A concise stereoselective total synthesis of (+)-artemisinin

Article abstract of DOI:10.1016/j.tet.2010.01.051

A protective group free, concise, and stereoselective total synthesis of (+)-artemisinin, starting from readily available (R)-(+)-citronellal, is described. Asymmetric 1, 4-addition, Aldol condensation, Ene reaction, regioselective hydroboration are the key steps involved in the total synthesis of the target molecule.

Full text of DOI:10.1016/j.tet.2010.01.051

Tetrahedron 66 (2010) 2005–2009
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A concise stereoselective total synthesis of (þ)-artemisinin
*
J.S. Yadav , B. Thirupathaiah, P. Srihari
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad-500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A protective group free, concise, and stereoselective total synthesis of (þ)-artemisinin, starting from
readily available (R)-(þ)-citronellal, is described. Asymmetric 1, 4-addition, Aldol condensation, Ene
reaction, regioselective hydroboration are the key steps involved in the total synthesis of the target
molecule.
Received 24 November 2009
Received in revised form 30 December 2009
Accepted 12 January 2010
Available online 18 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, we have reported a chiron approach for the total
synthesis of artemisinin starting from isolimonene.7 In continua-
Malaria continues to be one of the most widespread health
hazards affecting over 500 million people and causing over two
million deaths every year.1 The adverse reactions/side effects in
patients suffering with malaria caused from quinine, chloroquine
has overwhelmed their utility and increased the demand for better
therapeutic drugs. The identification of the sesquiterpenoid lactone
endoperoxide (þ)-Qinghaosu, also called as (þ)-artemisinin having
unusual trioxane structure with seven stereogenic centers and
tetracyclic framework from the Chinese medicinal herb2 has been
a major break-through in malarial therapy.3 Intrigued by the ar-
chitectural complexity, pharmacological properties and scarcity of
the material, artemisinin as well as its derivatives have become an
attractive target molecules for synthetic organic chemists toward
its total synthesis.4,5 The significant importance of this natural
product has also led to focus on the semisynthesis from other
naturally occurring precursors, such as arteannuic acid 2 and
arteannuin B 3 (Fig. 1).6
tion, we herein wish to report an efficient, concise protective group
free total synthesis of artemisinin.
Earlier synthetic strategies comprised of protective group ma-
nipulations, which lead to lengthy synthesis resulting in reduced
reaction efficiency. In our synthetic design, we identified the well
known ester 4 as the key precursor, which can be photooxygenated
to obtain target compound. Key precursor 4 was proposed to be
obtained by regioselective oxidation followed by esterification of 5.
Ene cyclization of the product obtained after methyl Grignard re-
action on 6 was presumed to give 5 and 6 in turn could be easily
synthesized from (R)-citronellal (Scheme 1).
H
H
1
H
H
O
H
H
OMe
5
4
H
H
H
H
CHO
O
O
O
O
H
H
O
H
H
O
O
H
OH
6
O
(R)-(+)-citronellal
Scheme 1. Retrosynthesis.
O
O
Artemisinin
1
Arteannuic acid
2
Arteannuin
3
2. Results and discussion
Figure 1. Natural products.
The synthesis began with an enamine mediated 1, 4-addition of
(R)-citronellal to methyl vinyl ketone (MVK) in presence of proline-
derived catalyst8 and ethyl 3,4-dihydroxybenzoate as a co-catalyst9
* Corresponding author. Tel.: þ91 40 27193030; fax: þ91 40 27160387.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.051

2006
J.S. Yadav et al. / Tetrahedron 66 (2010) 2005–2009
O
H
H
a
c
b
O
O
O
6
(R)-(+)-Citronellal
7
H
H
H
Catalyst
d
+
Ph
N
H
OH
OH
H
H
OMe
Ph
8a
8
5
Scheme 2. Reagents and conditions: (a) MVK, catalyst (5 mol %), ethyl 3,4-dihydroxybenzoate (20 mol %), neat, 0–4 ꢀC, 48 h, 70%. (b) KOH (0.1 N aq, 1.0 equiv), n-Bu4NOH (40% aq,
cat.), Et2O: THF: H2O (3:1:3), reflux, 8 h, 84%. (c) CH3MgI, Et2O, 2 h, rt, 92%. (d) SnCl4, benzene:Et2O (4:1), 0 ꢀC, 65%.
by following Nicoloau’s10 procedure to obtain 7 in 70% yield with
83% de (based on 1H NMR). Intramolecular Aldol condensation of 7
with aq KOH under reflux condition afforded compound 6 in 84%
yield. The enone 6 was treated with methyl magnesium iodide to
yield 8 and 8a as a mixture of diastereomers.11 As the stereo-
chemistry at C4 was not the critical parameter for us, we proceeded
further with this mixture for cyclization. Thus, treating di-
astereomeric mixtures of 8 and 8a with SnCl4 in benzene–diethyl
ether (4:1) gave required ene product 5 (purified by column chro-
matography using silica gel impregnated with AgNO3 and analyzed
by 1D & 2D NMR studies) in 65% yield (Scheme 2).12
The orientation of proton H-6 at this stage could not be resolved
due to complexity (merging of H-1 and H-10 ( 1.68)), and H-6 and
H-7 at ( 1.95) in the NMR spectrum (Fig. 2A). As the H-6 proton
orientation does not affect the further steps toward the total syn-
thesis,13 we proceeded further with this bicyclic skeleton for oxy-
genation toward the target synthesis.
d
d
The olefin 5 was subjected to regioselective hydroboration4f
using 9-BBN following a known protocol14 to get the required
primary alcohol 9 in 85% yield with 90% de as judged by GC–MS.
2D NMR studies of compound 9 also did not reveal the exact
orientation of H-6. Attempts to get a solid compound by deriva-
tization of 9 as the corresponding ester with benzoic acid,
4-nitrobenzoic
acid,
3,5-dinitrobenzoic
acid,
4-chloro-
benzenesulfonyl chloride, and 4-nitrobenzenesulfonyl chloride
were not successfull. However, the 4-nitrobenzene sulfonate
derivative showed significant NOESY correlations confirming the
stereochemistry of the H-6 to be anti to that of H1 (Fig. 2B). The 9
was oxidized to corresponding aldehyde 10 by Swern oxidation15
16
and subsequentially to acid 11 using NaClO2, NaH2PO4 in 80%
yield. The 11 was esterified with methyl iodide in presence of
K2CO3 to get key precursor 4. The 4 was subjected to photooxi-
dation following Haynes protocol5f (DCM, rose bengal, copper
triflate) to achieve the total synthesis of artemisinin (Scheme 3).
The product was recrystallized and its structure (Fig. 3) was
confirmed by X-ray analysis.17 The spectral data of the synthetic
compound was compared with the natural product and found to
be identical.
Figure 2. NOESY correlations.
H
H
H
H
b
a
c
H
H
O
H
H
H
H
5
OH
9
10
H
H
O
H
O
d
e
O
O
H
H
O
H
OH
H
H
O
H
O
OMe
1
11
4
Scheme 3. Reagents and conditions: (a) 9-BBN, 3 N NaOH, H2O2, 85%. (b) Swern oxidation, 94%. (c) NaClO2, NaH2PO4, 0 ꢀC, 80%. (d) CH3I, K2CO3, acetone, rt 89%. (e) (i) O2, rose
bengal, ꢁ30 ꢀC, 6 h, CH3CN, 500 W tungsten filament lamp, (ii) O2, Cu(OTf)2, CH3CN, ꢁ20 ꢀC, (iii) TsOH (cat.), CH2Cl2, 4 h, rt, 25%.

J.S. Yadav et al. / Tetrahedron 66 (2010) 2005–2009
2007
resulting homogeneous solution was stirred at 4 ꢀC for 48 h and the
reaction mixture was directly subjected to flash column chroma-
tography (silica gel, 8% EtOAc–hexane) to obtain 7 as a colorless oil
(2.52 g, 70%, ca. 16:1 dr). Rf¼0.60 (silica gel, 20% EtOAc–hexane).
27
[a
]
ꢁ27.9 (c 2.4, CHCl3). IR (neat):
n 2964, 2923, 2718, 1718, 1632,
D
1384 cmꢁ1. 1H NMR (CDCl3, 300 MHz),
d
0.99 (d, J¼7.0 Hz, 3H), 1.18–
1.33 (m, 1H), 1.34–1.52 (m, 1H), 1.60 (s, 3H), 1.68 (s, 3H), 1.69–1.78
(m, 2H),1.81–2.08 (m, 3H), 2.13 (s, 3H), 2.15–2.25 (m,1H), 2.37 (ddd,
J¼7.3, 7.9, 17.7 Hz, 1H), 2.52 (ddd, J¼5.8, 8.7, 17.7 Hz, 1H), 5.02–5.11
(m, 1H), 9.64 (d, J¼2.6 Hz, 1H). 13C NMR (CDCl3, 75 MHz):
d 16.9,
17.6, 19.7, 25.5, 25.6, 29.9, 33.3, 33.9, 41.4, 56.2, 123.8, 131.9, 205.2,
208.0. ESI-MS: m/z 247 (MþNa)þ. HRMS (ESI-MS) calcd. For
C14H24NaO2 (MþNaþ) 247.1669, found 247.1679.
4.1.2. (S)-4-((R)-6-Methylhept-5-en-2-yl) cyclohex-2-enone 6. To
a solution of 7 (2.1 g, 9.37 mmol) in Et2O (100 mL) and THF (30 mL)
was added KOH (100 mL, 0.1 N aq) and n-Bu4NOH (1.70 mL, 40%
aq). The reaction mixture was heated to reflux with vigorous stir-
ring for 8 h. Upon cooling to room temperature, the reaction mix-
ture was extracted with Et2O (3ꢂ100 mL). The combined organic
phase was washed with brine (1ꢂ100 mL) and dried over anhy-
drous Na2SO4. The solvent was filtered and then evaporated under
vacuum to obtain the crude residue, which was subjected to flash
column chromatography (silica gel, 4% EtOAc–hexane) to yield 6 as
Figure 3. ORTEP diagram of artemisinin.
3. Conclusions
a colorless oil (1.63 g, 84%, ca. 8:1 dr). Rf¼0.56 (silica gel,10% EtOAc–
25
hexane). [
a
]
D
ꢁ44.8 (c 1.5, CHCl3). IR (neat):
n 2960, 2924, 1682,
In conclusion, we have achieved a concise and an efficient total
synthesis of potent antimalarial drug (þ)-artemisinin. The key
precursor 4 was synthesized with an overall yield of 13.0% starting
from (R)-citronellal in eight steps. This strategy is found to be the
shortest of the syntheses known so far in the literature. This
strategy involves no protective groups18 and presents several ad-
vantages, such as readily accessible starting materials and high
yielding reactions. Further studies toward process development are
currently being investigated.
1452, 1381, cmꢁ1 1H NMR (CDCl3, 300 MHz),
. d 0.94 (d, 3H,
J¼6.8 Hz), 1.19–1.33 (m, 1H), 1.34–1.49 (m, 1H), 1.61 (s, 3H), 1.69 (s,
3H), 1.72–1.76 (m, 1H), 1.77–1.89 (m, 1H), 1.90–2.15 (m, 3H), 2.35
(ddd, J¼5.1, 13.4, 16.6 Hz, 1H), 2.42–2.47 (m, 1H), 2.52 (dt, J¼3.9,
16.6 Hz, 1H), 5.05–5.14 (m, 1H), 6.02 (ddd, J¼0.9, 2.8, 10.4 Hz, 1H),
6.88 (dt, J¼1.9, 10.4 Hz, 1H) ppm. 13C NMR (CDCl3, 75 MHz):
d 15.9,
16.4 17.6, 23.9, 25.6, 25.7, 33.8, 34.0, 35.9, 36.0, 37.4, 37.6, 40.9, 41.5,
124.0, 129.5, 129.8, 131.6, 131.7, 154.2, 155.3, 199.9. ESI-MS: m/z 207
(MþH)þ. HRMS calcd for C14H22ONa (MþNaþ) 229.1568, found
229.1579.
4. Experimental section
4.1. General methods
4.1.3. (S)-1-Methyl-4-((R)-6-methylhept-5en-2-yl) cyclohex-2-enol 8
and 8a. To a mixture of Mg turnings (0.524 g, 21.8 mmol) and
diethyl ether (5 mL) was added methyl iodide (1.36 mL, 21.8 mmol)
at 0 ꢀC under N2 atmosphere and stirred at room temperature for
2 h. To this Grignard reagent, the enone compound 6 (1.5 g,
7.28 mmol) dissolved in diethyl ether (15 mL) was added drop wise
at 0 ꢀC and the reaction mixture was allowed to stir at room tem-
perature for 2 h. The reaction mixture was quenched with saturated
NH4Cl solution (10 mL) at 0 ꢀC and the organic phase was sepa-
rated. The aqueous layer was extracted with ethyl acetate
(3ꢂ10 mL). The combined organic phase was washed with brine
(1ꢂ25 mL), dried over anhydrous Na2SO4. Filtration followed by
evaporation of the solvent under vacuum afforded crude residue,
which was subjected to column chromatography (silica gel, 7%
EtOAc–hexane) to give 8 and 8a as colorless oils (1.52 g, 95%).
IR spectra were recorded on Perkin–Elmer Infrared 683 spec-
trophotometer.1H (200 MHz and 300 MHz) and 13C (75 MHz)
NMR spectra were recorded on Varian Gemini (200 MHz) or
Bruker Avance (300 MHz) spectrometers using CDCl3 as solvent at
ambient temperature. The chemical shifts (d ppm) and coupling
constants (Hz) are reported in standard fashion with reference to
either internal tetramethylsilane (for 1H) or the central line
(77.0 ppm) of CDCl3 (for 13C). Optical rotations were measured
using Perkin–Elmer model no.343 digital polarimeter using
a 1 mL cell with a 1 dm path length. For low (MS) and High
(HRMS) resolution, m/z ratios are reported as values in atomic
mass units. Mass analysis was done in APCI mode or EI mode. All
reagents and solvents were reagent grade and used without fur-
ther purification unless specified otherwise. Column chromatog-
raphy was carried out using Acme’s silica gel (60–120 mesh or
100–200 mesh) packed in glass columns (20–25 g per 1 g of the
crude product). All reactions were performed under an atmo-
sphere of nitrogen in flame-dried or oven-dried glassware with
magnetic stirring. GC–MS was performed using DB5 column of
size 30 cmꢂ0.25 mm.
Rf¼0.55 (silica gel, 20% EtOAc–hexane). IR (neat):
n
3367, 2963,
0.79–0.91
2863, 1455, 1377, 1117 cmꢁ1. 1H NMR (CDCl3, 300 MHz):
d
(m, 3H), 1.06–1.23 (m, 1H), 1.28 (s, 3H), 1.30–1.76 (m, 6H), 1.61 (s,
3H), 1.69 (s, 3H) 1.78–2.17 (m, 4H), 5.05–5.15 (m, 1H), 5.47–5.70 (m,
2H). 13C NMR (CDCl3, 75 MHz):
d 15.7,16.4,17.6, 22.0, 22.3, 24.1, 25.7,
26.0, 28.4, 29.6, 33.7, 34.1, 36.3, 37.4, 38.3, 40.1, 40.6, 41.1, 69.8,124.7,
130.9, 131.3, 132.0, 133.0, 133.7, 134.5, 134.8. ESI-MS: m/z 245
(MþNa)þ. HRMS calcd for C15H26ONa (MþNaþ) 245.1881, found
245.1887.
4.1.1. (2S,3R)-3, 7-Dimethyl-2-(3-oxobutyl) oct-6-enal 7. The pre-
cooled mixture of (R)-(þ)-citronellal (2.5 g, 16.2 mmol) and methyl
vinyl ketone (1.97 mL, 24.3 mmol) was added to the mixture of
proline-derived catalyst (0.216 g, 0.8 mmol, 5 mol %) and ethyl 3, 4-
dihydroxybenzoate (0.590 g, 3.2 mmol, 20 mol %) at 0 ꢀC. The
4.1.4. (1R,4R,4aS,8aS)-4,7-Dimethyl-1-(prop-1en-2-yl)-
1,2,3,4,4a,5,6,8a-octahydronphthalene 5. To a stirred solution of
compounds 8 and 8a (0.350 g, 1.57 mmol) in benzene and diethyl
ether (4:1, 8 mL) was added stannic chloride (0.18 mL, 1.57 mmol)

2008
J.S. Yadav et al. / Tetrahedron 66 (2010) 2005–2009
at 0 ꢀC under nitrogen atmosphere. After 15 min the reaction
mixture was quenched with aq saturated NaHCO3 solution (5 mL).
The organic phase was separated and the aqueous phase was
extracted with Et2O (2ꢂ10 mL). The combined organic phase was
washed with brine (1ꢂ10 mL), dried over anhydrous Na2SO4.
Evaporation of the solvent under vacuum, followed by column
chromatography of the crude residue (silica gel impregnated with
1384 cmꢁ1. 1H NMR (CDCl3, 300 MHz):
d
0.93 (d, 3H, J¼6.8 Hz), 1.08
(d, 3H, J¼6.8 Hz), 1.61 (s, 3H), 1.12–1.74 (m, 8H), 1.75–2.05 (m, 4H),
2.29–2.48 (m, 1H), 5.29 (s, 1H), 9.67 (s, 1H). 13C NMR (CDCl3,
75 MHz): d 9.3, 16.8, 19.3, 23.4, 29.5, 30.8, 30.9, 35.1, 39.2, 39.4, 41.5,
49.4, 124.3, 135.8, 206.0. ESI-MS: m/z 243 (MþNa)þ. HRMS calcd for
C15H24NaO (MþNaþ) 243.1719, found 243.1717.
silver nitrate, hexane) gave 5 as a colorless oil (0.208 g, 65%). Rf¼0.3
4.1.7. (R)-2-((1R,4R4aS,8aR)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahyr-
onaphthalen-1-yl)propanoic acid 11. 2-Methyl 2-butene (1 mL) was
added to a stirred solution of aldehyde 10 (0.430 g, 1.95 mmol) in
tert-butyl alcohol (8 mL) at 0 ꢀC. To this solution was added
NaH2PO4 (1.52 g, 9.72 mmol) and NaClO2 (0.441 g, 4.83 mmol)
dissolved in H2O (5 mL) and the reaction mixture was stirred for
half an hour. After completion of the reaction, the organic layer was
separated and the aqueous layer was extracted with ethyl acetate
(3ꢂ10 mL). The combined organic layer was washed with brine
(2ꢂ10 mL) and dried over anhydrous Na2SO4. After evaporation of
the solvent, the crude product was purified by column chroma-
28
(silica gel impregnated with silver nitrate, hexane). [
a
]
ꢁ107 (c 1.1,
D
CHCl3). IR (neat):
(CDCl3, 300 MHz):
n
3072, 2924, 1643, 1448, 1375, 885 cmꢁ1. 1H NMR
d
0.93 (d, 3H, J¼6.6 Hz), 1.08–1.49 (m, 4H), 1.50–
1.59, (m, 2H), 1.62 (s, 3H), 1.69 (s, 3H), 1.64–1.76 (m, 2H), 1.90–2.01
(m, 4H), 4.66–4.73 (m, 2H), 5.34 (m, 1H). 13C NMR (CDCl3, 75 MHz):
d
17.2, 19.6, 19.7, 23.6, 29.4, 31.2, 33.0, 35.4, 39.4, 40.0, 47.9, 110.2,
125.3, 133.3, 149.0. APCI: m/z 205 (MþH)þ. HRMS calcd for C15H24
(MþHþ) 205.1951, found 205.1959.
AgNO3 column chromatography: To a solution of silver nitrate
(3.0 g) in H2O (5 mL) was added acetone (100 mL) and 12.0 g of silica
gel (60–120 mesh). The reaction mixture was stirred and subjected
to evaporation under vacuum (to remove water and acetone). Traces
of water present in the slurry were removed by azeotropic distilla-
tion with acetone (2ꢂ75 mL) using rotavapor. The dry silica with
AgNO3 was directly utilized for column chromatography.
tography, (silica gel, 10% EtOAc–hexane) to give 11 as a yellow liquid
26
(0.370 g, 80%). Rf¼0.3 (20% EtOAc–hexane). [
a]
ꢁ97 (c 1.1, CHCl3).
D
IR (neat):
200 MHz):
n .
3100, 2931, 1702, 1455, 1240 cmꢁ1 1H NMR (CDCl3,
d
0.90 (d, 3H, J¼7.0 Hz), 1.14 (d, 3H, J¼7.0 Hz), 1.18–1.36
(m, 4H), 1.63 (s, 3H), 1.36–1.83 (m, 7H), 1.88–2.07 (m, 3H), 2.77 (dq,
1H, J¼3.1, 7.0, Hz), 5.67 (d, 1H, J¼5.4 Hz). 13C NMR (CDCl3, 75 MHz):
4.1.5. (R)-2-((1R,4R,4aS,8aR)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahy-
d 14.4, 17.1, 19.6, 23.8, 28.1, 29.6, 31.1, 35.3, 39.8, 40.0, 43.6, 60.2,
dronaphthalene-1-yl)propan-1-ol
9. Compound
5
(0.120 g,
124.9,134.5,182.2. APCI: m/z 237 (MþH)þ. HRMS calcd for C15H25O2
0.59 mmol) in dry THF (3 mL) was charged into a (25 mL) two neck
round bottomed flask equipped with a magnetic spin bar, nitrogen
inlet, and a septum. To this was added 9-BBN (2.35 mL, 1.18 mmol,
0.5 M in THF) solution drop wise at 0 ꢀC and stirred for 24 h at room
temperature. Absolute ethanol was added (5 mL) at room temper-
ature followed by 3 N NaOH (5 mL) and then cooled to 0 ꢀC. Then
30% H2O2 (6 mL) was added drop by drop and the solution was
stirred for 12 h at room temperature. The organic phase was sep-
arated and the aqueous layer was extracted with ethyl acetate
(3ꢂ5 mL). The combined organic phase was washed with brine
(1ꢂ10 mL), dried over anhydrous Na2SO4. Evaporation of the sol-
vent under vacuum followed by column chromatography (silica gel,
(MþHþ) 237.1849, found 237.1854.
4.1.8. (R)-Methyl2-((1R,4R,4aS,8aR)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-
octhydronaphthale-1-yl)propanoate 4. Methyl iodide (0.17 mL,
2.67 mmol) was added drop by drop to the suspension of acid
compound 11 (0.210 g, 0.89 mmol) and K2CO3 (1.06 g, 4.45 mmol)
in dry acetone (10 mL) at 0 ꢀC, after addition of methyl iodide, the
ice bath was removed and the reaction mixture was stirred at room
temperature for 9 h. The solvent was removed under vacuum, and
the residue was diluted with ethyl acetate (10 mL) and H2O (5 mL),
the organic layer was separated and aqueous layer was extracted
with ethyl acetate (2ꢂ10 mL). The combined organic layer was
washed with the brine (1ꢂ10 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent followed by purification of the
crude product (silica gel column chromatography, 3% EtOAc: hex-
5% EtOAc–hexane) purification afforded 9 as a light yellow liquid.
25
(0.110 g, 85% with 90% de). Rf¼0.5 (20% EtOAc–hexane). [
(c 1.0, CHCl3). IR (neat):
1H NMR (CDCl3, 300 MHz):
a
]
ꢁ80.0
D
n
3326, 2930, 1632, 1451, 1379, 1027 cmꢁ1
.
d
0.89 (d, 3H, J¼6.6 Hz), 0.97 (d, 3H,
ane) afforded 4 as a light yellow liquid (0.20 g, 89%). Rf¼0.6 (10%
26
J¼6.9 Hz), 0.99–1.18 (m, 2H), 1.21–1.74 (m, 8H), 1.64 (s, 3H), 1.83–
EtOAc–hexane). [
a
]
ꢁ87 (c 3.0, CHCl3). IR (neat):
n
2930, 2859,
0.90 (d,
D
2.07 (m, 4H), 3.43 (dd, 1H, J¼8.7, 10.4 Hz), 3.75 (dd, 1H, J¼5.1,
1735, 1454, 1196, 1171 cmꢁ1. 1H NMR (CDCl3, 300 MHz):
d
10.5 Hz), 5.55–5.63 (m, 1H). 13C NMR (CDCl3, 75 MHz):
d
15.6, 16.9,
3H, J¼6.6 Hz),1.13 (d, 3H, J¼6.9 Hz),1.20–1.36 (m, 3H),1.37–1.78 (m,
19.5, 23.7, 27.7, 29.8, 31.1, 35.5, 36.1, 39.7, 39.9, 42.9, 65.3, 125.2,
134.3. APCI: m/z 223 (MþH)þ. HRMS calcd for C15H26O (MþHþ)
223.2056, found 223.2064.
7H), 1.64 (s, 3H), 1.79–2.11 (m, 3H), 2.76 (dq, 1H, J¼3.0, 7.2 Hz), 3.65
(s, 3H), 5.62–5.68 (m, 1H). 13C NMR (CDCl3, 75 MHz):
d 14.2, 16.9,
19.4, 23.6, 28.3, 29.4, 31.0, 35.2, 39.7, 40.0, 40.1, 43.4, 51.0, 124.7,
134.6, 176.2. ESI-MS: m/z 273 (MþNa)þ. HRMS calcd for C16H27O2
(MþH)þ 251.2006, found 251.2000.
4.1.6. (R)-2-((1R,4R,4aS,8aR)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahy-
dronaphthalen-1-yl)propanal
10. Oxalyl
chloride
(0.79 mL,
9.0 mmol) was charged into a (50 mL) two neck round bottomed
flask equipped with a magnetic stir bar, nitrogen inlet, and a sep-
tum. After addition of CH2Cl2 (5 mL), the solution was cooled to
ꢁ78 ꢀC. To this dimethyl sulphoxide (1.28 mL, 18.0 mmol) was
added and the resulting white suspension was stirred for 30 min.
Alcohol 9 (1.0 g, 4.50 mmol) in CH2Cl2 (10 mL) was added and the
reaction mixture was stirred for 1.5 h at ꢁ78 ꢀC. The reaction
mixture was treated with Et3N (3.75 mL, 27.0 mmol) and warmed
to room temperature over a period of one hour. After completion of
the reaction, the reaction mixture was diluted with CH2Cl2 (20 mL),
washed with water (1ꢂ10 mL), brine (1ꢂ10 mL), and dried over
anhydrous Na2SO4. The solvent was evaporated and the crude
product was purified by column chromatography (silica gel, 2%
EtOAc–hexane) to yield 10 as a light yellowish liquid. (0.930 g, 94%).
4.1.9. (þ)-Artemisinin 1. The methyl ester 4 (0.1 g, 0.40 mmol) was
dissolved in acetonitrile (15 mL) and irradiated with tungsten fil-
ament, 500 W in the presence of Rose Bengal sensitizer, under
a slow stream of O2, for 6 h at ꢁ30 ꢀC. The solvent was evaporated
under vacuum, and the residue was submitted to flash chroma-
tography (8% EtOAc–hexane) to give the hydroperoxide compound
(0.067 g, 60%). A solution of hydroperoxide compound (0.067 g,
0.23 mmol) in CH3CN (5 mL) was cooled to ꢁ20 ꢀC, under a slow
stream of O2 and treated with Cu(OTf)2 (0.008 g, 0.023 mmol). After
8 h, the reaction mixture was poured into saturated NaHCO3 solu-
tion (5 mL) and extracted with diethyl ether (15 mL). The combined
organic layer was washed with brine solution (10 mL) and dried
over anhydrous Na2SO4. The solvent was removed under vacuum
and the resulting crude mixture was redissolved in CH2Cl2 (5 mL)
and to this was added p-TsOH (0.003 g) at 0 ꢀC. After stirring for 5 h
Rf¼0.7 (10% EtOAc–hexane). IR (neat):
n 2928, 2870, 1718, 1632,

J.S. Yadav et al. / Tetrahedron 66 (2010) 2005–2009
2009
at room temperature, the reaction mixture was quenched with
References and notes
solid NaHCO3. The reaction mixture was filtered and the filtrate was
dried over anhydrous Na2SO4, Evaporation of the solvent, followed
by flash chromatography of the residue, (silica gel, 10% EtOAc–
hexane) gave 1 as a colorless solid (0.027 g, 25% yield). Rf¼0.6 (20%
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EtOAc–hexane). The obtained product was recrystallized with
24
hexane to afford 1 as colorless needles. Mp¼153–155 ꢀC. [
a
]
þ61
D
(c 0.2, CHCl3) IR (KBr):
n
2921, 2854, 1738, 1115, 994 cmꢁ1. 1H NMR
(CDCl3, 300 MHz):
d
1.00 (d, 3H, J¼5.8 Hz),1.02–1.13 (m,1H),1.21 (d,
4. Earlier contributions for total synthesis (a) Schmid, G.; Hofheinz, W. J. Am.
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3H, J¼7.3 Hz), 1.45 (s, 3H), 1.33–1.54 (m, 4H), 1.69–1.83 (m, 2H),
1.84–1.94 (m, 1H), 1.95–2.11 (m, 2H), 2.36–2.53 (m, 1H), 3.34–3.46
(m, 1H), 5.86 (s, 1H). 13C NMR (CDCl3, 75 MHz):
d 12.5, 19.8, 23.4,
24.8, 25.2, 32.9, 33.6, 35.9, 37.5, 45.0, 50.0, 79.5, 93.7, 105.4, 172.0.
APCI: m/z 283 (MþH)þ. HRMS calcd for C15H22NaO5 (MþNaþ)
305.1359, found 305.1371.
4.1.10. Nosylate data. p-Nitrobenzenesulfonyl chloride (0.022 g,
0.10 mmol) was added to the stirred solution of alcohol 9 (0.015 g,
0.067 mmol) and triethylamine (0.01 mL, 0.08 mmol) in dry CH2Cl2
(5 mL) at 0 ꢀC, catalytic amount of DMAP was added to this reaction
mixture and allowed to stir for 30 min at 0 ꢀC. The reaction was
quenched with H2O (3 mL) and the organic layer was separated.
The aqueous layer was extracted with CH2Cl2 (2ꢂ4 mL) and the
combined organic layers were washed with brine solution
(1ꢂ5 mL). Solvent was evaporated under vacuum and the crude
product was purified by silica gel column chromatography. Rf¼0.3
(5% EtOAc–hexane), eluted with (2% EtOAc–hexane) to afford
nosylate as a yellow sticky liquid (0.026 g, 95%). 1H NMR (CDCl3,
6. (a) For semi syntheses see Jung, M.; Yoo, Y.; ElSohly, H. N.; McChesney, J. D.
J. Nat. Prod. 1987, 50, 972–973; (b) Roth, R. J.; Acton, N. J. Nat. Prod. 1989, 52,
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300 MHz):
d
0.77–0.85 (m, 1H), 0.88 (d, 3H, J¼6.6 Hz), 0.94 (d, 3H,
J¼7.0 Hz), 0.98–1.14 (m, 1H), 1.20–1.46 (m, 5H), 1.47–1.69 (m, 6H),
1.71–2.01 (m, 2H), 2.11–2.27 (m, 1H), 3.93 (m, 1H), 4.23 (dd, 1H,
J¼4.9,5.1 Hz), 5.32–5.39 (m, 1H), 8.12 (d, 2H, J¼8.9), 8.42 (d, 2H,
J¼8.9 Hz). 13C NMR (CDCl3, 75 MHz):
d, 15.6, 16.7, 19.4, 23.7, 27.2,
26.5, 29.7, 30.9, 33.0, 35.3, 39.5, 39.6, 42.8, 74.6, 123.9, 124.4, 129.1,
135.2, 142.0. ESI-MS: m/z 430 (MþNa)þ. HRMS calcd for
C21H29NO5NaS (MþNaþ) 430.1660, found 430.1664.
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Acknowledgements
12. Similar procedure for ene reaction was adopted as reported in Naegeli, P.;
Kaiser, R. Tetrahedron Lett. 1972, 13, 2013–2016; (b) The data of our ene product
was compared from the literature Ngo, K.-S.; Brown, G. D. Tetrahedron 1999, 55,
15099–15108.
13. Both of the compounds with C6 proton oriented axially or equatorially were
utilized earlier for the total synthesis of artemisinin. See Refs. 4b and 4f.
14. Yu, J.; Liao, X.; Cook, J. M. Org. Lett. 2002, 4, 4681–4684.
BT thanks CSIR, New Delhi for financial assistance. The authors
thank Dr. S.P.S. Khanuja, Director, CIMAP, Lucknow, for providing
the artemisinin sample and thank Prof. R.K. Haynes for suggestions
on photooxidation step.
15. Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem. 1978, 43, 2480–2482.
16. Ziegler, F. E.; Wallace, O. B. J. Org. Chem. 1995, 60, 3626–3636.
17. The data from our X-ray analysis was found to be similar with the reported data
Lisgarten, J. N.; Potter, B. S.; Bantuzeko, C.; Palmer, R. A. J. Chem. Educ. 1998, 28,
539–543 (cif file is available as supplementary data).
18. (a) For literature on protective group free synthesis see Hoffmann, R. W. Syn-
thesis 2006, 3531–3541; (b) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature
2007, 446, 404–408.
Supplementary data
Electronic Supplementary Information (ESI) copies of 1H and
13C NMR spectra are available. Supplementary data associated
with this article can be found, in the online version, at doi:10.1016/
j.tet.2010.01.051.