Preparation of new anti-tubulin ligands through a dual-mode, addition-elimination reaction to a bromo-substituted α,β-unsaturated sulfoxide

Full text of DOI:10.1021/jo0004761

J . Org. Chem. 2000, 65, 8811-8815
8811
P r ep a r a tion of New An ti-Tu bu lin Liga n d s
th r ou gh a Du a l-Mod e,
Ad d ition -Elim in a tion Rea ction to a
Br om o-Su bstitu ted r,â-Un sa tu r a ted
Su lfoxid e
Zhi Chen,† Vani P. Mocharla,† J . Matt Farmer,†
George R. Pettit,‡ Ernest Hamel,§ and
Kevin G. Pinney*,†
F igu r e 1. Combretastatin A-4 (CA-4) and the CA-4 Prodrug.
Department of Chemistry and Biochemistry, P.O. Box 97348,
Baylor University, Waco, Texas 76798, Cancer Research
Institute and Department of Chemistry, Arizona State
University, Tempe, Arizona 85287-1604, and Screening
Technologies Branch, Developmental Therapeutics Program,
Division of Cancer Treatment and Diagnosis, National
Cancer Institute, Frederick Cancer Research and
Development Center, Frederick, Maryland 21702
Kevin_Pinney@Baylor.edu
Received March 29, 2000
In tr od u ction
The heralded success of the natural product combreta-
statin A-4 (CA-4)1 as an antimitotic agent and its prodrug
disodium phosphate salt construct (CA-4P) (Figure 1) as
a tumor vasculature targeting agent2 has led to the
preparation of a diverse set of anti-tubulin ligands
designed to mimic CA-4 (Figure 2).3 Our recent discov-
ery11 of a synthetic benzo[b]thiophene ligand that dem-
onstrates strong antimitotic activity, coupled with the
* To whom correspondence should be addressed. Tel: 254-710-4117.
Fax:, 254-710-2403.
F igu r e 2. Representative synthetic anti-tubulin polymeriza-
tion inhibitors.
† Baylor University.
‡ Arizona State University.
§ National Cancer Institute.
activity of benzo[b]thiophene analogues as selective
estrogen receptor modulators (SERMs)10 and the discov-
ery of diaryl ether analogues of CA-412,13 (Figure 3),
provided incentive for our current investigation of the
preparation of new anti-tubulin ligands 1 and 2 by 1,4
and 1,2 addition-elimination reactions to a bromo-
substituted, R,â-unsaturated sulfoxide.
We were intrigued by the idea of replacing the carbonyl
group of the benzo[b]thiophene antimitotic ligand (Figure
3) with an oxygen atom in order to study the effects of
substitution at the 3-position. This oxygen variation also
serves as a further evaluation of the apparent require-
(1) (a) Lin, C. M.; Ho, H. H.; Pettit, G. R.; Hamel, E. Biochemistry
1989, 28, 6984. (b) Pettit, G. R.; Cragg, G. M.; Singh, S. B. J . Nat.
Prod. 1987, 50, 386. (c) Pettit, G. R.; Singh, S. B.; Cragg, G. M. J . Org.
Chem. 1985, 50, 3404. (d) Pettit, G. R.; Cragg, G. M.; Herald, D. L.;
Schmidt, J . M.; Lohavanijaya, P. Can. J . Chem. 1982, 60, 1374.
(2) (a) Chaplin, D. J .; Pettit, G. R.; Hill, S. A. Anticancer Res. 1999,
19, 189. (b) Dark, G. G.; Hill, S. A.; Prise, V. E.; Tozer, G. M.; Pettit,
G. R.; Chaplin, D. J . Cancer Res. 1997, 57, 1829. (c) Iyer, S.; Chaplin,
D. J .; Rosenthal, D. S.; Boulares, A. H.; Li, L.-Y.; Smulson, M. E. Cancer
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Des. 1998, 13, 183. (e) Tozer, G. M.; Prise, V. E.; Wilson, J .; Locke, R.
J .; Vojnovic, B.; Stratford, M. R. L.; Dennis, M. F.; Chaplin, D. J . Cancer
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Int. J . Radiat. Oncol., Biol., Phys. 1998, 42, 891. (h) Beauregard, D.
A.; Thelwall, P. E.; Chaplin, D. J .; Hill, S. A.; Adams, G. E.; Brindle,
K. M. Br. J . Cancer 1998, 77, 1761.
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K.; Cullinan, G. J .; Pell, T. R.; Bryant, H. U. J . Med. Chem. 1997, 40,
1407. (b) J ones, C. D.; J evnikar, M. G.; Pike, A. J .; Peters, M. K.; Black,
L. J .; Thompson, A. R.; Falcone, J . F.; Clemens, J . A. J . Med. Chem.
1984, 27, 1057. (c) Schmid, C. R.; Sluka, J . P.; Duke, K. M. Tetrahedron
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P.; Pettit, G. R.; Bai, R.; Hamel, E. Bioorg. Med. Chem. Lett. 1999, 9,
1081.
(3) Hamel, E. Med. Chem. Rev. 1996, 16, 207.
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M. R.; Hamel, E.; Pettit, R. K. J . Med. Chem. 1998, 41, 1688.
(5) J onnalagadda, S. S.; ter Haar, E.; Hamel, E.; Lin, C. M.;
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10.1021/jo0004761 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/21/2000

8812 J . Org. Chem., Vol. 65, No. 25, 2000
Notes
primarily a dibrominated product (carbon positions 3 and
7) was obtained under these conditions. We therefore
evaluated the reaction both at room temperature and at
0 °C. The reaction was followed by GC, and dibromination
was observed even at room temperature. However, at 0
°C, a 90-94% yield of the monobrominated product 4 was
obtained. The difference in results could be caused by our
scaling down the reaction from 28 g10a to 10.5 g. The
monobromide 4 was oxidized with hydrogen peroxide in
the presence of trifluoroacetic acid to yield sulfoxide 5.10a
Use of excess hydrogen peroxide resulted in formation
of the corresponding sulfone. The bromosulfoxide 5 upon
treatment with 3,4,5-trimethoxyphenoxide, formed from
the corresponding phenol with NaH, gave the aryloxy-
substituted sulfoxide 6, which was subsequently reduced
with lithium aluminum hydride to afford the desired
diaryl ether 1.
Interestingly, upon treatment with 3,4,5-trimethoxy-
phenyl cuprate, the bromo-sulfoxide 5 underwent 1,2-
addition (rather than the anticipated 1,4 addition-
elimination) followed by ring opening and concomitant
elimination of bromide to form an alkyne derivative (10,
Scheme 2). To our knowledge, this is the first observation
of this type of 1,2-addition-ring-opening reaction in a
bromobenzo[b]thiophene sulfoxide. Following treatment
with LiAlH4, the corresponding sulfide analogue 2 was
obtained in good yield. Although spectroscopic analysis
strongly supported the structure assigned as alkyne 10,
we obtained an X-ray crystallographic analysis in order
to confirm the structure. Crystals of 10 suitable for X-ray
diffraction were obtained from a solution of hexanes/ethyl
acetate (60/40). Energy minimization14 of 10 predicts a
very similar structure as a low energy conformer. For the
formation of alkyne 10, we propose a mechanism that
involves initial attack of the cuprate at the sulfoxide
center to form a tetrahedral intermediate (Figure 4).
Collapse of the tetrahedral intermediate forces the five-
membered ring of the benzo[b]thiophene skeleton to open,
allowing the formation of a triple bond upon loss of the
F igu r e 3. Structural models for the preparation of analogues
1 and 2.
ment of sp2 hybridization of bridge atoms between the
two aryl rings, which seems important for compounds to
display maximal affinity for the colchicine binding site
on â-tubulin.
Resu lts a n d Discu ssion
The synthetic strategy shown in Scheme 1 (cf. ref 10)
was employed for the preparation of the new aryloxy
analogue 1 designed for tubulin binding. Although treat-
ment of thiophene 3 with Br2 has been reported to yield
thiophene 4 in chloroform at 60 °C,10a in our hands
Sch em e 1. Syn th esis of Dia r yl Eth er 1 by a 1,4-Ad d ition -Elim in a tion Rea ction

Notes
J . Org. Chem., Vol. 65, No. 25, 2000 8813
Sch em e 2. Syn th esis of Su lfid e 2 by a 1,2-Ad d ition -Elim in a tion Rin g-Op en in g Rea ction
Ta ble 1. In Vitr o Hu m a n Ca n cer Cell Lin e Stu d y of
Ben zo[b]th iop h en e An a logu es 1 a n d 6 a n d Alk yn es 2 a n d
10a
GI50 (µg/mL)b
BXPC-3 SK-N-SH SW1736 NCI-H460 FADU
DU-145
no. pancreas neuroblast thyroid lung-NSC pharynx prostate
1
2
6
0.23
0.33
2.1
0.063
NDc
1.9
0.73
ND
3.7
0.31
0.38
3.2
0.098
ND
3.4
0.42
0.39
7.3
10
3.7
ND
ND
4.2
ND
4.0
a
b
See ref 16. GI50 values are reported as concentrations in µg/
mL. c ND, not determined.
erization18 and was found to have an IC50 ) 0.88 ( 0.1
(S.D.) µM, which qualifies this ligand as a strong inhibi-
tor. In contemporaneous experiments, CA-4 yielded an
IC50 value of 1.0 ( 0.05 µM.
Compound 2 yielded an average GI50 value of 7.79 ×
10-7 M.16 When evaluated as a potential inhibitor of
tubulin polymerization, compound 2 yielded an IC50 value
of 3.0 ( 1.0 µM. Finally, compounds 6 and 10 were
essentially inactive as inhibitors of tubulin assembly (IC50
values > 40 µM).
F igu r e 4. Proposed mechanism for the formation of alkyne
10.
Con clu sion s
We have prepared two new anti-tubulin ligands 1 and
2 from a 1,4-addition-elimination reaction and a 1,2-
addition-ring-cleavage reaction, respectively, on a bromo-
substituted benzo[b]thiophene S-oxide precursor. This
dual mode of reactivity is understandable based on the
hard/soft nature of the two nucleophiles compared with
the hard/soft environment of the carbon terminus of the
R,â-unsaturated sulfoxide versus the sulfur atom of the
sulfoxide. The ligands were evaluated for their activity
against human cancer cell lines and as inhibitors of
tubulin polymerization. The compounds had similar
strong cytoxic activity. Aryl ether 1 strongly inhibited
tubulin polymerization and has recently been selected for
initial in vivo evaluation by the NCI in their hollow fiber
assay. Alkynyl sulfide 2 was about 3-4 times less active
than 1 as an inhibitor of tubulin polymerization.
bromine atom. This dual mode of 1,2 versus 1,4 attack
may be rationalized by considering the favorable interac-
tion of the hard nucleophilic oxygen anion with the hard
carbon terminus of the R,â-unsaturated sulfoxide com-
pared to the interaction of the relatively soft cuprate
nucleophile with the soft sulfoxide moiety.15
Biologica l Eva lu a tion . The four new compounds 1,
2, 6, and 10 were evaluated for their in vitro cytotoxicity
against human cancer cell lines (Table 1).16 Aryloxybenzo-
[b]thiophene 1 displays the most pronouced cytotoxicity
of the group. This compound was further evaluated
against the NCI 60 cell line panel,17 in which it demon-
strated an average GI50 ) 4.90 × 10-7 M. For comparison,
CA-4 showed an average GI50 ) 2.96 × 10-8 M against
the same NCI cell line panel. Aryl ether ligand 1 was
further evaluated for its ability to inhibit tubulin polym-
Exp er im en ta l Section
Gen er a l Meth od s. Proton (1H) and carbon (13C) NMR were
(14) Chem3D (version 3.5.1) by CambridgeSoft Corp.
(15) Ho, T.-L. Chem. Rev. 1975, 75, 1.
(16) Initial cytotoxicity studies were carried out in the laboratory
of Professor George R. Pettit (Cancer Research Institute, Arizona State
University) using the NCI experimental protocols as delineated in ref
17.
obtained at 300 and 75 MHz or 90 MHz, respectively, in the
(18) Verdier-Pinard, P.; Lai, J .-Y.; Yoo, H.-D.; Yu, J .; Marquez, B.;
Nagle, D. G.; Nambu, M.; White, J . D.; Falck, J . R.; Gerwick, W. H.;
Day, B. W.; Hamel, E. Mol. Pharmacol. 1998, 53, 62.
(17) Boyd, M. R.; Paull, K. D. Drug Dev. Res. 1995, 34, 91.

8814 J . Org. Chem., Vol. 65, No. 25, 2000
Notes
solvent indicated. Chemical shifts are expressed in ppm (δ).
Elemental analyses were carried out by Atlantic Microlab Inc.
(Norcross, GA) and are within (0.4% of the theoretical values
unless otherwise indicated. All reagents and solvents were
obtained from commercial sources and used without further
purification unless indicated. Lithium cuprate reactions requir-
ing an inert atmosphere were conducted under dry nitrogen, and
the glassware was oven dried at 120 °C. Tetrahydrofuran (THF)
was distilled from potassium, and methylene chloride (CH2Cl2)
was distilled from calcium hydride (CaH2) immediately prior to
use. Silica gel for flash chromatography was purchased from
Merck EM Science (300-450 mesh), and compounds were
visualized on analytical thin-layer chromatograms (TLC) by UV
light (254 nm).
In h ibition of Tu bu lin P olym er iza tion . The tubulin po-
lymerization assays were performed as described previously,18
except that Beckman DU7400/7500 spectrophotometers equipped
with “high performance” temperature controllers were used.
Unlike the manual control possible with the previously used
Gilford spectrophotometers, the polymerization assays required
use of programs provided by MDB Analytical Associates, South
Plainfield, NJ , since the Beckman instruments are microproces-
sor controlled. The Beckman instruments were unable to
maintain 0 °C, and the lower temperature in the assays
fluctuated between 2 and 4 °C. Temperature changes were,
however, more rapid than in the Gilford instruments with the
jump from the lower temperature to 30 °C taking about 20 s
and the reverse jump about 100 s.
2-(4′-Me t h o x y p h e n y l)-3-b r o m o -6-m e t h o x y b e n zo [b ]-
th iop h en e (4). A solution of bromine (6.20 g, 38.8 mmol) in
CHCl3 (50 mL) was added dropwise to a solution of 6-methoxy-
2-(4′-methoxyphenyl)benzo[b]thiophene 310b (10.5 g, 38.8 mmol)
in CHCl3 (300 mL) at room temperature. After the addition was
complete, the reaction was stirred at room temperature for 0.5
h, and GC was employed to monitor the reaction progress (GC
conditions: 200° C to 270 °C, 10 °C/min). The reaction mixture
was concentrated in vacuo to provide 2-(4′-methoxyphenyl)-3-
bromo-6-methoxybenzo[b]thiophene 4 (12.7 g, 36.4 mmol, 94%):
mp 83-85 °C; 1H NMR (CDCl3, 300 MHz) δ 3.87 (s, 3H), 3.40
(s, 3H), 7.00 (m, 2H), 7.07 (dd, J ) 8.9, 2.3 Hz, 1H), 7.65-7.75
(m, 4H).
3H), 3.76 (s, 3H), 3.75 (s, 6H). Anal. Calcd for C25H24O7S: C,
64.09; H, 5.16; S, 6.84. Found: C, 63.89; H, 5.21; S, 6.69.
2-(4′-Met h oxyp h en yl)-3-(3′,4′,5′-t r im et h oxyp h en oxy)-6-
m eth oxyben zo[b]th iop h en e (1). To an ice-cooled, well-stirred
solution of 3-(3′,4′,5′-trimethoxyphenoxy)-2-(4′-methoxyphenyl)-
6-methoxybenzo[b]thiophene S-oxide 6 (0.900 g, 1.92 mmol) in
THF (20 mL) was added lithium aluminum hydride (0.077 g,
2.03 mmol). After 3 h, the reaction was terminated with water
followed by an extraction/washing sequence with ethyl acetate,
brine, and drying over MgSO4. Removal of the solvent followed
by purification by flash chromatography (80:20 hexanes/EtOAc)
resulted in benzo[b]thiophene 1 (0.585 g, 1.29 mmol, 67%) as a
1
colorless solid: mp 129-131 °C; H NMR (CDCl3, 300 MHz) δ
7.66 (d, J ) 8.9 Hz, 2H), 7.31 (d, J ) 8.7 Hz, 1H), 7.25 (d, J )
2.2 Hz, 1H), 6.91 (d, J ) 9.0 Hz, 2H), 6.90 (dd, J ) 8.8, 2.3 Hz,
1H), 6.21 (s, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.71 (s,
6H); 13C NMR (CDCl3, 90 MHz) δ 159.2, 157.9, 154.1, 153.8,
139.0, 136.7, 133.1, 128.7, 128.0, 126.8, 124.9, 122.1, 114.3, 114.3,
105.3, 93.2, 61.0, 56.1, 55.6, 55.3; HRMS (EI) M+ calcd for
C25H24O6S 452.1248, found 452.1294. Anal. Calcd for
C
25H24O6S: C, 66.36; H, 5.35; S, 7.08. Found: C, 66.06; H, 5.42;
S, 7.08.
1-Br om o-3,4,5-tr im eth oxyben zen e (8).19 3,4,5-Trimethoxy-
aniline (7.33 g, 40.0 mmol) and tert-butylnitrite (6.88 g, 90%
technical grade, 60.0 mmol) were added to a solution of cupric
bromide (10.7 g, 48.0 mmol) in acetonitrile (160 mL) under dry
nitrogen. After the mixture was stirred for 10 min at 0 °C, the
temperature was raised to room temperature for 2 h. HCl (50
mL, 10%) was added, and the mixture was partitioned between
CH2Cl2 and a saturated NaCl solution (150 mL each). The
organic layer was washed once with a saturated NaCl solution,
dried with anhydrous sodium sulfate, and concentrated in vacuo
to obtain a solid that was purified by trituration with hexane.
Bromide 8 was obtained after filtration as a colorless solid (5.90
1
g, 23.9 mmol, 60%): mp 78-79 °C; H NMR (CDCl3, 300 MHz)
δ 3.84 (s, 3H), 3.86 (s, 6H), 6.75 (s, 2H).
1,2-B is (4′-m e t h o x y p h e n y l)-2′-(3′′,4′′,5′′-t r im e t h o x y -
p h en ylt h ioet h er )et h yn e S-Oxid e (10). A solution of 3,4,5-
trimethoxyphenylbromide 8 (2.47 g, 10.0 mmol) in ether (20 mL)
was added to a solution of n-butyllithium (8 mL, 2.5 M in hexane
solution, 20 mmol) in dry ether (100 mL) under dry nitrogen at
-78 °C. The solution was stirred for 1 h in order to form 3,4,5-
trimethoxyphenyllithum. This solution was added slowly to a
solution of copper iodide (0.952 g, 5.00 mmol) in dry ether (50
mL) at -23 °C. The mixture was stirred for 1 h to complete
formation of the cuprate reagent. Thiophene S-oxide 5 (0.913 g,
2.50 mmol) was added to the cuprate solution at -23 °C, and
stirring was continued for 12 h (-23 °C to rt). HCl (20 mL, 10%)
was added, and the mixture was partitioned between CH2Cl2
and a saturated NaCl solution. The organic layer was washed
with water, dried over anhydrous sodium sulfate, and after
filtration, the organic layer was concentrated in vacuo to provide
alkyne 10 as a yellow oil (1.20 g). Purification by column
chromatography afforded 1,2-bis(4′-methoxyphenyl)-2′-(3′′,4′′,5′′-
trimethoxyphenylthioether)ethyne S-oxide (10, 0.50 g, 1.11
mmol, 44%) as a colorless solid: mp 128-129 °C; 1H NMR
(CDCl3, 300 MHz) δ 3.69 (s, 6H), 3.81 (s, 3H), 3.85 (s, 3H), 3.91
(s, 3H), 6.90-6.96 (m, 3H), 7.07 (s, 2H), 7.43-7.48 (m, 3H), 7.57
(d, J ) 2.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 55.4, 55.8,
56.1, 60.8, 96.2, 101.9, 107.5, 112.6, 114.2, 114.6, 117.4, 132.9,
133.9, 140.1, 148.8, 153.7, 160.0, 160.5; HRMS (EI) M+ calcd
2-(4′-Me t h o x y p h e n y l)-3-b r o m o -6-m e t h o x y b e n zo [b ]-
th iop h en e S-Oxid e (5). To a solution of 3-bromo-2-(4′-meth-
oxyphenyl)-6-methoxybenzo[b]thiophene 4 (7.00 g, 20.0 mmol)
in anhydrous CH2Cl2 (50 mL) was added trifluoroacetic acid (50
mL). After 5 min of stirring, H2O2 (2.30 mL, 20.0 mmol, 30%
aqueous solution) was added. The resulting mixture was stirred
at room temperature for 2 h. Solid sodium bisulfite (1.00 g) was
added to the dark solution followed by H2O (15 mL). The mixture
was partitioned between CH2Cl2 and a saturated NaHCO3
solution (150 mL each). The layers were separated, and the
organic layer was extracted sequentially with saturated NaHCO3
and saturated NaCl solutions. The organic layer was dried by
anhydrous sodium sulfate and concentrated in vacuo to a solid
that was triturated with EtOAc. The crude product was obtained
after filtration as a yellow solid, which was recrystallized from
EtOAc to afford sulfoxide 5 (5.50 g, 15.1 mmol, 75%): mp 170-
1
173 °C; H NMR (CDCl3, 300 MHz) δ 3.87(s, 3H), 3.91 (s, 3H),
7.03 (d, J ) 8.9 Hz, 2H), 7.12 (dd, J ) 8.5, 2.3 Hz, 1H), 7.48-
7.56 (m, 2H), 7.78 (d, J ) 8.8 Hz, 2H).
2-(4′-Met h oxyp h en yl)-3-(3′,4′,5′-t r im et h oxyp h en oxy)-6-
m eth oxyben zo[b]th iop h en e S-Oxid e (6). To a well-stirred
solution of 3,4,5-trimethoxyphenol (0.514 g, 2.79 mmol) in DMF
(10 mL) was added NaH (0.103 g, 4.29 mmol). After the solution
was stirred at room temperature for 15 min, 3-bromo-2-(4′-
methoxyphenyl)-6-methoxybenzo[b]thiophene S-oxide 5 (1.25 g,
3.42 mmol) was added. After 2 h, the reaction mixture was
partitioned between an ethanol-ethyl acetate (10:90) mixture
and water. The aqueous phase was extracted three times with
an ethanol/ethyl acetate (10%) solution. The organic layer was
washed with water (five times), followed by brine, and dried over
MgSO4. Evaporation of the solvent gave a dark colored oil.
Trituration of the residue with an ether/hexane mixture resulted
in sulfoxide 6 as a yellow fluffy solid (1.15 g, 2.46 mmol, 88%):
1H NMR (CDCl3, 300 MHz) δ 7.65 (d, J ) 8.9 Hz, 2H), 7.34 (d,
J ) 2.3 Hz, 1H), 7.22 (d, J ) 8.5 Hz, 1H), 6.99 (dd, J ) 8.6, 2.4
Hz, 1H), 6.86 (d, J ) 8.9, 2H), 6.29 (s, 2H), 3.89 (s, 3H), 3.79 (s,
for
C25H24O6S 452.1248, found 452.1294. Anal. Calcd for
C25H24O6S: C, 66.36; H, 5.35; S, 7.08. Found: C, 66.20; H, 5.24;
S, 7.14.
1,2-B is (4′-m e t h o x y p h e n y l)-2′-(3′′,4′′,5′′-t r im e t h o x y -
ph en ylth ioeth er )eth yn e (2). Lithium aluminum hydride (0.038
g, 1.00 mmol) was added to the solution of 1,2-bis-(4′-methoxy-
phenyl)-2′-(3′′,4′′,5′′-trimethoxyphenylthioether)ethyne S-oxide
(10, 0.45 g, 1.0 mmol) in anhydrous THF (20 mL) under dry
nitrogen at 0 °C. After being stirred at 0 °C for 1 h, HCl (10 mL,
10%) was added, and the mixture was partitioned between CH2-
Cl2 and a saturated NaCl solution. The organic layer was washed
with water and dried with anhydrous sodium sulfate. The reside
(19) Getahun, Z.; J urd, L.; Chu, P. S.; Lin, C. M.; Hamel, E. J . Med.
Chem. 1992, 35, 1058.

Notes
J . Org. Chem., Vol. 65, No. 25, 2000 8815
(0.500 g) was purified by column chromatography to afford
sulfide 2 (0.400 g, 0.917 mmol, 92%) as a colorless solid: mp
117-118 °C; 1H NMR (CDCl3, 300 MHz) δ 3.70 (s, 3H), 3.82 (s,
3H), 3.83 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 6.47 (d, J ) 2.5 Hz,
1H), 6.67 (dd, J ) 8.5, 2.5 Hz, 1H), 6.81 (s, 2H), 6.87 (d, J ) 8.7
Hz, 2H), 7.43 (d, J ) 8.5 Hz, 1H), 7.47 (d, J ) 8.7 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) δ 55.7, 56.6, 61.4, 85.8, 94.9, 111.2, 111.9,
113.3, 114.3, 127.1, 133.3, 133.8, 143.2, 154.2, 160.1; HRMS (EI)
M+ calcd for C25H24O5S 436.1258, found 436.1344. Anal. Calcd
for C25H24O5S: C, 68.79; H, 5.54; S, 7.34. Found: C, 68.76; H,
5.61; S, 7.28.
Arizona Disease Control Research Commission, Out-
standing Investigator Grant CA-44344-06-11 awarded
by the DCTD, National Cancer Institute, DHHS, and
Drs. J -C. Chapuis, F. Hogan, and J . M. Schmidt. The
authors thank Mr. Tori M. Strong for his assistance with
a scale-up synthesis of diaryl ether 1 and Mr. J ason
Kautz for his assistance with the X-ray analysis.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of 1, 2, 6, and 10. An ORTEP diagram and tables
of crystallographic data for alkyne 10. This information is
available free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. K.G.P. thanks The Robert A.
Welch Foundation (Grant No. AA-1278), Baylor Uni-
versity, and Baylor University Research Committee for
financial support of this project. G.R.P. thanks The
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