Design, synthesis, derivatization, and structure-activity relationships of simplified, tricyclic, 1,2,4-trioxane alcohol analogues of the antimalarial artemisinin

Article abstract of DOI:10.1021/jm970711g

Novel C₄-(hydroxyalkyl)trioxanes 5d and 5e were designed and synthesized based on an understanding of the molecular mechanism of action of similar 1,2,4-trioxanes structurally related to the antimalarial natural product artemisinin (1). In vitr

Full text of DOI:10.1021/jm970711g

952
J . Med. Chem. 1998, 41, 952-964
Design , Syn th esis, Der iva tiza tion , a n d Str u ctu r e-Activity Rela tion sh ip s of
Sim p lified , Tr icyclic, 1,2,4-Tr ioxa n e Alcoh ol An a logu es of th e An tim a la r ia l
Ar tem isin in
J ared N. Cumming,† Dasong Wang,†,‡ Sheldon B. Park,†,§ Theresa A. Shapiro,| and Gary H. Posner*,†
Department of Chemistry, School of Arts and Sciences, The J ohns Hopkins University, Baltimore, Maryland 21218, and
Department of Medicine, School of Medicine, The J ohns Hopkins University, Baltimore, Maryland 21205
Received October 20, 1997
Novel C4-(hydroxyalkyl)trioxanes 5d and 5e were designed and synthesized based on an
understanding of the molecular mechanism of action of similar 1,2,4-trioxanes structurally
related to the antimalarial natural product artemisinin (1). In vitro efficacies of these two
new pairs of C4-diastereomers against chloroquine-sensitive Plasmodium falciparum support
conclusions about the importance to antimalarial activity of formation of a C4 radical by a
1,5-hydrogen atom abstraction. Derivatives 6, 7, and 21 of C4â-substituted trioxane alcohols
4a , 5d , and 5e were prepared, each in a single-step, high-yielding transformation. Four of
these new analogues, 6a -c and 7, are potent in vitro antimalarials, having 140 to 50% of the
efficacy of the natural trioxane artemisinin (1).
Sch em e 1
In tr od u ction
The chemotherapy of malaria has been aided by the
relatively recent discovery and development of natural
and synthetic endoperoxides. The parasites that cause
this disease, genus Plasmodium, are becoming increas-
ingly resistant to traditional therapies such as chloro-
quine and other alkaloids, sulfonamides (e.g., sulfadox-
ine), and diaminopyrimidines (e.g., pyrimethamine).1,2
The spread of multidrug resistance is particularly
troublesome with Plasmodium falciparum, which causes
cerebral malaria3,4 and other very serious consequences
and is responsible for nearly all of the annual 1-3
million deaths attributed to malaria.5,6 Research into
endoperoxide antimalarials began with isolation of the
1,2,4-trioxane artemisinin (qinghaosu, 1) in 1972 as the
active ingredient in a tea of Artemisia annua leaves
used for thousands of years in China and southeast Asia
to treat fever.7,8 Subsequent work on semisynthetic
derivatives of lactone-reduced dihydroartemisinin (2)
produced artemether (3a ) and arteether (3b) as oil-
soluble analogues and yielded artesunate (3c) and
artelinate (3d ) as water-soluble formulations (Scheme
1).9,10 Several million doses of these compounds have
been given in Asia, Africa, and Central America,11 and
they are at various stages of formal clinical development
as new malaria therapies.12-15
as part of the way in which damage is exacted on the
invaders.22 In addition, various studies indicate that
artemisinin may covalently bond to the porphyrin
portion of heme,23,24 and a recent report characterizes
the first artemisinin-porphyrin adduct formed during
a heme model degradation.25
A desire to further probe structure-activity relation-
ships (SAR) and to delve in more detail into the
molecular events following initial iron(II) activation of
the peroxide bond led many researchers in the past
decade to synthesize modified tetracyclic artemisinin
structures26-31 as well as numerous simplified trioxane
analogues.32-35 These studies have produced promising
therapeutic leads36,37 and have been used to develop a
ch em ica l understanding of how endoperoxide antima-
larials kill Plasmodia.16,38,39 Evidence gathered from
these investigations indicates that oxygen- and carbon-
centered radicals,40-43 one or more high-valent iron oxo
species, and reactive electrophilic alkylating species,
such as epoxides and dicarbonyl compounds, are formed
during iron(II)-induced decomposition of these sys-
tems.16
Artemisinin-type antimalarials seem to act by releas-
ing a cascade of potentially cytotoxic intermediates16
after activation of the crucial oxygen-oxygen bond by
ferrous species17 found in the parasite and/or in the
erythrocytes they infect.18,19 These peroxides cause
gross morphological changes in malaria parasites,20,21
and biochemical evidence points to protein alkylation
† Department of Chemistry.
‡ Current address: Schering-Plough Research Institute, Chemical
ResearchsAllergy and Immunology, K-15-1-1545, Kenilworth, NJ
07033.
§ Current address: Brantford Chemicals, Inc., Brantford, Ontario,
N3T 6B8 Canada.
| Department of Medicine.
S0022-2623(97)00711-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/12/1998

Analogues of the Antimalarial Artemisinin
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 953
Sch em e 2
a
Reagents: (a) TBDMSOTf/2,6-lutidine, 91%; (b) 1. LDA, 2. R4-
X, 59-94%; (c) MeLi, 68-94%; (d) 1O2; (e) 1. TBDMSOTf, 2. Et3N,
3. Bu4NF, 8-21% from 11.
F igu r e 1.
crystal structure of monomethyl terephthalate ester
12,47 made from C4R-methyl-C8a-(hydroxyethyl)trioxane
4a .
In this paper, we do the following: (1) report full
details on a series of C4-alkylated trioxanes 4 and 5a -c
(Figure 1) that demonstrated the central role of an
intermediate carbon-centered radical in the mechanism
of action of this class of compounds; (2) introduce C4-
(hydroxyalkyl)trioxanes 5d and 5e that were designed
to combine those structural characteristics of the first
series that are associated with high antimalarial activ-
ity; (3) show that derivatization of C4â diastereomers of
two of these trioxane alcohols 4a and 5d produces potent
antimalarials 6 and 7; and (4) make SAR generaliza-
tions related to the novel analogues reported herein.
Construction of most48 C4-alkylated, C8a-unsubsti-
tuted trioxanes 5 began with Wittig olefination of
commercially available 2-(2′-cyanoethyl)cyclohexanone
(13)49 to produce known enol ether 1434,45 (Scheme 3).
The presence of added lithium chloride during ylide
formation increased the ratio of desired Z-diastereomer:
undesired E-diastereomer from 1:1 to 2.5:1 with a good
overall yield.50,51 R-Deprotonation of the nitrile moiety
of enol ether 14 followed by coupling with suitable
electrophiles provided diastereomeric mixtures of sub-
stituted nitriles 15 that were usually converted directly
into trioxane precursor ketones 16 by treatment with
methyllithium. However, C4â-(triphenylstannyl)methyl
nitrile 15cz, isolated as a single diastereomer, did not
react with methyllithium, possibly due to the large steric
bulk of the C4 substitution. To reach the desired ketone
system 16cz, nitrile 15cz was instead reduced to the
corresponding aldehyde that was immediately treated
with methylmagnesium bromide to produce secondary
alcohols 17. Swern oxidation52,53 produced ketone 16cz
in equal overall yield to methyllithium addition to the
other C4-stannylmethyl-substituted nitriles 15cx and
15cy. With precursor ketones 16 in hand, singlet
oxygen-mediated dioxetane formation followed by silyl
Ch em istr y
Synthesis of C4-substituted, C8a-(hydroxyethyl)triox-
anes 441,44 proceeded from alcohol 8 (Scheme 2), syn-
thesized in three steps from commercial cyclohexanone
as described previously by this group.35 Protection of
this free alcohol as its silyl ether 9 allowed for smooth
alkylation of the conjugate base of the nitrile. The
desired functionality at what will become C4 in the final
product was then introduced with the appropriate
alkylating agent. Treatment of alkylated nitriles 10
with methyllithium produced ketones 11 as precursors
to the target trioxanes. On the basis of the J efford
protocol,45 addition of photochemically generated singlet
oxygen to the enol ether portion of these ketones
produced intermediate dioxetanes that were rearranged
in situ to the corresponding trioxanes with a Lewis acid
(silyl triflate)35,45 and then desilylated to produce the
desired C4-alkylated trioxane alcohols 4 as mixtures of
diastereomers at C4. These diastereomers were sepa-
rated by HPLC. Assignment of stereochemistry was
based on a series of rules developed using NMR spec-
troscopy and relative polarity,46 relating to an X-ray

954 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Cumming et al.
Sch em e 3
Sch em e 4
Sch em e 5
a
Reagents: (a) Ph3PCH2OMeCl/LHMDS/LiCl, 77%; (b) 1. LDA,
2. R4-X, 41% to quantitative; (c) MeLi, 43-98%; (d) 1. DIBAl-H,
2. MeMgBr, 65%; (e) 1. DMSO/(CF3CO)2O, 2. Et3N, 89%; (f) 1. 1O2,
2. TBDMSOTf, 3. Et3N, 10-74%; (g) for 5d and 5e, n-Bu4NF, 61-
66%.
triflate-induced rearrangement provided trioxanes 5a -c
directly and produced trioxane silyl ethers that were
desilylated without isolation to give trioxane alcohols
5d and 5e. In most cases, ketones 16 were transformed
into trioxanes without prior separation of diastereomers,
and the resulting mixtures of diastereomeric trioxanes
were then easily separated by HPLC. For C4-stannyl-
methyl ketones 16c, however, diastereomers were sepa-
rated p r ior to singlet oxygenation, and trioxanes 5c
were thus formed as single diastereomers. The stereo-
chemistries of these analogues 5 were assigned as with
trioxanes 4, according to the same spectroscopy- and
a
Reagents: (a) (PhO)2POCl/Et3N/DMAP, 86%; (b) KHMDS/
PhCH2Br, 81%; (c) KHMDS or NaH/pFPhCH2Br, 72-91%.
(hydroxyethyl)trioxane 4a was transformed into its
diphenyl phosphate ester 6a , benzyl ether 6b, and
p-fluorobenzyl ether 6c. Phosphate ester 6a was made
by reaction with the corresponding chlorophosphate.
Ethers 6b and 6c were prepared by Williamson cou-
pling59 with the appropriate benzyl bromides. Both C4â-
(hydroxyalkyl)trioxanes 5d and 5e were derivatized as
their p-fluorobenzyl ethers 7 and 21, respectively, in the
same fashion.
polarity-based rules,46 with a crystal structure of C4R
-
phenyltrioxane 5b as confirmation.41,48
Synthesis of C4-(hydroxyalkyl)trioxanes 5d 54 and 5e
required alkylation of the nitrile anion of enol ether 14
by the appropriate masked hydroxyalkyl species and
protection of the newly introduced hydroxyl group for
the balance of the synthesis (Scheme 3). En route to
C4-(hydroxymethyl)trioxanes 5d , addition of gaseous
formaldehyde (cracked at 160 °C in line with the
reaction)55 produced diastereomeric C4-hydroxymethyl
nitriles that were silylated to give C4-(silyloxy)methyl
nitriles 15d . The hydroxymethylation reaction was
sensitive to the temperature profile after addition of
formaldehyde, with a 2 h warming from -78 °C to room
temperature giving double the yield over all other
conditions evaluated. Toward C4-(p-(hydroxymethyl)-
benzyl)trioxanes 5e, substituted nitriles 15e were formed
with protection already in place using p-((silyloxy)-
methyl)benzyl bromide 18. This alkylating agent was
made by monoprotection (monosilylation)56 of 1,4-bis-
(hydroxymethyl)benzene (19) followed by conversion of
the remaining free benzyl alcohol into its benzyl bro-
mide57,58 (Scheme 4). C4-(Silyloxy)alkyl nitriles 15d and
15e were then carried forward in protected form ac-
cording the Scheme 3, with a final fluoride ion-induced
desilylation to afford desired trioxane alcohols 5d and
5e.
SAR Resu lts a n d Discu ssion
Chemical degradation studies on artemisinin and on
a number of first generation analogues have permitted
development of a unified scheme for their mechanism
of action16 (Scheme 6). This mechanistic view considers
iron(II) association with either oxygen-1 or -2 of the
peroxide bond17 of simplified trioxane A. If iron were
to remain with oxygen-1, the resulting oxy radical B
could collapse to a carbonyl followed either (i) by
homolytic cleavage of the C3-C4 bond and ring closure
to form ring-contracted product C or (ii) by fragmenta-
tion and loss of methyl formate to form diketone D. If
iron were associated with oxygen-2, the resulting oxy
radical E could either (iii) abstract the R-face hydrogen
atom from C4 (a 1,5-shift) to form carbon radical F ,
which can rearrange to epoxide G and then ultimately
to hydroxylated product H, or (iv) collapse to carbonyl
initiating loss of methyl formate to form diketone D. The
rearrangement of carbon radical F to epoxide G can
occur either directly or via â-scission of a high-valent
iron oxo species followed by a rebound epoxidation
process. We have previously provided evidence, through
reporter reactions indicative of intermediate high-valent
iron oxo species, that the â-scission pathway is active
in chemical degradations both of artemisinin60 and of
related trioxane analogues.44
Several of the trioxane alcohols discussed in this
paper were derivatized (Scheme 5). C4â-Methyl-C8a-

Analogues of the Antimalarial Artemisinin
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 955
Sch em e 6
Ta ble 1.a In Vitro Antimalarial Activities of C4-Substituted
Trioxanes against Chloroquine-Sensitive P. Falciparum
(NF54)64
Sch em e 7
IC50 (nM)
trioxane
R4
C4â
7.7
8.3
240
C4R
4a
4b
4c
4d
22
5a
5b
5cx
5cy
5cz
5d
Me
PhCH2
1300
1700
>2500
of the analogues. Considering the simple alkyl groups
methyl and benzyl in trioxanes 4a , 4b, and 5a , C4â
substitution (encourages formation of the C4 radical)
increases antimalarial activity over C4-unsubstituted
trioxanes 22 and 23, whereas C4R substitution (prevents
formation of the C4 radical) decreases efficacy relative
to these parent systems. In contrast, with analogues
whose C4â substitution stabilizes the resulting tertiary
radical m or e than simple alkyl,61,62 as in C4-((trimeth-
ylsilyl)methyl)trioxanes 4c and C4-phenyltrioxanes 5b,
antimalarial potency is actually low er ed compared to
that of the C4-unsubstituted systems.
Me3SiCH2
Me3SnCH2
H
>2500
120
PhCH2
Ph
310
2000
>2500
>2500
>2500
230
>2500
>2500
Me3SnCH2
n-Bu3SnCH2
Ph3SnCH2
HOCH2
p-(HOCH2)PhCH2
H
>2500
>2500
960
5e
23
600
artemisinin (1)
9.9
a
Antimalarial activity was determined by the method of Des-
jardins,65 as modified by Milhous,66 with details as reported
previously.67 The standard deviation for each set of quadruplicates
was an average of 8% (e31%) of the mean. R2 values for the fitted
curves were g0.992.
C4â-(Stannylmethyl)trioxanes 4d and 5c were de-
signed to in ter cep t a C4 radical like F by elimination
of R3Sn•,63 preventing â-scission of a high-valent iron
oxo species and thereby interrupting this degradation
pathway.60 Reaction of iron(II) with all three C4â-
(stannylmethyl)-C8a-unsubstituted-trioxanes 5c in fact
produced, as one of two major products, the expected
exocyclic olefin-containing system 24 (Scheme 7). In-
terestingly, C4â-(stannylmethyl)trioxanes 4d and 5c are
inactive (Table 1), despite their structural similarity to
C4-Alkylated trioxanes 4 and 5a -c (Table 1) demon-
strated the importance to antimalarial activity of the
1,5-hydrogen atom abstraction pathway and helped
identify restrictions on intermediate carbon-centered
radicals such as F .41,47 Indeed, substitution at C4
dramatically modulates the in vitro antimalarial activity

956 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Cumming et al.
Ta ble 2.a In Vitro Antimalarial Activities of Derivatives of
other active analogues (e.g. C4â-(silylmethyl)trioxane
4c), indicating that intermediates along the route from
carbon radical F to hydroxylated product H are signifi-
cant in conveying antimalarial efficacy.
Trioxane Alcohols against Chloroquine-Sensitive P. Falciparum
(NF54)64
An additional relationship between structure and
activity stands out from this original series of simplified
trioxanes. Comparison of the antimalarial efficacies of
various C4-substituted and -unsubstituted systems with
and without a C8a-hydroxyethyl moiety (e.g., 4b versus
5a , and 22 versus 23) reveals that those with the
hydroxyalkyl group present are more active than those
without. Unfortunately, the synthesis of these systems
is longer, especially for C4-substituted trioxanes 4 since
attachment of the C8a functionality is a separate step
from C4 alkylation41,47 (Scheme 2). C4-(Hydroxyalkyl)-
trioxanes 5d and 5e were designed to incorporate in
on e ch em ica l step favorable C4 substitution and the
presence of a hydroxyalkyl moiety. In vitro antimalarial
testing of C4-(hydroxymethyl)trioxanes 5d and C4-(p-
(hydroxymethyl)benzyl)trioxanes 5e revealed two struc-
ture-activity generalizations (Table 1). First, these
new systems further bolster conclusions that a C4
radical like F is important for antimalarial activity.
Noting that these trioxanes contain simple alkyl groups
at C4 like trioxanes 4a , 4b, and 5a , (1) C4â-substituted
diastereomers (that encourage a 1,5-hydrogen atom
transfer) are more active than their C4R-substituted
analogues (that block this shift), and (2) C4â diastere-
omers of these trioxanes are more active than the
unsubstituted parent trioxane 22 while C4R systems are
less active. The second structure-activity relationship
is that C4-hydroxyalkyl substitution is less effective than
at C8a in enhancing antimalarial activity. While C4â-
substituted C8a-(hydroxyethyl)trioxanes 4a and 4b are
potent antimalarials, C4â-(hydroxyalkyl)trioxanes 5d
and 5e are not.
trioxane
26a
26b
26c
22
6a
6b
6c
Z
IC50 (nM)
(PhO)2P(O)
PhCH2
p-FPhCH2
H
(PhO)2P(O)
PhCH2
p-FPhCH2
H
p-FPhCH2
H
p-FPhCH2
H
14
25
31
120
6.9
11
13
7.7
19
230
240
600
9.9
C
7
4â-4a
C
4â-5d
21
C
4â-5e
artemisinin (1)
a
Antimalarial activity was determined by the method of Des-
jardins,65 as modified by Milhous,66 with details as reported
previously.67 The standard deviation for each set of quadruplicates
was an average of 8% (e31%) of the mean. R2 values for the fitted
curves were g0.991.
parent alcohol 5d and with one-half the efficacy of
artemisinin.
In general, derivatives of C4-unsubstituted trioxane
alcohol 22 are substantially more active than the free
alcohol. Indeed, diphenyl phosphate ester 26a , benzyl
ether 26b, and p-fluorobenzyl ether 26c are potent in
vitro antimalarials,35 having 70% to 30% the efficacy of
artemisinin (Table 2). Dramatically, phosphate ester
26a and benzyl ether 26b are as efficacious as arteether
(3b) in vivo against chloroquine-resistant P. falciparum
in Aotus monkeys.37 In addition, p-fluorobenzyl ether
26c is gametocytocidal in vitro with a potency an order
of magnitude higher than artemisinin.68
Con clu sion s
On the basis of in vitro antimalarial activities of our
original C4-alkylated trioxanes 4 and 5a -c, we have
designed and synthesized C4-(hydroxyalkyl)trioxanes 5d
and 5e, incorporating those structural features from the
first series most beneficial to antimalarial efficacy. The
active C4â-diastereomers of these systems are available
in six and five chemical steps, respectively, in 13% and
12% overall yields. These new trioxane alcohols provide
additional support for the importance to antimalarial
activity of a C4 radical formed by 1,5-hydrogen atom
abstraction (Scheme 6, oxygen-2 pathway). Derivatives
of C4â-methyl-C8a-(hydroxyethyl)trioxane 4a , itself hav-
ing 130% the potency of artemisinin, are highly effica-
cious antimalarials. While C4â-(hydroxymethyl)- and
C4â-(p-(hydroxymethyl)benzyl)trioxanes 5d and 5e show
only modest activity, one derivative, p-fluorobenzyl
ether 7, is quite potent and available in fewer chemical
transformations than derivatives of C4â-alkylated C8a-
(hydroxyalkyl)trioxanes. These qualitative SAR gen-
eralizations may aid in subsequent design of additional
endoperoxide antimalarials as chemotherapeutic agents
to combat multidrug-resistant malaria.
All of the new derivatives reported in Table 2, with
the exception of ether 21 and of alcohols C4â-5d and C4â-
5e, are potent antimalarials, with in vitro efficacies from
140 to 50% of artemisinin. In addition, p-fluorobenzyl
ether 6c has comparable activity to artemisinin in
killing gametocytes69 and thus, as with ether 26c, is a
potential therapy for interrupting the transmission of
malaria from humans back to mosquitoes.70 In examin-
ing structure-activity relationships based on these
derivatives, it is apparent that for C4â-methyl-C8a-
(hydroxyethyl)trioxane 4a derivatization does not sig-
nificantly increase its efficacy as it did with C4-
unsubstituted trioxane alcohol 22. On the other hand,
with C4â-(hydroxyalkyl)trioxanes 5d and 5e, antima-
larial activity of p-fluorobenzyl ethers 7 and 21 was
increased. This jump in potency was more dramatic
with ether 7, with 12 times higher activity than its
Exp er im en ta l Section
Gen er a l. The following applies unless otherwise noted:
Reactions were run in flame-dried round-bottomed flasks
under an atmosphere of ultrahigh purity (UHP) argon. Di-

Analogues of the Antimalarial Artemisinin
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 957
ethyl ether (ether) and tetrahydrofuran (THF) were distilled
from sodium benzophenone ketyl prior to use. Methylene
chloride (CH2Cl2) was distilled from calcium hydride prior to
use. All other compounds were purchased from Aldrich
Chemical Co. and used without further purification. Analyti-
cal thin-layer chromatography (TLC) was conducted with silica
gel 60 F254 plates (250 µm thickness, Merck). Column chro-
matography was performed using short path silica gel (particle
size <230 mesh), flash silica gel (particle size 400-230 mesh),
or Florisil (200 mesh). Yields are not optimized. Purity of
products was judged to be >95% based on their chromato-
graphic homogeneity. High-performance liquid chromatogra-
phy (HPLC) was carried out with a Rainin HPLX system
equipped with two 25 mL/min preparative pump heads using
Rainin Dynamax 10 mm × 250 mm (semipreparative) columns
packed with 60 Å silica gel (8 µm pore size), either as bare
silica or as C-18-bonded silica. Melting points were measured
using a Mel-Temp metal-block apparatus and are uncorrected.
Nuclear magnetic resonance (NMR) spectra were obtained
either on a Varian XL-400 spectrometer, operating at 400 MHz
for 1H and 100 MHz for 13C or on a Varian XL-500 spectrom-
eter, operating at 500 MHz for 1H and 125 MHz for 13C.
Chemical shifts are reported in parts per million (ppm, δ)
downfield from tetramethylsilane. Splitting patterns are
described as singlet (s), doublet (d), triplet (t), quartet (q),
multiplet (m), and broad (br). Infrared (IR) spectra were
obtained using a Perkin-Elmer 1600 FT-IR spectrometer.
Resonances are reported in wavenumbers (cm-1). Low- and
high-resolution mass spectra (LRMS and HRMS) were ob-
tained with electronic or chemical ionization (EI or CI) either
(1) at J ohns Hopkins University on a VG Instruments 70-S
spectrometer run at 70 eV for EI and run with ammonia (NH3)
as a carrier gas for CI or (2) at the University of Illinois at
Champaign-Urbana on a Finnigan-MAT CH5, a Finnigan-
MAT 731, or a VG Instruments 70-VSE spectrometer run at
70 eV for EI and run with methane (CH4) for CI. Combustion
analyses were conducted by Atlantic Microlab (Norcross, GA).
extracted with appropriate volumes of ether. The organic
portions were combined, washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure.
Gen er a l P r oced u r e 4: Ir on (II)-In d u ced Tr ioxa n e Deg-
r a d a tion . To a stirred suspension of FeBr2 (2.0 equiv) in THF
(0.5 mL) was added dropwise a solution of trioxane (1.0 equiv)
in THF (0.5 mL). The mixture was stirred for 10-30 min and
then diluted with water (1 mL) and Et2O (10 mL). The
ethereal phase was washed with water (2 mL × 3), dried over
MgSO4, filtered, and concentrated in vacuo to give a crude
product.
C8a -(Silyloxy)eth yl Nitr ile 9. To a mixture of TBDMSOTf
(3.50 mL, 15.2 mmol) and 2,6-lutidine (2.35 mL, 20.2 mmol)
in CH2Cl2 (10 mL) at 0 °C was added via cannula a solution of
alcohol 835 (2.13 g, 9.54 mmol) in CH2Cl2 (10 mL). This
reaction was allowed to warm to room temperature and was
stirred for 3 h. The resulting mixture was cooled to 0 °C and
was quenched with water (20 mL) and diluted with ether (20
mL). The organic layer was separated, and the aqueous layer
was extracted with ether (20 mL × 2). The combined organic
portions were washed with brine (40 mL), dried over anhy-
drous MgSO4, filtered, and concentrated under reduced pres-
sure. The crude material was purified by column chromatog-
raphy (short path, 2% EtOAc/hexanes) to afford the desired
product 9 (2.93 g, 8.68 mmol, 91%) as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 5.87 (s, 1 H), 3.58 (dt, J ) 13.2, 3.6 Hz, 2
H), 3.52 (s, 3 H), 2.80 (m, 1 H), 2.31 (m, 2 H), 2.22 (m, 1 H),
l.88 (m, 1 H), 1.75 (m, 1 H), 1.70-1.48 (m, 6 H), 1.42 (m, 2 H),
0.90 (s, 9 H), 0.08 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 143.3,
120.6, 118.3, 61.5, 59.3, 38.3, 33.8, 32.9, 31.7, 31.3, 30.8, 30.2,
26.0, 18.0, 15.7, -5.3; IR (CHCl3) 2246, 1661 cm-1; LRMS (EI,
rel intensity) 337 (M+, 1), 322 (M - CH3+, 4), 280 (100), 248
(20), 174 (24), 151 (41), 123 (21), 89 (75), 73 (32); HRMS (EI)
m/z calcd for
294.1889.
C
18H28NSiO2 (M - t-Bu+) 294.1889, found
C4-Meth yl C8a -(Silyloxy)eth yl Nitr iles 10a . To a freshly
prepared solution of LDA (9.55 mmol) in THF/hexanes (45
mL/6 mL) at -78 °C was added a precooled solution of nitrile
9 (2.93 g, 8.68 mmol) in THF (7 mL) via cannula. This mixture
was warmed to room temperature, stirred for 10 min, and
cooled back to -78 °C. The resulting solution was treated with
methyl iodide (0.165 mL, 2.65 mmol) via syringe. This reaction
was stirred at -78 °C for 30 min, allowed to slowly warm to
room temperature over 8 h, quenched with water (30 mL), and
diluted with ether (30 mL). The organic layer was separated,
and the aqueous layer was extracted with ether (30 mL × 2).
The combined organic portions were washed with brine (60
mL), dried over anhydrous magnesium sulfate, filtered, and
concentrated under reduced pressure. The crude product was
purified by column chromatography (short path, 10% EtOAc/
hexanes) to afford the desired product 10a (2.88 g, 8.19 mmol,
94%), a 1:1 mixture of diastereomers, as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 5.85 (s, 2 H), 3.55 (m, 4 H), 3.54 (s,
3 H), 3.52 (s, 3 H), 2.90 (m, 1 H), 2.56 (m, 1 H), 2.40 (m, 1 H),
1.95 (m, 1 H), 1.72-1.20 (m, 22 H), 1.34 (d, J ) 6.8 Hz, 3 H)
1.29 (d, J ) 7.2 Hz, 3 H) 0.902 (s, 9 H), 0.899 (s, 9 H), 0.06 (s,
12 H); 13C NMR (100 MHz, CDCl3) δ 143.2, 143.0, 124.0, 123.8,
119.0, 118.9, 61.6, 61.4, 59.3 (2), 40.0, 38.9, 38.1, 38.0, 34.1,
33.8, 32.2, 32.1, 31.9, 31.8, 31.1, 30.7, 25.9 (2), 24.3, 23.4, 18.7,
18.0, 17.7, -5.3 (2); IR (CHCl3) 2238, 1661 cm-1; LRMS (CI,
Gen er a l P r oced u r e 1: F or m a tion of Lith iu m Diiso-
p r op yla m id e (LDA). To a -78 °C solution of diisopropyl-
amine (1.2 equiv based on 1.0 equiv of substrate) in THF
(volume needed to make the final concentration of LDA 0.25-
0.50 M) was added via syringe recently titrated n-butyllithium
(1.1 equiv, originally 1.6 M in hexanes). This mixture was
stirred at -78 °C for 5 min and then warmed to room
temperature and stirred for 20 min.
Gen er a l P r oced u r e 2: Tr ioxa n e F or m a tion by Sin glet
Oxygen a tion . A sulfonation (three-necked) flask was fitted
with a gas inlet line, an outlet line with stopcock, and a
septum. To this flask was added solid methylene blue (ca. 5
mg) followed by a solution of the starting ketone (1.0 equiv)
in CH2Cl2 (0.01 M). The resulting solution was cooled to -78
°C while UHP oxygen passed through a drying column was
bubbled (ca. 2-3 mL/s) through the solution. The reaction
mixture was then irradiated with UV light (medium-pressure
Hg lamp) with continuous O2 bubbling until TLC analysis
showed >95% consumption of starting material (typically 1-2
h). After irradiation, an argon source was introduced through
the septum, the outlet stopcock was closed, and the gas inlet
line was replaced with a stopper. To this reaction mixture,
still at -78 °C, was then added by cannula a -78 °C solution
of TBDMSOTf (1.1 equiv) in CH2Cl2 (0.50 M). The resulting
solution was stirred for approximately 8 h at -78 °C. At that
time, the reaction was quenched by addition via syringe over
2 min of Et3N (neat, 3.3 equiv). The mixture was allowed to
warm to at least -20 °C slowly over at least 2 h and was then
concentrated under reduced pressure.
NH3, rel intensity) 369 (M + NH4+, 1), 352 (M + H+, 100), 294
+
(11); HRMS (CI, NH3) m/z calcd for C18H32NSiO2 (M - CH3
322.2202, found 322.2202.
)
C4-Meth yl C8a -(Silyloxy)eth yl Keton es 11a . To a solu-
tion of C4-methyl nitriles 10a (1.53 g, 4.36 mmol) in ether (20
mL) at -78 °C was added via syringe MeLi (1.5 M in ether,
9.30 mL, 14.0 mmol). After being stirred for 1 h at -78 °C,
the reaction was slowly warmed to room temperature over 2
h. The mixture was cooled back to -78 °C and quenched with
water (20 mL) and diluted with ether (50 mL). The organic
phase was separated, and the aqueous phase was extracted
with ether (30 mL × 2). The organic portions were combined
and washed with brine (40 mL), dried over anhydrous MgSO4,
Gen er a l P r oced u r e 3: Desilyla tion by F lu or id e Ion .
To a solution of starting silyl ether (1.0 equiv) in THF (0.33
M) at 0 °C was added a 0 °C solution of n-Bu4NF (monohy-
drate, 2-3 equiv) in THF (0.67 M). The resulting solution was
stirred at 0 °C until the starting material was consumed
(generally at least 1 h). The reaction was quenched with H2O
and then diluted with appropriate volumes of ether and H2O.
The organic phase was separated, and the aqueous phase was

958 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Cumming et al.
filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography (short path,
10% EtOAc/hexanes) to afford the desired product 11a (1.41
g, 3.83 mmol, 88%), a 1:1 mixture of diastereomers, as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.82 (s, 1 H), 5.81
(s, 1 H), 3.59 (m, 4 H), 3.51 (s, 3 H), 3.48 (s, 3 H), 2.82 (m, 1
H), 2.74 (m, 1 H), 2.55 (m, 1 H), 2.46 (m, 1 H), 2.20 (m, 2 H),
2.14 (s, 3 H), 2.13 (s, 3 H), 1.94-1.80 (m, 2 H), 1.69-1.26 (m,
18 H), 1.13 (d, J ) 6.8 Hz, 3 H) 1.06 (d, J ) 7.2 Hz, 3 H) 0.91
(s, 9 H), 0.90 (s, 9 H), 0.06 (s, 6 H), 0.05 (s, 6 H); 13C NMR
(100 MHz, CDCl3) δ 213.6, 212.9, 142.7, 142.5, 120.1, 120.0,
61.7, 61.6, 59.1, 59.0, 45.8, 45.1, 38.3, 38.2, 37.7, 37.1, 33.9,
33.8, 32.0, 31.9, 31.5, 31.4, 30.6, 29.0, 28.8, 28.5, 26.0 (2), 17.7,
17.6, 17.5, 16.2, -5.3 (2); IR (CHCl3) 1714, 1661 cm-1; LRMS
(CI, NH3, rel intensity) 386 (M + NH4+, 3), 369 (M + H+, 100),
351 (10), 334 (19); HRMS (CI, NH3) m/z calcd for C21H41NSiO3
(M + NH4+) 369.2825, found 369.2831.
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column chroma-
tography (flash gel, 2% EtOAc/hexanes) to afford the desired
ketones 11b (1.48 g, 3.33 mmol, 91%), a 1:1 mixture of
diastereomers, as a colorless oil.
C4-Ben zyl-C8a -(h yd r oxyeth yl)tr ioxa n es C4r-4b a n d C4â
-
4b. Ketones 11b (644 mg, 1.46 mmol) were treated according
to general procedure 2 (5.0 equiv Et3N). The crude product
was purified by column chromatography (Florisil, 2% EtOAc/
hexanes) to afford a 1:1 mixture of the corresponding trioxane
silyl ethers (320 mg, 0.671 mmol, 46%). This material was
immediately treated according to general procedure 3 to afford
the desired C4-benzyl-C8a-(hydroxyethyl)trioxanes 4b (113 mg,
0.312 mmol, 46%), a 1:1 mixture of diastereomers, as a
colorless oil. These diastereomers were separated by HPLC
(silica, 40% EtOAc/hexanes, 3.0 mL/min, 254 nm) to give C4R
-
benzyltrioxane alcohol 4b and C4â-benzyltrioxane alcohol 4b.
C4-Meth yl-C8a -(h yd r oxyeth yl)tr ioxa n es C4r-4a a n d C4â
-
C4-Silylm et h yl C8a -(Silyloxy)et h yl Nit r iles 10c. To a
freshly prepared solution of LDA (1.95 mmol) in THF/hexanes
(7.0 mL/1.4 mL) at -78 °C was added a precooled solution of
nitrile 9 (618 mg, 1.83 mmol) in THF (2 mL). The resulting
mixture was warmed to room temperature, stirred for 10 min,
and then cooled back to -78 °C. To this solution was added
(trimethylsilyl)methyl bromide (0.270 mL, 1.89 mmol). The
reaction was slowly warmed to room temperature over 3 h and
stirred for an additional hour before being cooled to -78 °C
and quenched with H2O (10 mL). The resulting mixture was
diluted with ether (20 mL), the organic layer was separated,
and the aqueous layer was extracted with ether (20 mL × 2).
The combined organic portions were washed with brine (30
mL), dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by
column chromatography (flash gel, 10% EtOAc/hexanes) to
afford the desired product 10c (727 mg, 1.72 mmol, 94%), a
1:1 mixture of diastereomers, as a colorless oil.
C4-Silylm eth yl C8a -(Silyloxy)eth yl Keton es 11c. To a
solution of C4-silylmethyl nitriles 10c (933 mg, 2.20 mmol) in
ether (8 mL) at -78 °C was added via syringe MeLi (1.6 M in
ether, 4.2 mL, 6.7 mmol). The reaction was warmed to room
temperature, stirred for 2 h, then cooled back to -78 °C, and
quenched with H2O. The resulting mixture was warmed to
room temperature and diluted with water (10 mL) and with
ether (30 mL), the organic layer was separated, and the
aqueous layer was extracted with ether (20 mL × 2). The
combined organic portions were washed with brine (40 mL),
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by column
chromatography (flash gel, 10% EtOAc/hexanes) to afford the
desired ketones 11c (909 mg, 2.06 mmol, 94%), a 1:1 mixture
of diastereomers, as a colorless oil.
4a . C4-Methyl ketones 11a (790 mg, 2.14 mmol) were treated
according to general procedure 2 (70 mL of CH2Cl2, 3.0 equiv
of Et3N). Purification of the crude material by column chro-
matography (Florisil, 2% EtOAc/hexanes) afforded the corre-
sponding trioxane silyl ethers (260 mg, 0.649 mmol, 30%) as
a
1:1 mixture of diastereomers. This material was im-
mediately treated according to general procedure 3. The crude
product was purified by column chromatography (Florisil, 10%
EtOAc/hexanes) to give the desired C4-methyl-C8a-(hydroxy-
ethyl)trioxanes 4a (132 mg, 0.461 mmol, 71%), a 1:1 mixture
of diastereomers, as a colorless oil. These diastereomers were
separated by HPLC (silica, 40% EtOAc/hexanes, 3.0 mL/min,
254 nm) to give C4R-methyltrioxane alcohol 4a and C4â
-
methyltrioxane alcohol 4a .
1
C
4R-4a : tR ) 11.8 min; H NMR (400 MHz, CDCl3) δ 5.17
(d, J ) 1.2 Hz, 1 H), 3.78 (m, 1 H), 3.66 (m, 1 H), 3.49 (s, 3 H),
2.28 (m, 1 H), 2.06 (m, 1 H), 1.88-1.20 (m, 11 H), 1.37 (s, 3
H), 1.19 (d, J ) 6.9 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ
106.7, 99.6, 85.3, 61.6, 56.6, 45.3, 42.4, 33.9, 31.3, 30.2, 25.3,
24.6, 22.0, 21.9, 14.6.
1
C
4â-4a : tR ) 12.4 min; H NMR (400 MHz, CDCl3) δ 5.21
(d, J ) 1.2 Hz, 1 H), 3.78 (m, 1 H), 3.66 (m, 1 H), 3.50 (s, 3 H),
2.44 (m, 1 H), 2.06 (m, 1 H), 1.90-1.20 (m, 11 H), 1.30 (s, 3
H), 0.98 (d, J ) 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ
107.6, 100.1, 84.9, 61.6, 56.8, 47.5, 41.6, 39.9, 37.3, 33.9, 30.9,
30.2, 25.2, 23.2, 19.2.
4a : IR (CHCl3) 3683, 3395 cm-1; LRMS (CI, NH3, rel
intensity) 304 (M + NH4+, 41), 287 (M + H+, 1) 272 (17), 237
(49), 209 (53), 137 (100); HRMS (CI, NH3) m/z calcd for C15H30
NO5 (M + NH4+) 304.2124, found 304.2129.
-
C4-Ben zyl C8a -(Silyloxy)eth yl Nitr iles 10b. To a freshly
prepared solution of LDA (4.34 mmol) in THF/hexanes (30
mL/3 mL) at -78 °C was added a precooled solution of nitrile
9 (1.33 g, 3.95 mmol) in tetrahydrofuran (5 mL) via cannula.
The resulting mixture was warmed to 0 °C, stirred for 15 min,
and cooled back to -78 °C. The solution was treated with
benzyl bromide (0.495 mL, 4.19 mmol) via syringe. The
reaction was allowed to warm to room temperature over 4 h,
quenched with H2O (30 mL), and diluted with ether (30 mL).
The organic phase was separated, and the aqueous portion was
extracted with ether (25 mL × 2). The organic phases were
combined, washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. Purifica-
tion of the crude product by column chromatography (flash
gel, 1% EtOAc/hexanes) afforded the desired product 10b (1.56
g, 3.65 mmol, 92%), a 1:1 mixture of diastereomers, as a
colorless oil.
C4-Ben zyl C8a -(Silyloxy)eth yl Keton es 11b. To a 0 °C
solution of C4-substituted nitriles 10b (1.56 g, 3.65 mmol) in
ether (30 mL) was added by syringe MeLi (1.4 M in ether, 7.80
mL, 10.9 mmol). The resulting mixture was warmed to room
temperature and stirred for 2 h. The reaction was then cooled
to 0 °C, quenched with H2O (20 mL), and diluted with ether
(40 mL). The organic layer was separated, and the aqueous
layer was extracted with ether (30 mL × 2). The combined
organic layers were washed with brine (30 mL), dried over
C4-(Silylm eth yl)-C8a-(h ydr oxyeth yl)tr ioxan es C4r-4c an d
C
4â-4c. Ketones 11c (816 mg, 1.85 mmol) were treated
according to general procedure 2 (4 h irradiation, 1.5 equiv of
TBDMSOTf). The crude product was purified by column
chromatography (Florisil, 5% EtOAc/hexanes) to afford a 1:1
mixture of the corresponding trioxane silyl ethers (520 mg,
1.10 mmol, 59%) that were immediately treated according to
general procedure 3. Purification of the crude material by
column chromatography (Florisil, 15% EtOAc/hexanes) gave
C4-(silylmethyl)-C8a-(hydroxyethyl)trioxanes 4c (104 mg, 0.290
mmol, 26%), a 1:1 mixture of diastereomers, as a colorless oil.
This mixture was separated by HPLC (silica, 40% EtOAc/
hexanes, 3.0 mL/min, 254 nm) to give C4R-(silylmethyl)trioxane
alcohol 4c and C4â-(silylmethyl)trioxane alcohol 4c.
C4-Sta n n ylm eth yl C8a -(Silyloxy)eth yl Nitr iles 10d . To
a freshly prepared solution of LDA (5.16 mmol) in THF/
hexanes (15 mL/3 mL) at -78 °C was added dropwise a
solution of nitrile 9 (1.45 g, 4.30 mmol) in THF (3 mL). After
15 min of stirring at -78 °C, the solution was allowed to warm
to 0 °C and was then recooled to -78 °C. A solution of Me3-
SnCH2I (1.45 g, 4.73 mmol) in THF (3 mL) was then added,
the cold bath was removed, and stirring was continued for 1.5
h. The reaction was quenched with saturated NH4Cl (25 mL)
and diluted with Et2O (100 mL). The phases were separated,

Analogues of the Antimalarial Artemisinin
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 959
and the ethereal solution was washed with water (20 mL ×
2), dried over MgSO4, filtered, and concentrated in vacuo.
Column chromatography of the residue (flash gel, 5% Et2O/
hexanes) provided the desired product (1.30 g, 2.53 mmol,
59%), a 1:1 mixture of diastereomers, as a colorless oil.
C4-Sta n n ylm eth yl C8a -(Silyloxy)eth yl Keton es 11d . To
a -78 °C solution of C4-stannylmethyl nitriles 10d (1.20 g,
2.37 mmol) in Et2O (15 mL) was added dropwise MeLi (1.4 M
in Et2O, 8.40 mL, 11.8 mmol) over 10 min. The cooling bath
was removed, and stirring was continued for 1.5 h before the
reaction was quenched with water (10 mL) and diluted with
Et2O (50 mL). The phases were separated, and the ethereal
phase was washed with water (10 mL), dried over MgSO4, and
concentrated in vacuo. Column chromatography (flash gel, 5%
Et2O/hexanes) of the residue provided the desired product 11d
(0.860 g, 1.62 mmol, 68%), a 1:1 mixture of diastereomers, as
a colorless oil.
afforded the desired Z-enol ether 14 (8.62 g, 48.1 mmol, 53%,
less polar) as a pale yellow oil. The spectroscopic data were
consistent with those reported previously.34,45
C4-Ben zyl Nitr iles 15a . To a solution of LDA (3.5 mmol)
in THF/hexanes (0.70 mL/2.8 mL) at -78 °C was added via
cannula a precooled solution of enol ether 14 (567 mg, 3.16
mmol) in THF (29 mL). After 5 min of stirring at -78 °C, the
reaction mixture was warmed to room temperature and stirred
for 20 min. This bright yellow enolate solution was cooled to
-78 °C, and benzyl bromide (0.39 mL, 3.3 mmol) was added
via syringe over 2 min. The blue-green mixture was stirred
at -78 °C for 1 h, warmed to room temperature over 1 h, and
stirred for 2 h. This orange solution was cooled to 0 °C and
quenched by addition of H2O (5 mL). The resulting solution
was diluted with H2O (50 mL) and ether (30 mL). The organic
phase was separated, and the aqueous phase was extracted
with ether (50 mL × 2). The organic portions were combined,
washed with saturated aqueous NaCl, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography (short
path, 5% f 10% EtOAc/hexanes) to give the desired product
15a (840 mg, 3.1 mmol, 99%), a 1:1 diastereomeric mixture,
as a yellow oil.
C
4â-(Stan n ylm eth yl)-C8a-(h ydr oxyeth yl)tr ioxan e 4d. C4-
Stannylmethyl ketones 11d (450 mg, 0.850 mmol) were treated
according to general procedure 2 (60 mL of CH2Cl2, 3.0 equiv
of Et3N). The residue was purified by column chromatography
(flash gel, hexanes f 5% Et2O/hexanes) to provide the desired
trioxane silyl ethers (132 mg, 0.234 mmol, 28%). This material
was immediately treated according to general procedure 3.
Column chromatography of the crude product (flash gel, 25%
f 75% Et2O/hexanes) gave a 10:1 mixture of C4â-(stannyl-
methyl)-C8a-(hydroxyethyl)trioxane 4d and its C4R-stannyl-
methyl epimer (32 mg total mass, 0.071 mmol, 30%) as an oil.
Purification of the major diastereomer by HPLC (silica, 35%
EtOAc/hexanes, 3 mL/min, 254 nm) provided C4â-(stannyl-
methyl)trioxane alcohol 4d : tR ) 12.3 min.
C4-Ben zyl Keton es 16a . To a solution of C4-benzyl nitriles
15a (830 mg, 3.08 mmol) in ether (30 mL) at -78 °C was added
via syringe MeLi (6.6 mL, 9.2 mmol) over 5 min. The mixture
was stirred at -78 °C for 30 min then warmed to room
temperature and stirred for 6 h. The turbid reaction mixture
was cooled to 0 °C and quenched by addition of H2O (5 mL).
The resulting solution was diluted with H2O (50 mL) and ether
(30 mL). The organic phase was separated, and the aqueous
phase was extracted with ether (50 mL × 2). The organic
portions were combined, washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by column
chromatography (short path, 5% f 10% EtOAc/hexanes) to
give the desired product 16a (736 mg, 2.57 mmol, 84%), a 1:1
diastereomeric mixture, as an orange oil.
C
4r-Meth yltr ioxa n e Mon om eth yl Ter ep h th a la te Ester
12. Monomethyl terephthalate (17 mg, 0.096 mmol), 4-(N,N-
dimethylamino)pyridine (DMAP, 18.8 mg, 0.154 mmol), dicy-
clohexylcarbodiimide (23.8 mg, 0.116 mmol), and CH2Cl2 (2
mL) were mixed at 0 °C, warmed to room temperature, stirred
for 30 min, and cooled back to 0 °C. To this mixture was added
via cannula a solution of C4R-methyl-C8a-(hydroxyethyl)triox-
ane 4a (11 mg, 0.038 mmol) in CH2Cl2 (0.5 mL). After 10 min
at 0 °C, the reaction was warmed to room temperature and
stirred for an additional 30 min. The solvent was then
removed under reduced pressure. The resulting residue was
purified by column chromatography (Florisil, 5% EtOAc/
hexanes) to afford the desired product 12 (13.6 mg, 0.030
mmol, 79%) as a white solid: mp 116.0-117.0 °C. A crystal
of ester 12 suitable for X-ray analysis was obtained by
recrystallization from hexane.71
En ol Eth er 14. A 1.0 L round-bottomed flask was charged
with (methoxymethyl)triphenylphosphonium chloride (37.4 g,
109 mmol) and LiCl (3.84 g, 91.0 mmol). The mixture of solids
was flame-dried under vacuum just until it was a dry, loose
powder. After cooling, the flask was flushed with argon, and
THF (450 mL) was added. This slurry was cooled to -78 °C,
and LHMDS (1.0 M in THF, 200 mL, 200 mmol) was added
via cannula. The mixture was stirred at -78 °C for 15 min,
then warmed to room temperature, and stirred for 2 h. The
resulting brick red solution was cooled back to -78 °C, and a
precooled solution of 2-(2′-cyanoethyl)cyclohexanone (13, 13.7
g, 90.6 mmol) in THF (200 mL) was added via cannula. This
reaction was stirred at -78 °C for 15 min, then warmed to
room temperature, and stirred for 8 h, and finally quenched
at room temperature with H2O (10 mL) and then further
diluted with H2O (50 mL) after 10 min of stirring. As much
of the organic layer as possible was decanted, and the
remaining organic/aqueous mixture was diluted with ether
(100 mL). The phases were separated, and the aqueous was
washed with ether (100 mL). The organic portions were
combined, washed with saturated aqueous NaCl, dried over
MgSO4, filtered, and concentrated under reduced pressure. 1H
NMR of the crude mixture showed a 2.5:1.0 ratio of Z-enol
ether to E-enol ether. The material was filtered through a
plug of flash gel to afford the mixture of enol ethers (12.5 g,
69.7 mmol, 77%) as a yellow oil. Further purification by
column chromatography (flash gel, 1% f 10% EtOAc/hexanes)
C4-Ben zyltr ioxa n es C4r-5a a n d C4â-5a . C4-Benzyl ke-
tones 16a (350 mg, 1.22 mmol) were treated according to
general procedure 2. The resulting blue-green syrup was
crudely purified by column chromatography (florisil, 1% f 20%
EtOAc/hexanes) to give the desired product 5a (290 mg, 0.911
mmol, 74%), a 1:1 mixture of diastereomers, as a yellow oil.
These trioxane diastereomers were separated by HPLC (silica,
3% EtOAc/hexanes, 3.0 mL/min, 260 nm) to afford C4R
-
benzyltrioxane 5a and C4â-benzyltrioxane 5a as white solids:
Trioxane C4R-5a : tR ) 12.9 min; mp ) 81.5-82.5 °C.
Trioxane C4â-5a : tR ) 15.1 min; mp ) 121.0-123.0 °C.
C4-(Tr im et h ylst a n n yl)m et h yl Ket on es C4â-16cx a n d
C
4r-16cx. To a freshly prepared solution of LDA (17.3 mmol)
in THF/hexane (45 mL/17 mL) at -78 °C was added dropwise
a solution of enol ether 14 (3.00 g, 14.5 mmol) in THF (10 mL).
After 10 min of stirring at -78 °C, the solution was allowed
to warm to 0 °C and then recooled to -78 °C. A solution of
Me3SnCH2I (4.88 g, 15.9 mmol) in THF (10 mL) was added,
and stirring was continued for 2 h. The reaction was quenched
with saturated NH4Cl (25 mL) and diluted with Et2O (200 mL).
The ethereal solution was washed with water (50 mL × 2),
dried over MgSO4, filtered, and concentrated in vacuo to
provide the desired C4-alkylated nitriles (5.57 g, 15.6 mmol,
>100%), a 1:1 mixture of diastereomers, which was essentially
pure by TLC and was used without further purification.
To a -78 °C solution of the above C4-alkylated nitriles (5.30
g, 14.9 mmol) in Et2O (50 mL) was added dropwise MeLi (1.4
M in Et2O, 49.0 mL, 68.6 mmol) over 10 min. The cooling bath
was removed, and stirring was continued for 1.5 h before the
reaction was quenched with water (50 mL) and diluted with
Et2O (100 mL). The phases were separated, and the ethereal
phase was washed with water (50 mL), dried over MgSO4, and
concentrated in vacuo. Chromatography (flash gel, hexanes
f 10% EtOAc/hexanes) of the residue provided C4â-(trimeth-
ylstannyl)methyl ketone 16cx (less polar, 910 mg, 2.44 mmol,

960 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Cumming et al.
17%) and a 1:4 mixture of C4â-16cx and C4R-(trimethylstannyl)-
methyl ketone 16cx (1.43 g total mass, 3.83 mmol, 26%).
over 2 h. The reaction was quenched with MeOH (1.5 mL)
followed by water (1.5 mL). Stirring was continued for 20 min
over which time a white precipitate formed from the initially
gelatinous mixture. The mixture was filtered through Celite,
and the filtrate was concentrated in vacuo. The residue was
quickly eluted through a short pad of flash gel (10% Et2O/
hexanes) to provide the desired aldehyde (>90% pure, 1.81 g,
3.32 mmol, 95%) that was used without further purification.
To a -78 °C solution of the above C4â-substituted aldehydes
(1.73 g, 3.17 mmol) in THF (25 mL) was added dropwise
MeMgBr (1.4 M in Et2O, 6.4 mL, 9.0 mmol). The resulting
solution was stirred at -78 °C for 1 h, allowed to warm to
room temperature, and stirred for a further 30 min. The
reaction was quenched with water (10 mL) and diluted with
ether (50 mL), and the phases were separated. The ethereal
phase was washed with saturated NH4Cl (10 mL × 2) and
brine (10 mL), dried over MgSO4, filtered, and concentrated
in vacuo. Chromatography (flash gel, 15% Et2O/hexanes)
provided the desired alcohols 17 (1.20 g, 2.14 mmol, 68%), a
3:1 diastereomeric mixture, as a thick colorless oil.
To a 0 °C solution of DMSO (0.553 mL, 7.80 mmol) in CH2-
Cl2 (10 mL) was added a solution of trifluoroacetic anhydride
(0.826 mL, 5.85 mmol) in CH2Cl2 (3 mL) dropwise. The
solution was stirred for 15 min. A solution of alcohols 17 (1.15
g, 1.95 mmol) in CH2Cl2 (3 mL) was then added dropwise.
Stirring was continued for 30 min, and Et3N (1.90 mL, 13.6
mmol) was added. The solution was allowed to warm to room
temperature and stirred further for 20 min. The mixture was
diluted with Et2O (70 mL), washed with water (25 × 2 mL),
dried over MgSO4, filtered, and concentrated in vacuo. Chro-
matography (flash gel, 10% Et2O/hexanes) provided the desired
C
4â-((Tr im eth ylsta n n yl)m eth yl)tr ioxa n e 5cx. C4â-Alky-
lated ketone 16cx (490 mg, 1.22 mmol) was treated according
to general procedure 2 (50 mL of CH2Cl2, 2.5 equiv of Et3N).
Chromatography of the residue (flash gel, hexanes f 5% Et2O/
hexanes) provided the desired trioxane C4â-((trimethylstannyl)-
methyl)trioxane 5cx (124 mg, 0.306 mmol, 25%) as a white
solid: mp 44.0-46.0 °C.
C4-(Tr ibu tylsta n n yl)m eth yl Nitr iles 15cy. To a freshly
prepared solution of LDA (20.2 mmol) in THF/hexanes (50 mL/
13 mL) at -78 °C was added dropwise a solution of enol ether
14 (3.50 g, 16.9 mmol) in THF (10 mL). After 15 min of
stirring at -78 °C, the solution was allowed to warm to 0 °C
and then recooled to -78 °C. A solution of Bu3SnCH2I (8.00
g, 18.6 mmol) in THF (10 mL) was added, the cold bath was
removed, and stirring was continued for 1.5 h. The reaction
was quenched with saturated NH4Cl (25 mL) and diluted with
ether (200 mL). After separation of phases, the ethereal
solution was washed with water (50 mL × 2), dried over
MgSO4, filtered, and concentrated in vacuo. Column chroma-
tography of the residue (flash gel, hexanes f 25% Et2O/
hexanes) provided the desired product 15cy (6.20 g, 12.9 mmol,
72%), a 1:1 mixture of diastereomers, as a colorless oil.
C4-(Tr ibu tylsta n n yl)m eth yl k eton es C4â-16cy a n d C4r
-
16cy. To a -78 °C solution of C4-alkylated nitriles 15cy (5.70
g, 11.2 mmol) in Et2O (50 mL) was added dropwise MeLi (1.4
M in Et2O, 39.9 mL, 55.9 mmol) over 10 min. The bath was
removed, and stirring was continued for 1.5 h before the
reaction was quenched with water (50 mL) and diluted with
Et2O (100 mL). The phases were separated, and the ethereal
portion was washed with water (50 mL), dried over MgSO4,
and concentrated in vacuo. Column chromatography (flash
gel, hexanes f 20% EtOAc/hexanes) of the residue provided
C
4â-alkylated ketone 16cz (0.970 g, 1.73 mmol, 89%) as a
colorless oil.
C
4â-((Tr ip h en ylsta n n yl)m eth yl)tr ioxa n e 5cz. C4â-sub-
stituted ketone 16cz (650 mg, 1.16 mmol) was treated accord-
ing to general procedure 2 to give the desired C4â-((triphenyl-
stannyl)methyl)trioxane 5cz (135 mg, 0.228 mmol, 20%) as a
colorless oil.
C
4â-(tributylstannyl)methyl ketones 16cy (less polar, 2.90 g,
5.81 mmol, 52%) and C4R-(tributylstannyl)methyl ketones 16cy
(more polar, 2.52 g, 5.05 mmol, 46%) as colorless oils.
C
4r-((Tr ibu tylsta n n yl)m eth yl)tr ioxa n e C4r-5cy. C4R-
C4-(Hyd r oxym eth yl)tr ioxa n es C4r-5d a n d C4â-5d . We
have previously reported preparation and characterization of
intermediates en route to C4-(hydroxymethyl)trioxanes 5d .54
Conditions for formation and separation of these trioxanes,
as well as characterization of C4â-(hydroxymethyl)trioxane 5d
itself, were also reported at that time. We include in the
Supporting Information the latter information, along with data
for the previously unreported C4R-(hydroxymethyl)trioxane 5d ,
for convenience.
C4-(Silyloxy)methyl ketones 16d (200 mg, 0.585 mmol) were
treated according to general procedure 2. The resulting blue
syrup was purified by column chromatography (Florisil, 1%
f 10% EtOAc/hexanes) to give the corresponding trioxane silyl
ethers, a 1:1 mixture of diastereomers (ca. 140 mg, 0.376 mmol,
64%), as a yellow oil. A portion of this material (44 mg, 0.12
mmol) was treated according to general procedure 3. This
crude product was purified by column chromatography (Flo-
risil, 1% f 20% EtOAc/hexanes) to give the desired trioxane
alcohols 5d (20 mg, 0.078 mmol, 66%), a 1:1 diastereomeric
mixture, as a colorless oil. These trioxane alcohols were
separated by HPLC (silica, 5% i-PrOH/hexanes, 3.0 mL/min,
Alkylated ketone 16cy (650 mg, 1.30 mmol) was treated
according to general procedure 2 (60 mL of CH2Cl2, 3.6 equiv
of Et3N). The material was concentrated and the residue
purified by column chromatography (flash gel, hexanes f 5%
Et2O/hexanes) provided the desired C4R-((tributylstannyl)-
methyl)trioxane 5cy (70 mg, 0.13 mmol, 10%) as a colorless
oil.
C
4â-((Tr ib u t ylst a n n yl)m et h yl)t r ioxa n e C4â-5cy. C4â-
Alkylated ketone 16cy (730 mg, 1.40 mmol) was treated
according to general procedure 2 (60 mL of CH2Cl2, 3.6 equiv
of Et3N). The material was concentrated in vacuo, and the
residue purified by column chromatography (flash gel, hexanes
f 5% Et2O/hexanes) provided C4â-tributylstannylmethyl tri-
oxane 5cy (349 mg, 0.657 mmol, 45%) as a colorless oil.
C
4â-(Tr ip h en ylsta n n yl)m eth yl Nitr ile 15cz. To a freshly
prepared solution of LDA (17.4 mmol) in THF/hexanes (50 mL/
2.5 mL) was added dropwise over 5 min a solution of enol ether
14 (3.00 g, 14.5 mmol) in THF (10 mL). This mixture was
stirred at -78 °C for 15 min, the cooling bath was removed,
and stirring was continued for 15 min. The resulting solution
was cooled back to -78 °C, and a solution of Ph3SnCH2I (7.86
g, 15.9 mmol) in THF (10 mL) was added via cannula. The
reaction was stirred at -78 °C for 3 h, warmed to room
temperature, stirred for an additional hour, and quenched with
NH4Cl (25 mL). The mixture was then diluted with ether (200
mL), the phases were separated, and the ethereal solution was
washed with saturated aqueous NaHCO3 (50 mL) and water
(50 mL × 2), dried over MgSO4, filtered, and concentrated in
vacuo. Column chromatography of the residue (flash gel, 10%
Et2O/hexanes) provided the desired C4â-substituted product
15cz (3.23 g, 5.96 mmol, 41%): mp ) 103.5-105.0 °C.
230 nm) to afford C4R-(hydroxymethyl)trioxane 5d and C4â
(hydroxymethyl)trioxane 5d as white solids:
-
Trioxane C4R-5d : tR ) 14.1 min; mp ) 97.0-99.0 °C.
Trioxane C4â-5d : tR ) 16.2 min; mp ) 101.0-102.0 °C.
p -((Silyloxy)m et h yl)b en zyl Alcoh ol 20 (Beilst ein
4863197). Sodium hydride (60% in mineral oil, 1.6 g, 40 mmol)
was washed with anhydrous hexanes (5 mL × 2) and dried in
vacuo. This gray powder was suspended in THF (80 mL) at
room temperature, and solid 1,4-bis(hydroxymethyl)benzene
(5.0 g, 36 mmol) was added in three portions over 3 min. The
reaction was stirred for 45 min at which time it was a milky
white. To this alkoxide mixture was added TBDMSCl (5.7 g,
38 mmol) as a solid in three portions over 3 min. This addition
was highly exothermic. The reaction was stirred for 1 h. At
that time, the still turbid mixture was quenched with H2O (5
C
4â-(Tr ip h en ylsta n n yl)m eth yl Keton e 16cz. To a -78
°C solution of C4â-alkylated nitrile 15cz (2.00 g, 3.50 mmol)
in toluene (20 mL) was added dropwise DIBAL-H (1.0 M in
hexanes, 3.85 mL, 3.85 mmol). The mixture was stirred at
-78 °C for 1 h and then allowed to warm to room temperature

Analogues of the Antimalarial Artemisinin
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 961
mL) and then diluted with H2O (100 mL) and ether (100 mL).
The organic phase was separated, and the aqueous phase was
extracted with ether (100 mL × 2). The organic portions were
combined, washed with saturated aqueous NaCl, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. This crude product was purified by column chro-
matography (short path, 1% f 50% EtOAc/hexanes) to give
the desired product 20 (5.1 g, 20 mmol, 56%).
ethers, a 1:1 mixture of diastereomers (ca. 310 mg, 0.670 mmol,
65%), as a dark yellow oil. This material was combined with
that from a second singlet oxygenation/silyl triflate rearrange-
ment (total mass, 440 mg, 0.951 mmol) and was treated
according to general procedure 3. This crude product was
purified by column chromatography (Florisil, 5% f 50%
EtOAc/hexanes) to give the desired products 5e, a 1:1 diaster-
eomeric mixture (201 mg, 0.580 mmol, 61%), as a colorless oil.
These trioxane alcohol diastereomers were separated by HPLC
(C-18, 20% H2O/MeOH, 3.0 mL/min, 254 nm) to afford C4R-(p-
p-((Silyloxy)m eth yl)ben zyl Br om id e 18. To a solution
of N-bromosuccinimide (4.2 g, 24 mmol) in CH2Cl2 (75 mL) at
0 °C was added via syringe over several minutes dimethyl
sulfide (2.1 mL, 29 mmol). The bright yellow turbid mixture
was stirred at 0 °C for 10 min and then was cooled to -20 °C.
At this temperature, a precooled solution of p-((silyloxy)-
methyl)benzyl alcohol 20 (4.0 g, 16 mmol) in CH2Cl2 (8 mL)
was added via cannula. The resulting mixture was warmed
to 0 °C, kept at this temperature for 15 min, then warmed to
room temperature, and stirred for 2 h. At that time, the
reaction was quenched with H2O (5 mL) and then diluted with
H2O (100 mL) and CH2Cl2 (50 mL). The organic phase was
separated, and the aqueous phase was extracted with CH2Cl2
(100 mL). The organic portions were combined, washed with
saturated aqueous NaCl, dried over anhydrous MgSO4, fil-
tered, and concentrated under reduced pressure. This crude
product was purified by column chromatography (Florisil, 1%
f 5% EtOAc/hexanes) to give the desired product 18 (4.5 g,
14 mmol, 90%) as a colorless oil. It should be noted that benzyl
bromide 18 is extremely unstable to unmodified silica, with
95% of the material decomposing upon chromatography on
short path silica gel. As indicated above, Florisil was suitable
for this purification.
C4-(p-((Silyloxy)m eth yl)ben zyl) Nitr iles 15e. To a freshly
prepared solution of LDA (3.36 mmol) in THF/hexanes (6.5
mL/2.4 mL) at -78 °C was added via cannula a precooled
solution of enol ether 14 (540 mg, 3.01 mmol) in THF (23 mL).
After 5 min of stirring at -78 °C, the reaction mixture was
warmed to room temperature and stirred for 15 min. This
golden brown enolate solution was cooled to -78 °C, and a 1
M THF solution of p-((silyloxy)methyl)benzyl bromide 18 at
room temperature was added via syringe over 2 min. The
mixture was stirred at -78 °C for 1 h, warmed to room
temperature over 1 h, and stirred at room temperature for 2
h. The reaction was cooled to 0 °C and quenched by dropwise
addition of H2O (3 mL). The resulting mixture was diluted
with H2O (50 mL) and ether (50 mL). The organic phase was
separated, and the aqueous phase was extracted with ether
(50 mL × 2). The organic portions were combined, washed
with saturated aqueous NaCl, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. This crude
product was purified by column chromatography (short path,
1% f 10% EtOAc/hexanes) to give the desired product 15e
(1.09 g, 2.63 mmol, 88%), a 1:1 diastereomeric mixture, as a
yellow oil.
(hydroxymethyl)benzyl)trioxane 5e as a white solid and C4â
-
(p-(hydroxymethyl)benzyl)trioxane 5e as a colorless oil:
Trioxane C4R-5e: tR ) 20.8 min; mp ) 99.5-100.0 °C.
Trioxane C4â-5e: tR ) 18.9 min.
C
4â-Meth yltr ioxa n e P h osp h a te Ester 6a . To a 0 °C
solution of redistilled diphenyl chlorophosphate (8 µL, 0.04
mmol) and DMAP (2.6 mg, 0.021 mmol) in CH2Cl2 (0.5 mL)
was added via syringe Et3N (6 µL, 0.04 mmol). This mixture
was allowed to stir at room temperature for 40 min before a
solution of C4â-methyl-C8a-(hydroxyethyl)trioxane 4a (5.0 mg,
0.017 mmol) in CH2Cl2 (0.5 mL) was added via cannula. The
reaction was stirred at room temperature for 5 h and then
diluted with water (10 mL) and ether (20 mL). The organic
layer was separated, and the aqueous layer was extracted with
ether (5 mL × 2). The combined organic portions were washed
with brine (10 mL), dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified column chromatography (Florisil, 20% EtOAc/hex-
anes) to afford the desired product 6a (7.8 mg, 0.015 mmol,
86%) as a colorless oil. This material was further purified by
HPLC (silica, 20% EtOAc/hexanes, 3.0 mL/min, 254 nm): tR
) 20.3 min.
C
4â-Meth yltr ioxa n e Ben zyl Eth er 6b. To a 0 °C solution
of C4â-methyl-C8a-(hydroxyethyl)trioxane 4a (76.2 mg, 0.266
mmol) in THF (2 mL) was added via syringe KHMDS (0.50 M
in toluene, 2.66 mL, 1.33 mmol). This mixture was stirred
for 10 min at 0 °C, and then benzyl bromide (48 µL, 0.040
mmol) was added via syringe. The resulting solution was
stirred at 0 °C for 30 min, then warmed to room temperature,
and stirred for 2 h. The reaction was cooled back to 0 °C,
quenched with water (5 mL), and diluted with ether (5 mL).
The organic layer was separated, and the aqueous layer was
extracted with ether (10 mL × 2). The combined organic
portions were washed with brine (5 mL), dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
Column chromatography of the crude material (Florisil, 1%
f 4% EtOAc/hexanes) afforded the desired product 6b (80.9
mg, 0.215 mmol, 81%) as a colorless oil.
C
4â-Meth yltr ioxa n e p-F lu or oben zyl Eth er 6c. To a 0
°C solution of C4â-methyl-C8a-(hydroxyethyl)trioxane 4a (7.1
mg, 0.022 mmol) in THF (1 mL) was added via syringe
KHMDS (0.50 M in toluene, 0.30 mL, 0.15 mmol). This
mixture was stirred for 10 min at 0 °C, and p-fluorobenzyl
bromide (8.0 µL, 0.065 mmol) was added via syringe. The
resulting solution was stirred at 0 °C for 30 min, then warmed
to room temperature, and stirred for 18 h. The reaction was
then quenched with water (2 mL) at 0 °C and diluted with
ether (2 mL). The organic layer was separated, and the
aqueous layer was extracted with ether (5 mL × 2). The
combined organic portions were washed with brine (5 mL),
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. Column chromatography of the crude
material (Florisil, 10% EtOAc/hexanes) afforded the desired
product 6c (7.8 mg, 0.020 mmol, 91%) as a colorless oil. This
material was further purified by HPLC (silica, 3% EtOAc/
hexanes, 3.0 mL/min, 254 nm): tR ) 10.6 min.
C4-(p-((Silyloxy)m eth yl)ben zyl) Keton es 16e. To a solu-
tion of C4-substituted nitriles 15e (1.00 g, 2.42 mmol) in ether
(20 mL) at -78 °C was added via syringe MeLi (1.4 M in ether,
5.2 mL, 7.3 mmol) over 5 min. The resulting mixture was
stirred at -78 °C for 10 min and then warmed to room
temperature and stirred for 3 h. At that time, the reaction
was cooled to 0 °C and quenched with dropwise addition of
H2O (1 mL). The resulting mixture was diluted with H2O (25
mL) and ether (25 mL). The organic phase was separated,
and the aqueous phase was extracted with ether (25 mL × 2).
The organic portions were combined, washed with saturated
aqueous NaCl, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. This crude product was
purified by column chromatography (short path, 1% f 20%
EtOAc/hexanes) to give the desired product 16e (700 mg, 1.63
mmol, 68%), a 1:1 diastereomeric mixture, as a yellow oil.
C
4â-(((p-F lu or oben zyl)oxy)m eth yl)tr ioxa n e 7. In a flame-
dried 1 dram vial under argon, sodium hydride (60% in mineral
oil, 22 mg, 0.55 mmol) was washed with anhydrous hexanes
(1 mL × 2) and dried in vacuo. This gray powder was cooled
to 0 °C, and a room temperature solution of C4â-(hydroxy-
methyl)trioxane 5d (28 mg, 0.11 mmol) in DMF (0.75 mL) was
added dropwise via syringe directly onto the solid. Vigorous
release of gas occurred immediately. The flask containing the
C4-(p-(Hydr oxym eth yl)ben zyl)tr ioxan es C4r-5e an d C4â
-
5e. C4-Substituted ketones 16e (440 mg, 1.02 mmol) were
treated according to general procedure 2. The resulting blue
syrup was purified by column chromatography (Florisil, 1%
f 20% EtOAc/hexanes) to give the corresponding trioxane silyl

962 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Cumming et al.
starting alcohol was washed with DMF (0.30 mL), and this
rinse was also added via syringe to the reaction. After 10 min
at 0 °C, the mixture was warmed to room temperature and
stirred for roughly 45 min, as which time bubbling had ceased.
This dark beige turbid solution was cooled to 0 °C, and
p-fluorobenzyl bromide (68 µL, 0.55 mmol) was added neat
dropwise via syringe. The mixture was stirred at 0 °C for 10
min, then warmed to room temperature, and stirred for 3 h,
during which time its color slowly faded. The reaction was
then cooled back to 0 °C, quenched with dropwise addition of
H2O (1 mL), and diluted with H2O (2 mL) and ether (5 mL).
The organic phase was separated, and the aqueous phase was
extracted with ether (5 mL). The organic portions were
combined, washed with saturated aqueous NaCl, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. This crude product was purified by column chro-
matography (Florisil, 1% f 5% EtOAc/hexanes) to give the
desired product 7 (29 mg, 0.079 mmol, 72%) as a colorless oil.
This material was further purified by HPLC (silica, 5% EtOAc/
hexanes, 3.5 mL/min, 254 nm, tR ) 14.4 min) to afford a
colorless oil.
data, Professor Nirbhay Kumar (School of Hygiene and
Public Health, The J ohns Hopkins University) for the
gametocyte studies, and Professor Derek H. R. Barton
(Department of Chemistry, Texas A&M University) for
a preprint of ref 17.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
1
graphic data for ester 12, and H and 13C NMR, IR, and mass
spectral data for all compounds in the text except for those
leading to and including trioxanes 4a (Scheme 2) that are
described in the Experimental Section (24 pages). Ordering
information is given on any current masthead page.
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4â-(p-((F lu or oben zyloxy)m eth yl)ben zyl)tr ioxa n e 21.
In a flame-dried 1 dram vial under argon, sodium hydride (14
mg, 60% in mineral oil, 0.35 mmol) was washed with anhy-
drous hexanes (1 mL × 2) and dried in vacuo. This gray
powder was cooled to 0 °C, and a room temperature solution
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µL, 0.35 mmol) was added neat dropwise via syringe. The color
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with H2O (2 mL) and ether (5 mL). The organic phase was
separated, and the aqueous phase was extracted with ether
(5 mL). The organic portions were combined, washed with
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f 10% EtOAc/hexanes) to give the desired product 21 (28 mg,
0.061 mmol, 85%) as a colorless oil. This material was further
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nm, tR ) 22.7 min) to afford a colorless oil.
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Degr a d a tion of C4â-((Tr im eth ylsta n n yl)m eth yl)tr iox-
a n e 5cx. The aforementioned trioxane (10 mg, 0.023 mmol)
was treated according to general procedure 4. 1H NMR of the
crude mixture indicated a 1:5 ratio of exocyclic olefin 24:acetate
25. This material was purified by column chromatography
(flash gel, 5% f 25% Et2O/hexanes) to afford olefin 24 (0.7
mg, 0.003 mmol, 14%) as a white solid and acetate 25 (4.0 mg,
0.017 mmol, 72%) as an oil.
Exocyclic olefin 24: mp 138.0-140.0 °C.
Degr a d a tion of C4â-((Tr ibu tylsta n n yl)m eth yl)tr ioxa n e
5cy. The aforementioned trioxane (11 mg, 0.020 mmol) was
treated according to general procedure 4. 1H NMR of the
mixture indicated a 1:5 ratio of exocyclic olefin 24:acetate 25.
Degr a d a tion of C4â-((Tr ip h en ylsta n n yl)m eth yl)tr iox-
a n e 5cy. The aforementioned trioxane (10 mg, 0.017 mmol)
was treated according to general procedure 4. 1H NMR of the
mixture indicated a 1:10 ratio of exocyclic olefin 24:acetate 25.
Ack n ow led gm en t. We thank the NIH (AI-34885
and NCRR OPD-GCRC RR00722) and the Burroughs
Wellcome Fund for financial support. Also, we thank
Professor Mario Bachi (Weizmann Institute of Science,
Israel) for many helpful discussions about free radical
chemistry, Dr. N. Murthy of this department for X-ray

Analogues of the Antimalarial Artemisinin
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(71) We have deposited the atomic coordinates for ester 12 with the
Cambridge Crystallographic Data Center. The coordinates can
be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Center, 12 Union Road, Cambridge, CB2 1EZ,
U.K.
J M970711G