Structure-activity relationships of the antimalarial agent artemisinin. 5. Analogs of 10-deoxoartemisinin substituted at C-3 and C-9

Article abstract of DOI:10.1021/jm9603577

Novel 3- and 9-substituted analogs (4-19) of 10-deoxoartemisinin, 3, were prepared from the corresponding known lactones by one-pot reduction with sodium borehydride and boron trifiuoride etherate. Reproducibility problems associated with this heterogeneous reaction were encountered on small reaction scales, and thus alternative methodology was sought for this reduction. Conversion of the lactones to tetrahydropyrans via the corresponding intermediate lactols was made more reproducible using a two- step sequence involving low-temperature reduction with diisobutylaluminum hydride followed by deoxygenation with boron trifiuoride etherate in the presence of triethylsilane. In this manner, 10-deoxoartemisinin (3) could be obtained from artemisinin (1) in greater than 95% overall yield. All analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs were much more active than the natural product (+)- artemisinin (1) or 10-deoxoartemisinin (3). Conventional structure-activity relationships are discussed in relation to the bioassay data.

Full text of DOI:10.1021/jm9603577

J . Med. Chem. 1996, 39, 4149-4155
4149
Articles
Str u ctu r e-Activity Rela tion sh ip s of th e An tim a la r ia l Agen t Ar tem isin in . 5.
An a logs of 10-Deoxoa r tem isin in Su bstitu ted a t C-3 a n d C-9
Mitchell A. Avery,* Sanjiv Mehrotra, Theresa L. J ohnson, J ason D. Bonk, J effrey A. Vroman, and Robert Miller†
Department of Medicinal Chemistry and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of
Mississippi, University, Mississippi 38677, and Division of Experimental Therapeutics, Walter Reed Army Institute of
Research, Washington, D.C. 20307
Received May 15, 1996X
Novel 3- and 9-substituted analogs (4-19) of 10-deoxoartemisinin, 3, were prepared from the
corresponding known lactones by one-pot reduction with sodium borohydride and boron
trifluoride etherate. Reproducibility problems associated with this heterogeneous reaction were
encountered on small reaction scales, and thus alternative methodology was sought for this
reduction. Conversion of the lactones to tetrahydropyrans via the corresponding intermediate
lactols was made more reproducible using a two-step sequence involving low-temperature
reduction with diisobutylaluminum hydride followed by deoxygenation with boron trifluoride
etherate in the presence of triethylsilane. In this manner, 10-deoxoartemisinin (3) could be
obtained from artemisinin (1) in greater than 95% overall yield. All analogs were tested in
vitro against W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs were
much more active than the natural product (+)-artemisinin (1) or 10-deoxoartemisinin (3).
Conventional structure-activity relationships are discussed in relation to the bioassay data.
(+)-Artemisinin (1), a naturally occurring peroxidic
cadinane sesquiterpene possessing good antimalarial
activity,1,2 has been the subject of many total syntheses3
and structure-activity relationship (SAR) studies.4-6
Much of this intense interest stems from the need for
new antimalarial drugs with unconventional structures
and novel modes of action to be used for the treatment
of pervasive strains of drug-resistant Plasmodium fal-
ciparum.7 Simple derivatives obtained by stepwise
modification to the lactone carbonyl such as artemether
(2, R ) Me) or sodium artesunate (2, R ) COCH2CH2-
COONa) have provided clinically useful drugs that have
been marketed in Southeast Asia. Complete removal
of the lactone carbonyl results in 10-deoxoartemisinin
(3), a compound with excellent potency and chemical
stability.5
gen atom from the C-4 position resulting in a more
stable carbon radical.11 The fate of this radical inter-
mediate is not understood but is actively under inves-
tigation.12 Activity is improved if groups which stabilize
radicals are placed at C-4â but not at C-4R.13 This
behavior is also observed in simple trioxanes which
fragment to carbon radicals.14 Furthermore, total syn-
thesis of 13-carbaartemisinin, in which the nonperoxidic
trioxane ring oxygen atom at O-13 is replaced by a
methylene, leads to an abrupt loss of activity signaling
the mechanistic importance of an intact trioxane ring.15
While the intermediate carbon radical at C-4 is capable
of fragmentation by a deketalization-like process, it
would appear that stabilization of the radical at C-4 by
the adjacent oxygen atom at O-13 is crucial for antima-
larial potency. These studies have proven to be useful
in the design of new antimalarials.13
In addition to mechanism-based design which focuses
upon a single determinant in drug activity, empirical
methods, such as quantitative structure-activity rela-
tionship (QSAR) studies, are useful in addressing more
elusive structure-activity components. Very few re-
ports of a QSAR model for the artemisinin class of
antimalarials exist; a classical QSAR study based upon
derivatives of dihydroartemisinin was reported a num-
ber of years ago16 and was only recently followed by 3D-
QSAR studies from our laboratory.17,6 In an effort to
expand upon our pharmacophore model, we felt that it
would be necessary to obtain analogs substituted in as
many available positions as possible about the tetracy-
clic framework of the parent structure 1. Thus far we
have reported comprehensive modifications to C-917 and
C-3,18 as well as the heteroatom-modified N-11 ana-
logs.19 In this paper we focus upon the effect of the 10-
deoxomodification of C-3- and C-9-substituted analogs
of artemisinin on antimalarial potency. The results are
The mechanism of action of these antimalarials has
also been the subject of scrutiny as this knowledge is
likely to provide the basis for rational drug design
efforts.8-10 While the mode of action of artemisinin and
its analogs is not known with absolute certainty, it is
generally accepted from in vitro studies that scission of
the peroxide bond by Fe(II) leads to an intermediate
oxyradical that rapidly abstracts a neighboring hydro-
† Walter Reed Army Institute of Research.
X Abstract published in Advance ACS Abstracts, September 1, 1996.
S0022-2623(96)00357-3 CCC: $12.00 © 1996 American Chemical Society

4150 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Avery et al.
Sch em e 1
Sch em e 2a
a
Key: (a) 2 LDA, 50 °C; R-Br, 25 °C; (b) O3, CH2Cl2, -78 °C,
then H3O+, SiO2; (c) NaBH4, BF3‚OEt2; (d) LiAlH4, Et2O.
intended for inclusion into a comparative molecular field
analysis (CoMFA) which will be reported separately.
While immediate gratification was thus obtained, the
overall approach to these compounds seemed less than
satisfactory, particularly in light of the enhanced bio-
logical activity of analog 10. Apparently, the problem
of reproducibility in these reductions was related to
some aggregate involving the heterogeneous nature of
the reaction, the inherent difficulties in accurately
transferring minute quantities of hygroscopic reductant,
and the need to employ refluxing conditions to complete
the reduction. Lower reaction temperatures combined
with homogeneous conditions could provide a means to
reproducibly access 10-deoxo analogs of artemisinin, and
we therefore set out to examine this possibility. Based
on the precedented reduction of 2H-dihydropyrones,23
the combination of Lewis acid and hydride source
exemplified by Et3SiH/BF3 seemed ideally suited to our
needs (Scheme 3). While (+)-artemisinin (1) could not
be reduced directly to 10-deoxoartemisinin (3) with Et3-
SiH/BF3, dihydroartemisinin (2, R ) H) was smoothly
converted at low temperature to the desired tetrahy-
dropyran 3 in 96% yield. Further, this method was
insensitive to scale, being readily accomplished on the
gram or milligram level. It was also found that small-
scale reductions could be more conveniently conducted
utilizing diisobutylaluminum hydride in place of sodium
borohydride. As applied to the problematical case, it
was found that the lactone 26 could be reduced to lactol
and thence 10 as outlined in Scheme 3 in excellent yield.
Furthermore, the yield for the conversion of lactone 23
into 9-butyl-10-deoxoartemisinin (7) could be similarly
improved from 58% to 90%.
Ch em istr y
Upon treatment of the natural product (+)-artemisi-
nin (1) with NaBH4 and BF3 etherate in methanol-THF
by J ung’s procedure20 (1-100 g), known product 3 was
obtained in 68% yield. When this procedure was applied
to 1 or previously reported lactones substituted at C-9
(20-25) or C-3 (27-34) on small scales (20-100 mg),
yields of 3-9 and 11-18 were dramatically variable
from run to run. It was found that without suitable
modification to the reported procedure, small-scale
reactions would frequently result in extensive decom-
position. In fact, even with suitable monitoring of the
reaction for completion, the deoxo analog 10 could not
be prepared by this approach. Thus, it was discovered
that this reduction could only be safely achieved on
small scales by periodic interruption for TLC monitor-
ing. In this manner, the C-9-substituted analogs (4-
9) of artemisinin were obtained in yields ranging of 35-
58%, while C-3-substituted (C-9 ) desmethyl) analogs
11-18 were furnished in 32-64% yield (Scheme 1).
We also found that ester functionality was compatible
with this reduction sequence. Thus, treatment of the
ester lactone 34 with sodium borohydride and boron
trifluoride etherate provided the tetrahydropyran 18 in
55% purified yield. Upon reaction with sodium hydrox-
ide, 18 underwent simple ester hydrolysis to furnish the
carboxylic acid 19.
In order to access the elusive haloaromatic species 10,
alternative approaches were examined. As shown in
Scheme 2, alkylation of the synthetic intermediate 35
with 3-(p-chlorophenyl)propyl bromide21 led, as ex-
pected, to clean production of the erythro acid 36. As
previously described,22 low-temperature ozonolysis of 36
followed by in situ acidification proceeded, through a
series of rearrangements, to the desired lactone 26.
Attempted reduction of 26 using the J ung/McChesney
methodology20 (borohydride/Lewis acid) was unsuccess-
ful in providing 10. Rather than examine this reaction
in detail, the short term goal of rapidly furnishing
material for in vitro antimalarial bioassay was ac-
complished by alteration of the oxidation state prior to
ozonolysis. Thus, reduction of 36 with LiAlH4 in ether
gave alcohol 37 in good yield. Surprisingly, its ozonoly-
sis/cyclization to 10 was accomplished in only 7% yield!
Biologica l Activity
The analogs 1 and 3-19 were tested in vitro in
parasitized whole blood (human) against drug-resistant
strains of P. falciparum at the Walter Reed Army
Institute of Research by a modification of the procedure
of Desjardins24,25 involving uptake of tritiated hypox-
anthine. Two P. falciparum malaria parasite clones,
designated as Indochina (W-2) and Sierra Leone (D-6),
were utilized in susceptibility testing. The W-2 clone
is chloroquine-resistant and mefloquine-sensitive, while
the D-6 clone is chloroquine-sensitive but mefloquine-
resistant. The relative potency values for these analogs
were derived from the IC50 value for artemisinin (1)
divided by their IC50 values (Table 1) and then adjusted

SAR of 10-Deoxoartemisinin Analogs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4151
Sch em e 3
Ta ble 1. Relative in Vitro Antimalarial Activity of 3- and 9-Substituted Analogs of 10-Deoxoartemisinin against P. falciparum
relative activitya
structure
R1
R
D-6
W-2
anal. (C, H)
3
4
5
6
7
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3CH2
CH3(CH2)2
CH3(CH2)3
(CH3)2CHCH2
C6H5(CH2)4
C6H5(CH2)2
p-ClC6H4(CH2)3
(CH2)2CO2Et
(CH2)2CO2H
CH3
H
CH3CH2
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
C6H5(CH2)3
p-ClC6H4(CH2)3
H
H
H
H
H
H
H
H
H
659
567
190
466
550
2090
145
2506
3317
10
685
556
250
380
2
C15H24O4
C14H22O4
C16H26O4
C17H28O4
C18H30O4
C19H32O4
C23H32O4
C23H31ClO4
C15H24O4
C16H26O4
C17H28O4
C17H28O4
C23H32O4
C21H28O4
C22H31ClO4
C18H28O6
C16H24O6
237
914
473
5826
170
5073
6991
10
722
653
183
336
6
8
9
10
11
12
13
14
15
16
17
18
19
13
422
0.09
28
506
0.09
a
Relative activity ) 100 × [IC50(artemisinin, control value)/IC50(analog)]MW(analog)/MW(artemisinin), i.e., relative activity of artemisinin
) 100.
for molecular weight differences by multiplication of the
ratio of the molecular weight of the analog divided by
the molecular weight of artemisinin. This approach to
reporting activity is based in part on the fact that the
analogs were tested on different occasions in which the
IC50 for the control, artemisinin, had varied anywhere
from 0.4 to 9 ng/mL based on parasitemia levels and
clone. For example, an IC50 value of 0.099 ng/mL was
determined for 10 in the W-2 clone, while in parallel
artemisinin had an IC50 value of 2.28 ng/mL. On
another occasion, artemisinin had an IC50 value of 0.99
ng/mL.
derivative 7 and finally decreased as expected for the
pentyl homolog 8. Profound potency enhancement was
observed for the 3-aryl propanes 9 and 10 in both W-2
and D-6 clones, being in the range of 25-70 times more
potent than control. To our knowledge, analogs 7, 9,
and 10 are the most potent analogs of artemisinin yet
reported in vitro which lack the 10-acetal linkage.
It is interesting to note that the lactones 20-25
corresponding to the above tetrahydropyrans 4-9 (with
the exception of 26, the precursor to 10) showed a
similar but attenuated trend in activities. For example,
lactones 21 and 22 were the most potent in this series
(ethyl and propyl) at about 12 times the activity of
artemisinin, but potency dropped significantly with
butyl (23) and pentyl (24). Similarly, the 3-phenylpro-
pyl lactone 25 was reasonably potent at 4-6 times
control. It is clear that removal of the lactone carbonyl
in the series 3-10 provides excellent potency enhance-
ment and that overall trends relative to the lactones
20-26 are not radically altered but do seem to be offset
somewhat (e.g., ethyl most potent in lactone series and
butyl most potent in tetrahydropyran series).
Str u ctu r e-Activity Rela tion sh ip s
For the analogs of 10-deoxoartemisinin (3) substituted
at C-9 (5-10), or the desmethyl analog 4, certain
qualitative relationships emerge upon examination of
Table 1. In the W-2 clone, the homologous series
ranging from H to propyl shows a relatively steady
potency at 5 times the activity of control (artemisinin,
1). For butyl, 7, a dramatic improvement in potency
was seen at about 21 times control, while at pentyl, 8,
activity had dropped off somewhat to around 1.5 times
the potency of artemisinin. We have found that activity
in the W-2 clone is generally paralleled by the more
sensitive D-6 clone. Thus, potency ranged from 2 times
control for analog 4 up to 58 times control for the butyl
For the C-3 ethyl-substituted analog 11, a mere one-
carbon homologation of compound 4 leads to a signifi-
cant drop in potency. However, homologation by two
carbons (C-3 propyl analog 12) results in roughly a 70-
fold improvement over 11. For C-3 butyl 13, activity

4152 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Avery et al.
Ta ble 2. Calculated Logarithmic Partition Coefficients (log P)
for 10-Deoxoartemisinin Analogs
ferent products than those provided by artemisinin (1),
the biochemical significance is not clear.15 The existence
of a nontrivial structure-activity correlation for these
analogs suggests the possibility of selective transport-
mediated phenomena. Some evidence for this thesis is
provided by the observation of enhanced uptake of
dihydroartemisinin into parasitized, over nonparasit-
ized, red blood cells.28 Along these lines, we found it
interesting to note that while the ester 18 demonstrated
activity comparable to 10-deoxoartemisinin (3), the
carboxylic acid 19 was virtually devoid of antimalarial
activity. Further, free carboxylic acids attached at
either C-9 or N-11 positions demonstrated a thorough
lack of activity.17-19
calcd log P
structure
R1
R
CLogPa Tsarb
3
4
5
6
7
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3CH2
CH3(CH2)2
CH3(CH2)3
(CH3)2CHCH2
C6H5(CH2)4
C6H5(CH2)2
p-ClC6H4(CH2)3
(CH2)2CO2Et
(CH2)2CO2H
CH3
H
CH3CH2
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
C6H5(CH2)3
p-ClC6H4(CH2)3
H
H
H
H
H
H
H
H
H
2.58
2.07
3.11
3.64
4.17
4.70
5.06
5.77
2.59
3.12
3.65
3.52
5.07
4.01
5.25
2.08
1.14
3.26
2.86
3.65
4.05
4.45
4.84
5.66
6.18
3.42
3.82
4.22
4.15
5.83
5.04
5.95
2.96
2.59
8
9
10
11
12
13
14
15
16
17
18
19
Exp er im en ta l Section
All solvents were purchased as reagent grade and, where
appropriate, were distilled from CaH2 and stored over dry 4
Å sieves for at least 1 day prior to use. Solvent and reagent
transfers were accomplished via dried syringe, and all reac-
tions were routinely conducted under an inert atmosphere
unless otherwise indicated. Flash chromatography was ac-
complished using silica gel (Whatman 60, 230-400 mesh).
Preparative thin-layer chromatography utilized 1, 1.5, or 2 mm
thick Analtech Uniplates with F-256. Silica gel thin-layer
chromatography plates (250-µm) were also purchased from
Analtech. Unless otherwise noted, all NMR analyses were
conducted in CDCl3, on a Varian VXR-300 spectrometer, and
referenced to chloroform at δ 7.27. IR spectra were recorded
on a Digilab FTS-40 FT-IR and performed neat unless other-
wise noted. Mass spectral data were obtained on a VG 7070E-
HF instrument. Elemental analyses were within 0.4% as
determined by Desert Analytics, Tucson, AZ.
P r oced u r e for Red u ction of Ar tem isin in An a logs to
10-Deoxoa r tem isin in An a logs Usin g Na BH4/BF 3. Under
an inert atmosphere, a 0 °C solution of the artemisinin analog
(0.1 mmol) and BF3/Et2O (360 µL) in dry THF (0.6 mL) was
added dropwise via cannula to an ice-cold stirred solution of
NaBH4 (8 mg) in dry THF (0.6 mL). The reaction mixture was
stirred cold for 1 h and then heated at 60 °C in 5 min intervals,
monitoring for reaction progress by TLC. Total reaction times
varied but were commonly 10-30 min. After cooling again to
0 °C, the reaction mixture was poured over an ice-water slurry
and extracted three times with ether. The combined organic
layer was dried over anhydrous MgSO4, filtered, and evapo-
rated in vacuo to give the crude product. Purification was
accomplished on 1.5 mm silica gel preparative TLC plates
eluting with 20% EtOAc/hexane. Crystallization was usually
accomplished from cold hexane or pentane. Pure products
were stored in the freezer.
a
b
Reference 26. Reference 27.
had dropped only slightly. However, the effect of
branching (i.e., C-3 isobutyl, 14) is apparently detri-
mental toward antimalarial potency. This same effect
was noted for C-9-substituted lactones: n-Alkanes were
usually significantly more active than the homologous
isoalkanes. Interestingly, the effect on potency of
arylalkyl substitution at C-3 is completely different than
noted in the C-9 series. The 3-(p-chlorophenyl)propyl-
substituted analog 17, isomeric with highly potent 9-(p-
chlorophenyl)propyl analog 10, is practically devoid of
antimalarial activity. While the ethylphenyl derivative
16 is impotent, 4-phenylbutyl homolog 15 is about 3
times more active than control. These results support
the notion that antimalarial potency among artemisinin
analogs cannot be explained on the sole basis of hydro-
phobicity.
Calculated log P data (CLogP)26 for artemisinin
analogs, previously shown to correlate reasonably well
with measured log P,19 has been obtained for these
analogs as shown in Table 2. For the 3-(p-chlorophe-
nyl)propyl-substituted analogs 17 and 10 illustrated
above, log P data show that 17 is roughly as lipophilic
as 10. Subtraction of the fragment constant π for a
methyl group of about 0.56 brings the calculated log P
for 10 of 5.21 (derived by 5.77-0.56) into parity with
the calculated log P of 17 of 5.25. Furthermore, using
the entire dataset and attempting simple regression
analysis in Tsar27 with bulk independent variables such
as log P or molar refractivity was fruitless, yielding r2
values approaching zero. Polynomial regression analy-
sis after deletion of 16 provided the “best” statistical
correlation with r2 ) 0.348, where log RA ) -8.68 +
3.93 log P - 0.396 (log P)2. Verloop B1 (length)
parameters and log P were correlated loosely with log
relative activity (log RA), giving log RA ) 0.65(CLogP)
- 0.16B1 - 0.14; r2 ) 0.366. More extensive multiple
regression analyses in Tsar combining other parameters
such as moment of inertia, dipole, total dipole, bond
dipole, charges, topological, connectivity, and shape
indices were likewise without statistical significance.
At a glance, the removal of the lactone carbonyl might
not be expected to alter the postulated primary mode
of antimalarial action put forth by Posner and Mesh-
nick. While it is true that 10-deoxoartemisinin (3)
undergoes Fe(II)-promoted rearrangement to give dif-
Octa h yd r o-3,6-d im eth yl-3,12-ep oxy-12H-p yr a n o[4,3-j]-
1,2-ben zod ioxep in (4). From 9-desmethylartemisinin (20)
(0.06 g, 0.22 mmol) was obtained 31 mg (55%) of pure 4 as a
white solid (mp 87 °C). 1H NMR: δ 5.21 (s, 1H), 3.97 (dd, 1H,
J ) 4.7, 11.9 Hz), 3.79 (ddd, 1H, J ) 2.05, 12.0, 13.0 Hz), 2.41-
2.52 (m, 1H), 2.34-2.45 (ddd, 1H, J ) 3.9, 13.4, 14.5 Hz), 2.01-
2.09 (ddd, 2H, J ) 3.06, 4.77, 14.6 Hz), 1.85-1.94 (m, 1H),
1.67-1.79 (m, 2H), 1.46 (s, 3H), 1.25-1.31 (dd, 1H, J ) 6.48,
11.4 Hz), 1.11-1.19 (m, 2H), 0.98 (d, 3H, J ) 6.3 Hz). IR:
2949, 2921, 2865, 1467, 1370, 1255, 1090, 1052, cm-1. CIMS:
m/z 272 (M + NH4), 255 (M + H), 237 (M + H - H2O), 151.
Octah ydr o-3,6-dim eth yl-9-eth yl-3,12-epoxy-12H-pyr an o-
[4,3-j]-1,2-ben zod ioxep in (5). From 9-ethylartemisinin (21)
(0.03 g, 0.10 mmol) was obtained 10 mg (35%) of pure 5. 1H
NMR: δ 5.21 (s, 1H), 3.83 (ddd, 1H, J ) 1.1, 4.3, 11.6 Hz),
3.44 (dd, 1H, J ) 11.7, 11.7 Hz), 2.33-2.42 (m, 1H), 2.3 (ddd,
1H, J ) 4.0, 13.5, 14.5 Hz), 2.02 (ddd, 1H, J ) 3.1, 4.9, 14.5
Hz), 1.85-1.94 (m, 1H), 1.70 (dq, 1H, J ) 3.2, 13.1 Hz), 1.43
(s, 3H), 1.15 (dq, 2H, J ) 7.0, 14.9 Hz), 0.97 (d, 3H, J ) 6.2
Hz), 0.90 (t, 3H, J ) 7.3 Hz). IR: 2958, 2928, 2871, 1460,
1374, 1093, 1061 cm-1. CIMS: m/z 300 (M + NH4), 283 (M +
H), 265 (M + H - H2O), 251, 237, 179.
Octa h yd r o-3,6-d im eth yl-9-p r op yl-3,12-ep oxy-12H-p yr -
a n o[4,3-j]-1,2-ben zod ioxep in (6). From 9-propylartemisinin

SAR of 10-Deoxoartemisinin Analogs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4153
(22) (0.05 g, 0.16 mmol) was obtained 14 mg (29%, 37% based
on recovered starting material) of pure 6. 1H NMR: δ 5.20
(s, 1H), 3.80 (ddd, 1H, J ) 1.0, 4.3, 11.7 Hz), 3.42 (dd, 1H, J
) 11.7, 11.7 Hz), 2.43-2.52 (m, 1H), 2.38 (ddd, 1H, J ) 4.3,
13.4, 14.6 Hz), 2.01 (ddd, 1H, J ) 3.0, 4.7, 14.7 Hz), 1.83-
1.92 (m, 1H), 1.69 (ddd, 1H, J ) 3.0, 4.7, 14.7 Hz), 1.47-1.62
(m, 3H), 1.43 (s, 3H), 1.22-1.34 (m, 4H), 1.01-1.10 (m, 2H),
0.95 (d, 3H, J ) 6.3 Hz), 0.89 (t, 3H, J ) 7.3 Hz). IR: 2958,
2966, 2924, 2902, 2877, 2850, 1465, 1249, 1092, 1064, 1027
cm-1. FABMS: m/z 269 (M + H), 251, 223.
Octa h yd r o-3-p r op yl-6-m eth yl-3,12-ep oxy-12H-p yr a n o-
[4,3-j]-1,2-ben zod ioxep in (12). From 3-propyl-9-desmeth-
ylartemisinin (28) (34 mg, 0.11 mmol) was obtained 18 mg
(64%) of pure product 12 along with 4 mg of recovered starting
material. 1H NMR: δ 5.17 (s, 1H), 3.95 (ddd, 1H, J ) 1.1,
4.7, 11.9 Hz), 3.76 (ddd, 1H, J ) 2.1, 12.5, 12.5 Hz), 2.43 (dq,
1H, J ) 4.8, 13.5 Hz), 2.29 (ddd, 1H, J ) 4.0, 13.3, 14.4 Hz),
2.08 (ddd, 1H, J ) 3.2, 4.6, 14.5 Hz), 1.82-1.94 (m, 1H), 1.62-
1.72 (m, 4H), 1.32-1.56 (m, 4H), 1.24 (dd, 1H, J ) 6.5, 11.2
Hz), 1.10-1.18 (m, 2H), 0.95 (d, 3H, J ) 6.3 Hz), 0.88 (t, 3H,
J ) 7.3 Hz). IR: 2965, 2957, 2925, 2874, 2850, 1467, 1436,
2924, 2873, 2852, 1461, 1373, 1193, 1133, 1099, 1064 cm-1
.
DCIMS (NH3): 315 (M + NH4), 297 (M + H), 296 (M+), 294,
279. FABMS: m/z 297 (M + H), 295, 279, 264, 251.
Octah ydr o-3,6-dim eth yl-9-bu tyl-3,12-epoxy-12H-pyr an o-
[4,3-j]-1,2-ben zod ioxep in (7). From 9-butylartemisinin (23)
(0.06 g, 0.18 mmol) was obtained 0.03 g (58%) of pure 7. 1H
NMR: δ 5.22 (s, 1H), 3.80 (ddd, 1H, J ) 1.2, 4.1, 11.5 Hz),
3.46 (dd, 1H, J ) 11.8, 11.8 Hz), 2.40-2.50 (m, 1H), 2.40 (ddd,
1H, J ) 4.0, 13.5, 14.6 Hz), 2.03 (ddd, 1H, J ) 3.1, 4.9, 14.4
Hz), 1.85-1.94 (m, 1H), 1.71 (dq, 1H, J ) 3.3, 12.9 Hz), 1.50-
1.62 (m, 4H), 1.45 (s, 3H), 1.21-1.38 (m, 5H), 0.98 (d, 3H, J )
6.2 Hz), 0.90 (t, 3H, J ) 7.0 Hz). IR: 2945, 2925, 2858, 1461,
1373, 1098, 1064, 877 cm-1. CIMS: m/z 328 (M + NH4), 311
(M + H), 293, 275, 265, 207.
1244, 1182, 1092, 1072, 1027, 897 cm-1
. FABMS: m/z 283
(M + H), 237, 151.
Oct a h yd r o-3-b u t yl-6-m et h yl-3,12-ep oxy-12H -p yr a n o-
[4,3-j]-1,2-ben zod ioxep in (13). From 3-butyl-9-desmethyl-
artemisinin (29) (47 mg, 0.15 mmol) was obtained 10 mg (32%)
of pure 13 along with 14 mg of recovered starting material.
1H NMR: δ 5.17 (s, 1H), 3.96 (dd, 1H, J ) 5.3, 12.4 Hz), 3.75
(ddd, 1H, J ) 2.2, 12.5, 12.5 Hz), 2.38-2.52 (m, 1H), 2.29 (ddd,
1H, J ) 4.0, 13.8, 13.8 Hz), 2.05 (ddd, 1H, J ) 3.3, 4.7, 14.5
Hz), 1.84-1.96 (m, 1H), 1.64-1.82 (m, 4H), 1.22-1.32 (m, 3H),
1.10-1.18 (m, 2H), 0.95 (d, 3H, J ) 6.2 Hz), 0.86 (t, 3H, J )
7.7 Hz). IR: 2955, 2933, 2915, 2870, 1467, 1159, 1093, 1074,
1028, 947 cm-1. FABMS: m/z 297 (M + H), 279, 264, 251.
Oct a h yd r o-3-(2-m et h ylp r op yl)-6-m et h yl-3,12-ep oxy-
12H-p yr a n o[4,3-j]-1,2-ben zod ioxep in (14). From 3-isobu-
tyl-9-desmethylartemisinin (30) (16 mg, 0.05 mmol) was
obtained 9 mg (64%) of the pure product 14. 1H NMR: δ 5.17
(s, 1H), 3.95 (dd, 1H, J ) 4.6, 12.2 Hz), 3.74 (ddd, 1H, J ) 2.3,
12.6, 12.6 Hz), 2.34-2.48 (m, 2H), 2.30 (ddd, 1H, J ) 4.0, 13.3,
14.6 Hz), 2.02-2.11 (m, 1H), 1.83-1.94 (m, 2H), 1.50-1.72 (m,
3H), 1.18-1.26 (m, 2H), 1.08-1.17 (m, 1H), 0.95 (dd, 6H, J )
1.9, 8.4 Hz), 0.93 (d, 3H, J ) 10.4 Hz). IR: 2953, 2949, 2931,
Octa h yd r o-3,6-d im eth yl-9-p en tyl-3,12-ep oxy-12H-p yr -
a n o[4,3-j]-1,2-ben zod ioxep in (8). From 9-pentylartemisinin
(24) (105 mg, 0.3 mmol) was obtained 0.04 g (40%) of pure 8.
1H NMR: δ 5.21 (s, 1H), 3.81 (ddd, 1H, J ) 1.1, 4.2, 11.8 Hz),
3.46 (dd, 1H, J ) 11.7, 11.7 Hz), 2.42-2.52 (m, 1H), 2.39 (ddd,
1H, J ) 4.0, 13.5, 14.9 Hz), 2.04 (ddd, 1H, J ) 3.1, 5.0, 14.5
Hz), 1.88-1.96 (m, 1H), 1.71 (dq, 1H, J ) 3.4, 13.1 Hz), 1.44
(s, 3H), 1.24-1.28 (m, 5H), 0.96 (d, 3H, J ) 6.2 Hz), 0.87 (t,
3H, J ) 7.0 Hz). IR: 2952, 2924, 2869, 2856, 1465, 1130, 1097,
1066, 877 cm-1
307, 289, 279, 265, 221.
. CIMS: m/z 342 (M + NH4), 325 (M + H),
Octah ydr o-3,6-dim eth yl-9-(3-ph en ylpr opyl)-3,12-epoxy-
12H-p yr a n o[4,3-j]-1,2-ben zod ioxep in (9). From 9-(3-phe-
nylpropyl)artemisinin (25) (20 mg, 0.051 mmol) was obtained
10 mg (50%) of pure 9. 1H NMR: δ 7.15-7.34 (m, 5H), 5.21
(s, 1H), 3.80 (ddd, 1H, J ) 1.1, 4.2, 11.5 Hz), 3.45 (dd, 1H, J
) 11.7, 11.7 Hz), 2.57-2.70 (m, 2H), 2.50 (dddd, 1H, J ) 4.0,
7.6, 11.6, 11.6 Hz), 2.39 (ddd, 1H, J ) 4.0, 13.4, 14.5 Hz), 2.03
(ddd, 1H, J ) 3.0, 4.8, 14.7 Hz), 1.89 (dddd, 1H, J ) 2.9, 3.8,
6.7, 13.6 Hz), 1.63 (t, 2H, J ) 7.7 Hz), 1.44 (s, 3H), 1.27 (dd,
2H, J ) 6.4, 11.3 Hz), 0.96 (d, 3H, J ) 6.2 Hz). IR: 2927,
2867, 1452, 1097, 1067, 877 cm-1. CIMS: m/z 390 (M + NH4),
373 (M + H), 355, 337, 327, 269.
2924, 2878, 2864, 1467, 1188, 1092, 1075, 1030, 945, 900 cm-1
.
FABMS: m/z 297 (M + H), 279, 264, 251.
Octa h ydr o-3-(4-p h en ylbu tyl)-6-m eth yl-3,12-ep oxy-12H-
p yr a n o[4,3-j]-1,2-ben zod ioxep in (15). From 3-(4-phenyl-
butyl)-9-desmethylartemisinin (31) (36 mg, 0.093 mmol) was
obtained 15 mg (44%) of the pure product 15. 1H NMR: δ
7.14-7.27 (m, 5H), 5.17 (s, 1H), 3.95 (dd, 1H, J ) 4.2, 11.7
Hz), 3.75 (ddd, 1H, J ) 2.1, 12.6, 12.6 Hz), 2.59 (t, 2H, J ) 7.7
Hz), 2.39 (dq, 1H, J ) 4.8, 13.5 Hz), 2.27 (ddd, 1H, J ) 3.9,
13.9, 13.9 Hz), 2.00 (ddd, 1H, J ) 3.2, 4.8, 14.6 Hz), 1.82-
1.92 (m, 1H), 1.42-1.52 (m, 3H), 1.23 (dd, 2H, J ) 6.4, 11.4
Hz), 1.09-1.18 (m, 2H), 0.95 (d, 3H, J ) 6.2 Hz). IR: 2962,
2950, 2924, 2914, 2867, 2847, 1465, 1452, 1090, 1027, 946
cm-1. FABMS: m/z 373 (M + H), 355, 327, 173.
Octa h yd r o-3,6-d im eth yl-9-[3-(p-ch lor op h en yl)p r op yl]-
3,12-ep oxy-12H-p yr a n o[4,3-j]-1,2-ben zod ioxep in (10). To
a solution of alcohol 36 (0.27 g, 0.5 mmol) in dry CH2Cl2 (50
mL) at -78 °C was bubbled a stream of O3/O2 (4 psi, 0.04
L/min, 80 V) for 5 min until the reaction mixture turned faint
blue. The reaction mixture was then purged with O2 followed
by N2. To the mixture were added silica gel (2.5 g) and 15%
aqueous H2SO4 (250 µL). The mixture was then allowed to
come to ambient temperature and was subsequently stirred
for 4 days. The solids were filtered and washed with CH2Cl2
(20 mL) and EtOAc (20 mL). The filtrate was washed with
aqueous saturated NaHCO3, dried over anhydrous Na2SO4,
and evaporated to give crude product which was purified by
flash chromatography. Elution with hexane/EtOAc (80:20)
gave pure 10, 15 mg (7%). 1H NMR: 7.12-7.30 (m, 4H), 5.19
(s, 1H), 3.78 (ddd, 1H, J ) 1.3, 4.3, 7.2 Hz), 3.44 (dd, 1H, J )
11.7, 11.7 Hz), 2.60 (ddd, 2H, J ) 5.1, 7.4, 7.4 Hz), 2.43-2.53
(m, 1H), 2.37 (ddd, 1H, J ) 4.1, 13.4, 14.7 Hz), 2.01 (ddd, 1H,
J ) 3.0, 4.8, 14.7 Hz), 1.83-1.93 (m, 1H), 1.62 (t, 2H, J ) 7.8
Hz), 1.42 (s, 3H), 1.25 (dd, 2H, J ) 6.5, 11.1 Hz), 0.95 (d, 3H,
J ) 6.2 Hz). IR: 2926, 2913, 2866 1494, 1454, 1091, 1067
cm-1. DCIMS (NH3): m/z 424 (M + NH4), 407 (M + H).
Oct a h yd r o-3-et h yl-6-m et h yl-3,12-ep oxy-12H -p yr a n o-
[4,3-j]-1,2-b en zod ioxep in (11). From 3-ethyl-9-desmeth-
ylartemisinin (27) (27 mg, 0.095 mmol) was obtained 11 mg
(44%) of pure product 11. 1H NMR: δ 5.18 (s, 1H), 3.93 (dd,
1H, J ) 4.2, 11.9 Hz), 3.75 (ddd, 1H, J ) 1.7, 12.6, 12.6 Hz),
2.39 (dq, 1H, J ) 4.8, 13.3 Hz), 2.27 (ddd, 1H, J ) 3.9, 13.9,
13.9 Hz), 1.98-2.10 (ddd, 1H, J ) 3.0, 4.6, 14.4 Hz), 1.84-
1.96 (m, 1H), 1.68-1.78 (m, 3H), 1.22-1.28 (m, 2H), 1.1-1.18
(m, 2H), 0.96 (d, 3H, J ) 6.8 Hz), 0.94 (t, 3H, J ) 7.8 Hz). IR:
Octa h yd r o-3-(2-p h en yleth yl)-6-m eth yl-3,12-ep oxy-12H-
p yr a n o[4,3-j]-1,2-ben zod ioxep in (16). From 3-(2-phenyl-
ethyl)-9-desmethylartemisinin (32) (89 mg, 0.25 mmol) was
obtained 55 mg (64%) of the pure product 16. 1H NMR: δ
7.16-7.26 (m, 5H), 5.22 (s, 1H), 3.97 (dd, 1H, J ) 4.7, 12.2
Hz), 3.77 (ddd, 1H, J ) 1.7, 12.4, 12.4 Hz), 2.72-2.78 (m, 2H),
2.42-2.50 (m, 1H), 2.09 (ddd, 1H, J ) 3.2, 4.2, 14.5 Hz), 1.96-
2.03 (m, 2H), 1.62-1.80 (m, 2H), 1.25-1.30 (m, 3H), 1.11-
1.20 (m, 2H), 0.97 (d, 3H, J ) 6.3 Hz). IR: 2963, 2933, 2868,
2847, 1495, 1465, 1453, 1251, 1085, 1047, 1026, 700 cm-1
.
FABMS: m/z 345 (M + H), 307, 289.
Octa h yd r o-3-[3-(4-ch lor op h en yl)p r op yl]-6-m eth yl-3,12-
ep oxy-12H-p yr a n o[4,3-j]-1,2-ben zod ioxep in (17). From
3-[3-(4-chloropheny)propyl]-9-desmethylartemisinin (33) (13
mg, 0.03 mmol) was obtained 7 mg (56%) of the pure product
17. 1H NMR: δ 7.06-7.24 (m, 4H), 5.16 (s, 1H), 3.95 (dd, 1H,
J ) 5.4, 11.3 Hz), 3.76 (ddd, 1H, J ) 2.0, 12.5, 12.5 Hz), 2.59-
2.50 (m, 2H), 2.36-2.48 (m, 1H), 2.27 (ddd, 1H, J ) 3.9, 13.7,
13.7 Hz), 2.00 (ddd, 1H, J ) 3.7, 3.7, 14.6 Hz), 1.82-1.92 (m,
1H), 1.63-1.73 (m, 4H), 1.24 (s, 2H), 1.10-1.20 (m, 2H), 0.94
(d, 3H, J ) 6.3 Hz). IR: 2953, 2925, 2874, 2854, 1491, 1461,
1251, 1090, 1078, 1050, 1015 cm-1. DCIMS (isobutane): m/z
393 (M + H), 392 (M+), 271, 240, 204.
Octah ydr o-3-(2-car boeth oxyeth yl)-6-m eth yl-3,12-epoxy-
12H-p yr a n o[4,3-j]-1,2-ben zod ioxep in (18). From 3-(2-car-
boethoxyethyl)-9-desmethylartemisinin (34) (16 mg, 0.16 mmol)
was obtained 31 mg (55%) of pure product 18. 1H NMR: δ

4154 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Avery et al.
5.17 (s, 1H), 4.10 (q, 2H, J ) 7.1 Hz), 3.91 (dd, 1H, J ) 4.5,
11.8 Hz), 3.73 (ddd, 1H, J ) 2.1, 12.4, 12.4 Hz), 2.40-2.54 (m,
3H), 2.30 (ddd, 1H, J ) 3.9, 13.4, 14.4 Hz), 1.96-2.06 (m, 3H),
1.82-1.95 (m, 1H), 1.62-1.74 (m, 2H), 1.22 (t, 3H, J ) 7.1
Hz), 1.08-1.18 (m, 1H), 0.95 (d, 3H, J ) 6.3 Hz). IR: 2927,
2916, 2851, 1737, 1730, 1315, 1251, 1191, 1180, 1093, 1037,
951 cm-1. FABMS: m/z 341 (M + H), 323, 307, 289, 249.
Octah ydr o-3-(2-car boxyeth yl)-6-m eth yl-3,12-epoxy-12H-
p yr a n o[4,3-j]-1,2-ben zod ioxep in (19). To a solution of ester
18 (12 mg) in 95% EtOH (0.5 mL) was added 10% NaOH (0.5
mL). The reaction mixture was stirred at ambient tempera-
ture for 3 h and then poured onto ice-cold water. The mixture
was then neutralized with 10% HCl (0.5 mL) and extracted
with EtOAc (3 × 5 mL), and the combined organic layer was
washed with water (3 × 5 mL). The organic layer was then
dried over MgSO4, filtered, and evaporated to give a crude
product which was purified on a 1.5 mm silica gel preparative
plate (50% EtOAc/hexane) to give 4 mg (36%) of pure acid 19
as a white solid (mp 144-146 °C). 1H NMR: δ 5.18 (s, 1H),
3.92 (dd, 1H, J ) 4.2, 12.0 Hz), 3.75 (ddd, 1H, J ) 2.8, 12.1,
12.1 Hz), 2.51-2.62 (m, 1H), 2.40 (dq, 1H, J ) 4.5, 13.4 Hz),
2.31 (ddd, 1H, J ) 3.9, 13.9, 13.9 Hz), 1.92-2.08 (m, 3H), 1.62-
1.76 (m, 3H), 1.30-1.56 (m, 1H), 1.10-1.30 (m, 4H), 0.95 (d,
3H, J ) 6.3 Hz). IR: 2979, 2963, 2926, 2852, 1735, 1463, 1457,
1261, 1018, 1101, 748 cm-1. FABMS: m/z 313 (M + H), 308,
273, 257.
2,5,5-Tr im eth yl-2-[2′-[4′′-[(1S)-ca r boxy-5-(p-ch lor op h e-
n yl)pen t-2-yl]-(1′′R)-m eth yl-3′′-[(tr im eth ylsilyl)m eth ylen e]-
cycloh ex-2′′-yl]eth yl]-1,3-d ioxa n e (36). To an ice-cold so-
lution of diisopropylamine (469 µL, 3.3 mmol) in dry THF (4
mL) under N2 was added butyllithium (1.36 mL of 2.5 M
solution in hexane, 3.3 mmol). The mixture was stirred at 0
°C for 15 min and then cooled to -78 °C. The acid 35 (0.602
g, 1.52 mmol) in dry THF (4 mL) was added, and the mixture
was allowed to warm to ambient temperature over 30 min and
then heated at 50 °C for 2 h and recooled to 0 °C. 3-(p-
Chlorophenyl)propyl bromide (0.888 g, 3.81 mmol) was then
added via syringe, and the reaction mixture was stirred at
room temperature for 5 h, poured into ice-cold saturated
aqueous NH4Cl solution (25 mL), and extracted with EtOAc
(3 × 30 mL). The organic layer was washed with saturated
NaCl (40 mL), dried (MgSO4), filtered, and evaporated in vacuo
to give 0.721 g (87%) of 36 as a viscous liquid. 1H NMR: δ
7.23 (d, 2H, J ) 8.3 Hz), 7.10 (d, 2H, J ) 8.4 Hz), 5.26 (s, 1H),
3.54 (dd, 2H, J ) 2.3, 11.6 Hz), 3.38-3.48 (m, 2H), 2.71 (br t,
2H, J ) 10.5 Hz), 2.56 (m, 1H), 2.06 (br dd, 1H, J ) 2.9, 10.7
Hz), 1.72-1.94 (m, 3H), 1.31 (s, 3H), 1.15 (m, 1H), 1.01 (s, 3H),
0.86-0.94 (m, 6H), 0.09 (s, 9H). IR: (KBr) 3400-2500, 1700,
1598, 1491, 1454, 1246, 1091, 861, 748 cm-1. DCIMS (NH3):
m/z 566 (M + NH4), 549 (M+).
Octa h yd r o-3,6-d im eth yl-9-[3-(p-ch lor op h en yl)p r op yl]-
3,12-ep oxy-12H-p yr a n o[4,3-j]-1,2-ben zod ioxep in -10(3H)-
on e (26). To a solution of acid 36 (0.65 g, 1.1 mmol) in dry
CH2Cl2 (160 mL) at -78 °C was bubbled a stream of O3/O2 (4
psi, 0.04 L/min, 80 V) for 5 min until the reaction mixture
turned faint blue. The reaction mixture was then purged with
O2 followed by N2. To the mixture were added silica gel (2.5
g) and 15% aqueous H2SO4 (250 µL). The mixture was then
allowed to come to ambient temperature and was subsequently
stirred for 4 days. The solids were filtered and washed with
CH2Cl2 (30 mL) and EtOAc (20 mL). The filtrate was washed
with saturated aqueous NaHCO3, dried over anhydrous Na2-
SO4, and evaporated to give a crude product which was purified
by flash chromatography. Elution with hexane/EtOAc (80:20)
gave pure 26, 0.122 g (25%). 1H NMR: δ 7.23 (d, 2H, J ) 8.2
Hz), 7.09 (d, 2H, J ) 8.3 Hz), 5.83 (s, 1H), 3.14-3.24 (m, 1H),
2.52-2.72 (m, 2H), 2.34-2.48 (m, 1H), 1.96-2.09 (m, 3H),
1.67-1.82 (m, 4H), 1.44 (s, 3H), 0.98 (d, 3H, J ) 5.7 Hz). IR:
2951, 2925, 1740, 1491, 1112, 1031, 1000 cm-1. CIMS: m/z
459 (M + K+), 443 (M + Na+), 409, 347.
overnight at room temperature, cooled to 0 °C, quenched by
dropwise addition of 2:1 H2O:AcOH (4 mL), and extracted with
EtOAc (3 × 20 mL). The combined organic layer was sequen-
tially washed with saturated NaHCO3 solution (2 × 20 mL)
and water (2 × 20 mL), dried over anhydrous MgSO4, filtered,
and evaporated in vacuo to give a crude product which was
purified by flash chromatography to give 0.28 g (53%) of 37
as a viscous liquid. 1H NMR: δ 7.14-7.28 (m, 4H), 5.19 (s,
1H), 3.68 (d, 2H, J ) 3.2 Hz), 3.46-3.54 (m, 2H), 3.41 (dd,
2H, J ) 9.2, 10.8 Hz), 2.56 (t, 2H, J ) 7.4 Hz), 2.04-2.18 (m,
2H), 1.32 (s, 3H), 0.88-0.98 (m, 9H), 0.09 (s, 9H). IR: (KBr)
3600-3200, 2948, 2907, 2864, 1598, 1494, 1454, 1372, 1247,
1095, 825, 742, 694 cm-1. DCIMS (NH3): m/z 535 (M + H).
P r oced u r e for Red u ction of Ar tem isin in La cton e
An a logs to 10-Deoxoa r tem isin in An a logs Usin g Diisobu -
tyla lu m in u m Hyd r id e follow ed by Et3SiH/BF 3. To a
stirred solution of artemisinin (1) (90 mg, 0.319 mmol, 1.0
equiv) in 3 mL of dry CH2Cl2 at -78 °C was added DIBAL-H
(335 µL, 335 mmol, 1.05 equiv, 1.0 M in hexanes). The dry
ice/acetone bath was removed for long enough to allow
complete dissolution of the substrate and then replaced (about
1 min). After 1.25 h, the reaction was quenched with 1 mL of
saturated NaHCO3, and the mixture was diluted with 3 mL
of CH2Cl2 and allowed to warm to ambient temperature with
stirring. The mixture was diluted with 25 mL of CH2Cl2 and
washed (1 × 10 mL) with 10% HCl/saturated NH4Cl (1:15, v/v).
The CH2Cl2 layer was then dried (MgSO4), filtered, and
concentrated in vacuo to give 90 mg (100%) of a white solid
which was pure enough for the next step. The lactol from
above was dissolved in 3 mL of dry CH2Cl2 and cooled to -78
°C, whereupon 210 µL of Et3SiH (1.31 mmol, 4.1 equiv) was
added. The reaction mixture was stirred for 10 min, at which
time 45 µL of BF3‚OEt2 (0.366 mmol, 1.15 equiv) was added.
The resultant solution was allowed to stir for 3 h at -78 °C,
and the reaction was then quenched at -78 °C with 150 µL of
pyridine (1.85 mmol, 5.8 equiv). After 5 min, the reaction
mixture was poured into 10 mL of aqueous saturated NH4Cl
and extracted with EtOAc (3 × 30 mL). The combined organic
layers were washed with NH4Cl (2 × 15 mL), dried (MgSO4),
filtered, and concentrated in vacuo to give a white solid which
was purified by PTLC (silica gel) eluting with 75:25 Et2O/
hexanes to give 82 mg (96%) of pure product 3 as a white
crystalline solid. When this procedure was applied to lactones
23 and 26, purified product tetrahydropyrans 7 and 10 were
obtained in overall yields of 90% and 92%, respectively.
Ack n ow led gm en t. We wish to thank the U.S. Army
Medical Research and Development Command for sup-
port of this work under Contract No. DAMD17-91-C-
1099. This investigation also received partial financial
support from the UNDP/World Bank/WHO Special
Programme for Research and Training in Tropical
Diseases (TDR). We thank Dr. Bob Engle (WRAIR) for
helpful discussions.
Refer en ces
(1) Klayman, D. L. Qinghaosu (Artemisinin): an antimalarial drug
from China. Science 1985, 228, 1049-1055.
(2) Luo, X.-D.; Shen, C.-C. The Chemistry, Pharmacology, and
Clinical Applications of Qinghaosu (Artemisinin) and its Deriva-
tives. Med. Res. Rev. 1987, 7, 29-52.
(3) Zhou, W.-S.; Xu, X.-X. Total Synthesis of the Antimalarial
Sesquiterpene Peroxide Qinghaosu and Yingzhaosu A. Acc.
Chem. Res. 1994, 27, 211-216.
(4) Zaman, S. S.; Sharma, R. P. Some Aspects of the Chemistry and
Biological Activity of Artemisinin and Related Antimalarials.
Heterocycles 1991, 32, 1593-1638.
(5) J ung, M. Current Developments in the Chemistry of Artemisinin
and Related Compounds. Curr. Med. Chem. 1994, 1, 35-49.
(6) Avery, M. A.; Gao, F.; Mehrotra, S.; Chong, W. K.; J ennings-
White, C. The Organic and Medicinal Chemistry of Artemisinin
and Analogs. In Trends in Organic Chemistry; Council of
Scientific Research Integration, Eds.; Research Trends: Trivan-
drum, India, 1993; pp 413-468.
2,5,5-Tr im et h yl-2-[2′-[4′′-[1-h yd r oxy-5-(4-ch lor op h en -
yl)pen t-2-yl]-(1′′R)-m eth yl-3′′-[(tr im eth ylsilyl)m eth ylen e]-
cycloh ex-2′′-yl]eth yl]-1,3-d ioxa n e (37). To an ice-cold solu-
tion of the (chlorophenyl)propyl acid 36 (0.548 g, 1 mmol)
dissolved in THF (5 mL) was added LiAlH4 (4 mL of 1 M
solution in THF, 4 mmol). The reaction mixture was stirred
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