New method for the synthesis of ether derivatives of artemisinin

Article abstract of DOI:10.1080/00397911.2010.538887

Dihydroartemisinin can be converted to its ether derivatives in good yields by reaction with different alcohols in the presence of a catalytic amount of dodecatungstophosphoric acid hydrate. Easy handling, trouble-free workup by filtration, excellent yields, and very short reaction times are some of the highlights of this protocol. Copyright Taylor & Francis Group, LLC.

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New Method for the Synthesis of Ether
Derivatives of Artemisinin
Pranjal P. Bora a , Nabajyoti Baruah a , Ghanashyam Bez a & Nabin C.
Barua b
a Department of Chemistry, North Eastern Hill University, Shillong,
India
b Natural Product Chemistry Division, North Eastern Institute of
Science and Technology, Jorhat, India
Accepted author version posted online: 07 Oct 2011. Version of
record first published: 22 Dec 2011
To cite this article: Pranjal P. Bora, Nabajyoti Baruah, Ghanashyam Bez & Nabin C. Barua (2012):
New Method for the Synthesis of Ether Derivatives of Artemisinin, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:8, 1218-1225
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Synthetic Communications1, 42: 1218–1225, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.538887
NEW METHOD FOR THE SYNTHESIS OF ETHER
DERIVATIVES OF ARTEMISININ
Pranjal P. Bora,1 Nabajyoti Baruah,1 Ghanashyam Bez,1 and
Nabin C. Barua2
1Department of Chemistry, North Eastern Hill University, Shillong, India
2Natural Product Chemistry Division, North Eastern Institute of Science and
Technology, Jorhat, India
GRAPHICAL ABSTRACT
Abstract Dihydroartemisinin can be converted to its ether derivatives in good yields by reac-
tion with different alcohols in the presence of a catalytic amount of dodecatungstophospho-
ric acid hydrate. Easy handling, trouble-free workup by filtration, excellent yields, and very
short reaction times are some of the highlights of this protocol.
Keywords Antimalarial; dihydroartemisinin; dodecatungstophosphoric acid; ether
INTRODUCTION
In the world of drug development, derivatization of medicinally important
natural products remains a challenging but rewarding endeavor for the synthetic
chemist.[1] Derivatization of any drug molecule requires mild yet efficient protocols,
such that an attempt to introduce new functionality does not affect the pharmaco-
phore. Artemisinin 1, a clinically useful antimalarial agent isolated from the Chinese
traditional medicinal plant Artemisia annua, has drawn tremendous attention from
both chemists and pharmacologists because of its low toxicity and proven antimalar-
ial activity.[2] However, its practical utility is impaired by (i) low solubility in both oil
and water,[3] (ii) short plasma half-life,[4] and (iii) the high rate of recrudescence in
treated patients.[5] Chemical modification has resulted in improved analogs arte-
mether 2a and arteether 2b,[6] which are active against both chloroquine-sensitive
Received June 4, 2010.
Address correspondence to Ghanashyam Bez, Department of Chemistry, North Eastern Hill
University, Shillong 793022, India. E-mail: bez@nehu.ac.in
1218

ETHER DERIVATIVES OF ARTEMISININ
1219
and chloroquine-resistant P. falciparum and are used clinically for the treatment of
cerebral malaria (Figure 1).
The ether derivatives of artemisinin are usually synthesized from dihydroarte-
misinin 2 by reaction with the desired alcohol in the presence of acid catalysts such as
HCl,[7] para-toluenesulfonic acid (PTSA),[8] BF3 ꢀ Et2O,[9] or Me3SiCl,[10] but all these
catalysts have very long reaction times and require aqueous workup. BF3 ꢀ Et2O[9] or
Me3SiCl[10] has the additional drawback of moisture sensitivity. In a bid to synthe-
size ether derivatives directly from artemisinin, Singh et al.[11] carried out the
reduction of artemisinin and subsequent etherification in one pot in the presence
of a catalytic amount of Amberlyst-15 to achieve good yields, but results of this
method in large-scale synthesis remain to be seen.
In recent years, organic reactions catalyzed by cheap, operationally simple, and
environmentally friendly catalyst have become desirable to meet environmentally
friendly challenges. Industries prefer reaction protocols that give the product just
by filtration with no aqueous workup using hazardous organic solvents. Heteropoly
acids[12] are such catalysts and are finding enormous applications for acid-catalyzed
reactions. Their noncorrosive and environmentally compatible properties (as com-
pared to the mineral acids), high structural and thermal stability, and well-defined
redox and acidic properties make them unique among the acid catalysts. Neverthe-
less, they give fewer side reactions as compared to mineral acids, are recyclable,
and can be equally effective both in homogeneous as well as in heterogeneous systems.
Here, we are reporting an efficient method for conversion of dihydroartemisinin 2 to
its ether derivatives by reaction with corresponding alcohols in the presence of a cata-
lytic amount of dodecatungstophosphoric acid hydrate, a heteropoly acid (Scheme 1).
Initially, we added 1.25 equiv. of methanol to a solution of dihydroarte-
misinin[9b] in dichloromethane and stirred it at rt in the presence of 0.10 equiv. of
dodecatungstophosphoric acid hydrate. Upon monitoring with thin-layer chromato-
graphy (TLC), it was observed that no starting material was left after 3 h and two
less-polar products were formed. The reaction mixture was filtered through ordinary
filter paper, and the filtrate was concentrated under reduced pressure to get the crude.
Chromatographic separation gave the products in a 1:3 ratio of a- and b-isomers of
artemether[11] with quantitative overall yields. Having obtained this highly anti-
cipated and encouraging result, we wanted to try out the same reaction in non-
halogenated solvents. As evident from the results shown in Table 1, to our
dismay, it is clear that the reaction works best when CH2Cl2 is used as the reaction
Figure 1. Artemisinin derivatives.

1220
P. P. BORA ET AL.
Scheme 1. Synthesis of ether derivatives.
medium. In almost all the other nonhalogenated solvents, the reaction did not go to
completion and unreacted starting material was recovered even after running the
reactions up to 72 h.
Then we wanted to optimize the amount of catalyst required for the reaction.
The reaction took almost the same time when 0.05 equiv. of the catalyst was used,
but lowering the amount of catalyst to 0.03 equiv. resulted in complete conversion
after 5 h. The same catalyst can be used twice without losing any catalytic activity,
but use of the recovered catalyst for a third time resulted in longer reaction time
and poor reactivity. We could achieve only 72% yield of the product by using the
catalyst after the second recovery and unreacted starting material was observed even
after 10 h.
Having optimized different parameters such as the substrate catalyst ratio,
solvent, and reaction time, we wanted to explore the efficacy of our catalyst for syn-
thesis of other ether derivatives of artemisinin (Table 2). Because artemisinin is
known for its poor solubility in lipid, we wanted to see the efficiency of our protocol
for the formation of ethers having long hydrocarbon chains, which may impart
better lipophilicity and hence improve the antimalarial activity. It was heartening
to observe that the reactions (entries 3–6) went to completion in shorter times for
long-chain alcohols. As the ether derivatives of dihydroartemisinin are believed to
generate neurotoxin dihydroartemisinin under physiological conditions, we planned
to synthesize benzyl ethers of dihydroartemisinin (DHA) that may offer stability
against the cleavage of ether bond and reduce the formation of DHA.[13] They are
more selective toward the formation of the b-isomer and take almost the same time
to generate their ether derivatives with DHA (entries 12–16) in excellent yields. It has
Table 1. Optimization of solvent for synthesis of artemether from
dihydroartemisinina
Solvent
Temp. (ꢁC)
Time (h)
Yield (%)b
Diethyl ether
Tetrahydrofuran
Acetonitrile
25
25
25
25
25
72
48
72
48
72
58
77
53
71
48
1,2-Dimethoxyethane
Dioxane
a10 mol% of the catalyst was used.
bUnreacted starting materials were recovered.

ETHER DERIVATIVES OF ARTEMISININ
1221
Table 2. Etherification of DHA via Scheme 1a
Entry
Substrate
Product
Time (h)
Yieldb (%) (a=b)
1
2
3
4
5
MeOH
EtOH
2a
2b
2c
2d
2e
3
6
99 (1=3)
98 (1=3)
97 (1=2)
91 (1=2.5)
89 (1=2)
CH3(CH2)6CH2OH
CH3(CH2)10CH2OH
CH3(CH2)14CH2OH
1
1.2
1.5
6
2f
2
90 (1=3)
7
8
PhCH2CH2OH
Cholesterol
Propergyl alcohol
2g
2h
2i
3
5
98 (1=3)
88 (0=1)
95 (1=3)
92 (1=2)
92 (1=2)
98 (1=2.5)
92 (0=1)
9
1.5
1.5
2.5
3
=
CH2 CHCH2OH
10
11
12
13
2j
Cinnamyl alcohol
PhCH2OH
p-MeOC6H4CH2OH
2k
2l
2m
3
14
2n
3
93 (0=1)
15
16
p-ClC6H4CH2OH
p-NO2C6H4CH2OH
2o
2p
3
3
88 (1=3)
86 (1=3)
aConditions: dihydroartemisinin=alcohol=H3PW12O40.xH2O ¼ 1:1.25:0.05 CH2Cl2, rt.
bIsolated yield.
been observed that methoxy (entry 13) and methylenedioxy (entry 14) groups are
unaffected under this reaction condition. The presence of the methoxy group in
the ether derivative could be confirmed from the singlet integrating to three protons
1
at d 3.78 ppm in its H NMR spectra, while the existence of the methylenedioxy
group was evident from the singlet integrating to two protons at d 5.95 ppm. Inter-
estingly, the benzyl groups having methoxy and methylenedioxy groups showed
selective formation of only the b-isomers, as evident from their J values of the
1
protons on C-10 in the H NMR spectra. The presence of a doublet at d 4.88ppm
in 10b-[(4=-methoxyphenyl)methoxy]dihydroartemisinin (entry 14) with J ¼ 3.2 Hz
integrating one proton suggests the formation of a b-derivative, while a doublet
integrating to one proton at d 5.39ppm with J ¼ 3.5 Hz showed the formation of a
b-derivative of anisyl ether of DHA (entry 13). We could not find any explanation
to justify the experimental findings that favor b-selectivity of the aforementioned
compounds. p-Chloro- and p-nitro substituted benzyl ethers (entries 15 and 16)
showed the only preferential formation of the b-isomers to the a-isomers.
CONCLUSION
To sum up, we have demonstrated a simple and efficient method for the
synthesis of ether derivative of artemisinin catalyzed by dodecatungstophosphoric
acid, a heteropoly acid. As simple filtration is enough to remove the catalyst
and hence quench the reaction rather than the generally used aqueous workup,
the protocol may find application in large-scale synthesis of ether derivatives of
artemisinin.

1222
P. P. BORA ET AL.
EXPERIMENTAL
The dihydroartemisinin and the substituted benzyl alcohols were synthesized
by reduction of artemisinin and the substituted benzaldehydes with sodium borohy-
dride in methanol. Dodecaphosphotungstic acid was purchased from Sigma-
Aldrichs Chemicals Pvt. Ltd. and were used without any processing. 1H NMR
and 13C NMR spectra were recorded in CDCl3 on Brucker DRX 400 NMR
machines with tetramethylsilane (TMS) as internal standard while infrared (IR)
spectra (Perkin-Elmer) were recorded as thin films unless otherwise stated.
Phosphotungstic acid hydrate (0.253 g, 0.05 eqiuv) was added to a solution of
dihydroartemisinin (0.5 g, 1.76 mmol) in dry DCM (20 ml), and the reaction mixture
was stirred at room temperature for 5 min. To the mixture, MeOH (70 mg,
2.18 mmol, 1.25 equiv.) was added, and the reaction mixture was further stirred
for 3 h. The catalyst was removed by filtration, the filtrate was concentrated, and
the crude product was chromatographed by TLC to obtain 0.52 g of artemether
(1.74 mmol, 99% yield) with a- and b-isomers isolated in a 1:3 ratio (26% a-isomer
and 73% b-isomer).
1H and 13C NMR Data of Selected Compounds
10a-(Non-8-enyloxy)dihydroartemisinin, a-2f. 1H NMR (400 MHz,
CDCl3): d 0.84 (d, J ¼ 6.8 Hz, 3H), 0.91 (d, J ¼ 6.0 Hz, 3H) 1.19–1.74 (m, 17H), 1.42
(s, 3H), 1.81–1.87 (m, 1H), 1.95–2.01 (m, 3H), 2.29–2.41 (m, 3H), 3.35 (m, 1H), 3.91
(m, 1H), 4.76 (d, J ¼ 9.2 Hz, 1H), 4.92 (m, 2H), 5.29 (s, 1H), 5.77 (m, 1H) ppm.
13C NMR (100 MHz, CDCl3): d 12.6, 20.2, 24.4, 24.7, 25.9, 26.0, 28.8, 29.0, 29.3,
29.4, 29.5, 32.6, 33.8, 34.3, 36.3, 37.3, 45.3, 51.6, 69.2, 80.3, 91.1, 101.0, 104.2,
114.1, 139.2 ppm.
10b-(Non-8-enyloxy)dihydroartemisinin, b-2f. 1H NMR (400 MHz,
CDCl3): d 0.86 (d, J ¼ 6.8 Hz, 3H), 0.91 (d, J ¼ 6.4 Hz, 3H) 1.21–1.89 (m, 16H),
1.45 (s, 3H), 1.95–2.07 (m, 4H), 2.25–2.45 (m, 3H), 2.53–2.66 (m, 1H), 3.35 (m,
1H), 3.81 (m, 1H), 4.76 (d, J ¼ 3.2 Hz, 1H), 4.95 (m, 2H), 5.37 (s, 1H), 5.78 (m, 1H)
ppm. 13C NMR (100 MHz, CDCl3): d 13.0, 20.3, 24.4, 24.6, 26.2, 26.2, 28.9, 29.0,
29.2, 29.4, 29.6, 30.9, 33.8, 34.6, 36.4, 37.4, 44.4, 52.5, 68.4, 81.1, 87.8, 101.9, 104.0,
114.1, 139.1 ppm.
10a-(Prop-2-ynyloxy)dihydroartemisinin, a-2i. 1H NMR (400 MHz,
CDCl3): d 0.90 (d, J ¼ 6.8 Hz, 3H), 0.96 (d, J ¼ 6.0 Hz, 3H), 0.98–1.05 (m, 1H),
1.23–1.61 (m, 5H), 1.44 (s, 3H), 1.68–2.05 (m, 4H), 2.34–2.45 (m, 3H), 4.39 (dd,
J ¼ 16, 2.4 Hz, 1H), 4.56 (dd, J ¼ 16, 2.0 Hz, 1H), 4.69 (d, J ¼ 9.2 Hz, 1H), 5.35
(s, 1H) ppm. 13C NMR (100 MHz, CDCl3): d 12.4, 20.3, 22.2, 24.6, 29.7, 32.3, 34.2,
36.2, 37.3, 45.4, 51.5, 55.0, 74.2, 79.6, 80.3, 91.2, 97.5, 104.3 ppm.
10b-(Prop-2-ynyloxy)dihydroartemisinin, b-2i. 1H NMR (400 MHz,
CDCl3): d 0.93 (d, J ¼ 7.4 Hz, 3H), 0.95 (d, J ¼ 6.8 Hz, 3H), 1.20–1.54 (m, 1H),
1.23–1.61 (m, 4H), 1.44 (s, 3H), 1.62–2.06 (m, 4H), 2.33–2.41 (m, 3H), 2.63–2.69 (m,
1H), 4.31 (d, J ¼ 2.0 Hz, 2H), 4.98 (d, J ¼ 3.2 Hz,1H), 5.41 (s, 1H) ppm. 13C NMR
(100 MHz, CDCl3): d 12.8, 20.3, 24.4, 24.6, 25.8, 26.1, 30.5, 34.5, 36.3, 37.3, 44.3,
52.5, 54.9, 73.9, 79.7, 81.0, 88.0, 100.5, 104.1 ppm.

ETHER DERIVATIVES OF ARTEMISININ
1223
10b-[(4’-Methoxyphenyl)methoxy]dihydroartemisinin, b-2m. 1H NMR
(400 MHz, CDCl3): d 0.98 (d, J ¼ 6.0 Hz, 3H), 1.04 (d, J ¼ 7.5 Hz, 3H), 0.97–1.05
(m, 1H), 1.44 (s, 3H), 1.28–1.73 (m, 5H), 1.87–2.09 (m, 4H), 2.35–2.45 (m, 1H),
2.74–2.84 (m, 1H), 3.78 (s, 3H), 4.48 (d, J ¼ 12.4 Hz, 1H), 4.86 (d, J ¼ 12.4 Hz,
1H), 5.39 (d, J ¼ 3.5 Hz, 1H), 5.55 (s, 1H), 6.80–7.09 (m, 4H) ppm. 13C NMR
(100 MHz, CDCl3): d 12.9, 20.2, 24.3, 24.6, 26.0, 31.0, 34.5, 36.3, 37.3, 44.4, 52.5,
55.6, 80.9, 88.0, 101.5, 104.1, 114.5, 118.0, 151.6, 154.6 ppm.
10b-[(2’,3’-Methylenedioxy)phenyl)methoxy]dihydroartemisinin, b-2n.
1H NMR (400 MHz, CDCl3): d 0.91–0.95 (m, 6H), 1.23–1.34 (m, 1H), 1.45 (s,
3H), 1.40–1.93 (m, 5H), 2.01–2.06 (m, 4H), 2.34–2.38 (m, 1H), 2.64–2.70 (m, 1H),
4.42 (d, J ¼ 12.0 Hz, 1H), 4.78 (d, J ¼ 12.0 Hz, 1H), 4.88 (d, J ¼ 3.2 Hz, 1H), 5.45
(s, 1H), 5.95 (s, 2H), 6.77 (m, 2H), 6.81 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3):
d 13.0, 20.3, 24.5, 24.6, 26.2, 30.8, 34.5, 36.4, 37.3, 44.3, 52.5, 69.5, 81.1, 88.0, 100.9,
101.0, 104.1, 108.0, 108.0, 120.8, 132.1, 146.8, 147.5 ppm.
10b-[(4’-Chlorophenyl)methoxy]dihydroartemisinin, b-2o. 1H NMR
(400 MHz, CDCl3): d 0.91–0.95 (m, 6H), 1.22–1.34 (m, 1H), 1.45 (s, 3H),
1.42–1.91 (m, 5H), 2.01–2.07 (m, 4H), 2.34–2.42 (m, 1H), 2.65–2.69 (m, 1H), 4.48
(d, J ¼ 12.4 Hz, 1H), 4.86 (d, J ¼ 12.4 Hz, 1H), 4.89 (d, J ¼ 3.6 Hz, 1H), 5.44 (s,
1H), 7.23–7.31 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): d 13.0, 20.3, 24.5,
24.6, 26.1, 30.8, 34.5, 36.3, 37.4, 44.3, 52.5, 68.9, 81.1, 88.0, 101.3, 104.1, 128.4,
128.5, 133.1, 136.8 ppm.
10a-[(4’-Chlorophenyl)methoxy]dihydroartemisinin, a-2o. 1H NMR
(400 MHz, CDCl3): d 0.86–0.95 (m, 6H), 1.20–1.30 (m, 1H), 1.42 (s, 3H),
1.42–1.92 (m, 5H), 2.01–2.06 (m, 4H), 2.34–2.43 (m, 1H), 2.44–2.56 (m, 1H), 4.49
(d, J ¼ 8.8 Hz, 1H), 4.59 (d, J ¼ 12.8 Hz, 1H), 4.94 (d, J ¼ 12.8 Hz, 1H), 5.33 (s,
1H), 7.23–7.31 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): d 12.7, 20.2, 24.5,
24.7, 26.0, 32.6, 34.1, 36.2, 37.3, 45.3, 51.6, 69.0, 80.3, 91.2, 98.9, 104.3, 128.3,
128.9, 133.1, 136.7 ppm.
ACKNOWLEDGMENTS
SAIF, North Eastern Hill University (NEHU), is acknowledged for recording
NMR, mass, and elemental analysis. Financial help from the University Grants Com-
mission, SAP, Department of Chemistry, NEHU, is also gratefully acknowledged.
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