Antimalarial and antiplasmodial activities of norneolignans. Syntheses and SAR

Article abstract of DOI:10.1021/jm0508235

A systematic change of the substituents and side chain of the norneolignan hinokiresinol afforded a 10 fold improvement of the IC₅₀ value toward inhibition of the growth of Plasmodium falciparum. The more potent compounds controlled the parasit

Full text of DOI:10.1021/jm0508235

436
J. Med. Chem. 2006, 49, 436-440
Brief Articles
Antimalarial and Antiplasmodial Activities of Norneolignans. Syntheses and SAR
Dorthe Mondrup Skytte,† Simon Feldbæk Nielsen,‡ Ming Chen,§ Lin Zhai,§ Carl Erik Olsen, and Søren Brøgger Christensen†,*
Department of Medicinal Chemistry, The Danish UniVersity of Pharmaceutical Sciences, UniVersitetsparken 2,
DK-2100 Copenhagen Ø, Denmark, Lica Pharmaceuticals, FruebjergVej 3, DK-2100 Copenhagen Ø, Denmark,
Department of Clinical Microbiology, 7602 Copenhagen UniVersity Hospital, TagensVej 20, DK-2200 Copenhagen N, Denmark, and
Department of Natural Sciences, The Royal Veterinary and Agricultural UniVersity, Bu¨lowsVej 17, DK-1870 Frederiksberg C, Denmark
ReceiVed August 18, 2005
A systematic change of the substituents and side chain of the norneolignan hinokiresinol afforded a 10 fold
improvement of the IC50 value toward inhibition of the growth of Plasmodium falciparum. The more potent
compounds controlled the parasitemia in mice infected with Plasmodium berghei.
Chart 1
Introduction
Malaria is one of the most devastating diseases in the world
killing 1-3 million people and infecting 300-500 million each
year.1 The fight against malaria is complicated by the ability of
the pathogenic Plasmodium parasites to develop resistance to
existing drugs.1-3 Attempt to control the epidemic in the future
could be based on a combination of continued development of
new drugs, prevention of infection, and development of a
vaccine.2 In the absence of an efficient vaccine the only options
are prevention and development of new drugs. In the past the
most efficient method for developing new drugs against malaria
has been design of drugs using antiplasmodial natural products
as templates.4 During our continued search for appropriate
natural products we noticed that the norneolignan (+)-nyasol
(1, Chart 1) possesses a modest antiplasmodial activity with an
IC50 value of 12 µM against a chloroquine-susceptible strain of
P. falciparum as well as a chloroquine-resistant strain.5 The
E-isomer of nyasol, hinokiresinol (2), is also naturally occur-
ring5,6 and was found to possesses some antiplasmodial activity
with an IC50 value of about 50 µM.7 Hinokiresinol was believed
to be useful as a template for development of new antiplasmodial
compounds.
chalcones as starting materials12 enabled us to take advantage
of a library of chalcones prepared as potential antiparasitic
drugs.13
Results and Discussions
Chemistry. Analogues, in which the substituents of the
aromatic rings and the side chain were changed in a systematic
way, were prepared (Table 1). Variations of the substitution
pattern were made to represent different combinations of
electron-donating and electron-withdrawing groups on the
aromatic rings, that is donating-donating (2 and a), donating-
withdrawing (b, c, and d), withdrawing-donating (e, f, g, and
h), and withdrawing-withdrawing (i and j) (Table 1).
The synthetic procedure was based on the method developed
for synthesis of hinokiresinol using chalcones as starting
materials.7 The 1,4-addition of alkylmagnesium halide and
reduction with sodium borohydride to give a mixture of the two
epimeric alcohols (7a-j, 8a-j, 9a) succeeded in all attempted
cases (Scheme 1).
The final step in the synthesis of 2 was an elimination of
water provoked by heating a methanolic solution of 7 (R2 ) R3
) R2′ ) R3′ ) R5′ ) H, R4 ) R4′) tetrahydropyranyloxy) with
hydrochloric acid.7 In all the cases 7a, 7d, and 7e, this procedure
afforded substitution of the hydroxyl group with a methoxy
group. Replacement of the hydrochloric acid with p-toluene-
sulfonic acid in toluene under reflux afforded the desired
products in the cases of compounds 10a, 11a, 10c, 11c, 10d,
10j, and 11j in yields ranging from 30% to 85% (Scheme 1).
Substitution of p-toluenesulfonic acid with acidic ion-exchange
resin Dowex 50WX8-100 enabled the elimination to give
compounds 10a, 11a, 10b, 11b, 10g, 11h, 10i, and 11i, yields
ranging from 28% to 87%. The compounds 11d-g, 10e, and
10h were not formed under acidic conditions. Application of
Martin’s sulfurane dehydrating agent15,16 under basic conditions
successfully enabled synthesis of these compounds. In two cases
Hinokiresinol and nyasol both displays a number of other
biological activities. (+)-Hinokiresinol and (-)- and (+)-nyasol
all show binding affinity for the bovine uterine estrogen receptor,
but (+)-nyasol is found to bind approximately seven times
stronger than (-)-nyasol and (+)-hinokiresinol only has a poor
affinity.8 The compounds stimulate the growth of estrogen
dependent human breast cancer cells (T47D) indicating that they
are estrogen agonists. In addition (-)-nyasol increases hex-
obarbital sleeping time in mice,9 and nyasol possesses antifungal
activity10 and inhibits testosterone 5R-reductase.11
The antiplasmodial activity of hinokiresinol7 has encouraged
us to use this compound as a template for developing new
antimalarial drugs. The choice of a synthetic protocol using
* To whom correspondence should be addressed: Tel.: +45 3530 6253.
Fax: +45 3530 6041. E-mail: sbc@dfuni.dk.
† Department of Medicinal Chemistry.
‡ Lica Pharmaceuticals, present address: Leo Pharma, Industriparken 55,
DK-2750 Ballerup, Denmark.
§ Department of Clinical Microbiology.
Department of Natural Sciences.
10.1021/jm0508235 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/01/2005

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1 437
Table 1. Structure and Antiplasmodial Activities for Compounds 10, 11, and 13a
10 IC50 ( SD
(µg/mL)
11 IC50 ( SD
(µg/mL)
13 IC50 ( SD
(µg/mL)
compd
ring A
ring B
4′-OH
4′-OH
4′-OH
2′,4′-(OCH3)2
2′,4′-(Cl)2
2′,4′-(Cl)2
3′-F
rac-2
(+)-2
(-)-2
4-OH
4-OH
4-OH
13 ( 3
14 ( 3
20 ( 6
7 ( 2
-
-
-
-
-
-
-
-
-
-
-
a
b
c
d
e
f
g
h
i
4-OCH2CHdCH2
2,4-(OCH3)2
2-CH2N(CH3)2
2,3,4-(OCH3)3
2-F
4 ( 1
6 ( 2
7 ( 1
3 ( 1
4.1 ( 0.6
3.9 ( 0.7
6 ( 2
5.4 ( 0.2
3.9 ( 0.1
4.2 ( 0.1
13 ( 4
6.0 ( 0.6
6 ( 2
3′,5′-(OCH3)2
2′,4′-(OCH3)2
2′,4′-(OCH3)2
2′,4′-(OCH3)2
4′-F
6 ( 1
2-Br
8.8 ( 0.3
7 ( 2
3 ( 1
-
6.9 ( 0.7
-
-
2,4-(F)2
2,4-(Cl)2
4-F
1.5 ( 0.1
10 ( 1
8.2 ( 0.6
j
2-CF3
2′,4′-(Cl)2
a The antiplasmodial assay was performed as previously described.14
Scheme 1a
Scheme 2a
a Reagents and conditions: (e) Et3SiH, TFA, CH2Cl2, rt, 1-48 h.
In Vitro Antiplasmodial Activity. The antiplasmodial activi-
ties of the synthesized compounds were tested in an in vitro
malaria assay against a chloroquine-sensitive strain of P.
falciparum parasites, 3D7, according to a previously described
protocol.14 Introduction of different substituents on the aromatic
rings enabled investigation of the relationships between the
substitution pattern and the antiplasmodial activity. The results
are displayed in Table 1 and Table 2. All tests were performed
three times each time in triplicate. All the analogues display
better antiplasmodial activity than hinokiresinol. Introduction
of electron-withdrawing groups in either ring A (10e, 10f, 10g,
10h) or ring B (10b, 10c, 10d) increases the activity, whereas
substitution with electron-withdrawing fluorine atoms in both
rings (10i) reduces the potency to the level of hinokiresinol.
All compounds were synthesized as racemic mixtures. No
attempts were made to separate the enantiomers of the analogues
since the enantiomers of hinokiresinol (2) showed similar
activities.7
Reduction of the terminal double bond only slightly affects
the activities since the reduced compounds in general are as
potent as or a little more potent than the parent compounds
(compare series 10 with series 11, Table 1). A noticeable
exception, however, is compounds 10h and 11h where the
unsaturated compound (10h) is almost three times as active as
the analogue with saturated side chain (11h). The poor
importance of the double bonds reveals that no specific
electrostatic interactions between the binding site and the double
bonds are determining for the affinities.
a Reagents and conditions: (a) Alkyl Grignard reagent, CuI, THF, 0 °C,
2 h; (b) NaBH4, EtOH, rt overnight; (c) p-TsOH, toluene, reflux, 1-48 h;
(d) Dowex 50WX8-100 ion-exchange resin, reflux, 2 h to 6 days; (e)
Martin’s sulfurane, Et3N, toluene, reflux, 1-48 h. The substituents R2-R5′
are given in Table 1.
(7f and 7h) the reaction of alcohols with ion-exchange resin
resulted in formation of a mixture of the diastereomeric
tetrahydrofurans 13f and 13h. In general, the compounds with
electron-withdrawing substituents in the A-ring seem less willing
to eliminate water under acidic conditions while the substitution
pattern on the B-ring appears to affect the reactivity less.
The importance of the side chain and the double bond for
the antiparasitic effect was investigated by reduction of the
double bonds and extension or removal of the side chain using
compound 10a as a template. (Scheme 2). Reduction of the
alcohols 7a, 8a, and 9a with triethylsilane and trifluoroacetic
acid afforded 14a, 15a, and 16a, respectively. Prolonged
reduction of the chalcone 3a afforded the diphenylpropane 17a
(Table 2).
A series of analogues of compound 10a was prepared for
further investigation of the importance of lipophilicity and
electrostatic interactions (Table 2). Reduction of the central
alkene without affecting the terminal alkene (14a) and reduction
of both alkenes (15a) gradually increases the activity. This
clearly indicates that lipophilic interactions rather than electro-
static interactions are responsible for the increase in potency.

438 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
Brief Articles
Table 2. Antiplasmodial Activities for 5-(4-(Allyloxy)Phenyl)-3-(2,4-
dimethoxyphenyl)Propanes Modified at C-7 and C-7′
Table 3. In Vivo Activities for Compounds 10h and 16aa
% parasitemia
compd
control
chloroquine
10h
dose (mg/kg)
mean
SD
% inhibition
0
12.4
25
100
50
34.6
1.1
14.7
14.0
17.6
25.8
2.1
0.2
3.6
2.5
4.6
1.1
0
97
57
59
49
25
16a
25
a Mice were infected with Plasmodium berghei at day 0, treated with
the test substances 10h and 16a at day 4 and 5 and the parasitemia counted
at day 5.
aged us to screen two of the most potent compounds, 10h and
16a for rabbit muscle SERCA inhibitory activity, but no
inhibition was observed up to a concentration of about 3.5 µg/
mL.
In Vivo Antimalarial Activity. The two most active
compounds, 16a and 10h, were tested for in vivo antimalarial
activity in mice infected with Plasmodium berghei using
chloroquine as a positive control. The mice were infected with
parasites at day 0. Treatment with the test compounds started
at day 4 and the parasitemia was determined after 2 days of
treatment (day 5). Both compounds significantly decreased the
parasitemia in the mice at day 5, with 10h as the most active
almost bisecting the parasitemia on day 5 by a dose of 25 mg/
kg (Table 3). Limited solubility prevented injection of a larger
dose. No apparent toxicity was observed.
Conclusion
Methods for synthesis of hinokiresinol analogues have been
developed. The potencies of the hinokiresinol analogues were
successfully improved approximately 10 times from an IC50
value of 13 µg/mL (hinokiresinol) to an IC50 value of 1.5 µg/
mL (10h) by changing the substitution pattern on the rings. The
in vitro antiplasmodial activity of hinokiresinol is determined
by lipophilic interactions rather than specific electrostatic
interactions. Further optimization based on this observation
enabled an almost seven time improvement of the IC50 value
of 7a from 16 µg/mL to an IC50 value of 16a of 2.2 µg/mL.
The most active compounds, 10h and 16a, control an infection
of P. berghei in mice. Consequently, the norneolignan skeleton
is a promising template for development of new drugs against
malaria.
The antiplasmodial assay was performed according to Ziegler et al.14
Replacement of the ethyl group with a butyl group in the 7′-
position (12a) more than doubles the potency further supporting
the importance of lipophilic interactions. The even higher
potency of 16a, in which a butyl group has been introduced
and the internal double bond has been reduced, also substantiates
the importance of lipophilic interactions. Removal of the
substituent at C-7′ (17a) decreases the activity and the analogue,
in which a polar hydroxyl group (7a) is introduced, is even less
potent. These findings confirm that the antiplasmodial activity
of the compounds in general correlates to the lipohilicity of the
aliphatic part of the molecules.
In accordance with the above observation the tetrahydrofuran
analogues (13f and 13h) were active constituting a novel and
interesting class of antiplasmodial compounds. The limited
flexibility of these compounds restricts the number of allowed
conformations. The significant activities of the tetrahydrofurans
therefore might indicate that one or more of these isomers
represent one of the active conformations of the norneolignans.
Since no protocol exists for reliable synthesis of these derivatives
and since they in both cases were formed as a complex mixture
of up to eight stereoisomers, which could not be separated even
by HPLC, this path was not followed.
Experimental Section
General. (E)-1-(4-(allyloxy)phenyl)-3-(2,4-dimethoxyphenyl)-
prop-2-en-1-one (3a),13 (E)-3-(2,4-dichlorophenyl)-1-(2,4-dimethox-
yphenyl)prop-2-en-1-one (3b),19 (E)-3-(3-fluorophenyl)-1-(2,3,4-
trimethoxyphenyl)prop-2-en-1-one (3d),13 (E)-1-(2-fluorophenyl)-
3-(3,5-dimethoxyphenyl)prop-2-en-1-one(3e),13 (E)-1-(2-bromophenyl)-
3-(2,4-dimethoxyphenyl)prop-2-en-1-one (3f),13 (E)-1-(2,4-difluoro-
phenyl)-3-(2,4-dimethoxyphenyl)prop-2-en-1-one (3g), (E)-1-(2,4-
dichlorophenyl)-3-(2,4-dimethoxyphenyl)prop-2-en-1-one (3h),19
(E)-1,3-bis(4-fluorophenyl)prop-2-en-1-one (3i),13 and (E)-3-(2,4-
dichlorophenyl)-1-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (3j)20
were prepared according to literature methods.
Chalcones (3). General Procedure. To a solution of sodium
hydroxide (3.20 mmol, 0.128 g) in EtOH (30 mL) were added
equimolar amounts of the appropriate benzaldehyde (12.8 mmol)
and the appropriate acetophenone (12.8 mmol), and the reaction
mixture was stirred at room-temperature overnight. If the product
had precipitated, the reaction mixture was filtered, and the
precipitate was washed with water and recrystallized from EtOH
or EtOH-water. If no precipitation had occurred, the reaction
mixture was diluted with water (30 mL), neutralized with 1 M HCl
and extracted four times with EtOAc (40 mL). The combined
The reported SERCA inhibitory activities of the antiplasmo-
dial drugs artemisinin17 and curcumin18 and the structural
resemblance of especially curcumin and norneolignans encour-

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1 439
organic layers were dried over Na2SO4, filtered, concentrated in
vacuo, and purified by column chromatography.
reaction mixture was cooled, filtered, and concentrated in vacuo.
The product was purified by column chromatography.
1,3-Diphenylpent-4-en-1-ones (4a-j), 1,3-diphenylpentan-1-
ones (5a-j) and 1,3-Diphenylheptan-1-ones (6a). General pro-
cedure A. Under nitrogen, a solution of vinylmagnesium bromide
(1 M solution in THF, 2.2 equiv, 7.2 mmol, 7.2 mL) was added to
a suspension of cuprous iodide (0.1 equiv, 0.33 mmol, 0.063 g) in
THF (10 mL) and cooled to 0 °C. The reaction mixture was stirred
for 15 min at 0 °C. A solution of the appropriate chalcone (3) (1
equiv, 3.3 mmol) in THF (10 mL) was added to the reaction
mixture. Stirring was continued at 0 °C for 2 h. The reaction mixture
was quenched with saturated NH4Cl solution. The reaction mixture
was diluted with Et2O (75 mL) and was successively washed with
water (2 × 75 mL) and brine (75 mL). The organic layer was dried
over Na2SO4, filtered, and concentrated in vacuo. The product was
purified by column chromatography.
General Procedure B Under nitrogen, a solution of ethylmag-
nesium chloride (25% w/w solution in THF, 2.2 equiv, 7.2 mmol,
2.49 mL) was added to a suspension of cuprous iodide (0.1 equiv,
0.33 mmol, 0.063 g) in THF (10 mL) and cooled to 0 °C. The
reaction mixture was stirred for 15 min at 0 °C. A solution of the
appropriate chalcone (3) (1 equiv, 3.3 mmol) in THF (10 mL) was
added to the reaction mixture. Stirring was continued at 0 °C for 2
h. The reaction was quenched with saturated NH4Cl solution. The
reaction mixture was diluted with Et2O (75 mL) and was succes-
sively washed with water (2 × 75 mL) and brine (75 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated in
vacuo. The product was purified by column chromatography.
General Procedure C. Under nitrogen, a solution of n-
butylmagnesium chloride (20% w/w solution in THF/toluene, 2.2
equiv, 6.8 mmol, 3.96 g) was added to a suspension of cuprous
iodide (0.1 equiv, 0.31 mmol, 0.059 g) in THF (10 mL) and cooled
to 0 °C. The reaction mixture was stirred for 15 min at 0 °C. A
solution of the appropriate chalcone (3) (1 equiv, 3.1 mmol) in
THF (10 mL) was added to the reaction mixture. Stirring was
continued at 0 °C for 2 h. The reaction was quenched with saturated
NH4Cl solution. The reaction mixture was diluted with Et2O (75
mL) and was successively washed with water (2×75 mL) and brine
(75 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo. The product was purified by column
chromatography.
1,3-Diphenylpent-4-en-1-ols (7a-j), 1,3-Diphenylpentan-1-ols
(8a-j), and 1,3-Diphenylheptan-1-ols (9a). General Procedure.
The appropriate 1,3-diphenylpent-4-en-1-one (4, 1 equiv, 2.5 mmol)
or 1,3-diphenylpentan-1-one (5, 1 equiv, 2.5 mmol) or 1,3-
diphenylheptan-1-one (6, 1 equiv, 2.5 mmol) was dissolved in EtOH
(20 mL). NaBH4 (5 equiv, 12.4 mmol, 0.469 g) was added. After
stirring overnight at room temperature 5% NaOH solution (100 mL)
was added, and the mixture was extracted with Et2O (2 × 100 mL).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The product was purified by column
chromatography.
(E)-1,3-Diphenylpenta-1,4-dienes (10a-j), (E)-1,3-Diphenyl-
pent-1-enes (11a), (E)-1,3-Diphenylhept-1-enes (12a), and 5-Phen-
yl-tetrahydro-3-phenyl-2-methylfurans (13f and 13h). General
Procedure D for Synthesis of 10a, 10c, 10d, 10j, 11a, 11c, 11j.
The appropriate alcohol (7, 8, or 9) (1 equiv, 0.42 mmol) was
dissolved in toluene (6 mL). p-Toluenesulfonic acid monohydrate
(0.1 equiv, 0.04 mmol, 0.008 g) was added. The reaction flask,
equipped with Dean-Stark trap, was heated to reflux, and the
reaction mixture was stirred under reflux for 1 h to 48 h. The
reaction mixture was cooled and diluted with Et2O (15 mL). The
mixture was washed successively with water (2 × 15 mL) and brine
(15 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo. The product was purified by column
chromatography.
General Procedure F for Synthesis of 10e, 10f, 10h, 11d, 11e,
11f, 11g. The appropriate alcohol (7, 8 or 9) (1 equiv, 0.26 mmol)
was dissolved in toluene (50 mL). Et3N (5 mL) was added, and
the reaction mixture was heated to reflux. Martin’s sulfurane (2.5
equiv to 5 equiv, 0.66 mmol to 1.32 mmol, 0.44 g to 0.89 g) was
added, and the reaction mixture was stirred under reflux for 1 h to
48 h. The reaction mixture was cooled, and saturated NaHCO3
solution (50 mL) was added. The layers were separated, and the
aqueous layer was extracted with Et2O (2 × 25 mL). The combined
organic layers were washed with brine (50 mL), dried over Na2-
SO4, filtered, and concentrated in vacuo. The product was purified
by column chromatography.
3,5-Diphenylpent-1-ene (14a), 1,3-Diphenylpentane (15a), 1,3-
Diphenylheptane (16a), and 1,3-Diphenylpropane (17a). General
Procedure G. Ketone or alcohol (0.42 mmol) was dissolved in
TFA (3 mL) under nitrogen. Et3SiH (2.2 equiv, 0.93 mmol, 0.15
mL) was added, and the reaction mixture was stirred at room
temperature for 1.5 to 4.5 h. The reaction mixture was concentrated
in vacuo and was diluted with EtOAc (15 mL). The mixture was
successively washed with 1 M NaOH solution (15 mL) and brine
(15 mL). The organic layer was dried with Na2SO4, filtered, and
concentrated in vacuo. The product was purified by column
chromatography.
General Procedure H. As procedure G, but using CH2Cl2 as
solvent (4 mL), catalytic amount of TFA (0,1 mL) and 20 equiv of
Et3SiH (8.5 mmol, 1.35 mL). Stirring at room temperature for 20
h to 48 h.
In Vitro Antiplasmodial Screening. A Desjardin’s radioisotope
method for measuring the growth of a chloroquine sensitive strain
of Plasmodium falciparum (3D7) modified according to Ziegler et
al. was adopted.14 In shortly 50 µL of growth medium (RPMI 1640
with HEPES and supplemented with 0.45% Albumax II, 1.42 mM
L-glutamine, 133 µM hypoxanthine and 44 mg of gentamicine
sulfate/mL) containing test substances added from a dimethyl
sulfoxide (DMSO) stock was mixed with 50 µL of a suspension of
parasitized erythrocytes (blood type 0, hematocrit 5%; parasitemia
2 to 3%). The maximum final DMSO concentration in the growth
medium was 0.5%. The test samples were incubated for 24 h at 37
°C in an atmosphere consisting of 93% of nitrogen, 5% of carbon
dioxide, and 2% of oxygen. The incubation was continued for
additional 24 h after addition of a solution of [3H]phenylalanine
(25 µL, 1.6 MBq/mL). The cells were harvested on a filter plate,
and the incorporated [3H]phenylalanine counted in a scintillation
counter. Each compound was tested three times each time in
triplicate.
In Vivo Antimalarial Screening. Thirty NMRI mice were
allocated into six groups of each five mice. At day 0 red blood
cells (1×106) infected with Plasmodium berghei K173 and sus-
pended in 0.2 mL of inoculation solution (0.9% saline solution)
were injected in each mouse. At day 4, when the parasitemia was
2-9%, five of the groups of mice were injected ip with the dose
given in Table 3 dissolved in 0.9% of saline added 10% of Tween
80, pH adjusted to 4.5. In the control group two mice were not
treated at all, whereas the remaining three mice were injected with
the vehicle. The parasitemia was determined on day 5 in a blood
sample taken from the tail vein. One drop was placed on an object
glass and stained with Giesma, and the number of infected blood
cells were counted under a microscope.
Acknowledgment. This work was supported by the Danish
Ministry of Science Technology and Innovation. Dorte Brix has
performed the antiplasmodial screening.
General Procedure E for Synthesis of 10a, 10b, 10g, 10i, 11a,
11b, 11h, 11i, 12a, 13f, 13h. Alcohol (7, 8, or 9) (1 equiv, 0.36
mmol) was dissolved in toluene (10 mL). Dowex 50WX8-100
ion-exchange resin (7 mL), washed with toluene, was added, and
the reaction mixture was stirred under reflux for 2 h to 6 days. The
Supporting Information Available: Detailed experimental
procedures for the syntheses and NMR and HRMS spectra for the
new compounds are described. This material is available free of
charge via the Internet at http://pubs.acs.org.

440 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
Brief Articles
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