An unexpected product in the photooxygenation of a cyclic enol ether

Article abstract of DOI:10.1016/S0040-4039(01)01323-5

The photooxygenation product of a cyclic enol ether conjugated with an o-phenylene ring is a novel epoxy compound instead of a 1,2,4-trioxane analogue. The structure of the compound was elucidated by X-ray analysis.

Full text of DOI:10.1016/S0040-4039(01)01323-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6737–6739
An unexpected product in the photooxygenation of a cyclic
enol ether
Jin-Ming Wu and Ying Li*
Department of Synthetic Chemistry, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, Shanghai 200031, China
Received 23 March 2001; revised 12 July 2001; accepted 20 July 2001
Abstract—The photooxygenation product of a cyclic enol ether conjugated with an o-phenylene ring is a novel epoxy compound
instead of a 1,2,4-trioxane analogue. The structure of the compound was elucidated by X-ray analysis. © 2001 Elsevier Science
Ltd. All rights reserved.
Artemisinin and its derivatives are currently used in
clinical practice as effective antimalarial drugs. As the
1,2,4-trioxane ring is considered to be a structural
requirement for significant activity, a number of tri-
cyclic 1,2,4-trioxanes have been prepared as potential
antimalarial agents.1–7 Here, we would like to report a
synthesis aimed at compound 1 and identification of an
unexpected product 2.
5-Bromo-2,2-dioxolane ketal pentane 5 was prepared
in 64% yield from acetylbutyrolactone 3 by nucle-
ophilic substitution–decarboxylation in boiling 34%
HBr solution11 and ketalization with ethyleneglycol in
refluxing benzene solution containing p-TsOH.
Chlorination of o-xylene 6 according to the litera-
ture,12 followed by nucleophilic substitution with
sodium cyanide in refluxing acetonitrile afforded o-
methylbenzyl cyanide 7 in 90% yield.13 The alkylation
of 7 with 5 in the presence of sodium hydride in
Photooxygenation of cyclic enol ethers has been known
as a reliable synthetic method for the transformation of
deoxoartemisinin analogues.8–10 4-(4-Oxo)-pentyl-2-
benzopyran 11 was chosen as a cyclic enol ether which
was expected to yield C-nor-5,10-phenylene ring deoxo-
artemisinin analogue 1 by standard photooxygenation
(Scheme 1).
HMPA provided
8
in 80% yield,14 which was
hydrolyzed in boiling potassium hydroxide/ethylene
glycol solution to give 2-(2-methyl)-phenyl-6-oxo-
hepta-noic acid 9 in 84% yield. Compound 9 was
converted into 10 in 80% yield by bromination with
NBS–benzoyl peroxide–CCl4, cyclization in triethyl-
amine–acetone and ketalization with ethyleneglycol–p-
TsOH in benzene. Reduction of 10 in toluene by
DIBAL-H at −78°C and dehydration in acetone–p-
TsOH at room temperature gave the desired cyclic
enol ether 11 in 57% yield.15 Compound 11 was pho-
tooxygenized in methylene chloride in the presence of
methylene blue at −78°C under a bubbling stream of
oxygen to provide racemic 2 in 30% yield (Scheme
2)16.
It has been demonstrated by NMR, IR and elemental
analysis that compound 2 has a molecular formula of
C14H16O6 and comprises a hydroxyl group, a car-
bonꢀcarbon double bond, a carbonyl and an epoxide
moiety. The proton and carbon chemical shift assign-
ments for compound 2 are shown in Table 1. The
H–H COSY spectrum showed the relative positions of
Scheme 1.
Keywords: epoxy compound; 1,2,4-trioxane; cyclic enol ether; pho-
tooxygenation.
* Corresponding author. Fax: 086-021-64370269; e-mail: yli@
mail.shcnc.ac.cn
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01323-5

6738
J.-M. Wu, Y. Li / Tetrahedron Letters 42 (2001) 6737–6739
Scheme 2. Reagents and conditions: (a) 34% HBr, boiling, 80%; (b) (CH2OH)2, p-TsOH, C6H6, reflux-H2O, 80%; (c) SO2Cl2, BPO,
reflux, 50%; (d) NaCN, PEG-400, CH3CN, reflux, 90%; (e) 50% NaH, 5, HMPA, 80%; (f) KOH, (CH2OH)2, reflux; (g) 10% HCl,
84% from 8; (h) NBS, BPO, CCl4, reflux; (i) Et3N, acetone, rt; (j) (CH2OH)2, p-TsOH, C6H6, reflux-H2O, 80% from 9; (k)
DIBAL-H, toluene, −78°C; (l) acetone, p-TsOH, rt, 57% from 10; (m) methylene blue, O2, hv, CH2Cl2, −78°C; (n) TMSOTf; (o)
Et3N, 30% from 11.
Table 1. Proton and carbon chemical shift assignments for 2
No.
1H (ppm)
13C (ppm)
65.66
No.
1H (ppm)
13C (ppm)
1
1
3
4
4.68 (d, J=12.1 Hz, 1H)
3.51 (d, J=12.1 Hz, 1H)
5.30 (s, 1H)
8
9
191.82
54.89
63.20
33.56
17.03
26.67
112.42
24.34
3.43 (d, J=1.8 Hz, 1H)
99.97
84.60
67.62
10
11
12
13
14
15
1.75 (m, 2H)
1.59 (m, 2H)
1.77 (m, 2H)
5
5-OH
6
7
3.94 (s, 1H)
6.61 (d, J=10.6 Hz, 1H)
5.98 (dd, J=10.6, 1.8 Hz, 1H)
143.01
125.85
1.64 (s, 3H)
H atoms. The relative stereochemistry (Fig. 1) was
finally confirmed by X-ray diffraction analysis.17,18
The novel epoxide 2 shows moderate cytotoxicity
against P388 (IC50 <10−6 mol/L) and other bioactivities
in primary in vitro examinations. Further work is in
progress.18
Acknowledgements
This work was supported by the National Natural
Science Foundation of China (Grant No. 39870899).
We also thank Professor Yu-Lin Wu and Yi-Kan Wu
in the Shanghai Institute of Organic Chemistry, Chi-
nese Academy of Sciences for helpful discussion, and
Professor Jian Ding of this institute for the determina-
tion of cytotoxity.
Figure 1. X-Ray structure of 2.

J.-M. Wu, Y. Li / Tetrahedron Letters 42 (2001) 6737–6739
6739
References
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J=6.8 Hz, 1H), 7.20 (m, 3H), 3.95 (m, 5H), 2.34 (s, 3H),
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1
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1
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17. Single-crystal X-ray analysis of 2 (deposition number
,
CCDC 164721): wavelength 0.71069 A, temperature 293
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14). Crystal size 0.20×0.20×0.30 mm, a=15.149 (5), b=
3
,
,
10.602(1), c=16.274(3) A. Volume=2607(1) A . A total
of 5310 reflections were collected in the range 25 (18.4–
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1
16. Data for 2: mp 146–147°C; H NMR (400 MHz, CDCl3)
l: 6.61 (d, J=10.6 Hz, 1H), 5.98 (dd, J=10.6, 1.8 Hz,
1H), 5.30 (s, 1H), 4.68 (d, J=12.1 Hz, 1H), 3.94 (s, 1H),
3.51 (d, J=12.1 Hz, 1H), 3.43 (d, J=1.8 Hz, 1H), 1.77
(m, 2H), 1.75 (m, 2H), 1.64 (s, 3H), 1.59 (m, 2H); 13C
NMR (100 MHz, CDCl3), l: 191.82, 143.01, 125.85,
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18. The formation of novel epoxide 2 must relate to a quite
different mechanism. At this stage, it is hard to describe
the exact mechanism without any further evidence, but
three oxidations and two intramolecular epoxidations
might be involved (Scheme 3).
Scheme 3.