Solid-phase synthesis and biological activity of a combinatorial cross-conjugated dienone library

Article abstract of DOI:10.1002/chem.200500793

The solid-phase synthesis of a combinatorial cross-conjugated dienone library based on the structure of clavulones and their biological activity are reported. Clavulones are a family of marine prostanoids, and are composed of a cross-conjugated dienone sy

Full text of DOI:10.1002/chem.200500793

DOI: 10.1002/chem.200500793
Solid-Phase Synthesis and Biological Activity of a Combinatorial
Cross-Conjugated Dienone Library
[
a, c]
[a]
[a]
[b, d]
Makoto Kitade,
Hiroshi Tanaka, Sho Oe, Makoto Iwashima,
[a]
[
b]
Kazuo Iguchi, and Takashi Takahashi*
Abstract: The solid-phase synthesis of
a combinatorial cross-conjugated dien-
one library based on the structure of
clavulones and their biological activity
are reported. Clavulones are a family
of marine prostanoids, and are com-
posed of a cross-conjugated dienone
system bearing two alkyl side-chains.
The cross-conjugated dienone system
irreversibly reacted with two nucleo-
philes. Our strategy for the solid-phase
synthesis of the cross-conjugated dien-
ones involves the Sonogashira-coupling
reaction of a solid-supported cyclopen-
tenone 10 bearing an acetylene group,
74desired compounds from 98 candi-
dates, and were detected by their mass
spectra. Antiproliferative effects of the
crude compounds against HeLaS3 cells
showed that eleven samples showed
strong antitumor activity (IC <
0.05 mm). Further biological examina-
tion of four purified compounds by
using five tumor cell lines (A549,
HeLaS3, MCF7, TMF1, and P388) re-
vealed strong cytotoxicity comparable
to that of adriamycin.
followed by aldol condensation with al-
dehydes. The diphenyl derivative 7aA
was prepared from the solid-supported
cyclopentenone 10 in 56% total yield.
Combinatorial synthesis of a small li-
brary using twelve halides and eight al-
dehydes resulted in the production of
50
Keywords:
chemical biology
combinatorial
alkylation
·
·
·
·
clavulone
chemistry
prostanoids · solid-phase synthesis
Introduction
Biologically active natural products have served as effective
biochemical probes for the discovery of not only new drug
[
a] M. Kitade, Dr. H. Tanaka, S. Oe, Prof. Dr. T. Takahashi
Department of Applied Chemistry
[1,2]
targets but also new biomarkers.
The synthesis of small
Graduate School of Science and Engineering
Tokyo Institute of Technology
molecules based upon the structure of biologically active
natural products would be an effective and promising way
2
-12-1 Ookayama, Meguro, Tokyo 152-8552 (Japan)
[3,4]
for the identification of new biochemical probes.
Combi-
Fax : (+81)3-5734-2884
natorial chemistry can assist the high-speed synthesis of
these focused libraries. The combinatorial approach might
not be an economic route when compared with the tradi-
tional approach based on elucidating the best fragment at
each diverse site because fully combinatorial libraries con-
tain many redundant compounds. However, in the tradition-
al approach the compounds composed of the best fragments
would not often exhibit the strongest biological activity in
cell-based assay since the cell permeability of the small mol-
ecules would largely influence their biological activity.
E-mail: ttak@apc.titech.ac.jp
[
b] Dr. M. Iwashima, Prof. Dr. K. Iguchi
Faculty of Life Science
Tokyo University of Pharmacy and Life Science
1
432-1, Horinouchi, Hachioji, Tokyo, 192-0392 (Japan)
[
c] M. Kitade
Current address:
Cancer Research Laboratory, Hanno Research Center
Taiho Pharmaceutical Co., Ltd.
1
-27, Misugidai, Hanno-shi, Saitama, 357-8527 (Japan)
[
d] Dr. M. Iwashima
Current address:
Mammalian cross-conjugated dienone prostanoids such as
Department of Pharmacognosy
Faculty of Pharmaceutical Sciences
Toyama Medical and Pharmaceutical University
7
7
12,14
D -prostaglandin A (D -PGA ) (2) and 15-deoxy-D -pros-
2
1
taglandin J (15d-PGJ ) (3) are metabolites of cyclopente-
2
2
[5]
none prostanoids PGA , PGA , and PGJ (Scheme 1).
2
630, Sugitani, Toyama, Toyama 930-0194(Japan)
2
1
2
They display varied biological activities, the biological mech-
anisms of which, would be based on reversible and selective
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
1368
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 1368 – 1376

FULL PAPER
Scheme 2. Strategy for the solid-phase synthesis of cross-conjugated dien-
one library 7.
Scheme 1. Structure of cross-conjugated dienone prostanoids and their
proposed biological mechanism of action.
the hydroxyl group at the C12 position compared with that
of the the acetoxyl group improved reactivity of enone 7aA
towards electrophilic addition. Tuning the steric and elec-
tronic parameters of the two aromatic side-chains would be
effective not only for further improvement of the biological
activity, but also inducing selectivity in the alkylation reac-
tion.
alkylation with specific proteins at their C11 position to
[6,7]
give thermodynamically stable adducts 4a.
For example,
1
2,14
in 1995, the 15-deoxy-D -PGJ (2) ligand was found to
2
have a high affinity for the nuclear receptor PPARg, and to
modulate gene transcription by binding to this receptor via
alkylation with the highly reactive cross-conjugated dienone
Our strategy for the solid-phase synthesis of cross-conju-
gated dienones 7 is described in Scheme 2. We designed the
solid-supported 4-propynyl-4-hydroxylcyclopentenone 10 as
a key intermediate. Sonogashira-coupling reaction of cyclo-
pentenone 10 with the aryl iodide 11 and aldol condensation
with aldehyde 9 would enable the incorporation of the a-
and w-chains, respectively. In the previous report, the aldol
reaction involved b-elimination of the tert-alkyloxy group as
an undesired side-reaction. In the solid-phase synthesis, the
corresponding b-elimination does not reduce the purity of
the products because the b-eliminated products would be re-
leased from the resin. The cyclopentenone core 10 was im-
mobilized at the tert-hydroxyl group through a tetrahydro-
[6a]
system. On the other hand, marine prostanoid clavulone I
1) isolated from the Okinawan soft coral features the same
cross-conjugate dienone system along with a tert-acetoxyl
(
[8,9]
group at the C12 position and shows strong cytotoxicity.
The cross-conjugated dienone 1 could undergo sequential al-
kylation to provide the dicoupling product 5b, followed by
irreversible b-elimination of the C12 acetoxyl group to
afford enone 6. The irreversible alkylation is expected to be
effective for inducing stronger biological activity than such
mammalian prostanoids. Therefore, we started a project in-
volving the combinatorial synthesis of cross-conjugated di-
enones based on the structure of clavulones. There have
been many reports on the synthesis of clavulones as a single
[13]
pyranyl (THP) linker, that is stable to the two carbonÀ
carbon bond formations. Cleavage from the solid-support
under mildly acidic conditions yields the cross-conjugated
dienones 7 without decomposition.
[9,10]
target.
However, there are few examples of the synthesis
of their libraries. We have previously reported an effective
solid-phase synthesis of clavulones involving two carbonÀ
[11]
carbon bond-forming reactions.
Herein we report the
Preparation of solid-supported cyclopentenone 15 bearing
a terminal acetylene is shown in Scheme 3. Treatment of cy-
clopentenone 12 with 3-trimethylsilyl-2-propynyl lithium in
THF at À788C gave stereoselective diol 13 in 85% yield as
a single isomer. Removal of the TMS group under basic
conditions gave the terminal acetylene 14 in 85% yield, fol-
lowed by selective oxidation of the secondary alcohol to
afford cyclopentenone 15 in 65% yield. The latter was at-
tached to the resin through the THP linker. Exposure of
solid-phase synthesis of a combinatorial library of cross-con-
jugated dienones and the biological activity of the library
members.
Results and Discussion
The cross-conjugated dienones 7 attached to two aromatic
side-chains was designed as a scaffold in the library synthe-
sis (Scheme 2). We have already reported that the diphenyl
derivative 7aA possessing a hydroxyl group at the C12 posi-
tion irreversibly reacted with two nucleophiles under mildly
basic conditions, and showed strong antitumor activity
À1
3,4-dihydro-2H-pyran (DHP) polystyrene (1.10 mmolg ) to
a solution of diol 13 and pyridinium p-toluenesulfonate
(PPTS) in CH Cl at 408C for 24h provided the solid-sup-
2
2
ported terminal acetylene group of cyclopentenone 10. The
À1
IR spectra of 10 show a 3293 cm absorption derived from
[12]
(
IC =15 nm) in HeLaS3 cells. Lower steric hindrance of
the terminal acetylene group. The loading of 10 was estimat-
50
Chem. Eur. J. 2006, 12, 1368 – 1376
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www.chemeurj.org
1369

T. Takahashi et al.
Solid-phase synthesis of the diphenyl derivative 7aA was
examined. Incorporation of the w-chain was achieved by
treatment of compound 10 with phenyl iodide (11a), [Pd-
(
PPh ) ], CuI, and diisopropylethylamine in DMF for 24h
3 4
[14]
at 408C to give the solid-supported phenyl acetylene 8a.
Cleavage from the resin under acidic conditions provided
the phenyl acetylene 16a in quantitative yield based on 10.
Next, we explored the aldol reaction using phenyl acetylene
8
a. The resin was packed into Irori MicroKans. The solid-
supported ketone 8a was treated with potassium hexame-
thyldisilazane (KHMDS) in THF at À788C for 1 h to gener-
ate the enolate that was subsequently treated with benzalde-
hyde 9A to provide the solid-supported cross-conjugated di-
enone 17aA. The cross-conjugated dienone 17aA was
cleaved from the resin under acidic conditions, followed by
purification through column chromatography on silica gel,
to give the cross-conjugated dienone 7aA in 56% yield
1
13
based on compound 10. The analytical data ( H NMR,
C
NMR, and IR) of 7aA was identical with our previously re-
[12]
ported data.
Surprisingly, the yield of the products sug-
gested that the b-elimination of the tert-alkyloxy group did
not occur during the aldol reaction of 8a, presumably be-
cause the large steric hindrance of the solid-support could
hinder the attack of the base at the propargyl position.
Combinatorial synthesis of cross-conjugated dienones was
then investigated (Scheme 4). Eleven aryl iodides 11a–k and
a vinyl bromide 11l for the w-chain, and eight aldehydes
9
A–H for the a-chain were used as building blocks for the
preparation of a 96-member library (Figure 1). Sonogashira-
coupling reaction of the solid-supported acetylene group
with each of the twelve halides 11a–l was achieved utilizing
an Argonaut Quest210 Parallel Organic synthesizer. Use of
the Quest210 synthesizer was effective for minimization of
solvent and reagent quantities in the coupling reactions. The
resulting resins coupled with each building block were
packed into eight MicroKans to provide 96 MicroKans.
Aldol condensation of the twelve solid-supported ketones
Scheme 3. a) TMSCCCH
2
Li, THF, À788C, 85%; b) K
, RT, 65%; d) HM-DHP resin, PPTS, CH
08C, 24h, 54% based on the resin; e) [Pd(Ph P) ], CuI, NEt , DMF,
08C, 24h; f) 5% TFA/CH Cl quant, from 10; g) KHMDS, THF,
Cl , 56% from 10.
2
CO
3
, MeOH, RT,
8
4
4
5%; c) MnO
2
, CH
2
Cl
2
2
2
Cl ,
3
4
3
2
2
,
À788C, then 9A, À788C; h) 5% TFA/CH
2
2
8
a–l in MicroKans with each of the eight aldehydes 9A–H
ed by acidic cleavage followed by purification using column
chromatography on silica gel to be 54% yield based on the
resin.
was achieved in the same vessel to provide the solid-sup-
ported cross-conjugated dieneones 17aA–lH. Cleavage of
the compounds from each resin was achieved by using the
Scheme 4. Combinatorial synthesis of a combinatorial library 7: e), g), and h) as in Scheme 3.
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Chem. Eur. J. 2006, 12, 1368 – 1376

Combinatorial Chemistry
FULL PAPER
Figure 2. Purity of the combinatorial library 7, as estimated by HPLC-MS
analysis based on the UV absorption at 254nm.
detected by MS spectra. Aldehyde 9F and the vinyl bromide
1
1l did not perform well in the library synthesis because of
the low solubility of 9F in the reaction solvent and low reac-
tivity of 9l in the coupling reaction. Further HPLC analysis
based on the UV absorption at 254nm shows that there are
Figure 1. Building blocks for the synthesis of a combinatorial library 7.
1
2 compounds with over 70% purity and 33 compounds
with 40–70% purity (Figure 2).
Quest210 synthesizer. The cleaved solution was neutralized
with 2.0 equivalents of piperidinomethyl polystyrene
Biological evaluation: The alkylation reaction with biomole-
cules in cells can result in antiproliferative effects. We first
examined the cytotoxicity of all unpurified library com-
À1
(
3.48 mmolg ), followed by concentration in vacuo. It
should be noted that concentration of the crude products
without notarization resulted in decomposition of the cross-
conjugated dienones 7. The purity of the library compounds
was estimated by HPLC-MS analysis using the UV absorp-
tion at 254nm (Figure 2). In 98 trials, 76 compounds 7 were
[15]
pounds in HeLaS3 cells (Figure 3). Figure 4shows the li-
brary members 7jA, 7kA, 7aD, 7dD, 7hD, 7kD, 7hE, 7kE,
7iG, 7jG, and 7iH exhibiting very strong antitumor activity
(IC <0.05 mm). The phenyl, 2-pyridyl, 4-methoxylcarbonyl-
5
0
Figure 3. Cytotoxicity of crude library compounds 7 in HeLaS3 cells.
Chem. Eur. J. 2006, 12, 1368 – 1376
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1371

T. Takahashi et al.
basis not only of their biological activity, but also their hy-
drophilicity as hydrophobic compounds often result in non-
specific interaction with biomolecules. 5-Fluorouracil (5-FU)
and adriamycin (ADM) were used as positive controls. All
compounds showed very strong biological activity compara-
ble to adriamycin against four tumor cells except for TMF1.
Especially, the cytotoxicity of 7jG against HeLaS3 was four-
fold stronger than the lead compound 7aA. At this stage, it
is not clear if the cytotoxicity is caused by alkylation of spe-
cific targets or by random alkylation. However, the differ-
ence of cytotoxicity against TMF1 and the other cell lines is
promising, and we plan to elucidate the mechanism of
action in subsequent work.
Conclusion
We demonstrated the solid-phase synthesis of a cross-conju-
gated dienone library using the Sonogashira-coupling reac-
tion and aldol condensation. A 96-member combinatorial
synthesis using twelve aryl iodides 11a–l and eight alde-
hydes 9A–H provided 76 cross-conjugate dienones 7 with
good purity. From the library, eleven compounds showed
very strong cytotoxicity in HeLaS3 cells. Further biological
examination using four selected and purified compounds
against several tumor cell lines showed that all compounds
have strong cytotoxicity comparable to that of adriamicin,
except against TMF1 cells. Combinatorial synthesis of larger
libraries and identification of the target molecules are in
progress.
Figure 4. Structures of the members of the library 7 showing strong bio-
logical activity.
Experimental Section
General procedure: NMR spectra were obtained by using a JEOL Model
phenyl, pyrazoyl substituents at the a-chain would improve
cytotoxicity. On the other hand, although trans-cinnamalde-
hyde (9B) and furfural (9C) were converted to the desired
cross-conjugated dienones with good purity, the cross-conju-
gated dienones 7aB–7kB and 7aC–7kC exhibited relatively
low cytotoxicity. These results suggested that electron-with-
drawing groups at the a-chain could be effective for the
strong biological activity.
Further biological testing of the purified compounds
against five tumor cell lines (A549, HeLaS3, MCF7, TMF1,
and P388) was examined (Table 1). We selected four com-
pounds 7jA, 7dD, 7dG, and 7jG from the library on the
1
13
EX-270 (270 MHz for H, 67.8 MHz for C NMR spectra) or a JEOL
1
13
Model ECP-400 (400 MHz for H, 100 MHz for C NMR spectra) instru-
1
ment in the indicated solvent. H NMR spectral data are reported as fol-
lows: Chemical shifts are reported relative to tetramethylsilane
1
3
(
0.00 ppm) or chloroform (7.26 ppm). C signals are reported relative to
CDCl (77.0 ppm) or [D ]DMSO (39.7 ppm). FTIR spectra were record-
3
6
ed on a JASCO FT/IR-610 spectrometer and only significant diagnostic
bands are reported. Reverse-phase column chromatography was per-
formed using ODS-AM120-S50 resin (YMC). Silica gel thin-layer chro-
matography (TLC) was performed on plates precoated with Kieselgel
6
0F254(E. Merck AG, Darmstadt). High Performance Liquid Chroma-
tography (HPLC) was performed on a Hewlett–Packard1100 series in-
strument equipped with an XTerra MS C18 column (Waters, 2.5 mm,
2.1”20 mm). Mass spectra were provided by a Mariner Biospectrometry
Workstation (ESI-TOF) from PE Sci-
ence or a Micromass LCT (ESI-TOF)
Table 1. Cytotoxicity of purified cross-conjugated dienones 7jA, 7dD, 7dG, and 7jG in various tumor cells.
system.
Entry
Compound
IC50 [mm]
MCF7
(1R*,4S*)-1-(1-Trimethylsilylpropyn-
yl)-cyclopent-2-en-1,4-diol (13): n-Bu-
tyllithium (14.2 mL, 1.59m in hexane,
A549
HeLaS3
TMF1
P388
1
2
4
3
5
6
7jA
7dD
7dG
7jG
5-FU
ADM
0.058
0.048
0.077
0.086
1.44
0.009
0.016
0.040
0.0040.04 0.200
13.3
0.021
0.020
0.030
0.057
0.112
0.220
0.419
0.014
0.009
0.061
2
2.5 mmol) was added to a stirred so-
lution of diisopropylamine (3.4mL,
4.5 mmol) in dry tetrahydrofuran
40 mL) at 08C under argon. After
2
(
0
0.055
0.52
0.021
4.72
0.083
0.887
0.015
stirring for 20 min, the mixture was
cooled to À208C and 1-trimethylsilyl-
0.067
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Combinatorial Chemistry
FULL PAPER
propyne (3.3 mL, 22.5 mmol) in dry tetrahydrofuran (5.0 mL) was added.
After 20 min, a solution of 4-hydroxy-2-cyclopentenone (12) (950 mg,
washed with tetrahydrofuran (2”50 mL), tetrahydrofuran/water 1:1 (2”
50 mL), N,N-dimethylformamide (2”50 mL), methanol (2”50 mL), tet-
rahydrofuran (2”50 mL), and were dried in vacuo to afford the solid-
9
.79 mmol) in dry tetrahydrofuran (10 mL) was added at À788C to the
mixture. After stirring at À788C for 10 min, the reaction mixture was di-
luted with Et O and poured into saturated aqueous NH Cl (50 mL) at
8C. The aqueous layer was extracted with Et O (3”50 mL) and the
combined extracts were washed with brine (50 mL), and dried over anhy-
drous MgSO . After removal of the solvent, the residue was purified by
supported cyclopentenones 8a (1.56 g). IR (KBr): n˜ =3026, 2939, 1729,
À1
1600 cm
.
2
4
0
2
A part of the resin 8 (21 mg) was treated with a solution of trifluoroace-
tic acid (0.1 mL) in dichloromethane (2.0 mL) for 30 min at room tem-
perature. The mixture was filtered. The resulting resin was rinsed with
dry dichloromethane (3”3.0 mL). The filtrate was washed with saturated
4
column chromatography on silica gel (hexane/ethyl acetate 60:40) to
1
afford acetylene 13 (1.74g, 8.29 mmol, 85%) as a white solid. H NMR
NaHCO
solvent, the residue was purified by column chromatography on silica gel
MeOH/CH Cl 5:95) to provide phenylacetylene 16a (2.5 mg,
3 4
solution and brine, and dried over MgSO . After removal of the
(
270 MHz, CDCl
3
): d=6.00 (dd, J=2.0, 5.6 Hz, 1H), 5.93 (d, J=5.6 Hz,
1
H), 4.72 (m, 1H), 2.56 (dd, J=6.9, 14.2 Hz, 1H), 2.54 (s, 2H), 1.81 (dd,
(
3
1
3
J=3.6, 14.2 Hz, 1H), 0.17 ppm (s, 9H; Me
3
Si); C NMR (67.8 MHz,
1
0
1
2
3
.012 mmol, quant). H NMR (270 MHz, CDCl ): d=7.54(d, J=5.6 Hz,
H), 7.27–7.41 (m, 5H; aromatic), 6.23 (d, J=5.6 Hz, 1H), 2.90 (s, 2H),
.74(d, J=18.2 Hz, 1H), 2.58 ppm (d, J=18.2 Hz, 1H); C NMR
CDCl
3
): d=138.4, 136.2, 102.3, 82.5, 81.4, 75.5, 48.0, 32.4 ppm; IR (KBr):
À1
n˜ =3724, 2180, 1353, 1306, 1248, 1082 cm
.
13
(
0
0
1R*,4S*)-1-(1-Propynyl)-cyclopent-2-en-1,4-diol (14): K
2
CO
stirred solution of diol 12 (140 mg,
.667 mmol) in dry MeOH (10 mL) at room temperature under argon.
3
(108 mg,
(67.8 MHz, CDCl
3
): d=206.2, 164.3, 134.2, 131.7, 128.4, 122.6, 84.1, 83.9,
À1
.667 mmol) was added to
a
78.2, 48.5, 31.9 ppm; IR (KBr): n˜ =3378, 3059, 2927, 1716, 1598 cm
HRMS (ESI-TOF): m/z: calcd for
235.0729 [M+Na] .
;
14 2
C H12NaO : 235.0730, found:
+
After being stirred at the same temperature for 6 h, the reaction mixture
was filtered through Celite. After removal of the solvent in vacuo, the
residue was purified by column chromatography on silica gel (hexane/
ethyl acetate 90:10) to afford terminal acetylene 14 (78.5 mg,
0
Solid-phase synthesis of 7aA: Two MicroKans containing resins 8a sup-
ported with phenylacetylene (30 mg”2) were added to a reaction vessels
under argon. Tetrahydrofuran (4.0 mL) was added to the reaction vessel
to swell the resins. Subsequently, a solution of potassium bis(trimethylsi-
lyl)amide (1.20 mL, 0.600 mmol) in toluene (0.5m) at À788C under argon
was added to the reaction vessel. The reaction mixtures were stirred for
1 h at the same temperature. To the mixture, benzaldehyde (11A)
(0.305 mL, 3.00 mmol) in tetrahydrofuran (0.80 mL) was added to the re-
action vessel at À788C. After stirring for 1 h at the same temperature,
the reaction mixture was warmed at À208C and stirred for 30 min at this
temperature. The MicroKans were isolated by filtration and washed with
1
.568 mmol, 85%) as a white solid. H NMR (270 MHz, CDCl
3
): d=6.01
(
(
(
dd, J=2.0, 5.6 Hz, 1H), 5.96 (d, J=5.6 Hz, 1H), 4.76 (brs, 1H), 2.56
dd, J=6.9, 14.2 Hz, 1H), 2.52 (s, 2H), 2.05 (t, J=2.6 Hz, 1H), 1.83 ppm
1
3
3
dd, J=3.3, 14.2 Hz, 1H); C NMR (67.8 MHz, CDCl ): d=138.4, 136.0,
8
1
1
2.2, 80.4, 75.2, 70.5, 47.4, 30.8 ppm; IR (solid): n˜ =3295, 2119, 1642,
À1
422, 1354, 1091 cm ; HRMS (ESI-TOF): m/z: calcd for C
8
H
12NaO
2
:
+
61.0573, found: 161.0572 [M+Na] .
4
3
-Hydroxy-4-(prop-1-ynyl)-cyclopent-2-en-1-one (15): MnO
03 mmol) was added to a stirred solution of diol 14 (4.18 g, 30.3 mmol)
Cl (30 mL) at room temperature under argon. After being
2
(26.3 g,
4
cooled tetrahydrofuran/saturated aqueous NH Cl 1:1 (2”10 mL), metha-
in dry CH
2
2
nol (2”10 mL), tetrahydrofuran (2”10 mL), dichloromethane (2”
30 mL), and methanol (2”10 mL), and dried in vacuo to afford solid-sup-
ported dienone 14aA.
stirred at the same temperature for 60 h, the mixture was filtered through
Celite. After removal of the solvent in vacuo, the residue was purified by
column chromatography on silica gel (-hexane/ethyl acetate 50:50) to
afford enone 15 (2.71 g, 19.9 mmol, 65%) as a yellow oil. H NMR
(
2
2
1
2
Solid-supported dienone 14aA was treated with a solution of trifluoro-
acetic acid (0.1 mL) in dichloromethane (2.0 mL) for 30 min at room
temperature. The resulting resins were rinsed with dry dichloromethane
(3”5.0 mL). The filtrate was washed with saturated NaHCO3 solution
and brine, and dried over MgSO . After removal of the solvent, the resi-
due was purified by column chromatography on silica gel to give enone
1
400 MHz, CDCl
3
): d=7.50 (d, J=5.8 Hz, 1H), 6.20 (d, J=5.8 Hz, 1H),
.69–2.67 (m, 2H), 2.66 (d, J=18.5 Hz, 1H), 2.55 (d, J=18.5 Hz, 1H),
1
3
.14ppm (t, J=2.4Hz, 1H); C NMR (67.8 MHz, CDCl
3
): d=206.8,
4
64.5, 134.1, 78.9, 77.6, 71.9, 48.2, 30.6 ppm; IR (neat): n˜ =3407, 3291,
À1
1
931, 2120, 1715, 1590 cm
.
7aA (7.2 mg, 0.024mmol, 73% yield based on compound 10). H NMR
Solid-supported hydroxycyclopentenone (10): 3,4-Dihydro-2H-pyran-2-yl-
methoxymethyl polystyrene (2.30 g, 3.30 mmol, 1.10 mmolg ) was added
into a 50 mL reaction vessel in a Quest205 synthesizer. To the reaction
vessel was added a solution of 4-hydroxy-4-propargyl-2-cyclopentenone
3
(400 MHz, CDCl ): d=2.81(brs, 1H), 2.90 (d, J=17.0 Hz, 1H), 3.28 (d,
À1
J=17.0 Hz, 1H), 6.51 (d, J=6.8 Hz, 1H), 7.27–7.30 (m, 3H), 7.33–7.39
(m, 2H), 7.33–7.39 (m, 2H), 7.41–7.45 (m, 3H), 7.52 (s, 1H), 7.66 (d, J=
1
3
6.8 Hz, 1H), 7.98 ppm (brd, J=8.7 Hz, 2H); C NMR (100 MHz,
CDCl ): d=195.2, 160.8, 136.1, 135.3, 134.4, 133.4, 132.1, 131.6, 130.0,
128.8, 128.3, 128.2, 122.8, 84.1, 84.0, 78.1, 27.4 ppm; IR (neat): n˜ =3418,
(
0
15) (1.90 g, 52.1 mmol) and pyridinium p-toluenesulfonate (226 mg,
.900 mmol) in dry dichloromethane (18 mL) at room temperature under
3
À1
+
3
074, 2910, 1681, 1589 cm ; MS (ESI-TOF): m/z: 301 [M+H] ; HRMS
argon. After agitation at 408C for 24h, the reaction mixture was drained.
The remaining beads were washed with tetrahydrofuran (3”20 mL), tet-
rahydrofuran/water 1:1 (3”20 mL), methanol (3”20 mL), tetrahydrofur-
an/water 1:1 (3”20 mL), and methanol (3”20 mL), and were dried in
(
ESI-TOF): m/z: calcd for 323.1043; found: 323.1044
21 2
C H16NaO :
+
[
M+Na] .
Solid-phase synthesis of library 7
vacuo to afford the solid-supported cyclopentenone 10. IR (KBr): n˜ =
Sonogashira-coupling to provide 8a–l: Resin 10 supported with terminal
acetylene (300 mg) and CuI (0.3 mmol) were added into twelve 100 mL
reaction vessels in the Quest205 synthesizer. To the reaction vessels, solu-
tions of aryl iodide 11a–l (1.5 mmol) in N,N-dimethylformamide
(3.0 mL) and diisopropylethylamine (130 mL, 0.75 mmol), and [Pd-
(PPh ) ] (347 mg, 0.30 mmol) were added under argon. After agitation at
408C for 36 h, the reaction mixture was drained. The remaining beads
were washed with tetrahydrofuran (2”3.0 mL), tetrahydrofuran/water 1:1
(2”3.0 mL), N,N-dimethylformamide (2”3.0 mL), methanol (2”3.0 mL),
tetrahydrofuran (2”3.0 mL), and were dried in vacuo to afford the solid-
supported cyclopentenones 8a–l.
À1
3
293, 3024, 2858, 1719, 1601 cm
.
A part of the resin 10 (119 mg) was treated with a solution of trifluoro-
acetic acid (0.1 mL) in dichloromethane (2.0 mL) for 30 min at room
temperature. The resulting resin was rinsed with dry dichloromethane
(
3”5.0 mL). The filtrate was washed with saturated NaHCO
and brine, and dried over MgSO . After removal of the solvent, the resi-
due was purified by column chromatography on silica gel (MeOH/CH Cl
:95) to give the recovered-cyclopentenone 15 (9.9 mg, 72 mmol, 56%
based on the resin).
Solid-supported phenylacetylene (8a): The acetylene resin 10 (300 mg,
.185 mmol) and CuI (95.0 mg, 0.500 mmol) were added into 20 mL reac-
3
solution
3
4
4
3
5
0
Solid-phase synthesis of solid-supported cross-conjugated dienones
14aA–14lH: Each of the resins 8a–l (30 mg) was packed into eight Mi-
croKans encoded with an Rf Tag to provide a total of 96 MicroKans.
Eight reaction vessels involving the twelve different MicroKans 8a–l
were prepared. Tetrahydrofuran (36 mL) was added to the reaction ves-
sels to swell the resins. Subsequently, a solution of potassium bis(trime-
tion vessels in a Quest210 organic synthesizer. To the reaction vessel, a
solution of phenyl iodide (11a) (0.279 mL, 2.50 mmol) and diisopropyle-
thylamine (0.61 mL, 3.50 mmol) in DMF (15 mL), and [Pd(PPh ) ]
3 4
(
289 mg, 0.25 mmol) were added under argon. After agitation at 408C for
2
4h, the reaction mixture was drained. The remaining beads were
Chem. Eur. J. 2006, 12, 1368 – 1376
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1373

T. Takahashi et al.
Yield [mg] (%)
thylsilyl)amide (7.60 mL, 3.60 mmol;
.50m in toluene) was added to the re-
Table 2. Purity and cytotoxicity against HeLaS3 cells of 76 compounds in the combinatorial library 7.
0
2
1
+
Entry
R X
R CHO
Product
t
R
[min]
MS [M+H]
action vessels at À788C under argon.
The reaction mixtures were stirred at
À788C for 1 h. The eight aldehydes
/
Purity (HPLC area%)
1
2
3
4
5
6
7
8
9
11a
11b
11c
11d
11e
11 f
11g
11h
11i
11j
11k
11a
11b
11c
11d
11e
11 f
11g
11h
11i
11j
11k
11a
11b
11c
11d
11e
11 f
11g
11h
11i
11j
11k
11a
11b
11c
11d
11e
11 f
11g
11h
11i
11j
11k
11a
11b
11c
11d
11e
11 f
11g
11h
11i
11j
11k
11a
11b
11c
11d
11e
11 f
11i
9A7aA
9A7bA
9A7cA
9A7dA
9A7eA
9A7 fA
9A7gA
9A7hA
9A7iA
9A7jA
9A7kA
9B
9B
9B
9B
9B
9B
9B
9B
9B
9B
9B
9C
9C
9C
9C
9C
9C
9C
9C
9C
9C
9C
9D
9D
9D
9D
9D
9D
9D
9D
9D
9D
9D
9E
9E
9E
9E
9E
9E
9E
9E
9E
9E
9E
9G
9G
9G
9G
9G
9G
9G
9G
9H
4.62
5.0
301
315
372
372
4.2 (56)/73
4.9 (62)/31
6.0 (65)/86
5.8 (63)/77
1
1A–H (18.0 mmol) in tetrahydrofur-
3.36
3.39
3.34372
5.03
2.85
2.66
5.17
5.36
4.43
4.87
5.21
3.62
3.66
3.71
5.21
3.26
3.03
5.44
5.53
4.72
3.92
4.38
2.60
2.66
2.56
4.41
1.80
1.58
4.57
4.75
3.77
4.26
4.68
2.94373
2.94373
2.84373
4.74
2.12
2.02
4.88
5.09
4.05
4.56
4.20
3.32
3.35
3.39
4.94
2.96
2.72
5.14393
5.26
4.37
2.99
3.53
1.46
1.49
1.37
3.76
3.85
4.22
4.24
4.65
an (5.0 mL) were added to the differ-
ent reaction vessels at À788C. After
stirring for 1 h at that temperature, the
5.1 (55)/66
373
302
302
335
369
307
327
341
398
398
398
399
328
328
361
395
333
291
305
362
362
362
363
292
292
325
359
297
302
316
5.1 (55)/78
6.8 (90)/46
5.1 (68)/97
5.2 (62)/94
5.5 (60)/92
4.6 (60)/39
8.2 (101)/79
7.5 (88)/82
reaction
warmed at À208C and stirred for
0 min at this temperature. The Micro-
mixture
was
gradually
3
Kans were isolated by filtration and
washed with cooled tetrahydrofuran/
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
saturated aqueous NH
0 mL), methanol (2”30 mL), tetrahy-
drofuran (2”30 mL), dichloromethane
2”30 mL), methanol (2”30 mL), and
4
Cl 1:1 (2”
7aB
7bB
7cB
7dB
7eB
7 fB
7gB
7hB
7iB
3
10.3 (104)/82
10.4(105)/81
7.7 (78)/61
(
were dried in vacuo to afford 96 solid-
supported cross-conjugated dienones
9.0 (91)/78
1
4aA–14lH in MicroKans.
11.2 (137)/64
11.0 (135)/82
9.2 (102)/90
11.5 (117)/76
8.5 (102)/71
9.0 (124)/83
7.9 (104)/74
11.0 (122)/83
10.1 (112)/81
8.4(93)/71
Cleavage of compounds 7aA–7lH:
The MicroKans 14aA–14lH were sep-
arately treated with a solution of tri-
fluoroacetic acid (0.1 mL) in dichloro-
methane (2.0 mL) for 30 min at room
temperature in a different vessel of the
Quest210 synthesizer. After addition
of dichloromethane (3.0 mL), the reac-
tion mixture was neutralized with a pi-
7jB
7kB
7aC
7bC
7cC
7dC
7eC
7 fC
7gC
7hC
7iC
peridinomethyl polystyrene (316 mg,
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
8.9 (98)/83
À1
1
.1 mmol, 3.48 mmolg
)
for 30 min.
10.4 (143)/47
10.7 (147)/82
9.7 (120)/90
8.8 (98)/76
6.8 (92)/71
9.2 (122)/79
9.2 (117)/66
The mixture was filtered and the re-
sulting resins were rinsed with dry di-
chloromethane (3”5.0 mL). The com-
bined filtrate was concentrated in
vacuo to give crude enones 7aA–7lH
as yellow oils. Purity of the crude
enones 7aA–7lH was analyzed by
HPLC-MS based on the UV absorp-
tion at 254nm by using a YMC-Pack
ProC18 (5 mm, 4.6”50 mm column;
7jC
7kC
7aD
7bD
7cD
7dD
7eD
7 fD
7gD
7hD
7iD
7jD
7kD
7aE
7bE
7cE
7dE
7eE
7 fE
7gE
7hE
7iE
12.1 (130)/79
9.0 (97)/86
11.2 (121)/70
374
303
303
336
370
308
359
373
430
430
430
431
360
360
10.5 (113)/64
À1
flow rate: 10 mLmin , temperature:
11.5 (152)/60
10.5 (139)/92
10.3 (123)/85
8.6 (93)/87
9.6 (125)/41
9.1 (102)/61
9.7 (104)/84
11.0 (103)/80
10.7 (100)/62
8.1 (76)/73
4
08C, mobile phase: 0.1% HCOOH in
O/0.1% HCOOH in MeCN 70:30
0 min), 10:90 (5–8 min), for 7aA–7lF
and 7aH–7lH; 0.1% HCOOH in
O/0.1% HCOOH in MeCN 70:30
H
2
(
H
2
(
(
0 min), 10:90 (5–8 min) for 7aG–7kG
Table 2) Further purification of the
selected compounds was achieved by
column chromatography on silica gel.
1
8.9 (83)/76
10.4(116)/30
10.0 (112)/92
Compound 7jA: H NMR (270 MHz,
51
52
53
54
CDCl
3
): d=2.98 (d, J=17.1 Hz, 1H),
.25 (d, J=17.1 Hz, 1H), 6.51 (d, J=
.8 Hz, 1H), 7.40–7.54 (m, 7H), 7.63
3
6
7.1 (72)/89
7jE
427
365
305
319
376
376
376
377
339
373
279
293
8.0 (75)/89
8.7 (96)/25
5.6 (74)/50
5.5 (69)/42
8.6 (92)/23
8.1 (86)/32
7.3 (78)/18
7.1 (76)/43
7.9 (93)/51
7.8 (84)/58
4.1 (59)/33
6.6 (90)/18
(
d, J=6.8 Hz, 1H), 7.98 ppm (m, 2H);
1
3
55
7kE
7aG
7bG
7cG
7dG
7eG
7 fG
7iG
7jG
7aH
7bH
C NMR (67.8 MHz, CDCl3): d=
95.3, 160.7, 136.1, 135.5, 134.6, 133.5,
33.2, 132.1, 131.9, 130.2, 129.7, 128.8,
26.7, 125.2, 86.9, 82.7, 78.1, 27.2 ppm;
56
57
58
59
60
61
62
63
64
65
1
1
1
IR (neat): n˜ =3404, 3067, 1695,
À1
1
[
626 cm ; MS (ESI-TOF): m/z: 369
+
M+H] .
Compound 7dG: H NMR (270 MHz,
CDCl ): d=2.95 (s, 3H), 3.10 (s, 3H),
.13 (d, J=16.5 Hz, 1H), 3.32 (d, J=
6.5 Hz, 1H), 3.32 (s, 3H), 6.58 (d, J=
1
11j
11a
11b
3
3
1
9H
1374
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 1368 – 1376

Combinatorial Chemistry
Table 2. (Continued)
FULL PAPER
À1
1
(
C
705, 1639, 1087, 747 cm
ESI-TOF): m/z:
;
HRMS
for
calcd
2
1
+
Entry
R X
R CHO
Product
t
R
[min]
MS [M+H]
Yield [mg] (%)
H
N
O
: 373.1547; found: 373.1556
23
20
2
3
+
/
Purity (HPLC area%)
[M+H] .
1
66
67
68
69
70
71
72
73
74
11c
11d
11e
11 f
11g
11h
11i
9H
9H
9H
9H
9H
9H
9H
9H
9H
7cH
7dH
7eH
7 fH
7gH
7hH
7iH
2.93
2.97
2.89
4.69
2.33
2.03
4.84
5.05
4.07
350
350
350
351
280
280
313
347
285
6.2 (71)/17
6.9 (79)/15
5.3 (61)/11
6.0 (69)/35
4.6 (66)/45
4.7 (67)/32
5.0 (64)/38
4.8 (56)/49
4.7 (66)/14
Compound 7iG: H NMR (270 MHz,
3
CDCl ): d=7.63 (d, J=5.9 Hz, 1H),
7.37–7.15 (m, 4H), 7.17 (s, 1H), 7.01
(s, 1H), 6.59 (d, J=5.9 Hz, 1H), 3.85
(s, 3H), 3.32 (d, J=16.8 Hz, 1H),
J=16.8 Hz,
C NMR (67.8 MHz, CDCl
3.11 ppm
(d,
1H);
1
3
3
): d=
11j
11k
7jH
7kH
194.9, 161.2, 142.8, 142.5, 135.4, 133.9,
132.8, 19.9, 128.6, 123.5, 112.8, 86.8,
8
2.5, 78.5, 33.7, 29.3 ppm; FTIR
(
solid): n˜ =2922, 1697, 1646, 1477,
À1
5
7
1
.9 Hz, 1H), 7.01 (d, J=1.0 Hz, 1H), 7.17 (s, 1H), 7.27–7.32 (m, 4H),
1224, 826, 755 cm ; HRMS (ESI-TOF): m/z: calcd for C H ClN O :
1
9
15
2
2
+
.63 (brd, J=5.9 Hz, 1H), 8.76 ppm (brs, 1H); IR (neat): n˜ =3412, 2932,
339.0895; found: 339.0899 [M+H] .
À1
+
700, 1635 cm ; MS (ESI-TOF): m/z: 376 [M+H] .
1
Compound 7jG: H NMR (270 MHz, CDCl
3
): d=7.63 (d, J=5.9 Hz,
1
Compound 7iA: H NMR (270 MHz, CDCl
J=5.9 Hz, 1H), 7.53 (s, 1H), 7.50–7.38 (m, 2H), 7.35–7.20 (m, 5H), 6.53
3
): d=7.99 (m, 2H), 7.64(d,
1H), 7.50 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.18 (s, 1H), 7.02
(s, 1H), 6.60 (d, J=5.9 Hz, 1H), 3.85 (s, 3H), 3.35 (d, J=16.8 Hz, 1H),
3.14ppm (d, J=16.8 Hz, 1H); C NMR (67.8 MHz, CDCl ): d=194.8,
3
161.1, 142.7, 142.3, 135.4, 131.8, 130.0, 125.2, 123.6, 112.9, 88.5, 82.4, 78.5,
33.7, 29.3 ppm; FTIR (neat): n˜ = 3115, 2928, 2225, 1703, 1647, 1323 cm
HRMS (ESI-TOF): m/z: calcd for
1
3
(
d, J=5.9 Hz, 1H), 3.28 (d, J=17.0 Hz, 1H), 2.91 ppm (d, J=17.0 Hz,
1
3
1
1
H); C NMR (67.8 MHz, CDCl
3
): d=195.3, 161.0, 137.5, 137.2, 135.4,
À1
34.6, 133.0, 132.2, 130.2, 128.9, 128.7, 121.4, 85.2, 78.2, 29.8, 27.5 ppm;
;
À1
FTIR (neat): n˜ =3374, 2925, 1693, 1626, 1489, 826 cm ; HRMS (ESI-
TOF): m/z: calcd for C21
C
20
H
15
F
3
N
2
O
2
:
373.1158; found:
+
+
3
73.1155 [M+H] .
H
15ClNaO
2
: 357.0653, found: 357.0661 [M+Na]
.
Biological assay: Each cell line (A549, HeLaS3, MCF7, TMF1 and P388)
was seeded into a 96-multiwell plate and was incubated for 24h. The
cells were treated with 7jA, 7dD, 7jG, 7dD, 5-FU or Adriamycin for
1
Compound 7kE: H NMR (270 MHz, CDCl
7
(
3
): d=8.12–8.01 (m, 4H),
.68 (d, J=5.9 Hz, 1H), 7.51 (s, 1H), 7.21 (dd, J=1.0, 5.0 Hz, 1H), 7.12
dd, J=1.0, 3.6 Hz, 1H), 6.93 (dd, J=3.6, 5.0 Hz, 1H), 6.53 (d, J=5.9 Hz,
7
2 h. In the case of A549, HeLaS3, MCF7, and TMF1 cell lines, the cells
were fixed with glutaraldehyde and stained with crystal violet for estima-
tion of cell population. For the P388 cell lines, 20 mL per well of WST-8
solution was added and the plate was further incubated for 1.5 h. After
incubation, the absorbance was measured at 450 nm for an estimation of
the cell population.
1
1
1
H), 3.94(s, 3H; Me), 3.26 (d, J=17.1 Hz, 1H), 2.86 ppm (d, J=17.1 Hz,
H); C NMR (67.8 MHz, CDCl ): d=194.7, 166.6, 161.0, 138.0, 137.9,
3
1
3
34.7, 134.0, 132.1, 131.8, 130.0, 127.0, 126.9, 87.7, 78.0, 52.4, 28.0 ppm;
À1
FTIR (neat): n˜ =3329, 1924, 1719, 1628, 826 cm ; HRMS (ESI-TOF):
m/z: calcd for C21
+
H16NaO
4
S: 387.0662; found: 387.0669 [M+Na] .
1
Compound 7aD: H NMR (270 MHz, CDCl
3
): d=8.71 (brdd, 1H), 7.86
(
dt, J=2.0, 7.5 Hz, 1H), 7.67 (brd, 1H), 7.63 (brd, 1H), 7.39–7.22 (m,
4
H), 7.31 (s, 1H), 6.61 (d, 1H), 3.16 (d, J=16.8, 22.8 Hz, 1H), 3.08 ppm
1
3
(
d, J=16.8, 22.8 Hz, 1H); C NMR (67.8 MHz, CDCl
3
): d=195.1, 161.4,
Acknowledgements
1
8
1
53.1, 148.9, 144.8, 138.4, 135.3, 131.6, 128.7, 128.3, 128.0, 127.6, 123.8,
5.3, 83.7, 78.5, 30.3 ppm; FTIR (neat): n˜ =3060, 2917, 1705, 1646, 1589,
This work was supported by a Grant-in-aid for Scientific Research on
Priority Area (S) from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology. (Grant-in-aid No. 14103013). We thank Takashi
Kobunai, Satoko Okabe, and Kazuko Sakai (Taiho Pharmaceutical Co.
Ltd) for the cytotoxic assay.
À1
087, 692 cm ; HRMS (ESI-TOF): m/z: calcd for C20
H
15NO
2
: 302.1176
+
[
M+H] , found: 302.1178.
1
Compound 7kD: H NMR (270 MHz, CDCl
3
): d=8.71 (brd, 1H), 7.87
(
dt, J=6.0, 7.5 Hz, 1H), 7.68 (d, J=6.2 Hz, 1H), 7.64(brd, J=7.5 Hz,
1
1
6
1
1
1
H), 7.36 (dd, J=5.0, 12.5 Hz, 1H), 7.31 (s, 1H), 7.16 (dd, J=5.3 Hz,
H), 7.05 (brd, J=3.6 Hz, 1H), 6.90 (dd, J=3.6, 5.3 Hz, 1H), 6.60 (d, J=
.2 Hz, 1H), 3.13 ppm (s, 2H); C NMR (67.8 MHz, CDCl ): d=195.0,
3
1
3
[
1] a) D. A. Campbell, A. K. Szardenings, Curr. Opin. Chem. Biol. 2003,
, 296–303; b) L. F. Tietze, H. P. Bell, S. Chandrasekhar, Angew.
Chem. 2003, 115, 4128–4160; Angew. Chem. Int. Ed. 2003, 42, 3996–
7
61.4, 153.1, 148.9, 144.7, 138.4, 135.3, 131.7, 128.8, 127.8, 126.9, 126.5,
23.8, 89.3, 78.4, 30.6, 29.8 ppm; FTIR (neat): n˜ =2918, 1700, 1644, 1589,
À1
4028.
190, 830 cm ; HRMS (ESI-TOF): m/z: calcd for C18
H
13NO
2
S: 308.0740,
+
[2] a) J.-Y. Ortholand, A. Ganesan, Curr. Opin. Chem. Biol. 2004, 8,
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found: 308.0742 [M+H] .
1
Compound 7jD: H NMR (270 MHz, CDCl
3
): d=8.71 (brd, J=3.7 Hz,
1
7
H), 7.88 (dt, J=1.7, 7.9 Hz, 1H), 7.66 (d, J=5.9 Hz, 1H), 7.64(d, J=
.9 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.34–7.40
[
3] a) D. Brohm, S. Metzger, A. Bhargava, O. Muller, F. Lieb, H. Wald-
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(
m, 1H), 7.32 (s, 1H), 6.61 (d, J=5.9 Hz, 1H), 3.18 (dd, J=16.8 Hz, 2H),
2
002, 41, 307–311; b) M. A. Koch, R. Breinbauer, H. Waldmann,
1
3
3
1
8
8
3
.09 ppm (dd, J=16.8 Hz, 2H); C NMR (67.8 MHz, CDCl ): d=195.0,
61.2, 153.1, 148.9, 144.7, 138.4, 135.3, 131.8, 128.8, 127.8, 125.2, 123.9,
8.9, 82.6, 78.4, 30.3 ppm; FTIR (solid): n˜ =3081, 2920, 1701, 1643, 1320,
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À1
42 cm ; HRMS (ESI-TOF): m/z: calcd for C21
14 3 2
H F NO : 370.1049;
+
found: 370.1049 [M+H] .
1
Compound 7dD: H NMR (270 MHz, CDCl
3
): d=8.71 (brd, 1H), 7.87
(
dt, J=7.9, 2.0 Hz, 1H), 7.66 (d, J=5.9 Hz, 1H), 7.64(d, J=7.9 Hz, 1H),
7
5
1
1
1
.36 (dd, J=5.4, 7.9 Hz, 1H), 7.33–7.27 (m, 4H), 7.30 (s, 1H), 6.60 (d, J=
.9 Hz, 1H), 3.16 (d, J=1.68 Hz, 1H), 3.10 (s, 3H), 3.08 ppm (d, J=
1
3
3
6.8 Hz, 1H); C NMR (67.8 MHz, CDCl ): d=195.1, 170.8, 161.3, 153.1,
48.9, 144.8, 138.4, 136.5, 135.3, 132.6, 130.1, 128.7, 128.4, 127.7, 126.6,
23.8, 123.5, 86.3, 83.0, 78.5, 39.6, 35.4, 30.3 ppm; FTIR (solid): n˜ =2926,
Chem. Eur. J. 2006, 12, 1368 – 1376
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Received: July 11, 2005
Published online: November 18, 2005
1376
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 1368 – 1376