arteether served
as a positive control.
8. Typical procedure for the preparation of trioxanes: To a
precooled solution (0ꢁC) of hydroperoxide (7a–c, 1equiv)
and aldehyde or ketone (5–6equiv) in CH2Cl2 was added
concentrated HCl (4–5 drops) and the solution stirred at
0ꢁC for 3–6h. The reaction mixture was poured over satd
aq NaHCO3 and extracted with CH2Cl2. Standard
workup gave the crude trioxane, which was chromato-
graphed over silica gel (60–120 mesh) using EtOAc–
hexane (1:99) as eluent to furnish the pure trioxane.
9. Selected characteristic data. Hydroperoxide 7a: IR (neat,
cmÀ1) 3354; 1H NMR (200MHz, CDCl3): d 1.70–1.88 (m,
1H), 1.95–2.09 (m, 1H), 2.30 (m, 2H), 2.60 (br s, 1H, OH),
12. Puri, S. K.; Singh, N. Exp. Parasit. 2000, 94, 8–14.