Stereoselective total synthesis of (+)-artemisinin

Article abstract of DOI:10.1016/S0040-4039(02)02500-5

The total synthesis of the novel antimalarial drug, a sesquiterpene endoperoxide, (+)-artemisinin is described. The approach is flexible and stereoselective. The use of an intermolecular radical reaction on an intermediate iodolactone and a Wittig reaction on a ketone were employed for the synthesis.

Full text of DOI:10.1016/S0040-4039(02)02500-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 387–389
Stereoselective total synthesis of (+)-artemisininꢀ
J. S. Yadav,* R. Satheesh Babu and G. Sabitha
Organic Chemical Sciences, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 22 August 2002; revised 31 October 2002; accepted 1 November 2002
Dedicated to Dr. Sukh Dev on the occasion of his 80th birthday
Abstract—The total synthesis of the novel antimalarial drug, a sesquiterpene endoperoxide, (+)-artemisinin is described. The
approach is flexible and stereoselective. The use of an intermolecular radical reaction on an intermediate iodolactone and a Wittig
reaction on a ketone were employed for the synthesis. © 2002 Published by Elsevier Science Ltd.
take up the total synthesis of this potent antimalarial
drug.
Malaria remains an important health problem all over
the world (tropics and subtropics), which affects over
400 million people especially in Africa and South East
Africa, causing deaths in excess of 2 million each
year.1,2 Increasing resistance of the malaria parasite
Plasmodium falciparum, toward contemporary anti-
malarials is a cause for concern. The highly oxygenated
sesquiterpene lactone endoperoxide (+)-artemisinin 1
(Qinghaosu) emerged as a potent antimalarial against
several resistant strains of malaria without obvious
adverse reaction or side effects in patients. Artemisinin,
which has been isolated3,4 from Artemisia annua L.
Compositae (Qinghao), is an active constituent of tradi-
tional Chinese herbal medicine which has been used for
the treatment of malaria in China for more than 1000
years. The unprecedented unique chemical structure,
modest potency and the limited availability of this
important natural product delineated the need for a
ready synthetic entry to the tetracyclic framework of
artemisinin. Though many valuable contributions5–9
have been made towards the total synthesis of this
unique structurally complex molecule, the need for a
simple strategic route still remains, encouraging us to
In our retrosynthetic analysis (Scheme 1), we believed
that the key intermediate would be an a-hydroperoxy
aldehyde which can be easily obtained by photo-oxy-
genation from methyl vinyl ether 2 because, in a ketal-
ization-like process, simple cyclodehydration of the
a-hydroperoxy aldehyde should readily furnish the tet-
racyclic natural product 1. Thus, the next intermediate
in our analysis was the iodolactone 3 which has the
required stereochemistry and further, it can be easily
prepared from the starting (+)-isolimonene 4.
Scheme 1.
Keywords: artemisinin; stereoselective; iodolactone; tris(trimethylsilyl)silane.
ꢀ IICT communication No. 020715.
* Corresponding author. Fax: +91-40-716 0512; e-mail: yadav@iict.ap.nic.in
0040-4039/03/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02500-5

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J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 387–389
The keto group of lactone 7 was reacted (Scheme 4)
with ethanedithiol and BF3·Et2O in DCM at 0°C to
afford thioketal lactones 10, 11 in quantitative yield.6
Thioketalization facilitated the separation of the major
isomer 11,15 which was further subjected to hydrolysis
and esterification with diazomethane providing hydroxy
ester 12 in 50% yield. (The thioketal lactone 11 was also
isolated due to competing lactonization of the hydroxy
acid.) The hydroxy methyl ester 12 was transformed
into the keto ester 1316 using PCC as the oxidizing
agent in DCM at room temperature. A two dimen-
sional 1H NMR study of compound 13 revealed a
strong NOE between the two diaxial protons adjacent
to the carbonyl group. These observations confirmed its
structure.
As shown in Scheme 2, (+)-isolimonene 4 was subjected
to regioselective hydroboration using dicyclo-
hexylborane10 to give the required alcohol 5 in 82%
yield, which was converted to the corresponding acid 6
in 80% yield by Jones’ oxidation.11 The g,d-unsaturated
acid 6 was subjected to iodolactonization12 using KI, I2
in aq. NaHCO3 to afford iodolactones 3 and 3a as
separable diastereomers, isomeric at C3 in a 68:32 (b:a)
ratio in 70% yield. While this work was in progress, the
iodolactones were reported by Chavan et al.13 for the
synthesis of wine lactone.
The iodolactone 3 was subjected to an intermolecular
radical reaction with methyl vinyl ketone using
tris(trimethylsilyl)silane14 (TTMSS) and AIBN in tolu-
ene to yield the corresponding alkylated lactone 7 in
72% yield (Scheme 3) as an inseparable epimeric mix-
ture at C7 (8:2 b/a) along with 8 (ꢀ10%) and the
reduced product 9 (<5%).
The ketone 13 was subjected to Wittig reaction17 with
methoxymethyl
triphenylphosphonium
chloride,
KHMDS to furnish the required methyl vinyl ether 14
in 45% yield. The deprotection of thioketal 14 using
Scheme 2. Reagents and conditions: a. Dicyclohexylborane, THF, 0°C, 7 days, 82%. b. CrO3, H2SO4 in acetone at 0°C, 80%. c.
I2, KI, aq. NaHCO3 48 h in the dark, 70%.
Scheme 3. Reagents and conditions: d. methyl vinyl ketone, ((CH3Si)3)3SiH, AIBN in refluxing toluene using a syringe pump, 72%.
Scheme 4. Reagents and conditions: e. Ethanedithiol, BF3·Et2O in DCM at 0°C, 98%. f. 10% NaOH in MeOH reflux, 1% HCl to
congo red pH at −24°C. g. CH2N2 in Et2O, 50% for two steps. h. PCC, DCM at 0°C, 89%. i. methoxymethyl triphenylphospho-
nium chloride, 2 M KHMDS, THF:HMPA (8:2) 50°C 24 h, 45%. j. HgCl2, CaCO3 in CH3CN:H2O (9:1), 80%. k. O2, Rose Bengal
in MeOH at −78°C, hw, 4 h, dry HCl, 70% HClO4 in ether 28 h, 10%.

J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 387–389
389
HgCl2, CaCO3 resulted in the key intermediate 2 in 80%
yield. Compound 2 was transformed to the target
molecule 118 by photooxidation followed by acid
hydrolysis with 70% HClO4 as reported by Zhou et al.6
The synthetic material was found to be identical with
natural artemisinin in every respect (1H NMR, IR,
Mass, TLC and [h]D).
9. Liu, H. J.; Yeh, W. L.; Chew, S. Y. Tetrahedron Lett.
1993, 34, 4435–4438.
10. (a) Zweifel, G.; Ayyangar, N. R.; Brown, H. C. J. Am.
Chem. Soc. 1963, 85, 2072–2075; (b) Brown, H. C.;
Kulkarni, S. V.; Khann, V. V.; Racherla, V. J. Org.
Chem. 1992, 57, 6173–6177.
11. Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedors,
B. C. L. J. Chem. Soc. 1946, 39–45.
In conclusion, we have accomplished a highly efficient
and stereoselective total synthesis of (+)-artemisinin 1.
Our approach presents several advantages such as sta-
bility and availability of the starting material, high
yielding reactions and high stereoselectivity. Further,
the approach involves less steps compared to other
reported methods; hence we believe that the method
can be a valuable route for the synthesis of (+)-
artemisinin 1.
12. House, H. O.; Carlson, R. G.; Babad, H. J. Org. Chem.
1963, 28, 3359–3361.
13. Chavan, S. P.; Kharul, R. K.; Sharma, A. K.; Chavan, S.
P. Tetrahedron: Asymmetry 2001, 12, 2985–2988.
14. (a) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188–194;
(b) Ballestri, M.; Chatgilialoglu, C.; Clark, K. B.; Griller,
D.; Giese, B.; Kopping, B. J. Org. Chem. 1991, 56,
678–683.
15. Spectral data for 11: 1H NMR (200 MHz, CDCl3): l 0.98
(d, J=6.2 Hz, 3H, CH3), 1.14 (d, J=7.1 Hz, 3H, CH3),
1.17–1.29 (m, 2H, CH2), 1.37–1.43 (m, 1H), 1.56–1.75 (m,
4H, CH2), 1.76 (s, 3H, CH3), 1.82–1.93 (m, 2H, CH2),
2.12–2.19 (m, 1H, CH2CH(CH)CH), 2.22–2.27 (m, 1H,
OCHCH), 2.73–2.79 (m, 1H, OCCHCH3), 3.28–3.48 (m,
4H, SCH2CH2S), 4.38 (t, J=3.2 Hz, 1H, OCH). MS (EI):
315 (M+1). IR (neat): 1780 cm−1. Anal. calcd for
C16H26O2S2: C, 61.11; H, 8.33. Found: C, 61.08; H, 8.28.
Optical rotation [h]D: +32.10 (c 1.0, CHCl3).
Acknowledgements
We thank Malti-Chem Research Center, Baroda for
providing the starting material (+)-isolimonene. R.S.B.
thanks CSIR, New Delhi for the award of fellowship.
16. Spectral data for 13: 1H NMR (200 MHz, CDCl3): l 1.01
(d, J=6.8 Hz, 3H, CH3), 1.14 (d, J=7.4 Hz, 3H, CH3),
1.24–1.33 (m, 1H, CH2), 1.64–1.73 (m, 6H, CH2), 1.77 (s,
3H, CH3), 1.96–2.02 (m, 1H, CH2), 2.09–2.14 (m, 1H,
CHCH3), 2.32–2.35 (m, 1H, CH2CH(CO)CH), 2.60–2.66
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