Stereoselective preparation of 10α- and 10β-aryl derivatives of dihydroartemisinin

Article abstract of DOI:10.1002/ejoc.200300064

Lewis acid-catalysed arylation of the 10β-benzoate and, less effectively, the 10α-benzoate of dihydroartemisinin [DHA] with activated aromatic compounds, including naphthalenes, stereoselectively, provides 10α-aryl derivatives including disubstituted naphthalene derivatives. 2-Methoxynaphthalene provides the 1-, rather than the 3-substituted derivative. In contrast, 10β-aryl derivatives are obtained stereoselectively from the 10β-bromide, generated in situ from trimethylsilyl bromide and the TMS ether of 10α-DHA, and the corresponding aryl Grignard reagents. The 10α-aryl compounds are shown by NMR spectroscopy and X-ray crystallographic analysis to possess a chair pyranose ring with equatorial aryl group, whereas the 10β-aryl derivatives have a twist-boat pyranose ring with equatorial aryl group. The stereochemistry of the Lewis acid-catalysed arylations, which is common to that observed for the Lewis acid-catalysed arylation of pyranosyl glycosides with axial anomeric leaving groups in general, may be rationalized in terms of axial attack from the α or si face of the half-chair oxonium ion intermediate. On the other hand, the Grignard reagents activate the axial bromide to elimination through complexation, and thereby the aryl nucleophile attacks the incipient oxonium ion from the β or re face. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300064

FULL PAPER
Stereoselective Preparation of 10α- and 10β-Aryl Derivatives of
Dihydroartemisinin
Richard K. Haynes,*[a] Ho-Wai Chan,[a] Man-Ki Cheung,[a] Shuk Ting Chung,[a]
Wai-Lun Lam,[a] Hing-Wo Tsang,[a] Arnd Voerste,[a][‡] and Ian D. Williams[a]
Keywords: C-Arylation / Diastereoselectivity / Dihydroartemisinin / Glycosylation / Grignard reaction
Lewis acid-catalysed arylation of the 10β-benzoate and, less
effectively, the 10α-benzoate of dihydroartemisinin [DHA]
with activated aromatic compounds, including naphthalenes,
pyranose ring with equatorial aryl group. The stereochem-
istry of the Lewis acid-catalysed arylations, which is common
to that observed for the Lewis acid-catalysed arylation of
stereoselectively, provides 10α-aryl derivatives including di- pyranosyl glycosides with axial anomeric leaving groups in
substituted naphthalene derivatives. 2-Methoxynaphthalene
provides the 1-, rather than the 3-substituted derivative. In
contrast, 10β-aryl derivatives are obtained stereoselectively
from the 10β-bromide, generated in situ from trimethylsilyl
general, may be rationalized in terms of axial attack from the
α or si face of the half-chair oxonium ion intermediate. On
the other hand, the Grignard reagents activate the axial
bromide to elimination through complexation, and thereby
bromide and the TMS ether of 10α-DHA, and the corres- the aryl nucleophile attacks the incipient oxonium ion from
ponding aryl Grignard reagents. The 10α-aryl compounds
are shown by NMR spectroscopy and X-ray crystallographic
analysis to possess a chair pyranose ring with equatorial aryl
group, whereas the 10β-aryl derivatives have a twist-boat
the β or re face.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction[1]
Artemisinin (1, qinghaosu) and its derivatives artemether
(3) and artesunate (4) represent a distinct, highly effective
class of antimalarial drugs developed by Chinese
groups.[2Ϫ6] Arteether (5), first prepared in China, has been
developed as an injectable formulation outside China,[7] and
artelinate (6)[8] is to be developed as a formulation suitable
for intravenous administration. Thus, all derivatives cur-
rently in use, or to be developed, are either alkyl acetals or
an ester acetal derivative of dihydroartemisinin (DHA, 2).
The problem with such compounds, however, is that they
have short pharmacological half-lives, a reflection of their
acid lability, and facile metabolism to DHA,[8,9] a highly
neurotoxic compound.[10] In particular, artesunate is hydro-
lytically unstable, even at neutral pH, and has a half-life of
just several minutes.[11] Whilst a large amount of work has
been carried out with the aim of generating new deriva-
tives,[3,4] so far no putative second-generation artemisinin
derivative has been found suitable for carrying forward to
development as an antimalarial drug. The work has also
been given added impetus by the demonstrated biological
activity of artemisinin and its derivatives against other
parasitic[5,12Ϫ14] and cellular targets.[15Ϫ17] Particularly with
regard to the last activity, we were interested in generating
more-stable derivatives bearing intercalating groups at C-
10.[18] We have described the stereoselective preparation of
acetal ester and ether derivatives bearing such groups.[19]
Whilst some of these compounds display promising cyto-
Department of Chemistry, The Hong Kong University of toxic activities,[18] they possess, however, an acetal at C-10,
[a]
Science and Technology,
and so the stability problem has not been adequately ad-
dressed.
Improved stability is obtained if the acetal at C-10 is con-
verted into an ether through replacement of the exocyclic
oxygen atom by a hydrogen atom, or alkyl or aryl groups.
Clear Water Bay, Kowloon, Hong Kong, PR China
Fax: (internat.) ϩ 852-23581594
E-mail: haynes@ust.hk
[‡]
Current affiliation: Bayer AG, PF-F/S1, Geb. 6540, Bayer
Landwirtschaftszentrum,
40789 Monheim, Germany
2098
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300064
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10α- and 10β-Aryl Derivatives of Dihydroartemisinin
FULL PAPER
Thus, 10-deoxodihydroartemisinin (7) was prepared inde- of the monomeric arylated artemisinin derivative 13 with
pendently by two groups.[20,21] Derivatives of DHA in which the fluoride 12 in the presence of boron
the C-10 hydroxy group is replaced by an alkyl or aryl trifluorideϪdiethyl ether.[37]
group were made by indirect semisynthetic routes from
qinghao acid.[16,22Ϫ26] In this way, our group was the first
to prepare the carba analogues 8 and 9 of artemether and
artesunate respectively, and the allyl and aryl derivatives 10
and 11.[24] These procedures, however, typically involved
four to five steps, including generation and subsequent elab-
oration of a hydroperoxide to construct the artemisinin de-
rivative.[27,28]
The breakthrough in accessibility came with the demon-
stration by Pu and Ziffer[29] that C-glycosidation method-
ology may be used to prepare the β-allyl derivative 10 di-
rectly from DHA through the use of allyl(trimethyl)silane
and boron trifluorideϪdiethyl ether to activate the hydroxy
group to displacement. As only the β derivative was ob-
tained, it appeared that selective activation of α-DHA by
the boron trifluorideϪdiethyl ether and axial displacement
from the β or re face[1] by the allyltrimethylsilane was taking
place. As shall be seen below, however, this premise is incor-
rect. Transformation of the allyl group enabled other com-
pounds, including ‘‘carba-artemether’’ (8), to be prepared
Other examples of C-arylation processes have been re-
ported. Treatment of the α-acetate 18 of DHA with 2-naph-
thol in the presence of boron trifluorideϪdiethyl ether gave
the derivatives 20 and 21 as a 1:1 mixture in 68% overall
with relative ease. Other groups have subsequently reported
similar chemistry.[30,31]
yield.[38] Formation of compound 21 involving epimeriz-
ation at C-9 implied the intermediacy of the glycal 19,[3]
formed by Lewis acid-induced elimination of acetic acid
from compound 18.[38] The overall transformation was
therefore held to proceed by an acid-catalysed addition of
the naphthol to the glycal followed by OϪC rearrangement
of an intermediate naphthol ether, a characteristic reaction
attending Lewis acid-catalysed O-glycosidation reactions of
sugars with aromatic alcohols.[32,39] As shall be seen below,
this process is not likely to be the case. A reaction com-
mencing with acetate 18 and 1,3-dimethoxybenzene pro-
vided products 13 (26%) and 22 (9%).[40] Formation of the
latter, but not the former product, was presumed to proceed
1
via glycal 19. According to analysis of H NMR spectro-
scopic data, compound 21 possesses a twist-boat pyranose
In an extension of the Ziffer method, we turned to acti-
vated derivatives of DHA modelled on those used in C-
ring with an equatorial methyl group at C-9, and an equa-
glycosidation reactions,[32] and prepared 10β-(fluoro)(deoxo)-
torial aromatic group at C-10,[38] whereas compound 22
dihydroartemisinin (12) from DHA and (diethylamino)-
possesses a chair pyranose ring, with an axial methyl group
sulfur fluoride.[14,18,33] This compound decomposes on stor-
at C-9 and an equatorial aromatic substituent at C-10.[40,41]
age, however, and this instability, coupled with its expensive
preparation, the need to separate it from the less-stable 10α
isomer, and the low yield (51%), militate against its useful-
ness. Nevertheless, the same fluoride was used later by
Posner and coworkers to prepare C-10 alkyl, arylalkynyl
and aryl derivatives of DHA from electron-rich aromatics,
aluminium alkyls and arylalkynyls in the presence of boron
trifluorideϪdiethyl ether.[34,35] Thus, the α-aryl derivatives
13 (71%),[36] 14 (95%), and the furan 15 (72%) were ef-
ficiently prepared. The 3-substituted-2,7-(dimethoxy)naph-
thalene derivative 16 was also claimed, but, as seen below,
the actual product is likely to be a different regioisomer. In
a noteworthy extension of this work, the disubstituted di-
meric arylated derivative 17 was also obtained by treatment
Eur. J. Org. Chem. 2003, 2098Ϫ2114
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R. K. Haynes et al.
FULL PAPER
We report here the conversion of DHA into both 10α- duced benzoylation of the activated aromatic group by the
and 10β-C-arylated compounds by application of C-glycos- benzoates 25 or 26, with concomitant formation of DHA,
idation methodologies,[32] as part of a larger programme which undergoes condensation with the benzoate; the puta-
aimed at preparing new artemisinin derivatives tailored for tive diaryl ketone, however, was not detected. The stereo-
cytotoxic and antiparasitic activities.[13,14,18]
chemistry of this compound, with one artemisinyl unit
linked to the bridging oxygen atom via an equatorial bond
and the other via an axial bond, is in agreement with the
rule that the equatorial epimer of DHA reacts as a nucle-
ophile.[19] As an oxygen-centred nucleophile, this epimer of
DHA undergoes axial addition to the stabilized oxonium
Results and Discussion
α-Aryl Derivatives
Whilst DHA can be converted quantitatively into glycal cation produced from the benzoate and the Lewis acid, as
19 with boron trifluorideϪdiethyl ether in ether,[3,42] or with dictated by the anomeric effect.[19]
methanesulfonyl chloride in dichloromethane containing
triethylamine, reaction of the latter with 1,3,5-trimethoxyb-
enzene in the presence of Lewis acids was not stereoselec-
tive in giving mixtures of compounds 14 and 23 in low
yields. In attempting to apply the highly effective C-aryl gly-
cosidation methodology of Schmidt and coworkers[43] to
DHA, we prepared the equatorial α-(trichloro)acetimidate
intermediate 24 in situ from DHA and (trichloro)acetonitr-
ile.[19] Activation, however, of this intermediate with a vari-
ety of Lewis acids followed by treatment with reactive aro-
matic nucleophiles did not give satisfactory yields of prod-
ucts. This unsatisfactory outcome may be due to the
‘‘wrong’’ (equatorial) stereochemistry of the (trichloro)acet-
imidate; in the original work of Schmidt and co-workers,
axial (trichloro)acetimidates were used.[43] Therefore, we
used the β-benzoate 25 with an axial leaving group, pre-
pared from DHA by the Schmidt procedure,[19] and, for
comparative purposes, the α-benzoate[19,44,45] 26 with an
equatorial leaving group. Both compounds are indefinitely
stable and easily handled.
Figure 1. Structures of α-arylated 10-deoxo-10-dihydroartemisinin
derivatives and other products obtained fromreactions of DHA β-
benzoate 25 and α-benzoate 26 with activated aromatic compounds
in presence of BF3·OEt2 and SnCl4
Structures of arylated products obtained from the reac-
tions of β-benzoate 25 and α-benzoate 26 with a series of
activated aromatics in the presence of boron
trifluorideϪdiethyl ether or tin() chloride are depicted in
Figure 1, and the reaction conditions and results are sum-
The outcome of the reactions of the β-benzoate 25 with
marized in Table 1. The β-benzoate was generally the more 1,3-dimethoxybenzene (Table 1, Entries 1Ϫ6) was more
effective donor, and in the reaction of the N-methylindole complex than that reported for the β-fluoride 12.[34,35,37]
(Entries 12, 13), the α-benzoate failed to give the required The products were the α-arylated product 13,[36] the disub-
product at all. In many cases, the glycal 19 was formed as stituted aryl product 17, the glycal 19 and small amounts
a byproduct, together with varying amounts of the ‘‘α,β’’- of an aromatic regioisomer of compound 13, possibly com-
linked dimeric acetal 27, identified by comparison with an pound 28, which could not be separated from compound
1
authentic sample prepared from reaction of the β-benzoate 13. Compound 28 was detectable in mixtures by H NMR
25 and DHA with boron trifluorideϪdiethyl ether, or more spectroscopy, and was tentatively identified through the
directly, from DHA and p-toluenesulfonyl chloride and tri- similarities of chemical shifts of the methoxyl groups on the
ethylamine. The compound has been mentioned previously aromatic ring, 10-H, 9-H and the C-15 methyl group with
in the literature.[3,15,46] How it is formed in the arylation the corresponding protons in compound 14, as indicated in
reactions is not clear. Possibly, it arises by Lewis acid-in- the Exp. Sect. The use of a larger amount of the Lewis acid
2100
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Eur. J. Org. Chem. 2003, 2098Ϫ2114

10α- and 10β-Aryl Derivatives of Dihydroartemisinin
FULL PAPER
Table 1. Yields of α-arylated derivatives and other products obtained from reactions of DHA β-benzoate 25 and α-benzoate 26 with
activated aromatic compounds in presence of BF3·OEt2 and SnCl4
Entry 25 or 26 ArH (equiv. with respect to starting benzoate), reaction conditions
Arylated derivative,
yield (%)[a]
Other products,
yield (%)[a]
1
2
25
25
1,3-C6H4(OMe)2 (1.5 equiv.), BF3·OEt2 (0.2 equiv.), Ϫ30 °C, 60 min
1,3-C6H4(OMe)2 (1.5 equiv.), BF3·OEt2 (0.1 equiv.), Ϫ30 °C, 60 min
13
25[b]
3
19
33[c]
10
17
28
13
17
28
13
28
13
22
28
13
17
22
28
13
17
28
14
27
14
27
7[b]
19[b]
33
[d]
6[b]
14[b]
5[b]
16[b]
2[e]
Ͻ1[b]
9[b]
6
3
4
25
26
1,3-C6H4(OMe)2 (1.5 equiv.), BF3·OEt2 (0.1 equiv.), 0 °C, 60 min
1,3-C6H4(OMe)2 (1.5 equiv.), BF3·OEt2 (0.1 equiv.), 0 °C, 60 min
19
19
20[c]
47[c]
5
6
25
25
1,3-C6H4(OMe)2 (0.5 equiv.), BF3·OEt2 (0.2 equiv.), Ϫ30 °C, 60 min
1,3-C6H4(OMe)2 (1.5 equiv.), SnCl4 (0.1 equiv.), Ϫ30 °C, 60 min
19
27
19
40
7
1[f]
4[b]
20[b]
29
17[c]
7[b]
71
7
8
9
25
26
25
1,3,5-C6H3(OMe)3 (1.5 equiv.), BF3·OEt2 (0.1 equiv.), Ϫ30 °C, 60 min
1,3,5-C6H3(OMe)3 (1.5 equiv.), BF3·OEt2 (0.1 equiv.), Ϫ30 °C, 55 min
furan (1.5 equiv.), BF3·OEt2 (0.1 equiv.), Ϫ30 °C, 60 min
19
11
5
57
19
27
19
12
3
9
؊
27
37
[d]
10
11
12
13
14
25
25
25
25
25
furan (15.0 equiv.), BF3·OEt2 (2.0 equiv.), Ϫ30 °C, 60 min
pyrrole (1.5 equiv.), BF3·OEt2 (2.0 equiv.), Ϫ30 °C, 60 min
N-methylindole (1.5 equiv.), BF3·OEt2 (0.1 equiv.), Ϫ30 °C, 80 min
N-methylindole (1.5 equiv.) SnCl4 (0.1 equiv.), Ϫ30 °C, 65 min
1-methoxynaphthalene (1.5 equiv.), SnCl4 (0.1 equiv.), Ϫ30 °C, 75 min
15
29
30
30
31
32
35
82
21[g]
73
13
5
13
44
36
18
19
15
38
74
44
[d]
27
8[g]
30
[d]
19
[d]
[d]
[d]
[d]
15
16
17
18
25
25
26
25
2-methoxynaphthalene (1.5 equiv.), BF3·OEt2 (0.1 equiv.), Ϫ30 °C, 65 min 33
2-methoxynaphthalene (1.5 equiv.), SnCl4 (0.1 equiv.), Ϫ30 °C, 60 min
2-methoxynaphthalene (1.5 equiv.), SnCl4 (0.1 equiv.), Ϫ30 °C, 60 min
33
33
2,6-dimethoxynaphthalene (1.5 equiv.), SnCl4 (0.1 equiv.), Ϫ30 °C, 60 min 34
35
2,6-dimethoxynaphthalene (1.5 equiv.), SnCl4 (0.1 equiv.), Ϫ30 °C, 60 min 34
35
[d]
19
26
[d]
[d]
20
21
25
26
2,7-dimethoxynaphthalene (1.5 equiv.), SnCl4 (0.1 equiv.), Ϫ30 °C, 60 min 36
2,7-dimethoxynaphthalene (1.5 equiv.), SnCl4 (0.1 equiv.), Ϫ30 °C, 60 min 36
[a]
[b]
1
[c]
Isolated yields, except where indicated. Mixture of 13 and 28; yield estimated by H NMR spectroscopy. Mixture of 13 and 1,3-
1
[d]
[e]
dimethoxybenzene; yield estimated by H NMR spectroscopy.
22; yield estimated by H NMR spectroscopy. Mixture of 22 and 27, yield estimated by H NMR spectroscopy. Mixture of 27 and
30; yield estimated by H NMR spectroscopy.
No attempt was made to isolate other products. Mixture of 19 and
1 [g]
1
[f]
1
had little effect on the yield of 13 and reactions conducted and 17) that was identified unambiguously by X-ray crystal-
at higher temperatures resulted in overwhelming formation lography (Figure 3, Table 2). With 2,7-(dimethoxy)naphtha-
of the glycal 19 (Entries 3 and 4). Attempts to enhance the lene, the only arylation product obtained is therefore desig-
yield of disubstituted product 17 by using an excess of the nated as the 1-substituted product 36 (Entry 20); its spec-
β-benzoate at Ϫ30 °C also resulted in overwhelming forma- troscopic data is essentially identical with that reported pre-
tion of the glycal (Entry 5). The use of tin() chloride as viously for a compound designated as the 3-substituted
the Lewis acid was also effective in giving the product 17 regioisomer 16.[34,35] Other methoxynaphthalenes react
(Entry 6). With 2-methoxynaphthalene, the only product quite well with the β-benzoate to give monoadducts,[47] and
obtained was the 1-substituted compound 33 (Entries 16 in one case the diadduct 35 (Entry 18).
Eur. J. Org. Chem. 2003, 2098Ϫ2114
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R. K. Haynes et al.
FULL PAPER
Table 2. Crystallographic details for compounds 33, 40 and 52
Compound
33
40
52
CSD deposition number
Empirical formula
Formula mass
Temp. [K], Wavelength [A]
Crystal system
HING 28
C26H32O5
424.52
100(2), 0.71073
orthorhombic
P212121
10.2137(5)
10.6084(6)
40.654(2)
90
4404.9(4), 8
1.28
HING 4
C21H27FO4
362.43
295(2), 0.71073
orthorhombic
P212121
6.0150 (10)
14.2590 (10)
22.075 (3)
90
WILL 14
C29H32NO4
444.55
295(2), 0.71073
tetragonal
P43
9.3690 (10)
9.3690 (10)
26.782 (2)
90
2350.9 (4), 4
1.26
˚
Space group
˚
Unit cell a [A]
˚
b [A]
˚
c [A]
3
˚
V [A ], Z
1893.3 (4), 4
1.27
0.093
Density calcd. [g·cmϪ3
]
Abs. coeff. µ [mmϪ1
F(000)
]
0.082
952
1824
776
Description
Crystal size, mm
2Θ max.
Colourless plates
0.3 ϫ 0.2 ϫ 0.08
56.5
Colourless blocks
0.5 ϫ 0.5 ϫ 0.5
55.0
Colourless prisms
0.8 ϫ 0.6 ϫ 0.3
51.0
Reflections
27247
2629
3347
Independent data (Rint
)
10223 (0.069)
10223/0/559
1.02
2605 (0.027)
2602/0/235
1.01
2338 (0.082)
2335/1/298
1.01
Data/restraints/Parameters
GoF on F2
R indices I Ͼ 2σ (I)
R indices all data
Diff peak and hole (e·A
0.0636, 0.1081
0.1055, 0.1221
ϩ0.28/Ϫ0.29
0.0444, 0.1015
0.0694, 0.1160
ϩ0.20/Ϫ0.16
0.0464, 0.0907
0.0935, 0.1119
ϩ0.13/Ϫ0.17
Ϫ3
˚
)
Reaction of 2-naphthol and the β-benzoate 25 with boron
trifluorideϪdiethyl ether (0.1 equiv.) in dichloromethane at
Ϫ30 °C with quenching at Ϫ30 °C gave only the β-naph-
Stereochemical and Mechanistic Aspects
1
As established unambiguously by analysis of H NMR
thoxy compound 37[19] in high yield (98%). There was no spectra, and X-ray structural data for compound 33, each
trace of C-arylated products. At a higher temperature (0 α-product possesses a chair pyranose ring with an equa-
°C), a 71:29 mixture of the C-arylated products 20 and torial β-methyl group at C-9 and an equatorial α-substitu-
1
21[38] was obtained almost exclusively, as established by H ent at C-10.[19,49] Thus, the equatorial product is preferen-
NMR spectroscopic measurements on the crude product tially formed, which is in general accord with the C-aryl-
mixture. The β-naphthoxy compound 37, however, did not ation of glycosides, which have an anomeric axial leaving
rearrange to the C-arylated compounds above 0 °C in the group, activated by a Lewis acid.[32,43,50Ϫ53] This feature
presence of the Lewis acid.[48] The α-benzoate also reacted also is true for the arylation above of the 10β fluoride
with 2-naphthol at 0 °C to give the same C-arylated prod- 12.[34,35]
ucts 20 and 21 (71:29) and a trace of glycal 19. Treatment
of glycal 19 and 2-naphthol at 0 °C with the Lewis acid
(0.1 equiv.) also gave 20 and 21 (67:33). Thus, the high-
temperature conversion of the β-benzoate 25, and the con-
version of the α-benzoate 26 into the latter products, pro-
ceeds by way of elimination to glycal 19, stereorandom pro-
tonation at C-9, and direct addition of the naphthol nucle-
ophile through C-1Ј to the intermediate oxo-stabilized car-
bocation, as discussed below. This process must also be the
case for those reactions commencing with the α-acetate of
DHA.[38]
It is likely that the reactions proceed predominantly by
addition of the aromatic nucleophile from the si or α face in
an SN1 reaction involving the stabilized half-chair oxonium
ion[19] produced by dissociation of the Lewis acidϪaxial
benzoate leaving group ensemble (Scheme 1, a). A kinetic
anomeric effect will enhance formation of the oxonium ion
from the axial β-benzoate, since stabilization of the de-
veloping positive charge by overlap with the axial nonbond-
ing electron pair is possible without major conformational
change.[54,55] The addition of the aromatic nucleophile takes
place preferentially from the si face; this mode of attack
may be a reflection of the propensity of large nucleophiles
to undergo equatorial approach to sp2 centres in cyclohex-
ane systems, which will be especially favoured here because
of the presence of the axial C8ϪC8a bond (cf. Scheme 1,
a). It is apparent that dissociation of the Lewis
acidϪequatorial ester leaving group involving the α-benzo-
ate 26 is not as facile; this is due to the inability of the axial
2102
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10α- and 10β-Aryl Derivatives of Dihydroartemisinin
FULL PAPER
nonbonding electron pair on the oxygen atom in the chair cleophiles have been used generally under Lewis acid
pyranose ring to provide stabilization of the developing cat- catalysis.[32,34,50Ϫ53] It was reported long ago that aromatic
ion in the transition state. Therefore, the ring may undergo Grignard reagents react with glycosyl halides to form C-
a conformational change to a twist boat, where partici- aryl glycosides;[56,57] the reaction may also be applied to
pation by the lone pair is now possible; thus, elimination is nonaromatic Grignard reagents.[32,52] A potential advantage
consequent upon this conformational change (Scheme 1, b). of glycosyl halides is that they can be prepared in situ.
Formation of the oxonium-stabilized cation at the higher Thus, a fucopyranose TMS ether was converted on treat-
temperature results in competing elimination to the glycal ment with trimethylsilyl iodide into an axial glycosyl iodide,
19, followed by stereorandom protonation of the double which was treated in situ with alcohols to generate fucopyr-
bond at C-9, and arylation of the resulting cation at C-10 anosides.[58] We examined, therefore, the conversion of
from either the re (β) or si (α-) face (Scheme 1, b). In any DHA into a glycosyl halide, and treatment with arylmagne-
event, yields of arylated products invariably are lower if the sium halides to prepare C-aryl glycosides.
glycal, α-esters, or α-Schmidt trichloroacetimidate is used.
The 10α TMS ether 38 of DHA[19,59] is stable and easily
handled; it was treated with trimethylsilyl bromide
(TMSBr) in dichloromethane at 0 °C to give a solution con-
taining the 10β (axial) bromide 39. Whilst it was not pos-
sible to isolate the compound, its formation was revealed
1
by a H NMR spectroscopic examination of a CDCl3 solu-
tion of 38 and 1.05 equiv. of TMSBr. The spectrum dis-
played signals of the glycal 19 at δ ϭ 6.19 ppm (10-H), and
a doublet (J ϭ 3.3 Hz) at δ ϭ 6.60 ppm, corresponding to
10-Hα of 39, which therefore is equatorial and attached to
a chair pyranose ring (Figure 2).[19] There was no signal
corresponding to an α-bromide, which, on the basis of the
anomeric effect, is expected to be unstable. Significantly,
exhaustive attempts to prepare the bromide, or other
halides, with other halogenating agents on DHA 2 did not
succeed, and invariably, the glycal and other products
were obtained.
Scheme 1. Arylation of (a) β-benzoate 25 and (b) α-benzoate 26
with activated aromatics in the presence of boron
trifluorideϪdiethyl ether
Figure 2. Partial 1H NMR spectrum (300 MHz, CDCl3) in the
region δ ϭ 5.9Ϫ7.0 ppm of a mixture of the α-TMS ether 38 of
DHA (1.0 equiv.) and Me3SiBr (1.05 equiv.) in CDCl3 at 2 °C,
which illustrates the formation after 10 min of glycal 19 and β-
bromide 39
A parallel in the stereochemical outcome of the current
reactions is provided by that of the reactions of axial and
equatorial 2-alkoxy-1,3-dioxolanes with Grignard re-
agents.[54] Those epimers bearing axial alkoxyl groups re-
acted well, whereas the equatorial epimers failed to react
under similar conditions. The major difference to the Lewis
acid-catalysed arylations described above, however, is that
the Grignard reagents react with retention of configuration,
an outcome that is common with that of the reactions
described below.
In the event, treatment of the diethyl ether mixture, con-
taining bromide 39 generated in situ, with a variety of aryl
Grignard reagents provided the derivatives 11 and 40؊54
in acceptable yields. It was not possible to suppress forma-
tion of the glycal 19; when it could not be separated from
the arylated products, the crude mixture was treated with
m-chloroperbenzoic acid to convert it into the more-polar
β-Aryl Derivatives
Whilst a large number of carbon nucleophiles have been epoxide 55,[60] which could then be separated from the re-
used to convert glycosyl halides into C-glycosides, these nu- quired product by chromatography. Structures of products
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R. K. Haynes et al.
FULL PAPER
are depicted in Figure 3 and the yields are summarised in mation, with substitution of the halogen atom by an aryl
Table 3.
group, arises because the aryl group experiences a 1,3-diax-
ial interaction with the axial C8ϪC8a bond in the chair
conformer. This interaction is coupled with a loss of anom-
eric stabilization, normally provided by an electronegative
atom attached to C-10 (as in the ethers and esters), which
would act to constrain the conformational change from
chair to twist-boat.
Stereochemical and Mechanistic Aspects
Why is it that the Grignard reagents react with the β-
bromide to give β-arylated products, whereas the activated
aromatic compounds react with the β-benzoate under Lewis
acid catalysis to give the α-arylated products? In general, a
clean stereochemical outcome is not observed in the dis-
placement by organometallic reagents of an anomeric axial
leaving group in pyranoses where neighbouring group par-
ticipation may becloud the stereochemistry.[52,53] The rela-
tively clean formation of axial products in our case is com-
mon with that recorded for the reaction of axial 2-alkoxy-
1,3-dioxanes with aryl Grignard reagents,[54] and is likely to
proceed by a similar mechanism, namely formation of an
incipient half-chair oxonium ion from the axial β-bromide
39 enhanced by the kinetic anomeric effect indicated above.
The key here will be the complexation of the Grignard re-
agent with the bromide, probably by exchange of an ether
ligand, which also induces cleavage of the CϪBr bond.
Front-side attack on the oxonium ion by the aryl nucleoph-
ile from within the complex provides the product
(Scheme 2). It was noted previously by Eliel and Nader that
activation of the alkoxyl group in the 2-alkoxy-1,3-dioxane
by the Grignard reagent is a likely prerequisite for forma-
tion of the oxonium ion, a premise validated by the lack of
reactivity of organolithium reagents.
Figure 3. Structures of β- and α-arylated 10-deoxo-10-dihydroarte-
misinin derivatives obtained from the reactions of β-bromide 39,
generated in situ from the TMS ether of DHA 38, and aryl Grig-
nard reagents
1
In the H NMR spectra of the β-arylated products, 10-H
displays a coupling to 9-H (J10,9 ϭ ca. 6.6Ϫ7.6 Hz), which
is considerably larger than that (J10,9 ϭ ca. 3Ϫ4 Hz) charac-
teristic of axial β-ethers and esters in a chair pyranose
ring.[19] The data is consistent with equatorial aryl groups
in a twist-boat pyranose ring, in which the torsion angle
X-ray Structural Data
X-ray structural data of compound 33 confirms the α-
between 10-H and 9-H varies between ca. 34Ϫ40°.[49] The equatorial stereochemistry and chair conformation of the
conformational change from a chair to a twist-boat confor- pyranose ring of the aromatic adducts formed by the Lewis
Table 3. Yields of arylated derivatives from the reactions of β-bromide 39 and aryl Grignard reagents
Product
Ar
Yield (%)
Product
Ar
Yield (%)
11
40
41
42
43
44
45
46
phenyl
45
39
39
64
68
59
58
46
47
48
49
50
51
52
53
54
2Ј,4Ј,6Ј-trimethylphenyl
2Ј,4Ј,5Ј-trimethylphenyl
2Ј-naphthyl
6Ј-methoxynaphthyl
6Ј-methoxynaphthyl
9Ј-phenanthryl
55
55
43
17
14
37
51
34
4Ј-fluorophenyl
4Ј-chlorophenyl
4Ј-bromophenyl
4Ј-vinylphenyl
2Ј-methoxyphenyl
2Ј,4Ј-dimethoxyphenyl
2Ј,4Ј,6Ј-trimethoxyphenyl
4Ј-(1ЈЈ-morpholino)phenyl
4Ј-(N,N-dimethylamino)phenyl
2104
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Eur. J. Org. Chem. 2003, 2098Ϫ2114

10α- and 10β-Aryl Derivatives of Dihydroartemisinin
FULL PAPER
Scheme 2. Reaction of axial bromide 39 with aryl Grignard re-
agents
acid-catalysed reactions. Similarly, X-ray data for com-
pounds 40 and 52 confirm the β-stereochemistry of the
Grignard adducts in which the aromatic substituent is equa-
torial and the pyranose ring is twist-boat (Figure 4). Key
structural parameters are given in Table 4 and Table 5 to-
gether with the corresponding data for β-DHA (cf. com-
pound 2) bearing an axial hydroxy group in a chair pyran-
ose ring.[61]
Artemisinin and its derivatives have a relatively rigid 3-D
framework because of the constraints of its polycyclic sys-
tem that consists of two seven- and three six-membered
rings. The peroxy group forms part of both a dioxepane
and a trioxane ring. This latter ring is constrained within a
twist-boat conformation. The peroxy group has an
˚
O(1)ϪO(2) bond length of ca. 1.47 A and is asymmetric,
with the O(1)ϪC(1) bond (crystallographic numbering: Fig-
ure 3) being significantly longer and weaker than
˚
O(2)ϪC(3), which are typically 1.47 and 1.42 A, respec-
tively (Table 4). This feature is due to the additional oxygen
atom substituent at C(3) that renders it more electrophilic
than C(1). The asymmetry of the peroxide unit is also dem-
onstrated in the wider bond angle at O(1) of 113° compared
to 109° at O(2). Structural interest in the 10β aromatic de-
rivatives focuses on the ring conformation of the pyranose
(oxacyclohexane) ring [C(1)ϪC(2)ϪO(4)ϪC(10)ϪC(9)Ϫ
C(12)], which is the only flexible component of the poly-
cyclic system. The crystal structures of compounds 40 and
52 show this ring to be in a twist-boat conformation, which
is seen from analysis of both the ring torsion angles and
the atomic displacements from the mean plane of the ring
(Table 5). The orientation of the phenyl groups is approxi-
mately coplanar with the ring oxygen atom O(4). Table 5
also indicates that the H(9)ϪC(9)ϪC(10)ϪH(10) torsion
angle for compound 40 is 32.2°, and for 52 it is 40.3°, whilst
the H(9)ϪC(9)ϪC(12)ϪH(12) torsion angles are 23.9° and
17.7°, respectively, in the solid state. This feature is in
marked contrast to β-DHA in which the ring has a chair
conformation and the hydroxy group is axial, which is an
arrangement strongly favoured by the anomeric effect; the
H(9)ϪC(9)ϪC(10)ϪH(10) torsion angle is Ϫ57.2°.
Figure 4. ORTEP plots of (a) 2-methoxynaphthyl derivative 33
formed in the Lewis acid-catalysed reaction; (b) p-fluorophenyl (40)
and (c) phenanthryl (52) derivatives formed in the Grignard reac-
tions, indicating stereochemistry of the pyranose ring in each case.
Crystallographic numbering is given
Concluding Comments
The relatively clean stereochemical outcomes of the re-
spective Lewis acid-catalysed reactions on the β-benzoate
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R. K. Haynes et al.
FULL PAPER
Table 4. Selected bond lengths and angles for compounds 33, 40, 52 and β-DHA (2)
Compound
33
40
52
β-DHA 2
Torsion angles [°]
C(12)ϪC(1)ϪC(2)ϪO(4)
C(1)ϪC(2)ϪO(4)ϪC(10)
C(2)ϪO(4)ϪC(10)ϪC(9)
O(4)ϪC(10)ϪC(9)ϪC(12)
C(10)ϪC(9)ϪC(12)ϪC(1)
C(9)ϪC(12)ϪC(1)ϪC(2)
C(16)ϪC(10)ϪC(9)ϪC(15)
H(10)ϪC(10)ϪC(9)ϪH(9)
H(9)ϪC(9)ϪC(12)ϪH(12)
O(1)ϪC(1)ϪC(2)ϪO(3)
O(1)ϪC(1)ϪC(2)ϪO(4)
O(2)ϪO(1)ϪC(1)ϪC(2)
Ϫ50.4
Ϫ30.1
ϩ32.5
ϩ67.8
ϩ34.9
Ϫ23.7
Ϫ57.3
ϩ28.2
ϩ32.2
Ϫ23.9
Ϫ43.3
ϩ84.7
ϩ13.6
Ϫ32.8
ϩ29.9
ϩ69.8
ϩ41.0
Ϫ18.0
Ϫ55.6
ϩ34.5
ϩ40.3
Ϫ17.7
Ϫ44.4
ϩ82.4
ϩ16.1
Ϫ50.8
Ϫ54.9
Ϫ56.1
Ϫ54.9
Ϫ53.6
Ϫ50.6
Ϫ60.4[a]
Ϫ57.2
Ϫ52.8
Ϫ55.5
ϩ63.7
ϩ16.0
xf1ϩ53.6
xf1Ϫ56.9
xf1ϩ56.4
xf1Ϫ55.1
xf1Ϫ52.1
xf1Ϫ58.0
Ϫ179.5
xf1Ϫ53.9
xf1Ϫ55.6
xf1ϩ63.9
xf1ϩ15.7
˚
Ring displacements [A]
C(1) C(2) O(4)
C(10) C(9) C(12)
Conformation
ϩ0.21 Ϫ0.19 ϩ0.21
Ϫ0.23 ϩ0.25 Ϫ0.24
chair
ϩ0.38 Ϫ0.04 Ϫ0.36
ϩ0.38 Ϫ0.02 Ϫ0.32
twist boat
ϩ0.39 Ϫ0.08 Ϫ0.35
ϩ0.41 Ϫ0.07 Ϫ0.31
twist boat
ϩ0.21 Ϫ0.20 ϩ0.21
Ϫ0.22 ϩ0.23 Ϫ0.23
chair
[a]
For β-DHA, C(16) is replaced by the oxygen atom of an OH group.
acid-catalysed arylations. We have also found that treatment
of either benzoate epimer 25 or 26 with allylsilane in the
presence of boron trifluorideϪdiethyl ether gives only the
β-product 10. Therefore, like the Lewis acid-induced reac-
tions of alkylaluminium nucleophiles with the fluoride 12
Table 5. Other selected geometric parameters for compounds 33,
40, 52 and DHA (2)
Compound
33
40
52
β-DHA 2
O(1)ϪO(2)
O(1)ϪC(1)
O(2)ϪC(3)
O(3)ϪC(2)
O(3)ϪC(3)
O(4)ϪC(2)
O(4)ϪC(10)
C(10)ϪC(16)
1.472 (2) 1.468 (3) 1.472 (4) 1.471 (3)
1.462 (3) 1.471 (3) 1.469 (5) 1.462 (3)
1.417 (3) 1.418 (4) 1.415 (5) 1.414 (4)
1.408 (3) 1.420 (3) 1.425 (5) 1.405 (3)
1.432 (3) 1.424 (4) 1.412 (5) 1.427 (4)
1.417 (3) 1.403 (4) 1.399 (5) 1.430 (3)
1.440 (3) 1.429 (3) 1.439 (5) 1.432 (3)
1.517 (4) 1.507 (4) 1.507 (6) 1.396 (3)[a]
reported by Posner,[34,35] and of the silyl enol ethers with
[41]
´
´
the acetate 18 reported by Begue,
these reactions are
anomalous, and the exclusive formation of the β-product is
unexpectedly reminiscent of operation of the kinetic anom-
eric effect for these nucleophiles.
Apart from the fact that we have prepared new artemisi-
nin derivatives that bear a series of intercalating groups, as
indicated in the Introduction, these compounds are likely
to be hydrolytically much more stable than the current de-
rivatives used for treatment of malaria and, therefore, have
the potential for development as new drugs for treatment
of this disease.[62] Some of these compounds, however, will
be too lipophilic to be useful,[5] and will require further
functionalisation to enhance their overall polarity. As a pre-
liminary illustration of this concept, compound 43 was con-
verted into the benzoic acid derivative 56 (79%) by using
potassium permanganate and potassium hydrogen carbon-
ate in acetone.[63] This transformation thereby provides a
potentially more stable analogue of the most widely used of
the current artemisinin derivatives, namely artesunate 4,
and further, it possesses a UV chromophore that will greatly
facilitate analysis of this compound in pharmacokinetic
situations.
Bond angles (°)
C(1)ϪO(1)ϪO(2)
O(1)ϪO(2)ϪC(3)
C(2)ϪO(3)ϪC(3)
C(2)ϪO(4)ϪC(10)
O(3)ϪC(2)ϪO(4)
O(2)ϪC(3)ϪO(3)
O(4)ϪC(10)ϪC(9)
111.2 (2) 113.0 (2) 113.1 (2) 112.1 (2)
108.5 (2) 108.3 (2) 109.8 (3) 108.3 (2)
113.4 (2) 115.5 (2) 116.1 (3) 113.9 (2)
115.0 (2) 115.1 (2) 115.3 (3) 116.1 (2)
105.6 (2) 110.7 (2) 110.0 (3) 105.3 (2)
109.0 (2) 108.3 (2) 108.5 (3) 108.1 (2)
111.5 (2) 109.6 (2) 107.9 (3) 110.1 (2)
O(4)ϪC(10)ϪC(16) 106.8 (2) 107.8 (2) 107.1 (3) 111.0 (2)[a]
C(9)ϪC(10)ϪC(16) 113.2 (2) 114.4 (2) 117.3 (4) 111.1 (2)[a]
[a]
For β-DHA, C(16) is replaced by the oxygen atom of an OH
group.
and the Grignard reagents on the β-bromide provide a use-
ful complementarity in the preparation of stereodefined C-
10-arylated derivatives of dihydroartemisinin. Whilst in the
case of aryl nucleophiles, the stereochemical outcomes may
be predicted based on the rationalisations provided above,
it must be noted that, as recorded by Ziffer,[29] Lewis acid-
catalysed displacement of the hydroxy group in DHA by
allylsilane gives the β-product 10. Whilst this result fits ne-
atly into our previous proposal relating to selective acti-
vation, within the equilibrating mixture of epimers, of the
α-DHA having an equatorial hydroxy group,[19] the stereo-
chemistry of the allylation is the reverse of that of the Lewis
2106
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10α- and 10β-Aryl Derivatives of Dihydroartemisinin
FULL PAPER
2(5.00 g, 17.6 mmol) and triethylamine (3.19 mL, 2.32 g,
22.89 mmol, 1.3 equiv.) in dichloromethane (70 mL). The mixture
was warmed to room temperature over 1 d. The reaction was
poured into ice-water (ca. 150 mL). The aqueous layer was sepa-
rated and extracted with dichloromethane (2 ϫ 150 mL). The or-
ganic extracts were combined and dried (Na2SO4). Filtration and
evaporation of filtrate gave an oil, which on chromatography with
ethyl acetate/hexane (20:80) gave the dimer as a white powder
(2.12 g, 44%).
Experimental Section
General Remarks: The general experimental conditions were as de-
scribed previously.[19] All reactions were carried out under nitrogen.
Grignard reagents were either purchased or prepared in diethyl
ether or THF.
Glycal 19: Boron trifluorideϪdiethyl ether (15.2 mL, 119.72 mmol)
was added to a cold (0 °C) stirred mixture of dihydroartemisinin
(DHA) 2 (20 g, 70.42 mmol) in diethyl ether (1.5 L). The solution
was stirred at room temperature over 18 h. The solution was
washed with 5% aqueous NaHCO3 (3 ϫ 200 mL) and water (3 ϫ
200 mL), and then dried (MgSO4). Filtration and evaporation of
the filtrate gave a light-yellow solid, which was recrystallised with
hexane to give colourless needles (16.82 g, 90%), m.p. 95Ϫ97 °C
Lewis Acid-Mediated C-Arylation Reactions: Conditions and yields
are as given in Table 1. Representative preparations selected from
Table 1 are given below.
10α-(2Ј,4Ј-Dimethoxyphenyl)-10-deoxo-10-dihydroartemisinin (13):
Boron trifluorideϪdiethyl ether (6.5 µL, 7.3 mg, 0.05 mmol, 0.2
equiv.) was added to a cold (Ϫ 30 °C) solution of 10β-dihydroarte-
misinyl benzoate 25 (100 mg, 0.26 mmol) and 1,3-dimethoxyben-
zene (53 mg, 51 µL, 0.39 mmol, 1.5 equiv.) in dichloromethane
(5 mL) under nitrogen. After 1 h, the reaction was quenched with
water (1 mL). The organic layer was separated and washed with
saturated aqueous sodium bicarbonate (1 mL) and brine (1 mL),
and then dried (Na2SO4). Filtration and evaporation of the filtrate
gave an oil, which on chromatography with ethyl acetate/hexane
(12:88 then 20:80) gave a mixture of compounds 13 and 28 as an
inseparable mixture (33.1 mg, 32%) in a ratio of 1.0:0.32 in favour
of 13. A sample of the compound 13 was obtained as white needles
by recrystallisation of the mixture from dichloromethane/hexane,
m.p 141Ϫ143 °C [ref.[35] (for compound described experimentally
(ref.[42] 96Ϫ98 °C). [α]2D2 ϭ ϩ158.69 (c ϭ 1.22, CHCl3). H NMR:
1
δ ϭ 0.98 (d, J ϭ 5.8 Hz, 3 H, 6-Me), 1.02Ϫ1.39 (m, 2 H), 1.42 (m,
3 H, 9-Me), 1.44Ϫ1.74 (m, 8 H), 1.86Ϫ1.96 (m, 1 H), 2.00Ϫ2.10
(m, 2 H), 2.35Ϫ2.46 (m, 1 H), 5.54 (s, 1 H, H-12), 6.18 (q, J ϭ
1.33 Hz, 1 H, 10-H) ppm. 13C NMR: δ ϭ 16.8, 20.9, 25.05, 26.5,
30.6, 34.75, 36.9, 38.12, 45.1, 52.1, 79.6, 90.3, 105.2, 108.75, 135.6
ppm. IR (film): ν˜max ϭ 812, 828, 850, 858, 870, 880, 904, 938, 954,
972, 992, 1016, 1030, 1054, 1078, 1114, 1142, 1160, 1178, 1200,
1250, 1274, 1306, 1320, 1334, 1338, 1374, 1432, 1686, 2850, 2872,
2924, 2950, 2966, 3082 cmϪ1. MS (CI, NH3): m/z (%) ϭ 301 (2)
[(MH ϩ 2 NH4)ϩ], 286 (3) [MNH4ϩ, 2 ϫ 13C], 285 (15) [MNH4
,
ϩ
13C], 284 (88) [MNH4ϩ], 269 (2) [MHϩ, 2 ϫ 13C], 268 (18) [MHϩ,
13C], 267 (100) [MHϩ], 266 (13) [Mϩ]. C15H22O4 (266.34): calcd. C
67.65, H 8.33; found C 67.57, H 8.33.
as the 2-artemisininyl-substituted 1,3-dimethoxybenzene[36]
)
1
136Ϫ138 °C; ref.[40] 138Ϫ140 °C]. H NMR: δ ϭ 0.58 (d, J ϭ 7.3
Hz, 3 H, 9-Me), 0.98 (d, J ϭ 6.2 Hz, 3 H, 6-Me), 1.03Ϫ1.11 (m, 1
H), 1.42 (s, 3 H, 3-Me), 1.24Ϫ1.80 (m, 7 H), 1.84Ϫ1.94 (m, 1 H),
1.99Ϫ2.07 (m, 1 H), 2.34Ϫ2.41 (dt, J ϭ 4.1, 13.5 Hz, 1 H),
2.44Ϫ2.59 (m, 1 H), 3.75 (s, 3 H, OMe), 3.79 (s, 3 H, OMe), 4.93
(d, J ϭ 10.6 Hz, 1 H, 10-H), 5.39 (s, 1 H, H-12), 6.38 (d, J ϭ 2.3
Hz, 1 H, Ar-H), 6.51Ϫ6.55 (dd, J ϭ 2.6, 8.8 Hz, 1 H, Ar-H), 7.52
(d, J ϭ 8.2 Hz, 1 H, Ar-H) ppm. Present in the residue (10 mg)
obtained by evaporation of the mother liquors remaining from the
crystallisation was an inseparable mixture of compounds 13 and
28. The latter was tentatively identified as 10α-(2Ј,6Ј-dimeth-
oxyphenyl)-10-deoxo-10-dihydroartemisinin on the basis of its 1H
NMR spectrum, which is clearly differentiated from those of the
C-9 epimer[40] 22 and the β-arylated compound 45 (see below), but
very similar to that of the trimethoxy compound 14. 1H NMR: δ ϭ
0.56 (d, J ϭ 7.3 Hz, 3 H, 6-Me), 1.38 (s, 3 H, 3-Me), 0.83Ϫ1.90
(m, 12 H), 2.01 (m, 1 H), 2.41 (m, 1 H), 3.37Ϫ3.44 (m, 1 H), 3.76
(s, 3 H, OMe), 3.86 (s, 3 H, OMe), 5.15 (d, J ϭ 10.9 Hz, 1 H, 10-
H), 5.37 (s, 1 H, H-12), 6.47 (d, J ϭ 8.5 Hz, 1 H, Ar-H), 6.56 (d,
J ϭ 8.5 Hz, 1 H, Ar-H), 7.14 (t, J ϭ 8.2 Hz, 1 H, Ar-H) ppm.
Other products isolated were glycal 19 (22.5 mg, 33%), the dimeric
acetal 27 (7.1 mg, 10%) and the disubstituted aryl product 17 as a
white powder (3 mg, 3%). The latter compound was obtained in
better yield as follows. Tin() chloride (1  solution in dichloro-
methane, 25.7 µL, 25.7 µmol, 0.1 equiv.) was added to a cold (Ϫ
30 °C) stirred solution of 10β-dihydroartemisinyl benzoate (100 mg,
0.26 mmol) and 1,3-dimethoxybenzene (53 mg, 51 µL, 0.39 mmol,
1.5 equiv.) in dichloromethane (5 mL). After 1 h, the reaction was
quenched with water (1 mL). The organic layer was separated and
washed with saturated aqueous sodium bicarbonate (1 mL), and
brine (1 mL) and then dried (Na2SO4). Filtration and evaporation
of the filtrate gave an oil, which on chromatography with ethyl
acetate/hexane (12:88 then 20:80) gave a 1.0:0.4 mixture of com-
Preparation of Dimeric Acetal 27
Boron trifluorideϪdiethyl ether (1.95 µL, 2.19 mg, 15.4 µmol, 0.1
equiv.) was added to a cold (0 °C) stirred solution of 10α-dihy-
droartemisinyl benzoate 26 (60 mg, 0.15 mmol) and DHA 2
(44 mg, 0.15 mmol, 1 equiv.) in dichloromethane (5 mL). After 1 h,
the reaction was quenched with water (1 mL). The organic layer
was separated and washed with saturated aqueous NaHCO3
(1 mL), brine (1 mL) and then dried (Na2SO4). Filtration and evap-
oration of filtrate gave a residue, which on chromatography with
ethyl acetate/hexane (18:82) gave the product as a white foamy solid
(31.9 mg, 38%). Recrystallisation with dichloromethane/hexane
gave colourless rectangular plates, m.p. 140Ϫ142 °C. [α]2D0
ϭ
1
ϩ163.6 (c ϭ 0.83, CHCl3). H NMR: δ ϭ 0.86 (d, J ϭ 7.1 Hz, 3
H, 9-Me), 0.94 (m, 6 H, 6-Me, 9-Me), 0.95 (d, J ϭ 4.0 Hz, 3 H, 6-
Me), 1.17Ϫ1.36 (m, 4 H), 1.38 (s, 3 H, 3-Me), 1.43 (s, 3 H, 3-
Me), 1.45Ϫ1.57 (m, 3 H), 1.63Ϫ1.76 (m, 4 H), 1.83Ϫ1.90 (m, 2 H),
1.97Ϫ2.11 (m, 4 H), 2.17Ϫ2.47 (m, 6 H), 2.58Ϫ2.66 (m, 1 H), 4.72
(d, J ϭ 9.4 Hz, 1 H, 10-H), 5.01 (d, J ϭ 3.2 Hz, 1 H, 10-H), 5.42
(s, 1 H, H-12), 5.79 (s, 1 H, H-12) ppm. 13C NMR: δ ϭ 13.3, 13.7,
20.95, 21.0, 22.7, 24.9, 25.35, 25.4, 26.55, 26.8, 31.85, 33.6, 34.96,
35.51, 36.9, 37.2, 38.0, 38.1, 45.2, 46.1, 52.2, 53.4, 80.7, 81.8, 89.2,
91.3, 99.6, 102.4, 104.5, 104.55 ppm. IR (film): ν˜max ϭ 734, 877,
958, 979, 1012, 1044, 1092, 1376, 1451, 2874, 2926 cmϪ1. MS (CI,
CH4): m/z (%) ϭ 552 (6), 551 (20) [MHϩ]. C30H46O9 (550.7) calcd.
C 65.43, H 8.42; found C 65.57, H 8.52. Other products isolated
were the glycal 19 (3.7 mg, 9%), an inseparable mixture of 10α-
dihydroartemisinyl benzoate 26 and 10β-dihydroartemisinyl benzo-
ate 25 as a white powder (7.5 mg, 13%) in a ratio of 1.0:0.7 in
favour of 10α-dihydroartemisinyl benzoate, and an unknown com-
pound (6.5 mg).
A simpler preparation is as follows. A suspension of p-toluenesul-
fonyl chloride (4.36 g, 22.89 mmol, 1.3 equiv.) in dichloromethane
(30 mL) was added to a cold (0 °C) stirred mixture of DHA pounds 13 and 22 (30 mg, 27%), the glycal 19 (11.6 mg, 17%), and
Eur. J. Org. Chem. 2003, 2098Ϫ2114
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2107

R. K. Haynes et al.
FULL PAPER
the disubstituted aryl product 17 (25.4 mg, 29%) as a white powder.
The latter compound was recrystallised from ethyl acetate/hexane
to give colourless plates, m.p. 171Ϫ174 °C. [ref.[37] 168Ϫ169.2 °C]
[α]2D0 ϭ ϩ141.0 (c ϭ 0.64, CHCl3) [ref.[37] ϩ148.3 (c ϭ 0.89,
10α-(Indolyl-3Ј-yl)-10-deoxo-10-dihydroartemisinin (30): Tin()
chloride (1.0  in CH2Cl2, 0.026 mmol, 26 µL, 0.1 equiv.) was ad-
ded to a cold (Ϫ30 °C) stirred solution of 10β-benzoate 25 (100 mg,
0.26 mmol) and N-methylindole (49 µL, 51 mg, 0.39 mmol, 1.5
CHCl3)]. 1H NMR: δ ϭ 0.59 (d, J ϭ 7.0 Hz, 6 H, 2 ϫ 9-Me), 0.96 equiv.) in dichloromethane (5 mL). After 65 min, the reaction mix-
(d, J ϭ 6.2 Hz, 6 H, 2 ϫ 6-Me), 0.85Ϫ1.09 (m, 2 H), 1.44 (s, 6 H, ture was quenched with water (1 mL). The organic layer was sepa-
2 ϫ 3-Me), 1.17Ϫ1.90 (m, 14 H), 2.00 (m, 2 H), 2.03 (m, 2 H),
2.31Ϫ2.42 (dt, J ϭ 3.8, 13.8 Hz, 2 H), 2.57 (m, 2 H), 3.77 (s, 6 H,
rated and washed with saturated aqueous NaHCO3 (1 mL), and
brine (1 mL), and then dried (Na2SO4). Filtration and evaporation
2 ϫ OMe), 4.90 (d, J ϭ 10.6 Hz, 2 H, 2 ϫ 10-H), 5.39 (s, 2 H, 2 of the filtrate gave a residue, which on chromatography with ethyl
ϫ H-12), 6.31 (s, 1 H, Ar-H), 7.90 (br. s, 1 H, Ar-H) ppm. 13C
acetate/hexane (16:84) gave the product 30 as a pale foamy solid
NMR: δ ϭ 13.9, 20.75, 21.95, 25.3, 26.4, 34.8, 36.8, 37.7, 46.8, (74.9 mg, 73%), with other data in agreement with those previously
52.4, 56.0, 70.0, 80.5, 92.3, 104.3, 122.6, 127.65, 156.95 ppm. IR
(film): ν˜max ϭ 845, 881, 904, 932, 1044, 1066, 1134, 1103, 1134,
1206, 1298, 1380, 1457, 1510, 1639, 2920, 2880 cmϪ1. MS (FAB,
NBA): m/z (%) ϭ 670 (20) [Mϩ], 671 (10) [MHϩ], 672 (3) [MHϩ,
13C]. C38H54O10 (670.85): calcd. C 68.04, H 8.11; found C 67.85,
H 8.15.
reported.[35] Glycal 19 was also isolated as a 1:0.53 mixture with
unchanged N-methylindole (4.3 mg).
10α-(4Ј-Methoxynaphthyl)-10-deoxo-10-dihydroartemisinin (31) and
9-epi-10α-(4Ј-methoxynaphthyl)-10-deoxo-10-dihydroartemisinin
(32): Tin() chloride (1.0  in CH2Cl2, 0.26 mmol, 0.26 mL, 0.1
equiv.) was added to a cold (Ϫ30 °C) stirred solution of 10β-benzo-
ate 25 (1.0 g, 2.58 mmol) and 1-methoxynaphthalene (0.56 mL,
0.61 g, 3.87 mmol, 1.5 equiv.) in dichloromethane (50 mL). After
75 min, the reaction was quenched with water (10 mL). The organic
layer was separated and washed with saturated aqueous NaHCO3
(10 mL), brine (10 mL) and dried (Na2SO4). Filtration and evapor-
ation of filtrate gave a residue, which on chromatography with ethyl
acetate/hexane (8:92) gave first the product 32 as a beige powder
(50.1 mg, 5%), recrystallisation of which from ethyl acetate gave
colourless plates, m.p. 185Ϫ186 °C. [α]2D2 ϭ ϩ82.5 (c ϭ 0.66,
CHCl3). 1H NMR: δ ϭ 0.99 (overlapping dd, J ϭ 5.9, 6.7 Hz, 6
H, 6-Me and 9-Me), 1.04Ϫ1.64 (m, 10 H), 1.69Ϫ1.86 (m, 1 H),
1.96Ϫ2.12 (m, 3 H), 2.34Ϫ2.44 (m, 1 H), 3.99 (s, 3 H, OMe), 5.58
(s, 1 H, H-12), 5.86 (br. d, J ϭ 9.1 Hz,1 H, 10-H), 6.78 (d, J ϭ 7.9
Hz, 1 H, Ar-H), 7.41Ϫ7.50 (m, 3 H, 3 ϫ Ar-H), 8.25Ϫ8.28 (m, 1
H, Ar-H), 8.44 (d, J ϭ 8.8 Hz, 1 H, Ar-H) ppm. 13C NMR: δ ϭ
20.3, 20.5, 25.2, 26.3, 32.6, 34.6, 37.1, 37.7, 41.2, 47.9, 52.9, 55.8,
82.8, 91.5, 102.6, 103.3, 122.5, 124.9, 125.1, 126.15, 126.4, 128.6,
155.6 ppm. IR (film): ν˜max ϭ 766, 830, 889, 929, 992, 1006, 1052,
10α-(2Ј,4Ј,6Ј-Trimethoxyphenyl)-10-deoxo-10-dihydroartemisinin
(14): Boron trifluorideϪdiethyl ether (3.3 µL, 3.6 mg, 0.026 mmol,
0.1 equiv.) was added to a cold (Ϫ30 °C) stirred solution of 10β-
benzoate 25 (100 mg, 0.26 mmol) and 1,3,5-trimethoxybenzene
(65 mg, 0.39 mmol, 1.5 equiv.) in dichloromethane (7 mL). After
1 h at this temperature, the reaction mixture was quenched with
saturated aqueous NaHCO3 solution, and the mixture was ex-
tracted with dichloromethane (3 ϫ 10 mL). The organic layer was
washed with saturated aqueous NaHCO3 (1 mL) followed by brine
(1 mL), and then dried (Na2SO4). Filtration and evaporation of
filtrate gave an oil that was chromatographed with ethyl acetate/
hexane (2:8) to give firstly the glycal 19 (7.2 mg, 11%) and then the
product 14 as a white foam, which slowly deposited white microcry-
stals from hexane (79.8 mg, 71%), m.p. 67Ϫ69 °C (ref.[35] 68Ϫ71
°C), with other data in agreement with those previously re-
ported.[13,14,18,35] The final product isolated was the dimeric acetal
27 (7.1 mg, 5%).
1080, 1106, 1158, 1221, 1275, 1375, 1464, 1515, 1588, 2927 cmϪ1
.
10α-(2Ј-Furyl)-10-deoxo-10-dihydroartemisinin (15): This com-
pound was prepared by a method analogous to that for compound
14 above. Thus, from 10β benzoate 25 (193 mg, 0.50 mmol) and
furan (542 µL, 7.5 mmol, 15 equiv.) in dichloromethane (5 mL)
containing boron trifluorideϪdiethyl ether (123 µL, 1.0 mmol, 2
equiv.) was obtained a colourless residue, which after chromatogra-
phy with ethyl acetate/hexane (15:85) gave the product as a white
solid (53.7 mg, 32%), m.p. 96Ϫ97 °C (ref.[35] 97Ϫ98 °C), with other
data in agreement with those previously reported.[35]
MS (CI, CH4): m/z (%) ϭ 426 (2) [MHϩ, 13C], 425 (8) [MHϩ], 424
(5) [Mϩ]. C26H32O5 (424.5): calcd. C 73.56, H 7.60; found C 73.63,
H 7.67. The more-polar 10α-(4Ј-methoxynaphthyl)-10-deoxo-10-di-
hydroartemisinin 31 was isolated as a colourless gum (142.9 mg,
22
1
13%). [α]D ϭ ϩ89 (c ϭ 0.39, CHCl3). H NMR ([D]8toluene, 90
°C): δ ϭ 0.44 (d, J ϭ 7.04 Hz, 3 H), 0.82Ϫ1.00 (m, 5 H), 1.42 (s,
3 H, 3-Me), 1.02Ϫ1.55 (m, 7 H), 1.69Ϫ1.76 (m, 1 H), 1.86Ϫ1.92
(m, 1 H), 2.41Ϫ2.52 (m, 1 H), 3.44 (br. s, 1 H), 3.65 (s, 3 H, OMe),
4.91 (br. d, 1 H, J ϭ 10.5 Hz, 10-H), 5.31 (s, 1 H, H-12), 6.53Ϫ6.56
(m, 1 H, Ar-H), 7.36Ϫ7.52 (m, 2 H, 2 ϫ Ar-H), 8.47 (d, J ϭ 8.21
Hz, 1 H, Ar-H) ppm. IR (film): ν˜max ϭ 766, 880, 1056, 1095, 1223,
1271, 1376, 1394, 1464, 1514, 1586, 2872, 2936 cmϪ1. MS (CI,
CH4): m/z (%) ϭ 424 (16) [Mϩ], 425 (11) [MHϩ], 426 (4) [MHϩ,
13C], 427 (1) [MHϩ, 2 ϫ 13C]. C26H32O5 (424.5): calcd. C 73.56, H
7.60; found C 73.02, H 7.81. The glycal 19 was also isolated as a
white powder (208.1 mg, 30%).
10α-(Pyrrol-2Ј-yl)-10-deoxo-10-dihydroartemisinin (29): This com-
pound was prepared by a method analogous to that for compound
14 above. Thus, from 10β-benzoate 25 (700.8 mg, 1.80 mmol) and
pyrrole (624 µL, 9.00 mmol, 5 equiv.) in dichloromethane (5 mL)
containing boron trifluorideϪdiethyl ether (332 µL, 2.70 mmol, 3.0
equiv.) was obtained a colourless residue, which after chromatogra-
phy with ethyl acetate/hexane (30:70) gave the product as a colour-
less oil (487 mg, 82%). [α]2D0 ϭ ϩ198.7 (c ϭ 0.105, CHCl3). 1H
NMR: δ ϭ 0.93 (d, J ϭ 7.0 Hz, 3 H, 6-Me), 0.80Ϫ1.15 (m, 4 H),
10α-(2Ј-Methoxynaphthyl)-10-deoxo-10-dihydroartemisinin
(33):
1.15Ϫ1.68 (m, 7 H), 1.68Ϫ1.80 (m, 2 H), 1.93 (m, 1 H), 1.95Ϫ2.10 Tin() chloride (1.0  in CH2Cl2, 0.26 mmol, 0.26 mL, 0.1 equiv.)
(m, 1 H), 2.10Ϫ2.50 (m, 2 H), 2.58 (m, 1 H), 4.47 (d, J ϭ 10.8 Hz, was added to a cold (Ϫ30 °C) stirred solution of 10β-benzoate 25
1 H, 10-H), 5.39 (s, 1 H, H-12), 6.04 (m, 2 H, 3Ј-H, 4Ј-H), 6.71 (m, (1.0 g, 2.58 mmol) and 2-methoxynaphthalene (0.61 g, 3.87 mmol,
1 H, 5Ј-H), 8.80 (br. s, 1 H, NH) ppm. 13C NMR: δ ϭ 13.9, 14.0, 1.5 equiv.) in dichloromethane (50 mL). After 1 h, the reaction was
20.1, 21.2, 24.6, 25.9, 32.9, 34.0, 36.2, 37.2, 45.7, 51.8, 60.2, 71.9,
quenched with water (10 mL). The organic layer was separated and
80.5, 91.9, 104.1, 106.7, 107.2, 117.6, 129.9 ppm. IR (film): ν˜max ϭ washed with saturated aqueous NaHCO3 (10 mL), and brine
722, 1024, 1066, 1376, 1460, 2854, 2924 cmϪ1. MS (CI, butane): m/
z (%) ϭ 334 (100) [MHϩ]. C19H27NO4 (309.41): calcd. C 68.44, H
8.16, N 4.20; found C 68.77, H 8.56, N 3.85.
(10 mL), and then dried (Na2SO4). Filtration and evaporation of
filtrate gave a residue, which on chromatography with ethyl acetate/
hexane (8:92) gave the product as a white foamy solid (487.8 mg,
2108
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2098Ϫ2114

10α- and 10β-Aryl Derivatives of Dihydroartemisinin
FULL PAPER
44%). Recrystallisation from ethyl acetate gave colourless plates, 10α-(2Ј,7Ј-Dimethoxynaphthyl)-10-deoxo-10-dihydroartemisinin
m.p. 166Ϫ167 °C. [α]2D0 ϭ ϩ209.8 (c ϭ 1.31, CHCl3). 1H NMR:
δ ϭ 0.51 (d, J ϭ 7.3 Hz, 3 H, 6-Me), 1.00 (d, J ϭ 6.2 Hz, 3 H, 9-
(36): Tin() chloride (1.0  in CH2Cl2, 0.26 mmol, 0.26 mL, 0.1
equiv.) was added to a cold (Ϫ30 °C) stirred solution of 10β-benzo-
Me), 1.05Ϫ1.18 (m, 1 H), 1.43 (s, 3 H, 3-Me), 1.32Ϫ1.82 (m, 8 H), ate 25 (1.0 g, 2.58 mmol) and 2,7-dimethoxynaphthalene (0.73 g,
1.89Ϫ1.98 (m, 1 H), 2.04Ϫ2.12 (m, 1 H), 2.41Ϫ2.51 (dt, J ϭ 4.1, 3.87 mmol, 1.5 equiv.) in dichloromethane (50 mL). After 1 h, the
13.2 Hz, 1 H), 3.23Ϫ3.33 (m, 1 H), 3.89 (s, 3 H, OMe), 5.49 (s, 1
H, H-12), 5.65 (d, J ϭ 11.1 Hz, 1 H, 10-H), 7.18 (d, J ϭ 9.1 Hz,
reaction was quenched with water (10 mL). The organic layer was
separated and washed with saturated aqueous NaHCO3 (10 mL)
1 H, Ar-H), 7.24Ϫ7.32 (m, 1 H, Ar-H), 7.41Ϫ7.47 (m, 1 H, Ar-H), and brine (10 mL), and then dried (Na2SO4). Filtration and evap-
7.72 (t, J ϭ 2.1 Hz, 1 H, Ar-H), 9.21 (d, J ϭ 8.2 Hz, 1 H, Ar-H) oration of filtrate gave a residue, which on chromatography with
ppm. 13C NMR: δ ϭ 13.7, 20.8, 21.6, 25.3, 26.4, 31.5, 34.7, 36.8,
37.85, 46.7, 52.6, 57.2, 70.75, 81.4, 92.6, 104.5, 113.15, 121.1, 123.7,
126.0, 127.4, 128.2, 130.05, 130.3, 132.7, 154.8 ppm. IR (film):
ν˜max ϭ 732, 752, 809, 845, 879, 918, 933, 1042, 1057, 1084, 1100,
ethyl acetate/hexane (12:88 followed by 20:80) gave the product 36
as a white powder (840.6 mg, 74%). Recrystallisation from di-
chloromethane/hexane gave long colourless needles, m.p. 156Ϫ158
°C [ref.[34,35] (for compound described as the 3Ј-substituted re-
1129, 1249, 1376, 1510, 2871, 2943 cmϪ1. MS (CI, CH4): m/z (%) ϭ gioisomer) 149Ϫ151 °C]. [α]2D2 ϭ ϩ242.6 (c ϭ 0.77, CHCl3)
379 (100) [M Ϫ 3Me]ϩ, 424 (24) [Mϩ], 425 (22) [MHϩ], 426 (6)
[MHϩ, 13C]. C26H32O5 (424.5): calcd. C 73.56, H 7.68; found C
73.34, H 7.63.
{ref.[34,35] [α]2D5 ϭ ϩ246.4 (c ϭ 1.29, CHCl3)} H NMR: δ ϭ 0.46
(d, J ϭ 7.33 Hz, 3 H, 6-Me), 1.00 (d, J ϭ 6.45 Hz, 3 H, 9-Me),
1.43 (s, 3 H, 3-Me), 1.21Ϫ1.82 (m, 7 H), 1.88Ϫ1.97 (m, 1 H),
2.04Ϫ2.11 (m, 1 H), 2.37Ϫ2.47 (dt, J ϭ 4.11, 13.49 Hz, 1 H),
3.30Ϫ3.42 (m, 1 H), 3.88 (s, 3 H, OMe), 3.99 (s, 3 H, OMe), 5.48
(s, 1 H, H-12), 5.67 (d, J ϭ 10.85 Hz, 1 H, 10-H), 6.95 (dd, J ϭ
2.64, 9.10 Hz, 1 H, Ar-H), 7.02 (d, J ϭ 8.80 Hz, 1 H, Ar-H), 7.59
(d, J ϭ 8.80 Hz, 1 H, Ar-H), 7.59 (d, J ϭ 8.8 Hz, 1 H, Ar-H), 7.65
(d, J ϭ 8.80 Hz, 1 H, Ar-H), 8.36 (d, J ϭ 2.34 Hz, 1 H, Ar-H)
ppm. 13C NMR: δ ϭ 13.65, 20.8, 21.75, 25.2, 26.6, 30.8, 34.7, 36.8,
37.8, 46.7, 52.8, 56.5, 57.1, 70.5, 81.7, 93.4, 104.4, 105.0, 110.5,
117.2, 119.7, 125.7, 129.7, 129.8, 134.25, 155.6, 158.1 ppm. IR
(film): ν˜max ϭ 828, 1044, 1061, 1247, 1376, 1427, 1466, 1515, 1626,
1
10α-(2Ј,6Ј-Dimethoxynaphthyl)-10-deoxo-10-dihydroartemisinin (34)
and Bis(1,5-[10α-(10-deoxo-10-dihydroartemisininyl)])-2,6-dimeth-
oxynaphthalene (35): Tin() chloride (1.0  in CH2Cl2, 0.26 mmol,
0.26 mL, 0.1 equiv.) was added to a cold (0 °C) stirred solution of
10β-benzoate 25 (1 g, 2.58 mmol) and 2,6-dimethoxynaphthalene
(0.73 g, 3.87 mmol, 1.5 equiv.) in dichloromethane (50 mL). After
1 h, the reaction was quenched with water (10 mL). The organic
layer was separated and washed with saturated aqueous NaHCO3
(10 mL) and brine (10 mL), and then dried (Na2SO4). Filtration
and evaporation of filtrate gave a residue, which on chromatogra-
phy with ethyl acetate/hexane (14:86 followed by 20:80) gave the
product 34 as a white powder (203.9 mg, 18%). Recrystallisation
from dichloromethane/hexane gave clusters of colourless needles,
m.p. 171Ϫ173 °C. [α]2D0 ϭ ϩ197 (c ϭ 0.84, CHCl3). 1H NMR: δ ϭ
0.51 (d, J ϭ 7.04 Hz, 3 H, 9-Me), 1.00 (d, J ϭ 6.14 Hz, 3 H, 6-
Me), 0.90Ϫ1.15 (m, 2 H), 1.42 (s, 3 H, 3-Me), 1.23Ϫ1.81 (m, 8 H),
1.89Ϫ1.98 (m, 1 H), 2.03Ϫ2.12 (m, 1 H), 2.40Ϫ2.51 (dt, J ϭ 4.11,
14.07 Hz, 1 H), 3.20Ϫ3.27 (m, 1 H), 3.86 (s, 3 H, OMe), 3.87 (s, 3
H, OMe), 7.03 (d, J ϭ 2.93 Hz, 1 H, Ar-H), 7.11Ϫ7.16 (m, 2 H, 2
ϫ Ar-H), 7.62 (d, J ϭ 9.09 Hz, 1 H, Ar-H), 9.14 (d, J ϭ 9.38 Hz,
1 H, Ar-H) ppm. 13C NMR: δ ϭ 13.7, 20.8, 21.6, 25.3, 26.4, 31.7,
34.7, 36.8, 37.85, 46.7, 52.55, 55.5, 57.4, 70.8, 81.4, 92.5, 104.5,
106.3, 113.95, 118.5, 121.7, 128.1, 128.6, 129.05, 131.5, 153.4, 155.9
ppm. IR (film): ν˜max ϭ 737, 828, 850, 880, 920, 1042, 1129, 1152,
1196, 1248, 1375, 1452, 1509, 1661, 1629, 2873, 2937 cmϪ1. MS
(CI, CH4): m/z (%) ϭ 455 (53) [MH ϩ CH4]ϩ, 454 (38) [M ϩ
CH4]ϩ, 440 (5) [MHϩ, 13C], 439 (17) [MHϩ], 438 (13) [Mϩ], 409
(100) [MH Ϫ 3 Me]ϩ. C27H34O6 (454.6): calcd. C 71.34, H 7.54;
found C 70.99, H 7.55. The more-polar disubstituted naphthalene
35 was isolated as a white powder (175.2 mg, 19%). Recrystallis-
2873, 2940 cmϪ1
.
C-Arylations with Grignard Reagents
10β-Phenyl-10-deoxo-10-dihydroartemisinin (11): Trimethylsilyl bro-
mide (140 µL, 1.06 mmol) was added to a cold (0 °C) stirred solu-
tion of the DHA 10α-TMS ether 38[19] (372 mg, 1.04 mmol) in di-
chloromethane (5 mL). After 0.5 h, the solvent was removed by
careful evaporation under reduced pressure to leave a solid residue
that was cooled to 0 °C and treated with diethyl ether (5 mL) fol-
lowed by phenylmagnesium bromide (1.7  in diethyl ether,
1.40 mL, 2.38 mmol). The resulting mixture was warmed to room
temperature overnight, and then treated with saturated aqueous
NH4Cl. The aqueous layer was extracted with ether and the com-
bined ether layers were dried (MgSO4). Filtration and evaporation
of the filtrate left an oily residue, which after chromatography with
ethyl acetate/hexane (8:92) gave the product as a white solid
(159 mg, 45%). Recrystallisation from ether/hexane gave colourless
rectangular plates, m.p. 122Ϫ123 °C. [α]2D0 ϭ Ϫ36.0 (c ϭ 0.47,
1
CHCl3). H NMR: δ ϭ 0.54 (d, J ϭ 7.68 Hz, 3 H, 9-Me), 1.01 (d,
J ϭ 5.77 Hz, 3 H, 6-Me), 1.41 (s, 3 H, 3-Me), 1.28Ϫ1.60 (m, 5 H),
1.65Ϫ2.12 (m, 5 H), 2.31Ϫ2.42 (m, 1 H), 2.71Ϫ2.84 (m, 1 H, 9-H),
5.60 (s, 1 H, H-12), 5.75 (d, J ϭ 6.70 Hz, 1 H, 10-H), 7.19Ϫ7.34
(m, 5 H, Ph-H) ppm. 13C NMR: δ ϭ 13.6, 19.85, 24.7, 24.9, 25.7,
32.1, 34.2, 36.6, 37.5, 43.45, 51.5, 73.0, 81.1, 90.8, 102.2, 126.1,
126.2, 127.7, 141.0 ppm. IR (film): ν˜max ϭ 700, 740, 820, 852, 882,
904, 944, 954, 1010, 1038, 1058, 1076, 1112, 1208, 1376, 1452, 1494,
2874, 2938 cmϪ1. MS (CI, CH4): m/z (%) ϭ 345 (14) [MHϩ], 327
(14), 299 (100). C21H28O4 (344.45): calcd. C 73.26, H 8.14; found
C 73.58; H 8.32.
ation from methanol gave colourless rods, m.p. 153Ϫ154 °C. [α]2D0
ϭ
1
ϩ240 (c ϭ 0.57, CHCl3). H NMR: δ ϭ 0.48 (d, J ϭ 7.0 Hz, 6 H,
2 ϫ 6-Me), 1.02 (d, J ϭ 6.16 Hz, 6 H, 2 ϫ 9-Me), 0.82Ϫ1.17 (m,
4 H), 1.42 (s, 6 H, 2 ϫ 3-Me), 1.19Ϫ1.80 (m, 12 H), 1.86Ϫ1.97 (m,
2 H), 2.02Ϫ2.33 (m, 2 H), 2.40Ϫ2.50 (dt, J ϭ 3.8, 13.5 Hz, 2 H),
3.17Ϫ3.27 (m, 2 H), 3.86 (s, 6 H, 2 ϫ OMe), 5.47 (s, 2 H, 2 ϫ H-
12), 5.62 (d, J ϭ 11.0 Hz, 2 H, 2 ϫ 10-H), 7.18 (d, J ϭ 9.7 Hz, 2
H, 2 ϫ Ar-H), 9.20 (d, J ϭ 9.7 Hz, 2 H, 2 ϫ Ar-H) ppm. 13C
NMR: δ ϭ 13.8, 20.8, 21.6, 25.3, 26.4, 31.7, 34.7, 36.8, 37.8, 46.8,
10β-(4Ј-Fluorophenyl)-10-deoxo-10-dihydroartemisinin (40): Accord-
52.6, 57.1, 70.6, 81.5, 92.5, 104.4, 113.0, 120.5, 129.1, 129.4, 153.0 ing to the method above, from DHA 10α-TMS ether 38 (0.8 g,
ppm. IR (film): ν˜max ϭ 1041, 1057, 1129, 1256, 1318, 1376, 1454,
2.25 mmol), trimethylsilyl bromide (0.30 mL, 2.29 mmol), and then
(4-fluorophenyl)magnesium bromide (2.0  in ether, 2.25 mL,
1514, 1596, 1716, 2873, 2936 cmϪ1. MS (CI, CH4): m/z (%) ϭ 676
(28) [MH Ϫ 3Me]ϩ, 675 (67) [M Ϫ 3Me]ϩ, 722 (1) [MHϩ, 13C], 4.49 mmol, 2.0 equiv.), followed by chromatography with ethyl
721 (3) [MHϩ], 720 (9) [Mϩ]. C42H56O10 (720.9): calcd. C 69.98, H
7.83; found C 69.37, H 7.98.
acetate/hexane (3:97), a white solid was obtained (314.8 mg, 39%).
Recrystallisation from dichloromethane/hexane gave colourless rec-
Eur. J. Org. Chem. 2003, 2098Ϫ2114
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2109

R. K. Haynes et al.
FULL PAPER
tangular crystals, m.p. 134Ϫ135 °C. [α]2D0 ϭ Ϫ35.78 (c ϭ 0.83,
1.17Ϫ2.09 (m, 9 H), 2.28Ϫ2.38 (m, 1 H), 2.71Ϫ2.78 (m, 1 H), 5.20
1
CHCl3) ppm. 19F NMR: δ ϭ Ϫ118 ppm. H NMR: δ ϭ 0.48 (d, (d, J ϭ 10.9 Hz, 1 H, vinyl-H), 5.57 (s, 1 H, H-12), 5.69Ϫ5.76 (m,
J ϭ 7.7 Hz, 3 H, 9-Me), 0.99 (d, J ϭ 5.8 Hz, 3 H, 6-Me), 1.17Ϫ1.49 2 H, vinylϪH, 10-H), 6.71 (dd, J ϭ 17.6, 10.9 Hz, 1 H, vinyl-H),
(m, 8 H), 1.64Ϫ1.78 (m, 2 H), 1.82Ϫ1.90 (m, 1 H), 1.97Ϫ2.10 (m,
7.27 (d, J ϭ 8.3 Hz, 2 H, 2 ϫ Ph-H) ppm. IR (film): ν˜max ϭ 756,
2 H), 2.28Ϫ2.39 (m, 1 H), 2.65Ϫ2.77 (m, 1 H), 5.55 (s, 1 H, H-12), 788, 844, 882, 904, 944, 1010, 1074, 1116, 1200, 1376, 1406, 1452,
5.70 (d, J ϭ 6.7 Hz, 1 H, 10-H), 6.97Ϫ7.04 (m, 2 H, 2 ϫ Ph-H),
1512, 1630, 2876, 2948 cmϪ1 ppm. 13C NMR: δ ϭ 13.75, 19.97,
24.80, 24.98, 25.80, 32.19, 34.26, 36.73, 37.58, 43.58, 51.58, 73.07,
7.24Ϫ7.29 (m, 2 H, 2 ϫ Ph-H) ppm. 13C NMR: δ ϭ 14.3, 20.5,
25.4, 25.6, 26.35, 32.8, 34.8, 37.3, 38.1, 44.05, 52.1, 73.15, 81.75, 81.24, 90.89, 102.40, 113.09, 125.72, 126.36, 135.74, 136.75, 140.91
91.55, 102.9, 115.2 (d, JC,F ϭ 21.3 Hz, Ph), 128.3 (d, JC,F ϭ 7.8 Hz,
Ph), 137.4 (d, JC,F ϭ 3.09 Hz, Ph), 162.1 (d, JC,F ϭ 244.0 Hz, Ph)
ppm. IR (film): ν˜max ϭ 782, 838, 882, 906, 944, 1010, 1040, 1110,
ppm. MS (CI, NH3): m/z (%) ϭ 388 (100) MNH4ϩ], 325 (20).
C23H30O4 (370.49): calcd. C 74.56, H 8.16; found C 74.58, H 8.26.
1222, 1376, 1452, 1510, 1604, 2873, 2952 cmϪ1. MS (CI, NH3): m/
10β-(2Ј-Methoxyphenyl)-10-deoxo-10-dihydroartemisinin (44): Ac-
cording to the method above, from DHA 10α-TMS ether 38
(214 mg, 0.68 mmol), trimethylsilyl bromide (90 µL, 0.68 mmol),
and (2-methoxyphenyl)magnesium bromide (1.0  in ether, 1.2 mL,
1.2 mmol, 2 equiv.), followed by chromatography with ethyl acetate/
hexane (8:92), a white solid was obtained (133 mg, 59%), m.p.
ϩ
z (%) ϭ 382 (4) [MNHϩ, 2 ϫ 13C], 381 (25) [MNH4
,
13C], 380
(100) [MNH4ϩ], 363 (6) [MHϩ]. C21H27FO4 (362.45): calcd. C
69.59, H 7.51; found C 69.51, H 7.62.
10β-(4Ј-Chlorophenyl)-10-deoxo-10-dihydroartemisinin (41): Ac-
cording to the method above, from DHA 10α-TMS ether 38 (1.2 g,
3.37 mmol), trimethylsilyl bromide (0.44 mL, 3.37 mmol), and (4-
1
59Ϫ61 °C. [α]2D0 ϭ Ϫ41.4 (c ϭ 0.049, CHCl3). H NMR: δ ϭ 0.43
(d, J ϭ 7.6 Hz, 1 H, 9-Me), 1.01 (d, J ϭ 5.8 Hz, 3 H, 6-Me), 1.39
(s, 3 H, 3-Me), 1.19Ϫ2.11 (m, 10 H), 2.30Ϫ2.40 (m, 1 H),
2.86Ϫ2.99 (m, 1 H, 9-H), 3.84 (s, 3 H, OMe), 5.58 (s, 1 H, H-12),
5.94 (d, J ϭ 6.7 Hz, 1 H, 10-H), 6.83Ϫ7.50 (m, 4 H, 4 ϫ Ph-H)
ppm. 13C NMR: δ ϭ 13.45, 19.8, 24.75, 25.0, 25.7, 29.9, 34.2, 36.7,
37.5, 43.4, 51.3, 55.2, 68.6, 90.9, 109.2, 120.0, 126.4, 127.0, 134.85
ppm. IR (film): ν˜max ϭ 754, 854, 882, 944, 1010, 1052, 1102, 1110,
1178, 1240, 1284, 1374, 1462, 1492, 1590, 2874, 2938 cmϪ1. MS
(CI, CH4): m/z (%) ϭ 375 (12) [MHϩ], 374(16) [Mϩ], 342 (100),
329 (48), 311 (14), 284 (28), 182 (56), 148 (76), 137 (60), 121 (48).
C22H30O5 (374.48): calcd. C 70.56, H 8.07; found C 70.78, H 8.28.
chlorophenyl)magnesium bromide (1.0
 in ether, 5.1 mL,
5.1 mmol, 1.5 equiv.), followed by chromatography with ethyl acet-
ate/hexane (3:97), a white solid was obtained (497 mg, 39%).
Recrystallisation from dichloromethane/hexane gave colourless rec-
tangular crystals, m.p. 159Ϫ160 °C. [α]2D2 ϭ ϩ10.82 (c ϭ 0.098,
1
CHCl3). H NMR: δ ϭ 0.49 (d, J ϭ 7.7 Hz, 3 H, 9-Me), 0.99 (d,
J ϭ 5.6 Hz, 3 H, 6-Me), 1.17Ϫ1.49 (m, 8 H), 1.65Ϫ1.78 (m, 2
H), 1.81Ϫ1.90 (m, 1 H), 1.99Ϫ2.09 (m, 2 H), 2.28Ϫ2.39 (m, 1 H),
2.65Ϫ2.78 (m, 1 H), 5.55 (s, 1 H, H-12), 5.69 (d, J ϭ 6.7 Hz, 1 H,
10-H), 7.23Ϫ7.30 (m, 4 H, 4 ϫ Ph-H) ppm. 13C NMR: δ ϭ 14.4,
20.6, 25.5, 25.7, 26.5, 32.8, 34.9, 37.4, 38.3, 44.2, 52.2, 73.3, 81.9,
91.6, 103.1, 128.3, 128.7, 132.75, 140.4 ppm. IR (Nujol): ν˜max
ϭ
10β-(2Ј,4Ј-Dimethoxyphenyl)-10-deoxo-10-dihydroartemisinin (45):
According to the method above, from DHA 10α-TMS ether 38
(100 mg, 0.28 mmol), trimethylsilyl bromide (37 µL, 0.28 mmol),
and (2,4-dimethoxyphenyl)magnesium bromide (1.0  in ether,
0.56 mL, 0.56 mmol, 2 equiv.), followed by chromatography with
ethyl acetate/hexane (20:80 to 40:60), a white solid was obtained
(64 mg, 58%), m.p. 62Ϫ63 °C. [α]2D5 ϭ Ϫ64.21 (c ϭ 0.0114, CHCl3).
1H NMR: δ ϭ 0.40 (d, J ϭ 7.5 Hz, 3 H, 5-Me), 1.00 (d, J ϭ 5.7 Hz,
3 H, 6-Me), 1.20Ϫ2.10 (m, 13 H), 2.32 (m, 1 H), 2.84 (m, 1 H, 9-
H), 3.79, 3.80 (2 ϫ s, 6 H, 2 ϫ OMe), 5.54 (s, 1 H, H-12), 5.84 (d,
J ϭ 6.6 Hz, 1 H, 10-H), 6.42 (d, J ϭ 2.4 Hz, 1 H, Ph-H), 6.47 (dd,
J ϭ 8.4, 2.4 Hz, 1 H, Ph-H), 7.33 (d, J ϭ 8.4 Hz, 1 H, Ph-H) ppm.
IR (Nujol): ν˜max ϭ 726, 780, 832, 880, 946, 1010, 1040, 1120, 1156,
1208, 1286, 1258, 1376, 1464, 1506, 1590, 1614, 2920 cmϪ1. MS
(CI, CH4): m/z (%) ϭ 405 (15) [MHϩ], 359 (100) [M Ϫ 3CH3]ϩ,
317 (6), 275 (28), 221(8), 154 (22). C23H32O6 (404.51): calcd. C
68.29, H 7.97; found C 68.55, H 8.14.
782, 840, 902, 942, 1008, 1114, 1374, 1456, 1494, 2924 cmϪ1. MS
ϩ
(CI, NH3): m/z (%) ϭ 399 (8) [MNH4
(MNH4
,
13C, 37Cl], 398 (36)
, ,
37Cl], 397 (25) [MNH4 13C], 396 (100) [MNH4ϩ].
ϩ
ϩ
C21H27ClO4 (378.90): calcd. C 66.57, H 7.18; found C 66.42, H
7.05.
10β-(4Ј-Bromophenyl)-10-deoxo-10-dihydroartemisinin (42): Ac-
cording to the method above, from DHA 10α-TMS ether 38
(100 mg, 0.28 mmol), trimethylsilyl bromide (37 µL, 0.28 mmol),
and (4-bromophenyl)magnesium bromide (1.0  in ether, 0.56 mL,
0.56 mmol, 2 equiv.). followed by chromatography with ethyl acet-
ate/hexane (2:98 to 3:97), a white solid was obtained (75 mg, 64%).
Recrystallisation from dichloromethane/hexane gave colourless rec-
tangular crystals, m.p. 156Ϫ159 °C. [α]2D5 ϭ Ϫ45.14 (c ϭ 0.0216,
1
CHCl3). H NMR: δ ϭ 0.48 (d, J ϭ 7.8 Hz, 3 H, 6-Me), 0.98 (d,
J ϭ 5.7 Hz, 3 H, 9-Me), 1.40 (s, 3 H, 3-Me), 1.19Ϫ2.10 (m, 10 H),
2.33 (m, 1 H), 2.72 (m, 1 H, 9-H), 5.55 (s, 1 H, H-12), 5.70 (d, J ϭ
6.6 Hz, 1 H, 10-H), 7.19 (d, J ϭ 8.4 Hz, 2 H, 2 ϫ Ph-H), 7.43 (d,
J ϭ 8.4 Hz, 2 H, 2 ϫ Ph-H) ppm. IR (Nujol): ν˜max ϭ 780, 840,
882, 902, 942, 1008, 1112, 1374, 1454, 1492, 2924 cmϪ1. MS (CI,
CH4): m/z (%) ϭ 453 (18) [M(Br81) ϩ 2CH4]ϩ, 451 (20) [M(Br79)
ϩ 2CH4]ϩ, 425 (51) [M(Br81) ϩ 1]ϩ, 423 (53) [M(Br79) ϩ 1]ϩ, 407
(40), 405 (32), 392 (35), 390 (48), 379 (100), 377 (88), 335 (20), 333
(28), 267 (32), 221 (41), 209 (78), 191 (78), 191 (26), 163 (59).
10β-(2Ј,4Ј,6Ј-Trimethoxyphenyl)-10-deoxo-10-dihydroartemisinin
(46): According to the method above, from DHA 10α-TMS ether
38 (356 mg, 1.0 mmol), trimethylsilyl bromide (0.2 mL,1.5 mmol),
and (2,4,6-trimethoxyphenyl)magnesium bromide (0.25  in ether,
1.7 mL, 0.42 mmol, 1.5 equiv.), followed by chromatography with
ethyl acetate/hexane (25:75), a white solid was obtained (202 mg,
46%), m.p. 58Ϫ60 °C. [α]2D2 ϭ ϩ10.6 (c ϭ 0.016, CHCl3). 1H NMR:
δ ϭ 0.72 (d, J ϭ 7.7 Hz, 3 H, 9-Me), 1.00 (d, J ϭ 5.7 Hz, 3 H, 6-
Me), 0.84Ϫ1.11 (m, 1 H), 1.40 (s, 3 H, 3-Me), 1.20Ϫ1.57 (m, 3
H), 1.68Ϫ1.84 (m, 4 H), 1.97Ϫ2.08 (m, 2 H), 2.29Ϫ2.38 (m, 1 H),
10β-(4Ј-Vinylphenyl)-10-deoxo-10-dihydroartemisinin (43): Accord-
ing to the method above, from DHA 10α-TMS ether 38 (356 mg,
1.0 mmol), trimethylsilyl bromide (0.2 mL, 1.5 mmol), and (4-vi-
nylphenyl)magnesium bromide (0.5  in ether, 4.0 mL, 2.0 mmol, 2.64Ϫ2.72 (m, 1 H), 3.78 (s, 6 H, 2 ϫ OMe), 3.81 (s, 3 H, OMe),
2 equiv.), followed by chromatography with ethyl acetate/hexane
(5:95), a white solid was obtained (251 mg, 68%), m.p. 109Ϫ110
°C. [α]2D2 ϭ Ϫ64.6 (c ϭ 0.028, CHCl3). 1H NMR: δ ϭ 0.54 (d, J ϭ
5.52 (s, 1 H, H-12), 6.13 (s, 1 H, Ph-H), 6.16 (d, J ϭ 8.1 Hz, 1 H,
10-H) ppm. IR (film): ν˜max ϭ 954, 1006, 1126, 1154, 1204, 1456,
1608, 2938 cmϪ1. MS (CI, CH4): m/z (%) ϭ 435 (10) [MHϩ], 417
7.7 Hz, 3 H, 9-Me), 0.98 (d, J ϭ 5.7 Hz, 3 H, 6-Me), 7.37 (d, J ϭ (8), 389 (100), 371 (6), 347 (10), 329 (16), 221 (8): C24H34O7
8.3 Hz, 2 H, 2 ϫ Ph-H), 0.83Ϫ0.99 (m, 1 H), 1.38 (s, 3 H, 3-Me), (422.52): calcd. C 66.34, H 7.89; found C 66.57, H 8.04.
2110
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2098Ϫ2114

10α- and 10β-Aryl Derivatives of Dihydroartemisinin
FULL PAPER
10β-(2Ј,4Ј,6Ј-Trimethylphenyl)-10-deoxo-10-dihydroartemisinin (47):
124.8, 125.2, 125.65, 127.1, 127.4, 127.8, 134.85 ppm. IR (film):
According to the method above, from DHA 10α-TMS ether 38 ν˜max ϭ 750, 786, 824, 854, 886, 936, 954, 1010, 1040, 1074, 1106,
(356 mg, 1.0 mmol), trimethylsilyl bromide (0.2 mL, 1.5 mmol),
1208, 1376, 1452, 1510, 2874, 2950 cmϪ1. MS (CI, CH4): m/z (%) ϭ
and (2,4,6-trimethylphenyl)magnesium bromide (0.5  in ether, 395 (16) [MHϩ], 394 (32) [Mϩ, 32], 362 (44), 349 (84), 331 (16),
0.85 mL, 0.42 mmol, 1.5 equiv.), followed by chromatography with
ethyl acetate/hexane (5:95), a colourless oil was obtained (213 mg,
55%), which was recrystalllized from ethyl acetate to give the prod-
uct as a fine microcrystalline powder, m.p. 64Ϫ66 °C. [α]2D2 ϭ ϩ13.7
(c ϭ 0.019, CHCl3). 1H NMR: δ ϭ 0.64 (d, J ϭ 7.8 Hz, 3 H, 9-Me),
1.03 (d, J ϭ 5.9 Hz, 3 H, 6-Me), 0.84Ϫ1.04 (m, 1 H), 1.29Ϫ1.50 (m,
6 H), 1.64Ϫ1.90 (m, 4 H), 2.05Ϫ2.11 (m, 2 H), 2.27 (s, 3 H, Me),
2.32 (s, 3 H, Me), 2.26Ϫ2.40 (m, 1 H), 2.48 (s, 3 H, Me), 2.74Ϫ2.85
(m, 1 H), 5.55 (s, 1 H, H-12), 6.05 (d, J ϭ 7.6 Hz, 1 H, 10-H), 6.81
(s, 2 H, 2 ϫ Ph-H) ppm. 13C NMR: δ ϭ 13.2, 19.9, 20.6, 20.7,
22.3, 24.5, 25.0, 25.7, 30.4, 34.2, 36.8, 37.6, 43.9, 51.3, 71.82, 80.9,
90.7, 102.3, 128.4, 130.8, 133.5, 135.2, 135.6, 137.2 ppm. IR (Neat):
ν˜max ϭ 724, 756, 780, 848, 880, 896, 942, 958, 1008, 1076, 1106,
1208, 1376, 1452, 2874, 2938 cmϪ1. MS (CI, CH4): m/z (%) ϭ 387
(6) [MHϩ], 386 (8), 385 (10), 341 (100), 327 (8), 299 (8), 267 (14),
221 (10), 209 (4), 163 (8), 133 (8): C24H34O4 (374.53): calcd. C
74.58, H 8.87; found C 74.48, H 8.98.
304 (20), 291 (26), 182 (100), 168 (60). C25H30O4 (370.49): calcd. C
76.11, H 7.66; found C 76.24, H 7.69.
10β- and 10α-[2Ј-(6Ј-Methoxynaphthyl)]-10-deoxo-10-dihydroartem-
isinin (50 and 51): According to the method above, from DHA 10α-
TMS ether 38 (200 mg, 0.56 mmol), trimethylsilyl bromide (74 µL,
0.56 mmol), and 6-methoxy-2-(naphthyl)magnesium bromide (0.7
 in THF, 1.6 mL, 1.12 mmol, 2.0 equiv.), followed by chromatog-
raphy with ethyl acetate/hexane (10:90). The less-polar 10β-isomer
50 was obtained as a white powder (41 mg, 17%), m.p. 165Ϫ167
1
°C. [α]2D0 ϭ Ϫ49 (c ϭ 0.115, DMF). H NMR: δ ϭ 0.52 (d, J ϭ
7.7 Hz, 3 H, 9-Me), 0.88Ϫ0.94 (m, 1 H), 0.99 (d, J ϭ 5.6, 3 H, 6-
Me), 1.23Ϫ1.51 (m, 7 H), 1.58Ϫ2.09 (m, 5 H), 2.30Ϫ2.40 (m, 1 H),
2.78Ϫ2.86 (m, 1 H), 3.91 (s, 3 H, OMe), 5.54 (s, 1 H, H-12), 5.86
(d, J ϭ 3.7 Hz, 1 H, 10-H), 7.11Ϫ7.14 (m, 2 H, 2 ϫ Ar-H),
7.39Ϫ7.35 (m, 1 H, Ar), 7.67Ϫ7.74 (m, 3 H, 3 ϫ Ar-H) ppm. 13C
NMR: δ ϭ 14.5, 20.7, 25.6, 25.7, 26.5, 33.0, 35.0, 37.45, 38.3, 44.3,
52.3, 55.9, 73.9, 82.0, 91.7, 103.1, 106.3, 119.2, 125.0, 126.2, 126.8,
129.4, 130.1, 134.1, 137.1, 158.0 ppm. MS (CI, CH4): m/z (%) ϭ
426 (2) [MHϩ, 13C], 425 (8) [MHϩ], 424 (7) [Mϩ]. C26H32O5
(424.54): calcd. C 73.56, H 7.60; found C 73.35, H 7.70. The more-
polar component was the 10α-isomer 51, also obtained as a white
powder (32 mg, 14%), m.p. 146Ϫ148 °C. [α]2D2 ϭ ϩ129 (c ϭ 0.08,
10β-(2Ј,4Ј,5Ј-Trimethylphenyl)-10-deoxo-10-dihydroartemisinin (48):
According to the method above, from DHA 10α-TMS ether 38
(356 mg, 1.0 mmol), trimethylsilyl bromide (135 µL, 1.0 mmol),
and (2,4,5-trimethylphenyl)magnesium bromide (0.25  in ether,
4.4 mL, 1.10 mmol, 1.1 equiv.), followed by chromatography with
ethyl acetate/hexane (5:95), a colourless oil was obtained (212 mg,
55%), which was recrystallized from ethyl acetate to give the prod-
1
DMF). H NMR: δ ϭ 0.55 (d, J ϭ 7.2 Hz, 3 H, 9-Me), 0.99 (d,
J ϭ 6.2 Hz, 3 H, 6-Me), 1.05Ϫ1.13 (m, 1 H), 1.46 (s, 3 H, 3-Me),
1.53Ϫ1.68 (m, 4 H), 1.74Ϫ1.81 (m, 1 H), 1.87Ϫ1.96 (m, 1 H),
2.02Ϫ2.10 (m, 1 H), 2.43Ϫ2.49 (m, 1 H), 2.65Ϫ2.72 (m, 1 H), 3.91
(s, 3 H, OMe), 4.50 (d, J ϭ 10.7 Hz, 1 H, 10-H), 7.10Ϫ7.13 (m, 2
H, 2 ϫ Ar-H), 7.55Ϫ7.59 (m, 2 H, Ar-H), 7.70Ϫ7.73 (m, 3 H, 3 ϫ
Ar-H) ppm. 13C NMR: δ ϭ 14.8, 21.0, 22.2, 25.5, 26.75, 34.55,
34.9, 37.05, 38.1, 46.8, 52.7, 55.9, 79.15, 81.4, 92.8, 104.9, 106.3,
119.2, 126.5, 127.0, 127.65, 129.3, 130.1, 135.1, 136.7, 158.2 ppm.
MS (EI): m/z (%) ϭ 424 (4) [MHϩ]. C26H32O5 (424.54): calcd. C
73.56, H 7.60; found C 73.41, H 7.61.
uct as a fine microcrystalline powder, m.p. 140Ϫ141 °C. [α]2D0
ϭ
1
Ϫ55.6 (c ϭ 0.068, CHCl3). H NMR: δ ϭ 0.55 (d, J ϭ 7.7 Hz, 3
H, 9-Me), 1.11 (d, J ϭ 5.8 Hz, 3 H, 6-Me), 0.97Ϫ1.11 (m, 1 H),
1.40Ϫ1.55 (m, 7 H), 1.78Ϫ2.00 (m, 3 H), 2.10Ϫ2.19 (m, 2 H), 2.31
(s, 3 H, Me), 2.33 (s, 6 H, 2 ϫ Me), 2.38Ϫ2.48 (m, 1 H), 2.80Ϫ2.90
(m, 1 H), 5.67 (s, 1 H, H-12), 5.94 (d, J ϭ 6.7 Hz, 1 H, 10-H), 6.99
(s, 1 H, Ph), 7.32 (s, 1 H, Ph) ppm. 13C NMR: δ ϭ 13.65, 18.7,
19.2, 19.9, 24.8, 25.0, 25.6, 29.9, 34.2, 36.8, 37.6, 43.5, 51.3, 70.0,
81.1, 91.0, 102.1, 127.1, 130.8, 131.0, 134.0, 136.6, 133.1 ppm. IR
(Neat): ν˜max ϭ 754, 820, 880, 896, 934, 954, 978, 1040, 1000, 1056,
1100, 1120, 1180, 1202, 1220, 1374, 1278, 1452, 1502, 2874, 2922
cmϪ1. MS (CI, CH4): m/z (%) ϭ 387 (10) [MHϩ], 386 (44) [Mϩ,
44], 354 (60), 341 (84), 296 (6), 282 (18), 109 (20), 182 (28), 160
(100), 149 (56), 133 (38), 121 (30). C24H34O4 (374.53): calcd. C
74.58, H 8.87; found C 74.63, H 8.73.
10β-(9Ј-Phenanthryl)-10-deoxo-10-dihydroartemisinin (52): Accord-
ing to the method above, from DHA 10α-TMS ether 38 (0.3 g,
0.84 mmol), trimethylsilyl bromide (0.12 mL, 0.88 mmol), and 9-
(phenanthryl)magnesium bromide (0.6
 in THF, 4.22 mL,
2.53 mmol, 1.1 equiv.), followed by chromatography with ethyl
acetate/hexane (7:93), a white solid was obtained (140 mg, 37%),
1
m.p. 89Ϫ91 °C. [α]2D0 ϭ Ϫ68.8 (c ϭ 0.016, CHCl3). H NMR: δ ϭ
10β-(2Ј-Naphthyl)-10-deoxo-10-dihydroartemisinin (49): According
to the method above, from DHA 10α-TMS ether 38 (1.2 g,
3.37 mmol), trimethylsilyl bromide (0.47 mL, 3.54 mmol), and (2-
0.39 (d, J ϭ 7.6 Hz, 3 H, 9-Me), 1.06 (d, J ϭ 5.7 Hz, 3 H, 6-
Me), 1.41 (s, 3 H, 3-Me), 0.86Ϫ1.60 (m, 5 H), 1.73Ϫ1.84 (m, 2 H),
2.00Ϫ2.16 (s, 3 H), 2.37Ϫ2.48 (m, 1 H), 3.06Ϫ3.19 (m, 1 H), 5.75
(s, 1 H, H-12), 6.50 (d, J ϭ 6.5 Hz, 1 H, 10-H), 7.57Ϫ7.72 (m, 4
H, 4 ϫ Ph-H), 7.91Ϫ8.10 (m, 3 H, 3 ϫ Ph-H), 8.68Ϫ8.81 (m, 2 H,
2 ϫ Ph-H) ppm. 13C NMR: δ ϭ 13.2, 20.0, 24.95, 25.1, 25.8, 31.55,
34.3, 36.9, 37.7, 43.8, 51.45, 69.9, 81.4, 91.3, 102.5, 122.3, 123.2,
123.7, 123.8, 126.0, 126.0, 126.5, 126.7, 128.8, 129.6, 130.0, 130.1,
131.7, 135.2 ppm. IR (film): ν˜max ϭ 726, 748, 794, 832, 886, 906,
930, 956, 1010, 1040, 1110, 1220, 1246, 1376, 1450, 1498, 2362,
2874, 2922 cmϪ1. MS (CI, CH4): m/z (%) ϭ 445 (22) [MHϩ], 444
(100), 398 (40), 384 (16), 352 (16), 328 (44), 267 (6), 218 (84), 203
(48), 178 (60), 163 (44), 138 (70), 107 (62). C29H32O4 (443.57):
calcd. C 78.35, H 7.26; found C 78.56, H 7.54.
naphthyl)magnesium bromide (0.48

in THF, 14.0 mL,
6.75 mmol, 2.0 equiv.), followed by chromatography with ethyl
acetate/hexane (5:95), an inseparable mixture of 49 and glycal 19
(1.01 g) was obtained. Potassium carbonate (0.53 g, 3.58 mmol)
and m-chloroperbenzoic acid (0.88 g, 5.13 mmol) were added to a
cold (0 °C) stirred solution of this mixture in dichloromethane
(10 mL). After 21 h, the mixture was filtered and the filtrate was
removed to give a residue that was submitted to chromatography
with ethyl acetate/hexane (5:95) to afford the product 49 as a white
powder (565 mg, 43%), m.p. 145Ϫ146 °C. [α]2D0 ϭ Ϫ67.8 (c ϭ 0.027,
1
CHCl3). H NMR: δ ϭ 0.55 (d, J ϭ 7.7 Hz, 1 H, 9-Me), 1.02 (d,
J ϭ 6.1 Hz, 1 H, 6-Me), 1.42 (s, 3 H, 3-Me), 0.86Ϫ2.13 (m, 10 H),
2.33Ϫ2.48 (m, 1 H), 2.81Ϫ2.94 (m, 1 H, 9-H), 5.67 (s, 1 H, H-12), 10β-[4Ј-(1ЈЈ-Morpholino)phenyl]-10-deoxo-10-dihydroartemisinin
5.93 (d, J ϭ 6.6 Hz, 1 H, 10-H), 7.42Ϫ7.51 (m, 3 H, 3 ϫ Ar-H),
(53): According to the method above, from DHA 10α-TMS ether
38 (800 mg, 2.25 mmol), trimethylsilyl bromide (0.31 mL,
7.80Ϫ7.85 (m, 4 H, 4 ϫ Ar-H) ppm. 13C NMR: δ ϭ 13.65, 19.85,
24.8, 24.9, 25.7, 32.1, 34.15, 36.6, 37.5, 43.4, 51.5, 73.0, 90.9, 124.3, 2.36 mmol), and 4-(morpholino)phenylmagnesium bromide (0.46 
Eur. J. Org. Chem. 2003, 2098Ϫ2114
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2111

R. K. Haynes et al.
FULL PAPER
in THF, 7.3 mL, 3.37 mmol, 1.5 equiv.), followed by chromatogra-
single crystals. Specimens were mounted on glass fibres and glued
phy with ethyl acetate/hexane (20:80), a white solid was obtained with epoxy cement that had nearly set. This precaution was taken
(495 mg, 51%), m.p. 121Ϫ122 °C. [α]2D2 ϭ Ϫ39.14 (c ϭ 0.51,
to prevent significant crystal decomposition resulting from the per-
CHCl3). 1H NMR: δ ϭ 0.55 (d, J ϭ 7.7 Hz, 3 H, 9-Me), 0.88Ϫ0.97 oxide linkage present in the compounds. For compound 33, X-ray
(m, 1 H), 0.98 (d, J ϭ 5.6 Hz, 3 H, 6-Me), 1.16Ϫ1.35 (m, 3 H), intensity data were collected at 100 K with a Bruker SMART
1.38 (s, 3 H, 3-Me), 1.42Ϫ1.49 (m, 1 H), 1.56Ϫ1.87 (m, 3 H), APEX CCD diffractometer. The other compounds were studied at
1.98Ϫ2.08 (m, 2 H), 2.28Ϫ2.39 (m, 1 H), 2.66Ϫ2.78 (m, 1 H), 3.14 room temperature with a Bruker P4-RA 4-circle diffractometer fit-
(m, 4 H, 2 ϫ morpholino CH2), 3.86 (m, 4 H, 2 ϫ morpholino
ted with molybdenum rotating anode operating at 10 kW. A cus-
CH2), 5.56 (s, 1 H, H-12), 5.64 (d, J ϭ 6.6 Hz, 1 H, 10-H), 6.87 (d, tom-built 1.2-mm collimator was used with this instrument to allow
J ϭ 8.7 Hz, 2 H, 2 ϫ Ph-H), 7.22 (d, J ϭ 8.7 Hz, 2 H, 2 ϫ Ph-H)
data collection of the large specimens up to 1 mm dimension. All
ppm. 13C NMR: δ ϭ 13.9, 20.0, 24.8, 25.0, 25.8, 32.35, 34.3, 36.7, compounds crystallized in the chiral space groups orthorhombic
37.56, 43.65, 49.6, 51.6, 66.9, 73.0, 81.2, 90.8, 102.4, 115.2, 127.0, P212121, tetragonal P43 or monoclinic P21. This observation is con-
132.9, 149.8 ppm. MS (CI, CH4): m/z (%) ϭ 432 (3) [MHϩ, 2 ϫ sistent with their derivation from the enantiomerically pure chiral
13C], 431 (13) [MHϩ, 13C], 430 (45) [MHϩ], 429 (17) [Mϩ].
natural product artemisinin. The absolute configuration of the five
C25H35NO5 (429.56): calcd. C 69.90, H 3.26; found C 69.90, H compounds studied here was not directly confirmed from these
3.22.
experiments, but has been unambiguously established by numerous
previous structural studies within our group and by others.[61]
10β-(4Ј-N,N-Dimethylaminophenyl)-10-deoxo-10-dihydroartemisinin
(54): According to the method above, from DHA 10α-TMS ether
38 (1.5 g, 4.21 mmol), trimethylsilyl bromide (0.58 mL, 4.42 mmol),
and [4-(dimethylamino)phenyl]magnesium bromide (0.4  in THF,
21 mL, 8.43 mmol, 2 equiv.), followed by chromatography with
ethyl acetate/hexane (8:92), a white solid was obtained (551 mg,
34%), m.p. 154Ϫ155 °C. [α]2D2 ϭ Ϫ54.49 (c ϭ 0.69, CHCl3). 1H
NMR: δ ϭ 0.73 (d, J ϭ 7.8 Hz, 3 H, 9-Me), 1.06 (m, 1 H), 1.12
(d, J ϭ 6.1 Hz, 3 H, 6-Me), 1.41Ϫ1.49 (m, 2 H), 1.53 (s, 3 H, 3-
Me), 1.56Ϫ1.58 (m, 1 H), 1.78Ϫ1.99 (m, 4 H), 2.12Ϫ2.23 (m, 2 H),
2.44Ϫ2.52 (m, 1 H), 2.84Ϫ2.90 (m, 1 H), 3.07 (s, 6 H, NMe2), 5.71
(s, 1 H, H-12), 5.76 (d, J ϭ 6.6 Hz, 1 H, 10-H), 6.86 (d, J ϭ 8.8 Hz,
2 H, 2 ϫ Ph-H), 7.33 (d, J ϭ 9.1 Hz, 2 H, 2 ϫ Ph-H) ppm. 13C
NMR: δ ϭ 14.1, 20.1, 24.85, 25.1, 25.9, 32.55, 34.4, 36.8, 37.6,
40.9, 43.8, 51.7, 73.2, 81.2, 90.8, 102.3, 112.2, 126.9, 129.3, 149.2
ppm. MS (EI): m/z (%) ϭ 389 (2) [MHϩ, 13C], 388 (9) [MHϩ], 387
(64) [Mϩ], 343 (3) [M Ϫ NMe2]ϩ. C23H33NO4 (387.52): calcd. C
71.29, H 8.58, N 3.61; found C 70.85, H 8.60, N 3.69.
The crystal structures were successfully solved and refined using
the SHELX suite of X-ray computer programs throughout. A sum-
mary of the crystal data and structure determination parameters
for compounds 33, 40 and 52 are given in Table 2. Key geometric
features of the artemisinin moiety and the effect of 10-aryl substitu-
ents on the pyranose ring are given in Table 4 and 5.
CCDC-208727 and -175439 to -175442 for compounds 33,
40, 52Ϫ54 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, UK; Fax: (internat.) ϩ44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
Acknowledgments
Financial and material support from Bayer AG (Leverkusen, Ger-
many), Grant Nos. HKUST/BAY 95/96, 97/98 and 99/00 for the
preparation of new derivatives is gratefully acknowledged. Gen-
erous financial support from The Government of the HKSAR Uni-
versity Grants Council, Grants No HKUST 6184/99P and HKUST
6091/02P is also gratefully acknowledged.
Note Added in Proof (April 19, 2003): Phenyl-, benzyl-, allyl-,
vinyl- and n-butylzinc reagents are reported to react stereoselec-
tively with either 10α- or 10β-(benzenesulfonyl)-10-deoxo-10-dihy-
droartemisinin to give exclusively or predominantly 10β-substi-
tuted-10-deoxo-10-dihydroartemisinins, for example compounds 10
and 11; see: S. Lee, S. Oh, Tetrahedron Lett. 2002, 43, 2891Ϫ2894.
These excellent results clearly indicate that organometallic nucleo-
philes are predisposed to attack from the re (β) face, regardless of
the stereochemistry of the leaving group (cf. Scheme 2).
4Ј-(10β-Dihydroartemisinyl)benzoic acid (56): A suspension of com-
pound 43 (209 mg, 0.565 mmol), KMnO4 (268 mg, 1.70 mmol) and
NaHCO3 (24 mg, 0.283 mmol) in acetone (20 mL) was stirred at
room temperature. After 5 h, the precipitate was removed by fil-
tration through a pad of Celite. The residue was washed with ace-
tone, water was added, and the filtrate was concentrated. The resi-
due was then extracted with ethyl acetate (3 ϫ 15 mL) and the
combined organic extracts were dried (MgSO4). Filtration and
evaporation of filtrate gave a residue, which after chromatography
with ethyl acetate/hexane (40:60 to 60:40) gave a white solid
(173 mg, 79%), m.p. 177Ϫ178 °C. [α]2D2 ϭ Ϫ63.2 (c ϭ 0.019,
1
CHCl3). H NMR: δ ϭ 0.51 (d, J ϭ 7.6 Hz, 3 H, 9-Me), 1.01 (d,
J ϭ 5.5 Hz, 3 H, 6-Me), 0.87Ϫ1.02 (m, 1 H), 1.41 (s, 3 H, 3-Me),
1.23Ϫ2.10 (m, 9 H), 2.31Ϫ2.40 (m, 1 H), 2.76Ϫ2.83 (m, 1 H), 5.60
(s, 1 H, H-12), 5.82 (d, J ϭ 6.6 Hz, 1 H, 10-H), 7.45 (d, J ϭ 8.3, 2
H, 2 ϫ Ph-H), 8.09 (d, J ϭ 8.3 Hz, 2 H, 2 ϫ Ph-H) ppm. 13C
NMR: δ ϭ 13.4, 19.8, 24.7, 25.6, 29.05, 31.9, 34.0, 36.5, 37.4, 43.3,
51.35, 72.7, 81.1, 90.8, 102.3, 126.15, 127.3, 129.7, 147.4, 171.7
ppm. IR (film): ν˜max ϭ 732, 766, 802, 824, 854, 882, 908, 944, 954,
968, 980, 1012, 1040, 1056, 1074, 1116, 1178, 1208, 1222, 1286,
1314, 1376, 1424, 1452, 1512, 1578, 1612, 1688, 2252, 2546, 2670,
2878, 2954 cmϪ1. MS (CI, CH4): m/z (%) ϭ 389 (8) [MHϩ], 329
(100), 283 (36), 267 (20), 219 (26), 177 (80), 129 (64). C22H28O6
(388.46): calcd. C 68.02, H 7.27; found C 67.77, H 7.31.
[1]
A note about nomenclature: DHA 2 has a chair-like pyranose
ring. The ‘‘α’’-epimer has an equatorial hydroxy group, the
‘‘β’’-epimer an axial hydroxy group (see also ref.[19]). Arte-
mether 3 (axial methoxyl) is sometimes referred to as β-arte-
mether, to distinguish this compound from the ‘‘α’’-epimer
with an equatorial methoxyl group, in the malaria literature.
This ‘‘convention,’’ however, which has grown from the ‘‘nor-
mal’’ manner of representing structures of artemisinin and its
derivatives in the voluminous literature of artemisinin deriva-
tives (see refs. [2Ϫ7]), is the reverse of that normally used for
designating the stereochemistry of sugars and their glycosides,
in which, for example, α--glucopyranose possesses an axial
hydroxy group. This inconsistency is unfortunate, but for con-
venience, here we continue to use the artemisinin stereochem-
ical ‘‘convention.’’
X-ray Crystallographic Study: Single-crystal X-ray structure deter-
minations were carried out on five of the new compounds (33, 40,
52, 53 and 54). These compounds were recrystallized from CH2Cl2/
hexane by layer diffusion and, in general, afforded large colourless
2112
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2098Ϫ2114

10α- and 10β-Aryl Derivatives of Dihydroartemisinin
FULL PAPER
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Eur. J. Org. Chem. 2003, 2098Ϫ2114
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2113

R. K. Haynes et al.
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Received January 28, 2003
2114
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Eur. J. Org. Chem. 2003, 2098Ϫ2114