Synthesis of 6,7-dehydroartemisinic acid

Article abstract of DOI:10.1039/b104471k

The natural product 6,7-dehydroartemisinic acid from Artemisia annua has been synthesized in four steps from artemisitene, which was in turn prepared in four steps from commercially available artemisinin. The forward synthesis involves the acid degradation of artemisitene and some comparisons are made between the products from this reaction and the more extensively studied acid degradation reaction of its 11,13-dihydro analogue, artemisinin.

Full text of DOI:10.1039/b104471k

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Synthesis of 6,7-dehydroartemisinic acid
Lai-King Sy and Geoffrey D. Brown*
Chemistry Department, The University of Hong Kong, Pokfulam Rd., Hong Kong.
E-mail: gdbrown@hkucc.hku.hk; Fax: 852-2857 1586; Tel: 852-2859 7915
1
Received (in Cambridge, UK) 21st May 2001, Accepted 2nd July 2001
First published as an Advance Article on the web 11th September 2001
The natural product 6,7-dehydroartemisinic acid from Artemisia annua has been synthesized in four steps from
artemisitene, which was in turn prepared in four steps from commercially available artemisinin. The forward synthesis
involves the acid degradation of artemisitene and some comparisons are made between the products from this
reaction and the more extensively studied acid degradation reaction of its 11,13-dihydro analogue, artemisinin.
Introduction
The Chinese medicinal plant Artemisia annua has been the
subject of intensive phytochemical investigation following the
discovery of the potent anti-malarial sesquiterpene artemisinin
(qinghaosu) over twenty years ago.1 Around thirty-five further
cadinane and amorphane sesquiterpenes have now been iso-
lated from this species.2,3 Several total4–12 and partial13–17 syn-
theses have been described for artemisinin (1), and total5,18 and
partial6,19–30 syntheses of some of the other natural products
from A. annua, including artemisitene (2),19 deoxyartemisinin
(3),5,6,13,20,21 dihydroartemisinic acid (4),22 artemisinic acid (5),23
arteannuin B (6)6,24 (and its analogues),18 deoxyarteannuin B
(7),25 dihydro-epi-deoxyarteannuin
B
(8),22,26,27 epi-deoxy-
arteannuin B (9),25 arteannuin A (10),6,28 epoxyarteannuic acid
(11)29 and artemisilactone (12)30 (also referred to as artean-
nuins E and F)6 are now also reported in the literature (Fig. 1).
We herein describe the synthesis in eight steps of another
natural product from A. annua, 6,7-dehydroartemisinic acid
(13), which was first isolated by El-Feraly et al. in 1989.31
A reconstructive strategy, based on commercially available
artemisinin as the starting material, has been employed.
Results and discussion
Our retrosynthetic design for the synthesis of the target 11,13-
dehydroamorphane, compound 13, required the preparation of
the ∆11,13-unsaturated decalenone† methyl ester, compound 14
(Scheme 1). The selection of this intermediate was based on
recent work in which we have shown that the free acid form of
the 11,13-dihydro analogue of 14, compound 15a‡ [obtained
from acid degradation of artemisinin (1) via compound 16a‡],
could be converted into 13a,‡ the 11,13-dihydro analogue
of the target molecule, in good yield by Grignard reaction
(Scheme 2).22 According to close precedents in the literature32,33
we expected that 14 (or its free acid form 15) might in turn be
prepared from artemisitene (2) by an acid degradation reaction.
Two methods are reported in the literature for the preparation
of ∆11,13-unsaturated artemisitene (2) from commercially avail-
able artemisinin (1). El-Feraly and McPhail have adopted
Fig. 1 Natural products from A. annua which have been obtained by
either partial or total synthesis.
11,13-position both for artemisinin itself35 and for other 11,13-
dihydro natural products6,23 from A. annua. In practice, we have
found the procedure of El-Feraly and McPhail for desaturating
the 11,13-position of artemisinin to be the more effective.
In the forward synthesis, treatment of artemisinin with
sodium borohydride resulted in smooth transformation of the
ester functionality in 1 to a mixture of α- and β-lactol epimers
in dihydroartemisinin (17),36 as expected (Scheme 3). Enol
ether 18,37–40 obtained by dehydration of 17, was a surprisingly
stable compound, which could be stored for up to two years
without any significant autoxidation being noted. The only
side-product from the dehydration of 17 to 18 was the natural
product deoxyartemisinin (3), which became the major product
if the reaction was refluxed. Full NMR assignments for
deoxyartemisinin (3) are reported in Tables 1 and 3 for the first
time. Deoxyartemisinin may be formed by a Kornblum–de la
1
a photochemical route, involving the ene-type reaction of O2
with an enol ether;34 while Chinese workers have chosen an
oxidative selenation procedure to introduce unsaturation at the
† The IUPAC name for decalenone is 4,4a,5,6,7,8-hexahydro-
naphthalen-2(3H)-one.
‡ The suffix “a” is used herein to indicate the 11,13-dihydro analogue of
a compound.
DOI: 10.1039/b104471k
J. Chem. Soc., Perkin Trans. 1, 2001, 2421–2429
This journal is © The Royal Society of Chemistry 2001
2421

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Scheme 1 Retrosynthetic scheme for the preparation of 6,7-dehydro-
artemisinic acid 13 from artemisinin 1.
Scheme 3 Forward synthesis of artemisitene 2 from artemisinin 1.
Scheme 2 Recently reported preparation of 13a from the acid
degradation of 1.
Mare process operating on a peroxyhemiacetal intermediate,41
following “unzipping” of the 1,2,4-trioxane system of dihydro-
artemisinin in the presence of acid (Fig. 2).
Photo-oxygenation of the enol ether functional group in 18
yielded the secondary allylic hydroperoxide 19, accompanied by
1
the cleavage product 2040 (estimated at about 5% by H NMR
analysis of the crude mixture). The amount of formaldehyde-
substituted acetal 20 appeared to increase when attempts were
made to separate 19 and 20 by column chromatography on
silica gel; we propose that Hock cleavage is responsible for the
formation of 20 from 19 (Fig. 3) and that this reaction is cata-
lysed by the acidic properties of the stationary phase. Because
of the problems encountered when attempting to purify 19,
the crude photo-oxygenation reaction product was generally
used for conversion into artemisitene (2), in the next step.
Dehydration of 19 to 2 proceeded in good yield, resulting in
only one minor side-product, 21,38,41,42 which is also believed
to be formed by “unzipping” of the 1,2,4-trioxane ring in 19
(following homolytic cleavage of the secondary allylic hydro-
peroxide functional group) under basic conditions (Fig. 4). Full
NMR assignments for artemisitene (2) are reported in Tables 1
and 3 for the first time.
Fig. 2 Proposed mechanism for the formation of side-product 3 in the
photochemical conversion of artemisinin 1 to artemisitene 2.
2422
J. Chem. Soc., Perkin Trans. 1, 2001, 2421–2429

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Table 1 13C NMR data (δ, ppm) for compounds 2, 3, 13, 14, 16 and 18–23
Position
2
3
13
14
16
18
51.6
19
51.9
20
52.7
21
49.1
22
56.8
23
1
2
3
4
5
6
7
8
50.1
24.6
35.8
44.5
22.0
33.9
42.4
27.6
31.1
137.3
121.6
134.0
127.0
30.9
31.5
34.3
141.2
172.1
130.0
20.3
45.0
25.6
35.2
199.9
122.5
168.2
45.8
32.2
34.8
39.1
140.5
167.0
126.8
20.2
—
52.1
56.5
54.0
21.5
41.7
209.0
29.9
210.0
53.1
27.7
32.3
37.5
138.5
167.6
125.6
13.4
—
20.1
41.1
209.1
30.0
210.4
52.4
31.0
34.4
40.1
138.6
167.3
125.4
20.6
—
24.6
36.4
104.7
89.9
79.2
44.6
30.2
34.3
37.7
108.3
135.2
16.4
20.5
26.1
—
24.5
36.3
104.6
88.3
80.7
47.5
31.3
34.0
37.5
138.6
105.5
119.8
20.2
25.9
—
24.8
35.7
105.4
86.6
85.0
57.1
23.8
33.6
37.4
208.2
159.4
32.3
19.9
25.3
—
21.3
43.6
208.7
204.4
92.0
42.8
21.7
34.3
33.8
140.6
100.4
111.2
20.4
30.0
—
26.8
40.8
208.4
30.1
212.9
49.0
25.6
26.9
37.0
138.6
167.1
125.8
19.5
—
105.4
93.5
79.4
46.1
31.6
33.7
37.7
134.9
162.8
130.4
19.9
25.4
—
109.2
99.6
82.4
42.3
23.5
33.4
35.3
32.7
171.9
12.6
18.6
23.9
—
9
10
11
12
13
14
15
12-OMe
23.9
—
52.0
51.9
51.9
Fig. 4 Proposed mechanism for the formation of side-product 21 in
the photochemical conversion of artemisinin 1 to artemisitene 2.
(24a) isolated from acid degradation of 2, have been reported
previously from acid degradation of 1 (Fig. 6), and the
mechanisms suggested for their formation from artemisitene
in Fig. 5 parallel those previously proposed for the formation of
these products from the acid degradation of artemsinin.32,43
11,13-Dihydro analogues of the remaining decalenone reaction
products (14a, 25a and 26a) shown in Fig. 5 have also been
isolated from further reactions of 16a and 24a,32,44 although
such cyclized products have not been reported directly from the
acid degradation of 1 (the 11,13-dihydro analogue of 27 is not
known).
The 11,13-dihydro analogues of the two tricyclic products
shown in Fig. 7 (28a and 29a) have been reported on one
occasion from the acid degradation of 1.45 The relative ease of
formation of these two products from artemisitene may be the
result of the enhanced acidity of the H-7 proton in compound
16, which can form a more stable extended enolate on proton
abstraction, allowing the intramolecular aldol reaction shown
in Fig. 7 to proceed more readily. The two-dimensional NMR
results which were used to determine the unusual structures
of 28/29 are shown explicitly in Fig. 8. (NB Complete 13C and
1H assignments for all compounds reported in Tables 1–4 were
rigorously determined in the same way.)
Fig. 3 Proposed mechanism for the formation of side-product 20 in
the photochemical conversion of artemisinin 1 to artemisitene 2.
The solubility of artemisitene in the sulfuric acid–methanol
medium, which we have previously used for effecting acid
degradation of 1 to 16a in good yield, was greatly reduced as
compared to artemisinin itself, and this may be one of the
reasons why little reaction was observed when 2 was subjected
to the same conditions as those which are reported to give a
high yield of 16a from 1 (Scheme 2).22,26 Artemisitene (2) was
much more soluble in a methanolic medium incorporating
acetic acid in addition to sulfuric acid, which has previously
been reported to yield the 7-epimerized product 24a when
applied to artemisinin.6,32 However, under these conditions, 2
was converted into a complex mixture of products, including 14
and 22–29 in addition to 16 (Figs. 5 and 7).
11,13-Dihydro analogues for all of the 1,7-epimeric cyclo-
hexanones (16a, 22a and 23a) and the decalenone lactone
Thus, although acid degradation reactions of 2 can yield a
wide variety of products, most of which have parallels in the
J. Chem. Soc., Perkin Trans. 1, 2001, 2421–2429
2423

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Table 2 13C NMR data (δ, ppm) for compounds 24–33
Position
24
25
26
27
41.6
28
51.8
29
50.2
30
31
32
47.3
33
42.5
1
2
3
4
5
6
7
8
45.7
46.5
42.4
44.7a
44.6a
21.5
35.9
207.0
46.8
87.9
46.3
22.7
29.6
30.8
137.4
169.2
120.1
19.0
—
24.2
40.6
206.4
53.0
85.7
45.3
28.9
31.3
30.2
141.4
169.1
121.3
20.0
—
26.8
36.6
199.8
127.8
165.8
44.5
28.7
29.8
38.4
142.4
167.2
125.3
20.2
—
25.6
36.1
199.9
124.8
165.8
45.9
26.7
33.2
35.4
140.4
127.4
166.8
14.7
—
29.0
32.0
90.4
24.3
208.9
60.7
27.2
26.1
38.3
137.4
168.2
124.2
20.3
—
32.3
32.5
90.1
24.1
208.6
60.5
21.3
27.8
38.1
138.1
168.1
124.6
18.5
—
24.2b
35.3c
68.9
24.5b
36.0c
68.1
20.2
26.3
136.8
123.3
79.2
52.1
22.2
35.0
30.5
159.0
80.8
100.8
19.8
23.7
—
27.7
31.2
137.0
121.8
133.6
127.6
30.9
31.6
34.3
141.6
167.6
127.7
20.3
23.9
52.0
—
125.8
142.1
44.3a
32.3b
35.9c
38.9a
143.9
167.9
125.2
20.0
28.5
52.0
—
—
125.3
142.4
44.2a
31.7b
35.1c
40.0a
144.8
167.9
125.7
20.2
29.9
51.9
—
—
9
10
11
12
13
14
15
12-OMe
16
—
—
—
—
—
—
52.1
—
—
52.1
—
—
—
—
—
—
—
—
28.8d
31.7d
17
—
a Assignments interchangeable within column. b Assignments interchangeable within column. c Assignments interchangeable within column. d As-
signments interchangeable within column.
Fig. 5 Proposed mechanism for the formation of 14, 16 and 22–27 in the acid degradation of 2.
chemistry of its 11,13-dihydro analogue 1, the conditions
required for obtaining a clean reaction of 2 were clearly not the
same as for 1. Our attempts to find conditions which would
result in a better yield of 16 from 2 by systematic modifications
of the various acid degradation procedures for 132,33,40,42,44
which have been reported in the literature were unsuccessful.
However, it did prove possible to find conditions which resulted
directly in the desired decalenone methyl ester 14 (presumably
derived from the in situ intramolecular aldol reaction of 16—
see Fig. 5) in reasonable yield and with little contamination
by side-products formed by either epimerization at C-1/C-7
or as a result of methyl ester cleavage. This was fortuitous, as
2424
J. Chem. Soc., Perkin Trans. 1, 2001, 2421–2429

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Table 3 1H NMR data (δ, ppm) for compounds 2, 3, 13, 14, 16 and 18–23
Position
2
3
13
14
16
18
19
20
21
22
23
1
2α
2β
3α
3β
5
7
8α
8β
9α
9β
10
1.45
1.97
1.49
2.41
2.07
5.99
2.55
1.77
1.58
1.21
1.75
1.46
—
1.28
1.92
1.28
1.78
1.63
5.70
2.00
1.92
1.01
1.09
1.81
1.28
3.18
—
1.70
2.11
1.16
2.00
2.12
5.88
—
2.20
2.20
1.36
1.70
1.34
—
2.07
2.26
1.76
2.29
2.35
5.59
3.41
1.93
1.64
1.41
1.91
1.52
—
2.21
1.85
1.74
2.55
2.38
2.12
3.56
2.08
1.77
1.62
1.94
1.62
—
1.44
1.93
1.56
2.41
2.04
5.59
1.71
2.06
1.18
1.12
1.66
1.43
—
1.31
1.92
1.50
2.38
2.06
5.76
2.25
1.84
1.64
1.09
1.64
1.40
—
5.77
5.33
5.20
0.98
1.46
—
1.47
1.97
1.51
2.48
2.06
6.51
2.33
1.84
1.37
0.99
1.75
1.49
—
1.38
1.75
1.75
2.67
2.55
9.97
2.75
2.11
1.70
1.21
1.88
1.64
—
5.54
5.04
4.88
0.95
2.15
—
2.17
2.07
1.94
2.49
2.46
2.14
3.65
2.07
1.92
1.58
2.15
2.13
—
2.65
1.97
1.41
2.57
2.32
2.12
3.52
2.07
2.00
1.78
2.07
2.43
—
11
12
—
—
—
—
6.19
1.59
7.88
2.45
—
—
13aa
13bb
14
6.56
5.67
1.02
1.46
—
1.20
6.46
5.63
1.02
1.71
—
6.44
5.62
1.07
—
6.35
5.54
1.12
—
6.35
5.58
0.99
—
6.33
5.56
0.80
—
0.94
1.53
—
0.98
1.43
—
0.99
1.41
—
15
12-OMe
3.74
3.74
3.74
3.57
a Proton cis with 12-functional group. b Proton trans with 12-functional group.
Fig. 8 Critical 2D-NMR correlations used in determining the planar
structures of 28/29 from the acid degradation of 2. Arrows from 13C to
1H indicate two- and three-bond 13C–1H correlations observed in
HMBC; bold lines indicate 1H–1H correlations observed in 1H–1H
COSY.
conversion of 16 to 14 by Robinson annulation would have
required an additional synthetic step [cf. Scheme 2, in which, in
order to obtain 15a (the free acid 11,13-dihydro analogue of
14), the immediate product of acid degradation of artemisinin
1, compound 16a, must first be subjected to cyclization in the
presence of Ba(OH)2ؒ8H2O].32 From the above results, we con-
clude that the presence of unsaturation at the 11,13-position
in 2 results in a greater tendency to undergo intramolecular
aldolization reactions further to the opening of the 1,2,4-
trioxane ring and accompanying loss of formic acid, which are
normally associated with the treatment of 1 with strong acid.
This tendency leads to the direct isolation of decalenones 14,
25, 26 and 27, which have no analogies in the known acid
degradation reactions of 1. The explanation for this effect is not
immediately obvious.
Fig. 6 Some alternative products, 22a, 23a, 24a, 28a and 29a, which
have been reported in the literature from the acid degradation of 1.
Compounds 14a, 25a and 26a have been reported from further
reactions of 16a and 24a.
Addition of the Grignard reagent from methyl iodide to the
ketone group in 14 resulted in the expected approximately 1 : 1
epimeric mixture of tertiary allylic hydroxides 30 and 31. An
alternative addition product 32 was also formed if Grignard
reagent was used in excess (32 appears to be the product of two
successive Grignard reactions with the methyl ester group,
forming a tertiary alcohol, which then participates in SN2Ј
addition to the allylic alcohol group—itself formed by attack of
a third equivalent of methyl Grignard reagent at the 4-position
of the α,β-unsaturated ketone in 14—resulting in a five-
membered lactone ring, see Scheme 4). Although this epimeric
mixture of 30–31 could be separated by HPLC, it was generally
found more expedient simply to treat the crude mixture with
acid in order to induce dehydration, which cleanly yielded the
methyl ester of 6,7-dehydroartemisinic acid 33. The methyl
ester group in 33 could then be hydrolysed to the free acid by
treatment with base, thereby resulting in the target compound,
6,7-dehydroartemisinic acid 13 in good yield. The physical
properties of 13 obtained by synthesis were identical with those
Fig. 7 Proposed mechanism for the formation of 28 and 29 via
intermediate 16 (see Fig. 5) in the acid degradation of 2.
J. Chem. Soc., Perkin Trans. 1, 2001, 2421–2429
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Table 4 1H NMR data (δ, ppm) for compounds 24–33
Position
24
25
26
27
28
29
30
31
32
33
c
c
c
c
c
c
c
c
c
c
1
2α
2β
3α
3β
5α
5β
7
8α
8β
9α
9β
1.31
2.18
2.02
2.38
2.28
2.53
2.83
2.75
2.14
1.88
1.24
1.66
1.63
6.30
5.50
0.99
—
1.55
2.19
1.90
2.33
2.56
2.38
2.51
2.71
1.93
1.40
1.17
1.71
1.47
6.17
5.57
1.02
—
2.11
2.27
1.65
2.30
2.47
5.94
2.65
2.07
1.90
2.32
2.43
5.70
2.45
2.15
1.97
2.03
2.19
1.46
2.55
2.09
1.99
1.98
2.06
1.45
1.39
2.04
1.79
1.83
1.89
5.17
1.69
2.12
1.16
2.00
2.13
5.88
5.04
5.07
3.68
2.03
1.77
1.35
1.60
1.39
6.22
5.47
1.04
—
3.40
1.93
1.71
1.74
1.89
2.22
6.40
5.66
0.98
—
—
—
3.14
3.14
2.37
1.76
1.12
1.11
1.76
1.41
4.84
4.70
0.94
1.62
—
—
c
c
2.19
1.99
1.54
2.24
2.41
6.49
5.51
1.04
—
1.99
1.96
1.65
1.77
2.21
6.51
5.52
1.09
—
2.17
2.17
1.35
1.70
1.33
6.32
5.49
1.02
1.71
3.74
—
c
c
c
c
c
c
c
c
10
13aa
13bb
14
6.35
5.55
0.97
1.20
3.74
—
6.33
5.55
0.99
1.20
3.75
—
15
12-OMe
16
—
—
—
—
—
—
3.76
—
—
3.75
—
—
—
—
—
—
—
—
1.38d
17
—
—
1.27d
—
a Proton cis with 12-functional group. b Proton trans with 12-functional group. c Not assigned. d Interchangeable within column.
1
reported for the natural product (full 13C and H assignments
for 13, made by 2D-NMR as elsewhere, appear in Tables 1 and
3 for the first time and should replace some of the unassigned
and erroneous assignments (e.g. C-6 was previously wrongly
assigned as C-4) made in the initial report of 13 as a natural
product).31
silica gel 60–200 µm (Merck). HPLC separations were per-
formed using a Varian chromatograph equipped with RI
star 9040 and UV 9050 detectors and either a normal phase
Intersil PREP-SIL 20 mm × 25 cm column or a YMC diol 20
mm × 25 cm column, flow rate 8 ml minϪ1. Melting points were
recorded by a Perkin-Elmer differential scanning calorimeter 7
(DSC7). Optical rotations were measured by a Perkin-Elmer
343 Polarimeter (Na 589 nm); [α]D values are given in 10Ϫ1 deg
cm2 gϪ1 and CHCl3 was used as solvent.
Experimental
General
Forward synthesis of artemisitene (2) from artemisinin (1)
Chemical shifts are expressed in ppm (δ) relative to TMS as
internal standard. Proton chemical shifts, multiplicities, coup-
ling constants and integrals reported in this section are those
which are clearly resolved in one-dimensional 1H NMR without
recourse to 2D-NMR analysis (see Tables 1–4 for 2D-NMR
analysis). All NMR experiments were run on a Bruker DRX
Reduction of artemisinin (1). To a solution of 1 (2.4 g,
8.5 mmol) (ex Kunming pharmaceuticals, Kunming, China)
in MeOH (120 ml) cooled in an ice–salt bath was added
NaBH4 (2.4 g) over a period of 100 min. The temperature of
the reaction was maintained below 0 ЊC and stirring continued
for a further 75 min, before CH3COOH was added to neutralize
the mixture. HCl (3 M) was then added dropwise to precipitate
the product. The reaction mixture was left in the fridge over-
night, then filtered and the solid precipitate was re-dissolved
in CHCl3, dried (MgSO4) and solvent removed under reduced
pressure to yield 17 as a 1 : 1 mixture of 12α- and 12β-
500 instrument. HSQC, HMBC, H–1H COSY and NOESY
1
spectra were recorded with 1024 data points in F2 and 256 data
points in F1. High-resolution mass spectra were recorded in
EI mode at 70 eV on a Finnigan-MAT 95 MS spectrometer.
IR spectra were recorded in CHCl3 on a Shimadzu FT-IR-8201
PC instrument. Column chromatography was performed using
Scheme 4 Forward synthesis of 6,7-dehydroartemisinic acid 13 from artemisitene 2.
2426
J. Chem. Soc., Perkin Trans. 1, 2001, 2421–2429

View Article Online
diastereoisomers (2.3 g, 96% w/w) without the need for further
purification. The physical properties of 17 were identical with
those reported previously.36
then taken up in CHCl3 (3 × 100 ml), washed with H2SO4 (5%,
3 × 10 ml), NaHCO3 (5%, 3 × 10 ml) and brine (3 × 50 ml),
then dried (anhydrous Na2SO4) and solvent removed under
reduced pressure to yield a crude product (0.91 g, 91% w/w)
consisting of 2 (0.83 g; 88%) and a little of 21 (0.03 g; 3%).
Compound 2: Solid; mp 159–161 ЊC; [α]D ϩ85.2 (c 3.5,
CHCl3); IR νmax(CHCl3): 3028, 2959, 2932, 2876, 1724, 1629,
1456 cmϪ1; 1H NMR (δ, CDCl3): 6.56 (1H, s), 5.99 (1H, s), 5.67
(1H, s), 2.55 (1H, dd, J = 14.6, 4.5 Hz), 1.46 (3H, s), 1.02 (3H, d,
J = 5.8 Hz), see Table 3 for full assignments; 13C NMR: see
Table 1; CIMS: m/z (rel. int.) 281 [Mϩ ϩ 1] (81%), 263 (89), 245
(78), 235 (91), 217 (100), 177 (95); HREIMS: m/z (rel. int.)
248.1421 [Mϩ Ϫ O2, C15H20O3, requires 248.1412] (3%), 230
(40), 190 (100).
Dehydration of 17. Dry H3PO4 was freshly prepared by over-
night azeotropic distillation of a solution of H3PO4 (5.02 g) in
dry C6H6 (60 ml) in a Dean–Stark apparatus. To a solution
containing H3PO4 (0.20 g) and N,NЈ-dicyclohexylcarbodiimide
(DCC; 4.4 g, 21.2 mmol) in dry C6H6–DMSO (24 ml–3 ml), was
added 17 (2.0 g, 7.04 mmol). The mixture was stirred at room
temperature for 21 h and completion of the reaction was
determined by TLC. Aqueous oxalic acid solution (5%, 100 ml)
was then added and stirring was continued for a further 30 min
before addition of H2O (100 ml) and extraction by Et2O
(4 × 250 ml). The combined organic layers were washed with
brine (3 × 50 ml), dried (anhydrous Na2SO4) and solvent was
removed under reduced pressure. The residue was taken up in
EtOAc–n-hexane (3 : 7; 50 ml) and filtered to remove insoluble
dicyclohexylurea. Following removal of solvent, the crude
product (1.6 g; 80% w/w) was purified by column chroma-
tography (20% EtOAc–n-hexane) to yield 18 (1.28 g; 68%) and 3
(0.20 g; 11%).
Compound 21: Oil; [α]D Ϫ243 (c 0.2, CHCl3); IR νmax
-
(CHCl3): 3566, 2956, 2931, 2873, 1713 cmϪ1 1H NMR (δ,
;
CDCl3): 9.97 (1H, d, J = 1.2 Hz), 5.54 (1H, s), 5.04 (1H, s), 4.88
(1H, s), 2.75 (1H, d, J = 12.7 Hz), 2.67 (1H, ddd, J = 17.2,
9.7, 5.2 Hz), 2.55 (1H, ddd, J = 17.2, 7.8, 5.8 Hz), 2.15 (3H,
s), 0.95 (3H, d, J = 6.5 Hz), see Table 3 for full assignments;
13C NMR: see Table 1.
Compound 18: Oil; [α]D ϩ124.6 (c 6.5, CHCl3); IR νmax
-
Acid degradation of 2 in acetic acid–sulfuric acid–methanol.
Compound 2 (0.80 g, 2.86 mmol) was stirred in AcOH–H2SO4–
MeOH (10 ml–10 ml–10 ml) at 0 ЊC for 30 min. The reaction
mixture was poured into iced water (200 ml) and extracted with
CHCl3 (3 × 50 ml). The combined organic layers were then
washed with water (2 × 50 ml) and brine (50 ml), dried
(MgSO4) and the solvent removed on a rotary evaporator to
yield a crude mixture (330 mg, 41% w/w), which was separated
by HPLC (23% EtOAc–n-hexane): 14 (Rt 25.8 min, 6 mg, 1%);
16 (Rt 28.6 min, 92 mg, 12%); 22 (Rt 37.5 min, 8 mg, 1%); 23 (Rt
37.7 min, 37 mg, 5%); 24 (Rt 49.0 min, 15 mg, 2%); 25 (Rt 63.6
min, 73 mg, 11%); 28/29 (Rt 31.9 min, 12 mg, 2%).
(CHCl3): 3028, 2999, 2930, 1686, 1456 cmϪ1 1H NMR (δ,
;
CDCl3): 6.19 (1H, d, J = 1.1 Hz), 5.54 (1H, s), 1.59 (3H, d,
J = 0.8 Hz), 1.43 (3H, s), 0.98 (3H, d, J = 6.0 Hz), see Table 3
for full assignments; 13C NMR: see Table 1; HREIMS: m/z
(rel. int.) 266.1517 [Mϩ, C15H22O4, requires 266.1518] (42%),
237 (10), 166 (31), 162 (100), 133 (53).
Compound 3: Oil; [α]D Ϫ42.8 (c 5.1, CHCl3); IR νmax
(CHCl3): 3020, 2930, 2876, 1744, 1459 cmϪ1 1H NMR (δ,
;
CDCl3): 5.70 (1H, s), 3.18 (1H, dq, J = 4.5, 7.3 Hz), 2.00 (1H,
ddd, J = 14.0, 4.5, 4.0 Hz), 1.53 (3H, s), 1.20 (3H, d, J = 7.3 Hz),
0.94 (3H, d, J = 5.9 Hz), see Table 3 for full assignments; 13C
NMR: see Table 1; HREIMS: m/z (rel. int.) 266.1521 [Mϩ,
C15H22O4, requires 266.1518] (10%), 234 (10), 221 (100), 210
(18), 180 (25), 163 (100), 152 (50).
Compound 14: Oil; [α]D Ϫ97.6 (c 4.6, CHCl3); IR νmax
-
(CHCl3): 3011, 2955, 2875, 1717, 1666, 1632, 1441 cmϪ1; H
NMR (δ, CDCl3): 6.44 (1H, s), 5.63 (1H, s), 5.59 (1H, s), 3.74
(3H, s), 3.41 (1H, dd, J = 13.1, 3.5 Hz), 1.64 (1H, dddd,
J = 13.4, 13.4, 13.1, 2.3 Hz), 1.41 (1H, dddd, J = 13.4, 12.9,
12.9, 3.7 Hz), 1.07 (3H, d, J = 6.4 Hz), see Table 3 for full
assignments; 13C NMR: see Table 1; HREIMS: m/z (rel. int.)
248.1423 [Mϩ, C15H20O3, requires 248.1412] (18%), 233 (4), 216
(100), 189 (29), 188 (30).
1
Photo-oxygenation of 18. A stirred solution of 18 (1.2 g, 4.51
mmol) in acetone (100 ml) containing Methylene Blue (5.0 mg)
was subjected to strong light (500 W bulb) and maintained at
25 ЊC. After 4 h, when TLC showed the complete disappearance
of the starting material, acetone was removed under reduced
pressure and replaced by Et2O (100 ml) in order to precipitate
the photosensitizer. Insoluble Methylene Blue was filtered off
and the crude product mixture (1.15 g; 96% w/w) was separated
by column chromatography (25% EtOAc–n-hexane) to yield 19
(1.06 g, 79%) and 20 (0.14 g, 10%) as a minor side-product.
Compound 19: Solid; mp 148–150 ЊC; [α]D ϩ158 (c 0.8,
CHCl3); IR νmax (CHCl3): 3387 (br), 3028, 2932, 2854, 1456,
1379 cmϪ1; 1H NMR (δ, CDCl3): 9.39 (1H, s, -OOH), 5.77 (2H,
s), 5.33 (1H, s), 5.20 (1H, s), 2.38 (1H, ddd, J = 13.6, 13.6, 4.0
Hz), 2.25 (1H, dd, J = 11.5, 4.2 Hz), 2.06 (1H, ddd, J = 13.6,
4.3, 4.3 Hz), 1.84 (1H, dddd, J = 12.9, 4.2, 3.4, 3.4 Hz), 1.46
(3H, s), 1.09 (1H, dddd, J = 12.9, 11.9, 11.9, 3.6 Hz), 0.98 (3H,
d, J = 6.3 Hz), see Table 3 for full assignments; 13C NMR: see
Table 1; CIMS: m/z (rel. int.) 281 [Mϩ ϩ 1 Ϫ H2O] (6%), 265
(82), 235 (50), 219 (100), 177 (78).
Compound 16: Oil; [α]D Ϫ46.7 (c 0.3, CHCl3); IR νmax
-
(CHCl3): 3120, 2926, 1767, 1713, 1438 cmϪ1 1H NMR (δ,
;
CDCl3): 6.35 (1H, s), 5.54 (1H, s), 3.74 (3H, s), 3.56 (1H, dd,
J = 13.2, 5.2 Hz), 2.55 (1H, ddd, J = 17.4, 9.6, 5.2 Hz), 2.38 (1H,
ddd, J = 17.4, 9.3, 6.2 Hz), 2.21 (1H, ddd, J = 10.5, 9.3, 5.2 Hz),
2.12 (3H, s), 1.12 (3H, d, J = 6.0 Hz), see Table 3 for full
assignments; 13C NMR: see Table 1; HREIMS: m/z (rel. int.)
266.1516 [Mϩ, C15H22O4, requires 266.1518] (1%), 248 (50), 234
(23), 191 (18), 176 (100).
Compound 22: Oil; [α]D ϩ9.7 (c 0.3, CHCl3); IR νmax(CHCl3):
3011, 2955, 1715 cmϪ1; 1H NMR (δ, CDCl3): 6.35 (1H, s), 5.88
(1H, d, J = 0.4 Hz), 3.74 (3H, s), 3.65 (1H, dd, J = 11.4, 5.6 Hz),
2.14 (3H, s), 0.99 (3H, d, J = 7.1 Hz), see Table 3 for full
assignments; 13C NMR: see Table 1; HREIMS: m/z (rel. int.)
266.1512 [Mϩ, C15H22O4, requires 266.1518] (3%), 248 (56), 234
(32), 191 (20), 176 (100).
Compound 20: Oil; [α]D Ϫ54 (c 1.0, CHCl3); IR νmax(CHCl3):
2987, 2874, 1730, 1706 cmϪ1; 1H NMR (δ, CDCl3): 7.88 (1H, d,
J = 0.9 Hz), 6.51 (1H, s), 2.45 (3H, s), 2.33 (1H, dd, J = 13.1, 3.4
Hz), 1.41 (3H, s), 0.99 (3H, d, J = 5.8 Hz), see Table 3 for full
assignments; 13C NMR: see Table 1; HREIMS: m/z (rel. int.)
266.1514 [Mϩ Ϫ O2, C15H22O4 requires 266.1518] (1%), 237
(16), 219 (100), 177 (22), 163 (90), 159 (40), 124 (82).
Compound 23: Oil; [α]D ϩ16.3 (c 0.5, CHCl3); IR νmax
-
(CHCl3): 3034, 2955, 1713, 1438 cmϪ1; H NMR (δ, CDCl3):
6.33 (1H, s), 5.56 (1H, s), 3.75 (3H, s), 3.52 (1H, dd, J = 12.2,
5.9 Hz), 2.65 (1H, ddd, J = 9.1, 4.8, 4.8 Hz), 2.57 (1H, ddd,
J = 17.6, 8.6, 5.7 Hz), 2.43 (1H, m), 2.32 (1H, ddd, J = 17.6,
13.5, 6.7 Hz), 2.12 (3H, s), 0.80 (3H, d, J = 7.2 Hz), see Table 3
for full assignments; 13C NMR: see Table 1; HREIMS: m/z
(rel. int.) 266.1520 [Mϩ, C15H22O4, requires 266.1518] (1%),
248 (60), 234 (25), 191 (12), 176 (100).
1
Dehydration of 19. Compound 19 (1.0 g, 3.36 mmol) was
dissolved in Ac2O–pyridine (6 ml–0.3 ml) and the solution
was stirred at room temperature for 50 min. Completion of the
reaction was determined by TLC and the reaction mixture was
Compound 24: Oil; [α]D Ϫ1.5 (c 0.8, CHCl3); IR νmax(CHCl3):
1
3026, 2963, 1763, 1719, 1456 cmϪ1; H NMR (δ, CDCl3): 6.30
J. Chem. Soc., Perkin Trans. 1, 2001, 2421–2429
2427

View Article Online
(1H, d, J = 3.4 Hz), 5.50 (1H, d, J = 3.4 Hz), 2.83 (1H, d,
J = 16.3 Hz), 2.75 (1H, m), 2.53 (1H, ddd, J = 16.3, 1.8, 1.8 Hz),
2.38 (1H, dd, J = 15.1, 1.8 Hz), 2.28 (1H, ddd, J = 15.1, 14.8, 5.5
Hz), 0.99 (3H, d, J = 6.4 Hz), see Table 4 for full assignments;
13C NMR: see Table 2; HREIMS: m/z (rel. int.) 234.1246 [Mϩ,
C14H18O3, requires 234.1256] (26%), 216 (26), 176 (80), 111
(100).
when a larger excess of Grignard reagent was used in the
reaction.
Compound 30 (Rt 22.1 min; 68 mg, 32%): Oil; [α]D Ϫ48.2
(c 1.2, CHCl3); IR νmax(CHCl3): 3460 (br), 3007, 2953, 2870,
1717, 1628, 1439 cmϪ1 1H NMR (δ, CDCl3): 6.35 (1H, d,
;
J = 1.0 Hz), 5.55 (1H, dd, J = 1.0, 1.0 Hz), 5.04 (1H, s), 3.74
(3H, s), 3.14 (1H, ddd, J = 11.6, 1.0, 1.0 Hz), 1.20 (3H, s), 0.97
(3H, d, J = 6.2 Hz); 13C NMR: see Table 2 for partially assigned
data; HREIMS: m/z (rel. int.) 264.1735 [Mϩ, C16H24O3, requires
264.1725] (1%), 246 (78), 231 (20), 214 (11), 187 (100), 171 (23).
Compound 31 (Rt 19.3 min; 75 mg, 35%): Oil; [α]D Ϫ54.8
(c 1.3, CHCl3); IR νmax(CHCl3): 3420 (br), 3034, 2926, 2858,
1717, 1440 cmϪ1; 1H NMR (δ, CDCl3): 6.33 (1H, d, J = 1.0 Hz),
5.55 (1H, d, J = 1.0 Hz), 5.07 (1H, s), 3.75 (3H, s), 3.14 (1H, d,
J = 13.1 Hz), 1.20 (3H, s), 0.99 (3H, d, J = 6.2 Hz); 13C NMR:
see Table 2 for partially assigned data; HREIMS: m/z (rel. int.)
264.1721 [Mϩ, C16H24O3, requires 264.1725] (1%), 246 (90), 231
(23), 214 (12), 203 (16), 187 (100), 171 (27).
Compound 32 (Rt 9.8 min, 3% EtOAc–n-hexane; 12 mg,
6%): Oil; [α]D Ϫ4.3 (c 0.38, CHCl3); IR νmax(CHCl3): 3020, 2932,
2872, 1456 cmϪ1; 1H NMR (δ, CDCl3): 5.17 (1H, s), 4.84 (1H, d,
J = 2.6 Hz), 4.70 (1H, d, J = 2.6 Hz), 2.37 (1H, d, J = 9.2 Hz),
1.62 (3H, s), 1.38 (3H, s), 1.27 (3H, s), 0.94 (3H, d, J = 6.2 Hz),
see Table 4 for full assignments; 13C NMR: see Table 2;
HREIMS: m/z (rel. int.) 246.1979 [Mϩ, C17H26O, requires
264.1984] (36%), 231 (63), 228 (83), 213 (100), 201 (45), 171
(50).
Compound 25: Oil; 1H NMR (δ, CDCl3): 6.17 (1H, d, J = 1.2
Hz), 5.57 (1H, d, J = 1.2 Hz), 2.71 (1H, dd, J = 9.5, 6.8 Hz), 2.56
(1H, dddd, J = 15.6, 4.4, 2.5, 2.2 Hz), 2.51 (1H, dd, J = 15.0, 2.2
Hz), 2.38 (1H, d, J = 15.0 Hz), 2.33 (1H, ddd, J = 15.6, 12.8, 7.1
Hz), 2.19 (1H, m), 1.02 (3H, d, J = 6.5 Hz), see Table 4 for
assignments; 13C NMR: see Table 2; HREIMS: m/z (rel. int.)
234.1252 [Mϩ, C14H18O3, requires 234.1256] (91%), 206 (100),
177 (65), 161 (65).
Compound 26: Oil; [α]D ϩ4.1 (c 0.3, CHCl3); IR νmax(CHCl3):
1
3028, 2957, 2872, 1719, 1668, 1624, 1439 cmϪ1; H NMR (δ,
CDCl3): 6.22 (1H, s), 5.94 (1H, s), 5.47 (1H, d, J = 1.6 Hz), 3.76
(3H, s), 3.68 (1H, m), 2.47 (1H, ddd, J = 16.2, 4.8, 3.0 Hz), 1.04
(3H, d, J = 6.4 Hz), see Table 4 for assignments; 13C NMR: see
Table 2; HREIMS: m/z (rel. int.) 248.1410 [Mϩ, C15H20O3,
requires 248.1412] (100%), 233 (45), 216 (85), 201 (15), 188 (75).
Compound 27: isolated as an inseparable mixture with 23.
Characterized as a mixture by 2D-NMR. 1H NMR (δ, CDCl3):
6.40 (1H, s), 5.70 (1H, s), 5.66 (1H, s), 3.75 (3H, s), 3.40 (1H,
m), 0.98 (3H, d, J = 7.1 Hz), see Table 4 for assignments; 13C
NMR: see Table 2; HREIMS: as for 23.
Compound 28: Oil; [α]D ϩ57.5 (c 0.2, CHCl3); IR νmax
-
1
(CHCl3): 3020, 2949, 1769, 1718 cmϪ1; H NMR (δ, CDCl3):
6.49 (1H, s), 5.51 (1H, s), 1.46 (3H, s), 1.04 (3H, d, J = 7.2 Hz),
see Table 4 for full assignments; 13C NMR: see Table 3;
HREIMS: m/z (rel. int.) 234.1251 [Mϩ, C14H18O3, requires
234.1256] (15%), 209 (15), 176 (100).
Dehydration of 30 and 31. To the crude mixture of 30 and 31
(0.09 g, 0.34 mmol) in Et2O (10 ml) was added H2SO4 (70%,
2 ml). The reaction mixture was stirred overnight at room
temperature, extracted by Et2O (3 × 20 ml), washed with brine
(3 × 10 ml), dried (MgSO4) and solvent was removed under
reduced pressure to yield 33 (0.07 g; 83%) without the need for
further purification.
Compound 29: isolated as an inseparable mixture with 28.
Characterized as a mixture by 2D-NMR. 1H NMR (δ, CDCl3):
6.51 (1H, s), 5.52 (1H, s), 1.45 (3H, s), 1.09 (3H, d, J = 6.9 Hz),
see Table 4 for assignments; 13C NMR: see Table 2; HREIMS:
as for 28.
Compound 33: Oil; [α]D ϩ13.5 (c 0.9, CHCl3); IR νmax
-
(CHCl3): 2930, 2874, 1713, 1618, 1456, 1437 cmϪ1; 1H NMR (δ,
CDCl3): 6.32 (1H, d, J = 1.8 Hz), 5.88 (1H, s), 5.49 (1H, d,
J = 1.8 Hz), 3.74 (3H, s), 1.71 (3H, s), 1.02 (3H, d, J = 5.9 Hz),
see Table 4 for full assignments; 13C NMR: see Table 2;
HREIMS: m/z (rel. int.) 246.1623 [Mϩ, C16H22O2, requires
246.1620] (12%), 203 (50), 187 (100), 111 (85).
Forward synthesis of 6,7-dehydroartemisinic acid (13) from
artemisitene (2)
Acid degradation of 2 in sulfuric acid–methanol. To a solution
of 2 (0.8 g, 2.86 mmol) in MeOH (18 ml) cooled in an ice bath,
was added conc. H2SO4 (12 ml) and the reaction was stirred
at room temperature for 3 h. H2O (50 ml) and CHCl3 (50 ml)
were added to the reaction mixture, which was extracted by
CHCl3 (3 × 100 ml). The combined organic layers were washed
by Na2CO3 solution (5%, 3 × 20 ml) and brine (3 × 50 ml),
dried (MgSO4) and solvent was removed under reduced
pressure to obtain a crude product (0.74 g, 93% w/w), which
was separated by CC (30% EtOAc–n-hexane) to yield 14
(0.50 g, 70%).
Hydrolysis of the ester in 33. To a solution of 33 (0.02 g,
0.08 mmol) in MeOH–H2O (10 ml–10 ml) was added KOH
powder (0.05 g). The reaction mixture was refluxed overnight,
then acidified by dropwise addition of HCl (10%) to pH 2,
extracted by CHCl3 (3 × 30 ml), washed with brine (3 × 10 ml),
dried (MgSO4) and solvent removed under reduced pressure
to yield 13 (0.016 g; 85%) without the need for further
purification.
Compound 13: Oil; [α]D ϩ160.0 (c 1.6, CHCl3); IR νmax
-
(CHCl3): 3400–2700 (br), 3020, 2928, 1693, 1435 cmϪ1 1H
;
NMR (δ, CDCl3): 6.46 (1H, d, J = 2.0 Hz), 5.88 (1H, br s), 5.61
(1H, d, J = 2.0 Hz), 1.71 (3H, s), 1.02 (3H, d, J = 6.1 Hz),
see Table 3 for full analysis; 13C NMR: see Table 1; HREIMS:
m/z (rel. int.) 232.1458 [Mϩ, C15H20O2, requires 232.1463]
(50%), 217 (16), 187 (100), 153 (35).
Reaction of 14 with a methyl Grignard reagent. To small Mg
chips (0.044 g, 1.79 mmol) in anhydrous Et2O (30 ml) was
added MeI (0.132 ml, 1.43 mmol) in anhydrous Et2O (10 ml)
and the reaction mixture was refluxed under N2 for 2 h. A
solution of 14 (0.2 g, 0.81 mmol) in anhydrous Et2O (20 ml) was
added dropwise and reflux continued for a further 2.5 h until
the reaction was complete, as determined by TLC. The reaction
mixture was cooled by an ice bath and H2O (20 ml) was added
to destroy the excess Grignard reagent. The reaction mixture
was then extracted by Et2O (3 × 30 ml) and the combined
organic layers were washed with brine (3 × 10 ml), dried (Mg-
SO4) and the solvent was removed under reduced pressure to
yield a crude mixture consisting of 30 and 31 (0.15 g, 75% w/w)
which could be separated by HPLC (20% EtOAc–n-hexane–
0.5% CH3COOH).
Acknowledgements
We thank the Generic Drug Research Project of the Chemistry
Department of the University of Hong Kong for providing a
postdoctoral fellowship to Dr Lai-King Sy. Mr Kin-Fai Ho,
Gary performed some preliminary synthetic studies. This
research was funded by a grant from the CRCG.
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2428
J. Chem. Soc., Perkin Trans. 1, 2001, 2421–2429

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