Photochemical reaction of three dihydroartemisinin esters: acetate, benzoate and succinate under 254 nm UV light in CH2Cl2 have been studied. The result showed, that these artemisinin derivatives are easily decomposed forming different elimination and rearrangement compounds

Sung et al, Tran Van

English

Vietnam Academy of Science and Technology: Journals Online

 
 
 
 
122
Journal of Chemistry, Vol. 47 (1), P. 122 - 126, 2009 
 
Photochemical Reaction of Dihydroartemisinin 
Esters 
Received 26 December 2008 
Tran Duc Quan, Tran Van Sung 
Institute of Chemistry - Vietnam Academy of Science and Technology 
 
abstract 
Photochemical reaction of three dihydroartemisinin esters: acetate, benzoate and succinate 
under 254 nm UV light in CH2Cl2 have been studied. The result showed, that these artemisinin 
derivatives are easily decomposed forming different elimination and rearrangement compounds. 
 
I - Introduction 
Artemisinin (quinghaosu 1) isolated for the 
first time by Chinese scientist from Artemisia 
annua L. [1, 2] showed antimalarial activity. 
Currently artemisinin and its derivatives are 
used for treatment of malaria.  Many works on 
chemistry and pharmacology of artemisinin and 
its derivatives were reported, however the 
photochemistry of which is very few. We 
reported previously the photochemistry of some 
oxoalkyl aldehydes of dihydroartemisinin [3]. 
This work deals with photochemical reactions of 
three dihydroartemisinin esters, e.g. the acetate, 
benzoate and succinate. 
II - Experimental 
The NMR spectra were measured with a 
NMR-500 MHz AVANCE spectrometer at 500 
MHz (1H) and 125 MHz (13C), in CDCl3 at 
Institute of Chemistry-Vietnam Academy of 
Science and Technology, Hanoi. 
1. Synthesis of the starting materials, 
compounds 3-5 
a) Synthesis of Dihydroartemisinin (DHA, 2) [3] 
The synthesis of DHA is described in [3]. 5 
g artemisinin was reacted with NaBH4 in 
anhydrous MeOH at -5oC. The mixture was 
diluted with EtOAc, washed with NaCl 5%, and 
then H2O, dried over Na2SO4, evaporated in 
vacuo and recrystallized in n-hexane/EtOAc. 
After filtration, the obtained product was 
washed with cooled n-hexane/CH2Cl2 mixture, 
and dried at room temperature over night to 
yield 4.88 g dihydroartemisinin (97%). 
b) Synthesis of α-dihydroartemisinin acetate (3) 
[4] 
The reaction mixture of 2.84 g 
dihydroartemisinin, 3 ml pyridine, 0.2 g 4-
dimethylaminopyridine (DMAP) and 2 ml 
acetic anhydride in 70 ml anhydrous CH2Cl2 
was stirred at room temperature about 30 hour, 
(checked by TLC). The reaction mixture was 
washed with HCl 5%; NaHCO3 5% and H2O. 
The organic phase was dried over Na2SO4 
evaporated in vacuo and recrystallized in n-
hexane/CH2Cl2 to yield 3.12 g of 3 (95.7%). 
3: 1H-NMR (500MHz, CDCl3): δ 5,80 (d, J 
= 8.6 Hz, 1H, H12); 5.44 (s, 1H, H5); 2.60 - 
2.52 (m, 1H); 2.41 - 2.35 (m, 1H); 2,13 (s, 3H, 
H2'); 1.44 (s, 3H, H15); 0.97 (d, J = 6.2 Hz, 3H, 
H14); 0.85 (d, J = 7.2 Hz, 3H, H13).  
13C-NMR (125MHz, CDCl3): 169.74 (C1'); 
104.41 (C4); 91.82 (C12); 91.46 (C5); 80.08 
(C6); 51.55 (C1); 45.22 (C7); 37.24 (C10); 
36.20 (C3); 34.07 (C9); 31.73 (C11); 25.94 
 
 
 
 
123
(C15); 24.55 (C2); 21.97 (C8); 21.07 (C2');  20.17 (C14); 12.04 (C13). 
 
O
O
O
O
O
O
O
OH
O
O
3. R = - OCOCH3
4. R = -
5. R = - OCOCH2CH2COOH
1 2
O
O
OCOCH3
O
O h 254nm
CH2Cl2
O
O
OCO(CH2)2COOH
O
O
h 254nm
CH2Cl2
O
O
OCOC6H5
O
O
h 254nm
CH2Cl2
O
O
R
O
O
9. R = - OCH3
2. R = OH
+
5
3
4
O
O
OH
O
O
2
O
OCOC6H5
7
O
O
O+ + C6H5COOH
+ HOOC(CH2)2COOH
8
10
13
1
23
4
5
6 7
8
9
10
11
12
13
14
15
1
2
3
4
5
6 7
8
9
10
11
12
13
14
15
O
O
O
O
6
1
23
4
5
6
7 8
910
1112
13
14
15
O
O
O
O
6
O
O
R
O
O
1
23
4
5 6
7
8
910
1112
13
14
15
O
O
1''
2'' 3''
4''
5''6''
1' 2'
2' 3' 4'1'
1'
O
O
O
O +
1
2
3
4
5
6 7
8
9
10
1112
13
14
15 11   
Schema 1: Photochemical reactions of three dihydroartemisinin esters 
 
b) Synthesis of α-dihydroartemisinin benzoate 
(4) [5] 
Solution of 2.84 g dihydroartemisinin, 3 ml
 pyridine, 0.2 g DMAP and 2.1 g benzoyl 
chloride in 100 ml CH2Cl2. was stirred at room 
temperature about 30 hours, (checked by TLC). 
The mixture was washed with HCl 5%; 
 
 
 
 
124
neutralized with NaHCO3 5% and H2O, dried 
over Na2SO4, evaporated in vacuo and 
recrystallized in n-hexane/CH2Cl2. The crystal 
were filtered, washed with cooled n-
hexane/CH2Cl2 solution, and dried to yield 3.66 
g (94.1%) compound 4. 
4: 1H-NMR (500MHz, CDCl3): δ 8.15 (d, 
J = 7.4 Hz, 2H, phenyl); 7.55 (t, J = 7.4 Hz, 1H, 
phenyl); 7.40 (t, J = 7.4 Hz, 2H, phenyl); 6.0 (d, 
J = 9.8 Hz, 1H, H12); 5.52 (s, 1H, H5); 1.43 (s, 
3H, H15); 0.98 (d, J = 6.2 Hz, 3H, H14); 0.92 
(d, J = 7.2 Hz, 3H, H13). 
13C-NMR (125MHz, CDCl3): 165.24 (C1'); 
133.25 (C1"); 130.07 (C2"; C6"); 129.62 (C4"); 
128.26 (C3"; C5"); 104.37 (C4); 92.50 (C12); 
91.55 (C5); 80.14 (C6); 51.63 (C1); 45.33 (C7); 
37.24 (C10); 36.24 (C3); 34,11 (C9); 31.97 
(C11); 25.92 (C15); 24.56 (C2); 22.03 (C8); 
20.20 (C14); 12.20 (C13). 
c) Synthesis of α-dihydroartemisinin 
succinate (5) 
α-dihydroartemisinin succinate (5) was 
synthesized with the same procedure as for 4 
with the yield of 97.6%. 
5: 1H-NMR (500 MHz, CDCl3): δ 
11,15(s,br, 1H, OH); 5.81 (d, J = 8.7 Hz, 1H, 
H12); 5.44 (s, 1H, H5); 2.76 - 2.64 (m, 4H); 1,4 
(s, 3H, H15); 0.96 (d, J = 6.9 Hz, 3H, H14); 
0.85 (d, J = 7.1 Hz, 3H, H13). 
13C-NMR: (125 MHz, CDCl3): 177,32 (C1'); 
170.69 (C4'); 104.07 (C4); 91.95 (C12); 91.14 
(C5); 79.74 (C6); 51.23 (C1); 44.91 (C7); 36.85 
(C10); 35.90 (C3); 33.78 (C9); 31.46 (C11); 
28.61 (C2'); 28.36 (C3'); 25.53 (C15); 24.25 
(C2); 21.60 (C8); 19.87 (C14); 11.60 (C13). 
2. Photochemical reactions of compounds 3-5 
a) Photochemical reaction of  3 
Solution of 1,5 g 3 in 100 ml anhydrous 
CH2Cl2 in 250 ml quartz round flask, under N2 
was irradiated with a 254 nm fluorescent 15W 
lamp at room temperature for 60 minutes, 
checked by TLC. The reaction mixture was 
evaporated in vacuo and the residue 
chromatographed over silica gel with n-
hexane:CH2Cl2:MeOH (40:15:1) as solvent to 
give 405 mg (27%) dihydroartemisinin 
dehydrate (6).  
6: 1H-NMR (500MHz, CDCl3): δ 6,18 (q, 
J=1.03 Hz, 1H, H12); 5,54 (s, 1H, H5); 1,58 (s, 
3H, H13); 1,42 (s, 3H, H15); 0,98 (d, J=5,9 Hz, 
3H, H14). 
13C-NMR (125MHz, CDCl3): 134.97(C12); 
108.10(C11); 104.52 (C4); 89.66 (C5); 78.94 
(C6); 51.41 (C1); 44.42 (C7); 37.46 (C10); 
36.20 (C3); 34.09 (C9); 29.96 (C8); 25.85 
(C15); 24.39 (C2); 20.27 (C14); 16.17 (C13). 
b) Photochemical reaction of 4 
A solution of 1.94 g dihydroartemisinin 
benzoate (4) in 100 ml anhydrous CH2Cl2 was 
irradiated with a 15W fluorescent lamp (254 
nm, under N2) for about 120 minutes. The 
solution was evaporated under reduced pressure, 
the residue was crystallized in n-hexane/CH2Cl2; 
it yielded after filtration 108 mg (20%) benzoic 
acid (8). The filtrate was evaporated, 
chromatographed over silica gel to give 170 mg 
(12%) dihydroartemisinin (2), 407 mg (21%) of 
dihydoartemisinin G benzoate (7) [6 - 8]. 
7: 1H-NMR (500 MHz, CDCl3): δ 8.08 (d, 
J = 1.1 Hz, 2H, phenyl); 7.55 (t, J = 6.1 Hz, 1H, 
phenyl); 7.40 (t, J = 6.4 Hz, 2H, phenyl); 6.29 
(s. 1H. H5); 6.07 (d, J = 9.6 Hz, 1H, H12); 2.08 
(s, 3H, H15); 0.94 (d, J = 6.3 Hz, 3H, H14); 
0.92 (d, J = 6.7 Hz, 3H, H13). 
13C-NMR (125 MHz, CDCl3): 168.56 (C4); 
164.93 (C1'); 133.29 (C1"); 130.08 (C2"; C6"); 
129.42 (C4"); 128.24 (C3"; C5"); 93.71 (C12); 
91.09 (C5); 80.11 (C6); 68.78 (C3); 54.96 (C1); 
47.29 (C7); 35.41 (C9); 34.04 (C11); 30.39 
(C10); 27.52 (C2); 22,54 (C8); 21.39 (C15); 
20.44 (C14); 12.09 (C13). 
c) Photochemical reaction of 5 
With the same procedure as for compound 
4. 1.92 g dihydoartemisinin succinate (5) was 
irradiated. The irradiation mixture yielded four 
compounds after chromatography: 
dihydoartemisinin (2) 42.8 mg (12%), 
dihydroartemisinin dehydrate 6 199 mg (15%), 
β-artemether (9) 74 mg (5%) and succinic acid 
(10) 118 mg (20%), 
 
 
 
 
125
9:  1H-NMR (500MHz, CDCl3): δ 5.38 (s, 
1H, H5); 4.68 (d, J = 3.36, 1H, H12); 3.42 (s, 
3H, OCH3); 1.44 (s, 3H, H15); 0.95 (d, J = 6.4 
Hz, 3H, H14); 0.90 (d, J = 7.4 Hz, 3H, H13). 
13C-NMR (125 MHz, CDCl3): 104.05 (C4); 
103.37 (C12); 87.77 (C5); 81.10 (C6); 55.93 
(C1'); 52.59 (C1); 44.51 (C7); 37.40 (C10); 
36.46 (C3); 34.64 (C9); 30.91 (C11); 26.18 
(C15); 24.70 (C2); 24.47 (C8); 20.33 (C14); 
12.94 (C13). 
The 1H- and 13C-NMR data of 9 are in 
agreement with [11]. 
III - Results and Discussion 
Dihydroartemisinin (2) was obtained by 
NaBH4 reduction of artemisinin (1) in methanol 
with good yield (> 95% of 1). The 
dihydroartemisinin esters 3, 4 and 5 (α-form) 
were prepared in very high yields by reaction 
between dihydroartemisinin (2) with acetic 
anhydride, benzoyl chloride and succinic
 anhidride, respectively. Interestingly, starting 
from dihydroartemisinin (α:β form ≈ 1:1) we 
received as reaction products only the α-
dihydroartemisinin esters (≥95% yield), which 
were purified by crystallization. The photolysis 
of the esters 3, 4 and 5 has been carried out with 
fluorescent 15W-lamp (254 nm), under N2 - 
atmosphere at room temperature. 
When irradiated in dichloromethane 60 
minutes, the dihydroartemisinin acetate (3) 
afforded the elimination product 6 in 27% yields 
after column chromatography. The formation of 
compound 6 can be happened through an 
elimination of one molecule acetic acid maybe 
by the heat of the UV light. The elimination 
reaction of this type has also been observed 
before on the photolysis of an ether derivative of 
dihydroartemisinin [3]. Compound 6 has been 
obtained as a by-product in the synthesis of 
many dihydro-artemisinin derivatives. The 1H- 
and 13C-NMR spectra of 6 are given in Figs. 1 
and 2. 
  
Figure 1: 1H- NMR of 6 Figure 2: APT- and 13C-NMR of 6 
 
A different, interesting result has been 
obtained by photolysis of dihydroartemisinin 
benzoate under the same condition, but with 
longer irradiation time. Here we received the 
dihydroartemisinin (2) (12%) as isomer mixture, 
the rearrangement compound 7 (21%) and 
benzoic acid. Compound 7 is a derivative of the 
naturally - occurring artemisinin G, the 
dihydroartemisinin G benzoate [8]. Compound 
11 which is similar to 7 has been obtained on 
the photolysis of β-dihydroartemisinyl 
butylaldehyde (254 nm, benzene) [3]. The 
presence of a small amount of 
dihydroartemisinin is probably due to the 
hydrolysis of compound 4 under a trace of water 
in the solvent. The 1H- and 13C-NMR spectra of 
7 are given in Figs. 3 and 4. 
Under the same irradiation condition as for 
compound 4, the artesunate (dihydro-
artemisinin monosuccinate 5) yielded after 
chromatography on silica gel the elimination 
product 6 (15%), dihydroartemisinin (2, isomer 
 
 
 
 
126
Figure 3: 1H- NMR of 7 Figure 4: 
13C-NMR of 7 
 
mixture), β-artemether (9) and succinic acid. 
Similarly as for compound 4, it maybe happened 
here also a hydrolysis of 5 under trace of water 
in the solvent to yield dihydroartemisinin, which 
again insitu reacts with a trace of methanol to 
give artemether. Irradiation of 5 in methanol as 
solvent afforded the same results. 
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Photochemical Reaction of ihydroartemisinin esters

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Photochemical Reaction of ihydroartemisinin esters

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