Synthesis, structural characterisation and biological evaluation of fluorinated analogues of resveratrol

Article abstract of DOI:10.1016/j.bmc.2009.05.007

Resveratrol is a potential chemopreventive agent and can be isolated from grape skins and other dietary sources. The Wittig reaction and the decarbonylative Heck reaction were employed to synthesise analogues of this stilbene. Fluorinated derivatives of t

Full text of DOI:10.1016/j.bmc.2009.05.007

Bioorganic & Medicinal Chemistry 17 (2009) 4510–4522
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis, structural characterisation and biological evaluation
of fluorinated analogues of resveratrol
Brian W. Moran a,b, Frankie P. Anderson a,b, Aoife Devery b, Stephen Cloonan a, William E. Butler a,
Sunil Varughese c, Sylvia M. Draper c, Peter T. M. Kenny a,b,
*
a School of Chemical Sciences, Dublin City University, Glasnevin, Dublin 9, Ireland
b National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
c School of Chemistry, Trinity College Dublin, Dublin 2, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Resveratrol is a potential chemopreventive agent and can be isolated from grape skins and other dietary
sources. The Wittig reaction and the decarbonylative Heck reaction were employed to synthesise ana-
logues of this stilbene. Fluorinated derivatives of this stilbene were synthesised maintaining the 3,40,5-
substitution pattern. The hydroxyl groups were also replaced by amino groups and the biological activity
evaluated. The compounds were assayed on a variety of cell lines, primarily the non-small lung carci-
noma cell line DLKP-A. Analogues were evaluated alone and in combination with a known chemothera-
peutic agent epirubicin.
Received 13 February 2009
Revised 29 April 2009
Accepted 4 May 2009
Available online 8 May 2009
Keywords:
Resveratrol
Stilbene
Ó 2009 Elsevier Ltd. All rights reserved.
Fluorine
Nitro, Amine, Anticancer
1. Introduction
a disease preventative dietary supplement,10 or as a topical
treatment.11
Secondary phenolic metabolites from plants display diverse
biological activities. Epicatechins from green tea and the isoflava-
noid genistein from soya products, have been shown to prevent tu-
mour formation1 and osteoporosis,2 respectively. Resveratrol
(3,40,5-trihydroxy-trans-stilbene) 1 is a naturally occurring phyto-
alexin present in grapes and other food products. It has been
shown to possess anti-oxidant, anti-inflammatory, anti-platelet,
cancer preventative and anti-cancer properties.3–5
Resveratrol came to prominence during the course of research
into the so-called ‘French paradox’.6 This concept stems from the
observation that the population of France have a relatively high
fat diet accompanied by a steady, albeit moderate intake of alcohol
in the form of red wine, whilst their incidence of coronary heart
disease is lower than expected. This trihydroxy stilbene has dis-
played in vitro growth inhibition in a number of human cancer cell
lines.7 In spite of its wide range of activity, the mechanistic basis of
the in vivo activity of resveratrol remains unknown.8 Numerous
studies have pointed to its ability to function as a cellular anti-oxi-
dant while others have demonstrated the inhibition of signalling
kinases as its key function.9 In addition to its potential as a tool
to study protein signalling, it may also serve as a therapeutic lead,
Resveratrol is only present in small amounts in plant sources
and its quantity depends on the stress situation of the plant. Isola-
tion from plant sources is not viable, as it has been reported that
only 92 lg of resveratrol are present in one gram of dried grape
skins. Although both cis- and trans-isomers of resveratrol are found
in nature, it is only the trans-isomer that exhibits bioactivity.12
Reliable and efficient synthetic routes to resveratrol are therefore
highly desirable. The majority of published routes for the synthesis
of resveratrol are based on Wittig-like reactions. However stereo-
selective synthetic routes such as the Heck, Stille and Negishi reac-
tions have more recently been employed.13
We now report the synthesis, structural characterisation and
biological evaluation of fluorinated analogues of resveratrol. Main-
taining the 3,40,5-substitution pattern of resveratrol may result in
novel stilbenes with improved biological activity.
2. Chemistry
A series of fluorinated analogues were synthesised maintaining
the resveratrol substitution pattern in order to prepare a novel
compound with greater bioactivity than that of resveratrol 1
(Fig. 1). Fluorinated resveratrol analogues were synthesised, some
with hydroxyl groups and others with protected hydroxyl groups.
In addition, novel compounds containing the known hydroxyl bio-
isostere, the amino group were also prepared.
* Corresponding author. Tel.: +353 1 7005689; fax: +353 1 7005503.
E-mail address: peter.kenny@dcu.ie (P.T.M. Kenny).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.05.007

B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
4511
Yield
Table 1
OH
Fluorinated resveratrol derivatives 2–10
Compound
Isomer
R
R0
R00
HO
2
3
4
5
6
7
8
9
(E)
(E)
(E)
(E)
(E)
(E)
(E)
(E)
(E)
F
F
F
F
F
48
22
26
19
29
58
65
81a
76a
OCH3
F
OCH2CH3
F
OCOCH3
F
OH
F
OCH3
F
OCH2CH3
F
OCOCH3
F
OH
OCH3
F
OCH2CH3
F
OCOCH3
F
OCOCH3
OH
Figure 1. Resveratrol 1.
10
The decarbonylative Heck reaction was employed as an efficient
method for the synthesis of resveratrol (Scheme 1).14,15 Utilising
this reaction, compounds 2–8 were synthesised (Table 1). Com-
pound 9 was prepared via the acetoxy analogue 7, which was sub-
sequently deprotected.16 Analogue 10 was prepared in a similar
fashion but in this case ammonium acetate only deprotected one
of the available two acetoxy groups of compound 8.
A second series of analogues (11–19) was prepared maintaining
fluorine atoms at the 3 and 5 positions with an amino group
replacing the 40-hydroxyl group (Table 2). These amino derivatives
were synthesised by reduction of the corresponding nitro ana-
logue. The classic Wittig reaction yielded the nitrostilbene isomers
11 and 12 (Scheme 2). The nitro isomers were separated via frac-
tional crystallisation from ethanol, but could not be differentiated
by proton NMR studies due to overlap of signals.
Crystals of isomer 11 were grown from toluene for single crystal
X-ray studies and were shown to be those of the trans-isomer. The
monoclinic unit cell of nitrostilbene 11 is shown in Figure 2. This
compound 11 crystallises in the monoclinic space group P21/n with
four independent molecules per asymmetric unit. The hydrogen
bonding contacts to both oxygen and fluorine are also indicated
in the unit cell diagram. The contact distance between hydrogen
and oxygen is 2.530 Å and between hydrogen and fluorine is
2.567 Å.
a
Yield of deprotection step.
Table 2
40-Nitro and amino resveratrol analogues
Compound
Isomer
R
R0
R00
Yield
11
12
13
14
15
16
17
18
19
20
21
22
(E)
(Z)
(E)
(Z)
(E)
(E)
(E)
(E)
(E)
(E)
(E)
(E)
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
NO2
NO2
NH2
NH2
NHCOCH3
NHCOCF3
N(CH3)2
NH-BOC-glycine
NH-BOC- -alanine
NH-BOC-b-alanine
NH-BOC- -valine
NH-glycine*
49a
46a
88b
80b
70c
62c
32a
17d
18d
12d
11d
92e
L
L
a
Yield of stilbene formation.
Yield of nitro reduction.
Yield of amine acylation.
Yield of amino acid coupling.
Yield of amino acid deprotection.
b
c
d
e
*
Isolated as trifluoroacetate salt.
Reduction of the nitro stilbene was achieved using iron(III)
chloride hexahydrate and iron pindust.17 Reduction of both iso-
mers was carried out separately in quantitative yields affording
the trans and cis amino derivatives (13 and 14). An amino acetyl
15, an amino trifluoroacetyl analogue 16 and a tertiary amine
derivative, (E)-3,5-difluoro-40-dimethylaminostilbene 17 were
subsequently prepared.
Amino acid derivatives were also synthesised. A BOC-protected
amino acid derivative 18 was prepared by coupling (E)-3,5-di-
fluoro-40-aminostilbene 13 to BOC-protected glycine using the
standard coupling reaction with N-ethyl-N0-(3-dimethylaminopro-
pyl)carbodiimide hydrochloride (EDC) as an activation agent.18,19
Deprotection of the BOC-glycine analogue 18 was achieved by stir-
ring in a 50% solution of trifluoroacetic acid in dichloromethane,
resulting in a quantitative yield of (E)-3,5-difluoro-40-aminogly-
cinestilbene trifluoroacetate salt 22. This procedure was also em-
ployed using different amino acids to generate further analogues
19–21.
carried out via the decarbonylative Heck reaction. The cis-isomer,
(Z)-3,5-dinitro-40-fluorostilbene 24 was prepared via the classical
Wittig reaction for comparative purposes.
Reduction of the 3,5-dinitro-40-fluorostilbenes (23 and 24) via
the iron(III) chloride reduction procedure furnished the diamino
isomers (25 and 26). By controlling the equivalents of reducing
agents used in the reaction, it was possible to isolate stilbenes with
only one nitro group reduced. This was carried out using both dini-
tro-isomers (23 and 24) individually, thereby producing (E)-3-ni-
tro-5-amino-40-fluorostilbene 27 and (Z)-3-nitro-5-amino-40-
fluorostilbene 28.
The acetyl derivatives of the 3,5-diamino-40-fluoro series (29
and 30) were also synthesised. BOC-protected amino acid deriva-
tives (31–34) were prepared using the standard EDC coupling
reaction.
3. Biological evaluation
Stilbene analogues (23–35) with nitrogen substituents at the 3
and 5 positions and a fluorine atom at the 40 position were synthes-
ised (Table 3). Synthesis of (E)-3,5-dinitro-40-fluorostilbene 23 was
Resveratrol 1 has been shown to prevent and slow the progres-
sion of a wide variety of illnesses, including cancer, cardiovascular
disease and ischaemic injuries.3–5 It also enhances stress resistance
O
R''
Pd(OAc)2
R
Cl
NEM
R
p-xylene
R''
120oC
18hr
R'
R'
Scheme 1. Synthesis of (E)-3,5-40-substituted stilbene via Heck reaction.

4512
B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
R
O
-
R'
Ph
Ph
R
P+
Ph
NaOH
rt 1hr
H
O
P
Ph
Ph
Ph
R''
R'
R''
R
O
P
Ph
Ph
Ph
R'
R''
Scheme 2. Synthesis of (E)-3,40,5-substituted stilbene via Wittig reaction.
Table 3
3,5-Dinitro and/or diamino resveratrol derivatives
Compound
Isomer
R
R0
R00
Yield
23
24
25
26
27
28
29
30
31
32
33
34
35
(E)
(Z)
(E)
(Z)
(E)
(Z)
(E)
(E)
(E)
(E)
(E)
(E)
(E)
NO2
NO2
NH2
NH2
NO2
NO2
NO2
NO2
NH2
NH2
NH2
NH2
NHCOCH3
NHCOCF3
NH-BOC-glycine
NH-BOC-
NH-BOC-b-alanine
NH-BOC- -valine
NH-glycine*
F
F
F
F
F
F
F
F
F
F
F
F
F
65a
35a
77b
65b
17b
23b
78c
56c
56d
38d
60d
12d
95e
NHCOCH3
NHCOCF3
NH-BOC-glycine
NH-BOC-
NH-BOC-b-alanine
NH-BOC- -valine
NH-glycine*
L
-alanine
L-alanine
L
L
a
Yield of stilbene formation.
Yield of nitro reduction.
Yield of amine acylation.
Yield of amino acid coupling.
Yield of amino acid deprotection.
b
c
d
e
*
Isolated as trifluoroacetate salt.
is the upregulation of cellular transporter proteins belonging to the
ABC superfamily. These transporters confer resistance by prevent-
ing the intercellular accumulation of chemotherapeutic drugs. The
most widely studied member of this family is ABCB1 or P-glyco-
protein (P-gp) and is one of the major reasons for failure of cancer
therapy. Another member that has been proven responsible for
treatment failure is the multidrug resistance protein family. Over-
coming MDR has become the key focus in the treatment of many
tumours. Modulation of an ABC transporter protein can occur in
a number of ways, including down-regulation of its protein or
mRNA levels, direct inhibition of its transport function or by com-
peting with other substrates thus decreasing the efflux of drugs
from the cell.
Figure 2. X-ray crystal structure and unit cell of (E)-3,5-difluoro-40-nitrostilbene 11
with hydrogen-bonding interactions.
and extends the lifespan of various organisms from yeasts to ver-
tebrates.20 Cancer prevention is one of the mostly widely re-
searched areas today. In vitro and in vivo studies have identified
resveratrol as an effective candidate for cancer chemoprevention
as it blocks each step in the carcinogenesis process.21 These prop-
erties are mainly due to its antioxidant activity on molecular tar-
gets involved in tumour initiation, promotion and progression.22
Multidrug resistance (MDR) is a phenomenon whereby previ-
ously sensitive tumour cells develop resistance to a wide variety
of structurally unrelated compounds. One mechanism of resistance
Herein we report the biological activity of fluorinated and ami-
no derived resveratrol analogues. Preliminary assessment of the
bioactivity of the resveratrol derivatives was determined by assay-

B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
4513
Table 4
IC50 values
ing in non-small cell lung carcinoma and melanoma cell lines. The
in vitro models chosen for investigating the potential of the resve-
ratrol compounds were DLKP, DLKP-A and HT-144. The DLKP-A cell
line is a daughter cell line of DLKP, a poorly differentiated squa-
mous non-small cell lung carcinoma. The P-glycoprotein (P-gp)
membrane pump is the main mechanism of multidrug resistance
(MDR) of the DLKP-A cell line.23 It highly expresses P-gp, while
expressing very low levels of multidrug resistance protein 1
(MRP1). DLKP, on the other hand, expresses highly active MRP1,
while lacking the P-gp cell membrane transporter. Derivatives that
showed inhibitory potency against the lung cell lines were then
subjected to further investigations in combination studies with a
known chemotherapeutic agent epirubicin 36 (Fig. 3). The chemo-
therapeutic drug epirubicin, is used for both MDR transporter pro-
teins as it is a well known P-gp and MRP1 substrate. A cross section
of some 10 compounds synthesised were selected for biological
studies. The compounds were selected based on their solubility
in aqueous solutions and also when added to cell media. A mini-
mum amount of dimethylsulfoxide (DMSO) was used to solubilise
the compounds, before solubility of the solution was tested in
media. A minimum concentration of 0.5 mg/ml in the media was
required for a compound to undergo biological evaluation. This is
due to the toxicity of the solvent DMSO in cell culture systems if
present at higher concentrations.
(lM) of selected resveratrol derivatives on the non-small lung cell
carcinoma cell lines, DLKP and DLKP-A and the melanoma cell line HT-144
Compound
DLKP
DLKP-A
HT-144
1
7
8
10
7
25
6
21
39
2
1
5
0.3
5
15
10
19
14
21
n/aa
3
2
3
2
2
40
36
56
59
54
—
8
1
2
3
3
9
10
15
22
25
29
30
35
2
<10
>50
ꢀ50
28
20 10
>50
—
—
—
—
ꢀ50
4
20 10
>50
>50
—
a
Due to DMSO effects, IC50 calculation not possible.
treatment. The end point determinations were made using the acid
phosphatase assay.24
With regard to the MDR status of resveratrol and its 10 ana-
logues, resveratrol had a slight interaction with both the MRP1
and P-gp transporter proteins while compound 30 was a modula-
tor of the P-gp but not of the MRP1 transporter protein (Fig. 4).
In both the DLKP and DLKP-A cell lines, resveratrol acted in an
additive manner when in combination with epirubicin (Epi.
The compounds tested have the greatest anti-proliferative
activity in the DLKP cell line, followed closely by DLKP-A as shown
by their IC50 values. The melanoma cell line, HT-144, is up to four
times less sensitive to resveratrol and its analogues. Compounds 7
0.01
cell line. The combination of the fluorinated/amino derivatives
(10 M) with the P-gp/MRP1 substrate, 0.01 M epirubicin, re-
lM and Res. 10 lM). This was not the case with the HT-144
l
l
(7
1
l
M), 9 (6 0.3
l
M) and 22 (<10
M) on the DLKP cells (Table 4). Compounds 8
M), 15 (39 M), 25 (>50 M), 29
M) and 35 (>50 M) showed a decrease in
l
M) have similar toxicity to
sulted in no change in the anti-proliferative potential of epirubicin
on the DLKP cells. Therefore, these compounds did not affect the
transporter function of MRP1. A similar outcome was observed
on the HT-144 cell line. On the other hand, a change in the potency
resveratrol 1 (10
(25
2
l
5
l
l
M), 10 (21
5
l
2
l
l
(ꢀ50
M), 30 (28
4
l
l
cytotoxicity when compared to resveratrol. Resveratrol
1
of 1.5 lM epirubicin on the DLKP-A cells was observed when in
(15
3
l
M) and compound 7 (10
2
l
M) were the most potent
combination with compounds 8, 9, 10, 22, 30 and 35. Similar to
the interaction observed between resveratrol and epirubicin on
this cell line, compounds 8, 9, 10, 22 and 35 also acted in an addi-
anti-proliferation agents in the DLKP-A cell line. The 3,5-diacetyl
analogue 29 and the 3,5-diamino acid salt 35, had an IC50 value
greater than 50
lM, as did the trans-diamino stilbene 25, which
tive manner when combined with epirubicin. In Figure 4, 1.5
lM
is outside the parameters of the experimental design. The HT-
144 melanoma cell line had the greatest resistance to resveratrol
and the four fluorinated resveratrol analogues (7–10). Due to this
insensitivity, the amino derivatives were not tested in this cell line.
epirubicin caused a 34% decrease in proliferation, 10 M com-
l
pound 30 caused a 16% reduction in proliferation, however when
they were combined they collectively reduced proliferation by
80%. This increased anti-proliferative effect by the ditrifluoroacetyl
derivative 30 is known as synergism and is characteristic of an
MDR modulator (Tables 5 and 6).
Resveratrol 1 (40
greatest cytotoxic effects on HT-144. Compounds 8 (56
(59 M) and 10 (54 M) had very similar IC50 values in
9
lM) and compound 7 (36
1
l
M) had the
2
lM), 9
3
l
3
l
Four compounds namely 2, 3, 4 and 7 were accepted for anti-
cancer assessment by the National Cancer Institute under the
Development Therapeutic Program (DTP). The compounds were
first assessed using a primary anticancer screen. Previous work
carried out by the DTP used an in vitro model consisting of 60 hu-
man tumour cell lines as the primary anticancer screen. Analysis of
this data indicated that approximately 95% of the actives from the
60 cell line screen can be identified using only three lines. For this
reason the DTP is now using a three cell line panel consisting of
MCF7 (Breast), NCI-H460 (Lung) and SF-268 (CNS) as its primary
anticancer assay. This 3-cell line, one dose assay has been in use
by the DTP for several years for the evaluation of combinatorial li-
braries and has proven to be an effective pre-screen. The inclusion
of this assay allows for a more detailed evaluation of agents that
have exhibited some ability to inhibit the growth of human tumour
cells in culture.
the HT-144 cell line. Both DLKP and DLKP-A were seeded at the
same density (1 ꢁ 103 cell/well) whereas HT-144 was seeded at
3 ꢁ 103 cells/well. The increased cell number employed with HT-
144 assays was due to the requirement of contact for cell growth,
in other words, HT-144 cells need to grow at higher density and
establish cell to cell contacts to proliferate at a rate appropriate
for in vitro toxicity assays. All cell lines had 5 day drug exposure
O
OH
O
OH
OH
In this assay each cell line was inoculated and preincubated on a
microtiter plate. Test agents were then added at a single concentra-
tion and the culture was incubated for 48 h. End point determina-
tions were made with alamar blue. Results for each test agent were
reported as the percent of growth of the treated cells when com-
pared to the untreated control cells. Compounds that reduced the
growth of any one of the cell lines to approximately 32% or less
OCH3O
HO
OH
O
O
H2N
Figure 3. Epirubicin 36.

4514
B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
DLKP
DLKP-A
Alone
100
90
80
70
60
50
40
30
20
10
0
Combination
Epi 0.01uM
Res 10uM
Cpd 30 10uM
Epi 1.5uM
Res 10uM
Cpd 30 10uM
Figure 4. Combination assay of resveratrol, 1, and its amino derivative, 30, with epirubicin (0.01
l
M and 1.5 M) on the DLKP and DLKP-A cell lines.
l
Table 7
Table 5
The growth percentage of human tumour cells in culture when treated with various
fluorinated analogues of resveratrol compared to the untreated control cells
Combination assay data of 1, 7, 8, 9 and 10 with epirubicin on the DLKP, DLKP-A and
HT144 cell lines
Compound
Concn
l
M
Breast
Lung
CNS
Cell proliferation (%)
Alone
St dev (%)
Combination
St dev (%)
2
3
4
7
100
100
100
100
82
84
67
22
101
105
60
111
111
105
1
DLKP
Epirubicin 0.01
Resveratrol 10
7 5
8 5
9 5
10 5
DLKP-A
Epirubicin 10
Resveratrol 10
7 5
8 5
9 5
l
M
83.8
38
52
100
74
98
14
2
23
5
11
6
lM
18
40
10
70
96
4
4
2
40
4
7
l
l
l
M
M
M
l
M
Table 8
Pharmacological values (
l
M) of compound 7 against a selection of tumour cell lines
GI50 IC50
54.6
l
M
78.6
66
50
89
85
7
5
20
5
5
6
lM
36
50
68
56
75
5
30
8
12
4
Tumour cell line
lM
lM
lM
lM
lM
Leukaemia HL-60 (TB)
Lung EKVX
Colon HT29
116.7
116.7
80.6
90.9
83.1
78.7
73.7
60.3
70.1
83.1
75.9
100.5
79.8
10 5
l
M
90
CNS SNB-75
HT144
Epirubicin 0.005
Resveratrol 20
7 20
8 20
9 20
Melanoma SK-MEL-28
Ovarian SK-OV-3
Renal RXF 393
Prostate DU-145
Breast T-47D
l
M
91
100
85
100
105
110
8
10
3
5
5
96.5
lM
82
75
90
93
100
18
13
20
8
202.4
127.7
127.7
l
l
l
M
M
M
10 20
l
M
12
10
were passed on for evaluation in the full panel of 60 cell lines over
a 5-log dosage.
Table 6
The results of this assay indicated that fluorinated analogues of
resveratrol may have potential as anticancer agents. Analogues 2
and 3 showed mild toxicity against the breast tumour cell line with
approximately 20% inhibition recorded but no inhibition of growth
was measured in the lung or CNS cell lines. Compound 4 showed
improved activity in both the breast and lung cell lines with 40%
inhibition recorded for the lung tumour cell lines. The difluoro
derivative, compound 7 was the most potent analogue in breast,
lung and central nervous system tumour cells. It was shown to lim-
it the growth of breast cancer by 78%. Growth of lung cancer cells
only increased by 7% when treated with compound 7. The most
interesting result was that compound 7 limited the growth of
CNS tumour cells by 99% over a two-day period. This compound
was then assessed in the 60 cell line assay that included human tu-
mour cells from leukaemia, lung cancer, colon cancer, central ner-
vous system, melanoma, ovarian cancer, renal cancer, prostate
cancer and breast cancer. The GI50, IC50, LC50 and TGI values were
calculated for each cell line (Tables 7 and 8).
Combination assay data of 1, 15, 22, 25, 29, 30 and 35 with epirubicin on the DLKP
and DLKP-A cell lines
Cell proliferation (%)
Alone
St dev (%)
Combination
St dev (%)
DLKP
Epirubicin 0.01
Resveratrol 10
15 10
22 10
25 10
29 10
30 10
35 10
l
M
64
38
75
25
87
94
95
91
4
2
1
9
1
4
3
3
lM
17
49
21
58
56
56
54
3
2
11
6
5
4
l
l
l
l
l
l
M
M
M
M
M
M
3
DLKP-A
Epirubicin 1.5
Resveratrol 10
15 10
22 10
25 10
29 10
30 10
35 10
l
M
66
67
78
85
98
96
84
92
3
5
2
11
1
1
lM
36
59
42
76
86
19
58
8
5
25
1
2
7
lM
lM
lM
lM
lM
lM
1
8
Compound 7 displayed broad spectrum anticancer activity. It
was most active against the leukaemia cell line giving an IC50 value
17

B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
4515
of 54.29
l
M. It inhibited the growth of cancer most effectively with
M. The
tate 50:1 gave the title product 2 as white crystalline needles
the colon tumour cell line HT29 with a GI50 value of 80.6
l
(0.93 g, 48%).
cytotoxicity of compound 7 is comparable to previously published
results.25 The biological activities of resveratrol analogues have
been best utilised by chemoprevention and cancer growth inhibi-
tion. Cytotoxicity has not been shown to be an essential compo-
nent of potent growth inhibition and chemopreventative agents.
Mp 48–50 °C. Lit.26 mp 47 °C.
Anal. Calcd for C14H9F3: C, 71.79; H, 3.87. Found: C, 72.04; H,
3.99.
IR (KBr):
m .
2956, 2857, 1597, 1510, 1233, 961, 831 cmꢂ1
1H NMR (400 MHz, DMSO-d6): d 7.69–7.73 (2H, m, –ArH 20 and
60), 7.48 (1H, d, J = 16.4 Hz, –CH), 7.38–7.41 (2H, m, –ArH 30 and 50),
7.24–7.32 (3H, m, –ArH 2, 6 and –CH), 7.15–7.20 (1H, m, –ArH 4).
13C NMR (100 MHz, DMSO-d6): d 164.2 (d, –ArC 3), 162.3
(d, –ArC 40), 161.8 (d, –ArC 5), 141.4 (t, –ArC 1), 133.2 (d, –ArC
10), 130.6 (–CH), 129.0 (d, –ArC 20 and 60), 126.4 (d, –CH), 116.0
(–ArC 30 and 50), 109.6 (d, –ArC 2), 109.4 (d, –ArC 6), 102.9 (t, –
ArC 4).
4. Conclusions
In conclusion, the resveratrol derivatives 2–35 were synthes-
ised, fully characterised and a selection of these resveratrol ana-
logues were assayed in lung cancer and melanoma cell lines.
Several display a potency equal to and in the case of (E)-3,5-di-
fluoro-40-acetoxystilbene 7, greater than that of the parent com-
pound resveratrol. Compound 7 was further evaluated on a panel
of 60 cell lines by the National Cancer Institute under the Develop-
ment Therapeutic Program (DTP). The results of this assay indi-
19F NMR (376 MHz, DMSO-d6): d ꢂ34.8 to ꢂ34.9 (2F, m), ꢂ37.8
to ꢂ37.9 (1F, m).
5.2.2. (E)-3,5-Difluoro-40-methoxystilbene (3)
The experimental procedure is identical to the preparation of
cated that compound
7 was a broad spectrum anticancer
compound
2
except 3,5-difluorobenzoyl chloride (1.32 g,
derivative, as activity was observed against leukaemia, colon, lung,
breast, melanoma, prostate, ovarian, central nervous system and
renal cancer lines. It was also shown that in combination studies
with epirubicin (E)-3,5-di(trifluoroacetylamino)-40-fluorostilbene
30 gave the greatest synergy and the greatest anti-proliferative ef-
fect, suggesting a possible interaction with the multi-drug resis-
tance pump, P-glycoprotein.
7.5 mmol) and 4-vinylanisole (1.0 g, 7.5 mmol) were used. Recrys-
tallisation from hexane/ethyl acetate 12:1 furnished 3 as yellow
crystalline needles (0.41 g, 22%).
Mp 107–109 °C. Lit.26 Mp 108–110 °C.
Anal. Calcd for C15H12O1F2: C, 73.16; H, 4.91. Found: C, 72.93; H,
4.98.
IR (KBr):
m .
2963, 2833, 1586, 1511, 1240, 962, 838 cmꢂ1
1H NMR (400 MHz, DMSO-d6): d 7.54 (2H, d, J = 8.4 Hz, –ArH 20
and 60), 7.35 (1H, d, J = 16.4 Hz, –CH), 7.27–7.30 (2H, m, –ArH 2 and
6), 7.01–7.10 (2H, m, –ArH 4 and –CH), 6.96 (2H, d, J = 8.8 Hz, –ArH
30 and 50), 3.76 (3H, s, –OCH3).
5. Experimental
5.1. General procedures
13C NMR (100 MHz, DMSO-d6): d 164.2 (d, –ArC 3), 161.8 (d, –ArC
5), 159.8 (–ArC 40), 141.8 (t, –ArC 1), 131.4 (–CH), 129.2 (–ArC 10),
128.5 (–ArC 20 and 60), 124.2 (t, –CH), 114.5 (–ArC 30 and 50), 109.3
(d, –ArC 2), 109.1 (d, –ArC 6), 102.4 (t, –ArC 4), 55.4 (–OCH3).
19F NMR (376 MHz, DMSO-d6): d ꢂ35.0 (2F, t, JC–F = 5.2 Hz).
All chemicals were purchased from Sigma–Aldrich, Lennox
Chemicals or Fluorochem Limited and used as received. A commer-
cially purchased sample of resveratrol 1 (Sigma–Aldrich, R5010)
was used as a control in all biological assays performed and acid
phosphatase assay kit purchased from Sigma–Aldrich (CS0704).
Commercial grade reagents were used without further purification.
When necessary all solvents were purified and dried; and stored
under argon. Triethylamine was distilled and stored over potas-
sium hydroxide pellets. Riedel-Haën silica gel was used for thin
layer and column chromatography. Melting point determinations
were carried out using a Stuart melting point (SMP3) apparatus
and are uncorrected. Elemental Analysis was carried out by the
Microanalytical Laboratory at University College Dublin. Electro-
spray ionisation mass spectra were obtained on a Bruker Esquire
3000 series ion trap mass spectrometer. IR spectra were obtained
on a Perkin–Elmer Spectrum GX FT-IR system. UV spectra were ob-
tained on a UV–vis–NIR Perkin–Elmer Lambda 900 spectrometer.
NMR spectra were obtained on a Bruker AC 400 NMR spectrometer
operating at 400 MHz for 1H NMR, 376 MHz for 19F NMR and
100 MHz for 13C NMR. The 1H and 13C NMR chemical shifts (d)
are relative to tetramethylsilane and the 19F NMR chemical shifts
(d) are relative to trifluoroacetic acid. All coupling constants (J)
are in hertz (Hz).
5.2.3. (E)-3,5-Dimethoxy-40-fluorostilbene (4)
The experimental procedure is identical to the preparation of
compound
2 except 3,5-dimethoxybenzoyl chloride (1.65 g,
8.2 mmol) and 4-fluorostyrene (1.0 g, 8.2 mmol) were used.
Recrystallisation from hexane/ethyl acetate 50:1 furnished 4 as
yellow crystalline needles (0.55 g, 26%).
Mp 48–49 °C. Lit.26 Mp 46–48 °C.
Anal. Calcd for C16H15O2F1: C, 74.4; H, 5.85. Found: C, 73.49; H,
5.35.
IR (KBr):
m .
2933, 2830, 1598, 1506, 1306, 961, 847 cmꢂ1
1H NMR (400 MHz, DMSO-d6): d 7.62–7.66 (2H, m, –ArH 20 and
60), 7.28 (1H, d, J = 16.4 Hz, –CH), 7.19–7.23 (2H, m, –ArH 30 and 50),
7.13 (1H, d, J = 16.4 Hz, –CH), 6.78 (2H, d, J = 2.4 Hz, –ArH 2 and 6),
6.43 (1H, t, J = 2.4 Hz, –ArH 4), 3.78 (6H, s, –OCH3).
13C NMR (100 MHz, DMSO-d6): d 162.1 (d, –ArC 40), 161.0 (–ArC
3 and 5), 139.3 (–ArC 1), 133.8 (–ArC 10), 128.7 (–CH), 128.6 (d,
–ArC 20 and 60), 128.0 (–CH), 115.9 (d, –ArC 30 and 50), 104.7
(–ArC 2 and 6), 100.2 (–ArC 4), 55.5 (–OCH3).
19F NMR (376 MHz, DMSO-d6): d ꢂ38.8 to ꢂ38.9 (1F, m).
5.2. Synthesis of resveratrol derivatives
5.2.4. (E)-3,5-Difluoro-40-ethoxystilbene (5)
The experimental procedure is identical to the preparation of
5.2.1. (E)-3,40,5-Trifluorostilbene (2)
compound
2
except 3,5-difluorobenzoyl chloride (1.83 g,
3,5-Difluorobenzoyl chloride (1.45 g, 8.2 mmol) and 4-fluoro-
styrene (1.0 g, 8.2 mmol) were added to a solution of palladium
acetate (0.092 g, 0.41 mmol) and N-ethylmorpholine (3.37 g,
8.2 mmol) in xylene (50 ml). The solution was heated at 120 °C
for 18 h and then filtered. The solvent was removed in vacuo to
yield a crude brown solid. Recrystallisation from hexane/ethyl ace-
6.7 mmol) and 4-ethoxystyrene (1.0 g, 6.7 mmol) were used.
Recrystallisation from hexane/ethyl acetate 25:1 furnished 5 as
yellow spherical crystals (0.32 g, 19%).
Mp 82–84 °C.
Anal. Calcd for C16H14O1F2: C, 73.83; H, 5.42. Found: C, 73.61; H,
5.85.

4516
B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
IR (KBr):
m
2907, 2357, 1610, 1042, 844, 647 cmꢂ1
.
1H NMR (400 MHz, CDCl3): d 7.44–7.48 (2H, m, –ArH 20 and 60),
1H NMR (400 MHz, DMSO-d6): d 7.52 (2H, d, J = 8.8 Hz, –ArH 20
and 60), 7.35 (1H, d, J = 16.4 Hz, –CH), 7.27–7.31 (2H, m, –ArH 2 and
6), 7.03–7.09 (2H, m, –ArH 4 and –CH), 6.94 (2H, d, J = 8.8 Hz, –ArH
30 and 50), 4.03 (2H, q, J = 6.8 Hz, –OCH2–), 1.32 (3H, t, J = 6.8 Hz,
–OCH2CH3).
7.03–7.13 (5H, m, –ArH 2, 6, 30, 50 and –CH), 6.94 (1H, d, J = 16.0 Hz,
–CH), 6.84 (1H, t, J = 2.4 Hz, –ArH 4), 2.32 (6H, s, CH3).
13C NMR (100 MHz, CDCl3): d 169.4 (–C@O), 162.9 (d, –ArC 40),
151.6 (–ArC 3 and 5), 139.9 (–ArC 1), 133.2 (d, –ArC 10), 129.8
(–CH), 128.6 (d, –ArC 20 and 60), 127.1 (d, –CH), 117.2 (–ArC 2
and 6), 116.1 (d, –ArC 30 and 50), 114.2 (–ArC 4), 21.5 (–CH3).
19F NMR (376 MHz, CDCl3): d ꢂ38.0 to ꢂ38.1 (1F, m).
13C NMR (100 MHz, DMSO-d6): d 164.2 (d, –ArC 3), 161.8 (d,
–ArC 5), 159.1 (–ArC 40, 141.9 (t, –ArC 1), 131.4 (–CH), 129.0
(–ArC 10), 128.5 (–ArC 20 and 60), 124.1 (–CH), 115.0 (–ArC 30 and
50), 109.2 (d, –ArC 2), 109.1 (d, –ArC 6), 102.4 (t, –ArC 4), 63.4
(–OCH2–, ꢂVE DEPT), 14.9 (–OCH2CH3).
5.2.8. (E)-3,5-Difluoro-40-hydroxystilbene (9)
Ammonium acetate (4.5 g, 54.4 mmol) was added to a solution
of (E)-3,5-difluoro-40-acetoxystilbene (2.0 g, 7.3 mmol) in aqueous
methanol (4:1) and the solution was stirred at room temperature
for 3 h. The title product was extracted with ethyl acetate and
dried over MgSO4. The solvent was removed in vacuo to furnish
9 as an orange solid (1.03 g, 81%).
19F NMR (376 MHz, DMSO-d6): d ꢂ35.0 (2F, t, JC–F = 5.2 Hz).
5.2.5. (E)-3,5-Diethoxy-40-fluorostilbene (6)
The experimental procedure is identical to the preparation of
compound
8.2 mmol) and 4-fluorostyrene (1.0 g, 8.2 mmol) were used.
Recrystallisation from hexane/ethyl acetate 25:1 furnished 6 as
yellow crystalline needles (0.68 g, 29%).
Mp 58–60 °C.
Anal. Calcd for C18H19O2F1: C, 75.50; H, 6.68. Found: C, 75.60; H,
6.59.
2
except 3,5-diethoxybenzoyl chloride (1.87 g,
Mp 142–144 °C. Lit.27 Mp 141–142 °C.
Anal. Calcd for C14H10O1F2: C, 72.40; H, 4.34. Found: C, 72.27; H,
4.61.
IR (KBr):
m .
3364, 2926, 1592, 1246, 1104, 961 cmꢂ1
1H NMR (400 MHz, DMSO-d6): d 8.04 (1H, s, –OH), 7.43 (2H, d,
J = 8.4 Hz, –ArH 20 and 60), 7.24–7.31 (3H, m, –ArH 2, 6 and –CH),
6.97–7.01 (2H, m, –ArH 4 and –CH), 6.81 (2H, d, J = 8.8 Hz, –ArH
30 and 50).
IR (KBr):
m .
2974, 2351, 1591, 1505, 1382, 1184, 968, 832 cmꢂ1
1H NMR (400 MHz, DMSO-d6): d 7.61–7.65 (2H, m, –ArH 20 and
60), 7.27 (1H, d, J = 16.0 Hz, –CH), 7.20 (2H, t, J = 8.8 Hz, –ArH 30 and
50), 7.10 (1H, d, J = 16.4 Hz, –CH), 6.74 (2H, d, J = 2.4 Hz, –ArH 2 and
6), 6.39 (1H, t, J = 2.4 Hz, –ArH 4), 4.03 (4H, q, J = 7.2 Hz, –OCH2–),
1.33 (6H, t, J = 7.2 Hz, –OCH2CH3).
13C NMR (100 MHz, DMSO-d6): d 164.2 (d, –ArC 3), 161.8 (d,
–ArC 5), 158.3 (–ArC 40), 142.0 (t, –ArC 1), 131.8 (–CH), 128.7
(–ArC 20 and 60), 127.6 (–ArC 10), 123.1 (d, –CH), 116.0 (–ArC 30
and 50), 109.0 (d, –ArC 2), 108.9 (d, –ArC 6), 102.1 (t, –ArC 4).
19F NMR (376 MHz, DMSO-d6): d ꢂ35.0 (2F, t, JC–F = 8.6 Hz).
13C NMR (100 MHz, DMSO-d6): d 162.0 (d, –ArC 40), 160.2 (–ArC
3 and 5), 139.2 (–ArC 1), 133.9 (d, –ArC 10), 128.7 (–ArC 20 and 60),
128.6 (–CH), 127.9 (–CH), 115.9 (d, –ArC 30 and 50), 105.1 (–ArC 2
and 6), 100.9 (–ArC 4), 63.3 (–OCH2–, ꢂVE DEPT), 14.9 (–OCH2CH3).
19F NMR (376 MHz, DMSO-d6): d ꢂ38.8 to ꢂ38.9 (1F, m).
5.2.9. (E)-3-Acetoxy-5-hydroxy-40-fluorostilbene (10)
The experimental procedure is identical to the preparation of
compound
9
except (E)-3,5-diacetoxy-40-fluorostilbene (0.1 g,
0.32 mmol) was used. The title product was extracted with ethyl
acetate and dried over MgSO4. The solvent was removed in vacuo
to furnish 10 as a white powder (1.05 g, 76%).
Mp 118–120 °C.
5.2.6. (E)-3,5-Difluoro-40-acetoxystilbene (7)
The experimental procedure is identical to the preparation of
compound
2
except 3,5-difluorobenzoyl chloride (4.38 g,
24.6 mmol) and 4-acetoxystyrene (4.0 g, 24.6 mmol) were used.
Recrystallisation from hexane/ethyl acetate 12:1 furnished 7 as
yellow planar crystals (3.94 g, 58%).
Anal. Calcd for C16H13O3F1: C, 70.58; H, 4.81. Found: C, 70.35; H,
5.00.
IR (KBr):
m .
3336, 2364, 1770, 1586, 1509, 1206, 852 cmꢂ1
Mp 142–144 °C.
Anal. Calcd for C16H12O2F2: C, 70.07; H, 4.41. Found: C, 69.72; H,
1H NMR (400 MHz, CDCl3): d 7.40–7.43 (2H, m, –ArH 20 and 60),
7.01–7.06 (2H, m, –ArH 30 and 50), 6.97 (1H, d, J = 16.6 Hz, –CH),
6.85 (1H, d, J = 16.6 Hz, –CH), 6.78 (2H, d, J = 8.8 Hz, –ArH 2 and
6), 6.49 (1H, t, J = 2.0 Hz, –ArH 4), 6.13 (1H, s, –OH), 2.33 (3H, s,
CH3).
4.46.
IR (KBr):
m .
2926, 2351, 1752, 1616, 1208, 968 cmꢂ1
1H NMR (400 MHz, DMSO-d6): d 7.63 (2H, d, J = 8.4 Hz, –ArH 20
and 60), 7.44 (1H, d, J = 16.4 Hz, –CH), 7.32–7.36 (2H, m, –ArH 2 and
6), 7.23 (1H, d, J = 16.4 Hz, –CH), 7.17 (2H, d, J = 8.8 Hz, –ArH 30 and
50), 7.08–7.14 (1H, m, –ArH 4), 2.29 (3H, s, –CH3).
13C NMR (100 MHz, CDCl3): d 170.6 (–C@O), 162.9 (d, –ArC 40),
157.2 (–ArC 3), 151.9 (–ArC 5), 140.1 (–ArC 1), 133.3 (d, –ArC 10),
129.1 (–CH), 128.5 (d, –ArC 20 and 60), 127.6 (–CH), 116.0 (d, –ArC
30 and 50), 111.9 (–ArC 6), 111.6 (–ArC 2), 108.8 (–ArC 4), 21.6 (–
CH3).
13C NMR (100 MHz, DMSO-d6): d 169.5 (–C@O), 164.2 (d, –ArC
3), 161.8 (d, –ArC 5), 150.7 (–ArC 40), 141.4 (t, –ArC 1), 134.3
(–ArC 10), 130.8 (–CH), 128.1 (–ArC 20 and 60), 126.6 (–CH), 122.5
(–ArC 30 and 50), 109.6 (d, –ArC 2), 109.5 (d, –ArC 6), 102.7 (t,
–ArC 4), 21.1 (–CH3).
19F NMR (376 MHz, CDCl3): d ꢂ39.3 to ꢂ39.4 (1F, m).
5.2.10. (E/Z)-3,5-Difluoro-40-nitrostilbene (11/12)
19F NMR (376 MHz, DMSO-d6): d ꢂ34.8 (2F, t, JC–F = 8.6 Hz).
3,5-Difluorobenzyl triphenyl phosphonium bromide (11.7 g,
25 mmol) and 4-nitrobenzaldehyde (4.7 g, 31.25 mmol) were dis-
solved in dichloromethane (150 ml) and stirred at room tempera-
ture. A 50% w/v sodium hydroxide solution was added dropwise
to the stirred solution [0.4 ml NaOH solution per 1 mmol of alde-
hyde]. The solution was stirred at room temperature for 1 h then
washed with brine and water. The solvent was removed in vacuo
to yield both isomers as a yellow solid. Recrystallisation from eth-
anol gave the trans-isomer as a bright yellow powder 11 (3.2 g,
49%). Crystals of 11 suitable for X-ray analysis were grown from
toluene. The resulting mother liquor was evaporated to dryness
to yield the cis product as a pale yellow powder 12 (3.0 g, 46%).
5.2.7. (E)-3,5-Diacetoxy-40-fluorostilbene (8)
The experimental procedure is identical to the preparation of
compound
2
except 3,5-diacetoxybenzoyl chloride (1.03 g,
4.0 mmol) and 4-fluorostyrene (0.48 g, 4.0 mmol) were used.
Recrystallisation from hexane/ethyl acetate 3:1 furnished 8 as
white crystalline needles (0.82 g, 65%).
Mp 161–162 °C.
Anal. Calcd for C18H15O4F1: C, 68.78; H, 4.81. Found: C, 68.91; H,
4.65.
IR (KBr):
m .
3119, 2929, 1774, 1655, 1509, 1401, 1197, 912 cmꢂ1

B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
4517
5.2.10.1. trans-Isomer (11). Mp 199–201 °C.
Anal. Calcd for C14H9N1O2F2: C, 64.37; H, 3.47; N, 5.36. Found: C,
64.12; H, 3.47; N, 5.21.
5.2.12. (Z)-3,5-Difluoro-40-aminostilbene (14)
The experimental procedure is identical to the preparation of
compound 13 except (Z)-3,5-difluoro-40-nitrostilbene (1.0 g,
3.8 mmol) was used. Purification by column chromatography with
hexane/ethyl acetate as eluant furnished 14 as a brown oil (1.0 g,
80%).
IR (KBr):
1618, 1589, 1509, 1439, 1336, 1116, 974, 865, 748, 707, 691,
665 cmꢂ1
m 3085, 2929, 2831, 2442, 2209, 1927, 1793, 1726,
.
UV (kmax) (ACN): 337 nm.
Bp 180–185 °C.
1H NMR (400 MHz, DMSO-d6): d 8.27 (2H, d, J = 8.8 Hz, –ArH 30
and 50), 7.86 (2H, d, J = 9.2 Hz, –ArH 20 and 60), 7.59 (1H, d,
J = 16.4 Hz, –CH), 7.51 (1H, d, J = 16.4 Hz, –CH–), 7.43 (2H, m,
–ArH 2 and 6), 7.21 (1H, tt, J = 2.4 and 9.2 Hz, –ArH 4).
13C NMR (100 MHz, DMSO-d6): d 162.8 (d, J = 244.2 Hz, –CF),
162.6 (d, J = 244.0 Hz, –CF), 146.6 (–ArC 40), 143.1 (–ArC 10), 140.2
(t, J = 9.9 Hz, (–ArC 1), 130.8 (–CH), 129.3 (–CH), 127.6 (–ArC 20
and 60), 124.1 (–ArC 30 and 50), 109.9 (d, J = 25.6 Hz, –ArC 2 and
6), 103.6 (t, J = 25.9 Hz, –ArC 4).
Anal. Calcd for C14H11N1F2: C, 72.72; H, 4.79; N, 6.06. Found: C,
72.52; H, 4.93; N, 5.88.
IR (ATR):
m 3461, 3372, 3214, 3010, 1616, 1603, 1583, 1514,
1445, 1429, 1307, 1176, 1113, 988, 966, 871, 830, 794, 666 cmꢂ1
.
UV (ACN): kmax 238 nm; 314, 336 (sh) nm.
1H NMR (400 MHz, DMSO-d6): d 7.05 (1H, tt, J = 2.2 and 9.2 Hz,
–ArH 4) 6.93 (4H, d, J = 8.4 Hz, –ArH 2, 6, 20 and 60), 6.55 (1H, d,
J = 12.4 Hz, –CH), 6.46 (2H, d, J = 8.4 Hz, –ArH 30 and 50), 6.29 (1H,
d, J = 12.4 Hz, –CH), 5.34 (2H, s, –NH2).
19F NMR (376 MHz, DMSO-d6): d ꢂ109.82 (2F, t, JC–F = 9.4 Hz).
13C NMR (100 MHz, DMSO-d6): d 162.3 (d, J = 243.8 Hz, –CF),
162.2 (d, J = 243.7 Hz, –CF), 148.7 (–ArC 40), 141.6 (t, J = 9.9 Hz,
–ArC 1), 133.0 (–CH), 129.7 (–ArC 20 and 60), 123.3 (–CH), 122.8
(–ArC 10), 113.4 (–ArC 30 and 50), 111.2 (d, J = 25.1 Hz, –ArC 2 and
6), 102.0 (t, J = 25.8 Hz, –ArC 4).
5.2.10.2. cis-Isomer (12). Mp 73–75 °C.
Anal. Calcd for C14H9N1O2F2: C, 64.37; H, 3.47; N, 5.36. Found: C,
64.35; H, 3.67; N, 5.16.
19F NMR (376 MHz, DMSO-d6): d ꢂ110.47 (2F, t, JC–F = 8.8 Hz).
IR (KBr):
m 3106, 3081, 2836, 2442, 1928, 1640, 1587, 1503,
1447, 1432, 1340, 1321, 1179, 1127, 1104,996, 970, 882, 860,
5.2.13. (E)-3,5-Difluoro-40-acetylaminostilbene (15)
(E)-3,5-Difluoro-40-aminostilbene (0.96 g, 4.16 mmol) was dis-
solved in ethyl acetate (5ml) and three drops of pyridine. Acetic
anhydride (1.18 ml, 12.47 mmol) was added dropwise to this solu-
tion and the reaction was stirred at room temperature for 40 min
before washing with water and brine. Recrystallisation from hex-
ane/ethyl acetate yielded the title compound 15 as a white powder
(0.79 g, 70%).
842, 767, 750, 732, 695, 666 cmꢂ1
.
UV (ACN): kmax 314 nm.
1H NMR (400 MHz, DMSO-d6): d 8.17 (2H, d, J = 9.2 Hz, –ArH 30
and 50), 7.48 (2H, d, J = 8.4 Hz, –ArH 20 and 60), 7.17 (1H, tt, J = 2.4
and 9.4 Hz, –ArH 4) 6.84–6.92, (4H, m, –ArH 2 and 6, –CH, –CH).
13C NMR (100 MHz, DMSO-d6): d 162.4 (d, J = 245.0 Hz, –CF),
162.3 (d, J = 244.7 Hz, –CF), 146.4 (–ArC 40), 143.0 (–ArC 10), 139.6
(t, J = 9.9 Hz, –ArC 1), 130.9 (–CH), 130.4 (–CH), 129.8 (–ArC 20
and 60), 123.7 (–ArC 30 and 50), 111.6 (d, J = 25.5 Hz, –ArC 2 and
6), 103.3 (t, J = 25.8 Hz, –ArC 4).
Mp 217–220 °C.
IR (KBr):
m 3290, 3098, 3047, 3021, 1663, 1619, 1584, 1522,
1408, 1369, 1314, 1118, 980, 961, 847, 810, 673 cmꢂ1
.
19F NMR (376 MHz, DMSO-d6): d ꢂ109.57 (2F, t, JC–F = 8.0 Hz).
UV (ACN): kmax 327 nm.
1H NMR (400 MHz, DMSO-d6): d 10.07 (1H, s, –NH–), 7.62 (2H,
d, J = 8.8 Hz, –ArH 30 and 50), 7.53 (2H, d, J = 8.4 Hz, –ArH 20 and
60), 7.30–7.38 (3H, m, –ArH 2, 6 and –CH), 7.06–7.16 (2H, m,
–ArH 4 and –CH), 2.06 (3H, s, –CH3).
5.2.11. (E)-3,5-Difluoro-40-aminostilbene (13)
(E)-3,5-Difluoro-40-nitrostilbene (1.42 g, 5.4 mmol) was dis-
solved in a 10:1 mixture of ethanol and acetic acid (22 ml) and
heated to reflux temperature. Iron(III) chloride hexahydrate
(0.25 g, 0.93 mmol), followed by iron pindust (2.22 g, 39.7 mmol)
was added with vigorous stirring and the solution refluxed for
3 h. The solution was filtered and diluted with water. The product
was extracted with diethyl ether and dried over sodium sulfate.
Purification by column chromatography with hexane/ethyl acetate
as eluant yielded compound 13 as a brown powder (1.1 g, 88%).
Mp 110–112 °C.
13C NMR (100 MHz, DMSO-d6): d 168.3 (–C@O), 162.7 (d,
J = 243.0 Hz, –CF), 162.6 (d, J = 243.1 Hz, –CF), 141.4 (t, J = 9.7 Hz,
–ArC 1), 139.5 (–ArC 10), 131.1 (–CH), 131.0 (–ArC 40), 127.3 (–ArC
20 and 60), 124.6 (–CH), 119.0 (–ArC 30 and 50), 108.9 (d,
J = 12.0 Hz, –ArC 2 and 6), 102.2 (t, J = 26.0 Hz, –ArC 4), 24.0 (–CH3).
19F NMR (376 MHz, DMSO-d6): d ꢂ110.26 (2F, t, JC–F = 7.5 Hz).
5.2.14. (E)-3,5-Difluoro-40-(trifluoroacetyl)aminostilbene (16)
The experimental procedure is identical to the preparation of
compound 15 except (E)-3,5-difluoro-40-aminostilbene (1.45 g,
6.28 mmol) was used. Recrystallisation from hexane/ethyl acetate
yielded compound 16 as a beige powder (1.27 g, 62%).
Mp 188–191 °C.
Anal. Calcd for C14H11N1F2: C, 72.72; H, 4.79; N, 6.06. Found: C,
72.48; H, 4.90; N, 5.97.
Mass Spectrum: [M+H]+ found 232.4.
C14H12N1F2 requires, 232.24.
IR (KBr):
1617, 1586, 1447, 1429, 1312, 1268, 1183, 1138, 1116, 997, 979,
965, 881, 839, 818, 670 cmꢂ1
m 3483, 3466, 3396, 3380, 3206, 3091, 3025, 1894,
Anal. Calcd for C16H10N1O1F5: C, 58.72; H, 3.08; N, 4.28. Found:
C, 58.58; H, 3.09; N, 4.19.
.
IR (KBr):
m 3296, 3095, 1705, 1619, 1589, 1541, 1450, 1291,
UV (ACN): kmax 315 nm; 242 (sh), 339 (sh) nm.
1248, 1186, 1155, 1118, 984, 958, 913, 841, 808, 734, 669 cmꢂ1
.
1H NMR (400 MHz, DMSO-d6): d 7.20–7.30 (5H, m, –ArH 20, 60,
–CH, –ArH 2 and 6), 7.00 (1H, tt, J = 2.2 and 9.4 Hz, –ArH 4), 6.89
(1H, d, J = 16.4 Hz, –CH), 6.57 (2H, d, J = 8.4 Hz, –ArH 30 and 50),
5.45 (2H, s, –NH2).
UV (ACN): kmax 321 nm.
1H NMR (400 MHz, DMSO-d6): d 11.38 (1H, s, –NH–), 7.73 (2H,
d, J = 8.8 Hz, –ArH 30 and 50), 7.65 (2H, d, J = 8.4 Hz, –ArH 20 and 60),
7.42 (1H, d, J = 16.8 Hz, –CH), 7.36 (2H, m, –ArH 2 and 6), 7.24 (1H,
d, J = 16.8 Hz, –CH), 7.13 (1H, tt, J = 2.2 and 9.2 Hz, –ArH 4).
13C NMR (100 MHz, DMSO-d6): d 162.8 (d, J = 243.7 Hz, –CF),
162.6 (d, J = 243.6 Hz, –CF), 154.4 (q, J = 36.8 Hz, –C@O), 141.0 (t,
J = 9.8 Hz, –ArC 1), 136.3 (–ArC 10), 133.6 (–ArC 40), 130.6 (–CH),
127.4 (–ArC 20 and 60), 126.1 (–CH), 121.1 (–ArC 30 and 50), 115.7
13C NMR (100 MHz, DMSO-d6): d 162.7 (d, J = 242.9 Hz, –CF),
162.6 (d, J = 243.0 Hz, –CF), 149.4 (–ArC 40), 142.1 (t, J = 9.8 Hz,
–ArC 1), 132.1 (–CH), 128.1 (–ArC 20 and 60), 123.7 (–ArC 10),
120.3 (–CH), 113.7 (–ArC 30 and 50), 108.2 (d, J = 25.1 Hz, –ArC 2
and 6), 101.2 (t, J = 26.1 Hz, –ArC 4).
19F NMR (376 MHz, DMSO-d6): d ꢂ110.55 (2F, t, JC–F = 7.5 Hz).

4518
B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
(q, J = 286.9 Hz, –CF3), 109.2 (d, J = 25.4 Hz, –ArC 2 and 6), 102.6 (t,
J = 26.0 Hz, –ArC 4).
7.36 mmol) were used. Purification by column chromatography
with hexane/ethyl acetate as eluant gave the title compound 19
as a white powder (0.54 g, 18%).
19F NMR (376 MHz, DMSO-d6): d ꢂ73.83 (3F, s, –CF3), ꢂ110.14
(2F, t, JC–F = 7.5 Hz).
Mp 227–229 °C.
Anal. Calcd for C22H24N2O3F2: C, 65.66; H, 6.01; N, 6.96. Found:
C, 65.38; H, 5.96; N, 6.80.
5.2.15. (E)-3,5-Difluoro-40-dimethylaminostilbene (17)
The experimental procedure is identical to the preparation of
compounds 11/12 except 3,5-difluorobenzyl triphenyl phospho-
nium bromide (2.5 g, 5.33 mmol) and 4-dimethylaminobenzalde-
hyde (0.99 g, 6.66 mmol) were used. Recrystallisation from
ethanol gave the trans product 17 as yellow crystals (0.45 g, 32%).
Mp 139–141 °C.
IR (KBr):
m 3335, 2986, 2939, 1674, 1587, 1517, 1444, 1411,
1366, 1316, 1250, 1161, 1112, 1073, 979, 959, 841, 666, 630 cmꢂ1
.
UV (ACN): kmax 325 nm.
1H NMR (400 MHz, DMSO-d6): d 10.08 (1H, s, –NH) 7.66 (2H, d,
J = 8.8 Hz, –ArH 30 and 50), 7.56 (2H, d, J = 8.8 Hz, –ArH 20 and 60),
7.32–7.39 (3H, m, –ArH 2, 6 and –CH), 7.06–7.18 (3H, m, –CH,
Anal. Calcd for C16H15N1F2: C, 74.11; H, 5.83; N, 5.40. Found: C,
74.19; H, 5.96; N, 5.38.
–ArH 4 and –NH), 4.13 (1H, quin, J = 7.2,
1.28 (3H, d, J = 7.2 Hz, –CH3).
a-H), 1.39 (9H, s, t-CH3),
IR (KBr):
1522, 1445, 1355, 1316, 1220, 1194, 1116, 977, 964, 876, 841,
805, 674 cmꢂ1
m
3094, 3020, 2898, 2862, 2810, 2359, 1883, 1599,
13C NMR (100 MHz, DMSO-d6): d 171.9 (–COCH2), 162.8 (d,
J = 243.5 Hz, –CF), 162.6 (d, J = 243.5 Hz, –CF), 155.2 (–COOt-Butyl),
141.3 (t, J = 10.0 Hz, –ArC 1), 139.2 (–ArC 40), 131.2 (–CH), 131.0
(–ArC 10), 127.4 (–ArC 20 and 60) 124.7 (–CH), 119.2 (–ArC 30 and
50), 109.0 (d, J = 25.3 Hz, –ArC 2 and 6), 102.3 (t, J = 26.1 Hz, –ArC
.
UV (ACN): kmax 364 nm.
1H NMR (400 MHz, DMSO-d6): d 7.43 (2H, d, J = 8.8 Hz, –ArH 30
and 50), 7.24–7.31 (3H, m, –ArH 2, 6 and –CH), 6.93–7.03 (2H, m,
–ArH 4 and –CH), 6.72 (2H, d, J = 8.8 Hz, –ArH 20 and 60), 2.94
(6H, s, –CH3).
4), 78.0 (–C(CH3)3), 50.4 (a-C), 28.2 (–C(CH3)3), 17.9 (–CH3).
19F NMR (376 MHz, DMSO-d6): d ꢂ110.24 (2F, t, J = 9.4 Hz).
13C NMR (100 MHz, DMSO-d6): d 161.2 (d, J = 243.0 Hz, –CF),
162.7 (d, J = 243.0 Hz, –CF), 150.3 (–ArC 10), 142.1 (t, J = 9.5 Hz,
–ArC 1), 132.0 (–CH), 128.0 (–ArC 30 and 50), 123.9 (–ArC 40),
121.1 (–CH), 112.0 (–ArC 20 and 60), 108.4 (d, J = 19 Hz, –ArC 2
and 6), 101.4 (t, J = 26.5 Hz, –ArC 4), 39.8 (–CH3).
5.2.18. (E)-3,5-Difluoro-40-N-(BOC-b-alanine)aminostilbene (20)
The experimental procedure is identical to the preparation of
compound 18 except (E)-3,5-difluoro-40-aminostilbene (0.58 g,
2.51 mmol)
and
N-tert-butoxycarbonyl-b-alanine
(0.48 g,
2.51 mmol) were used. Purification by column chromatography
with hexane/ethyl acetate as eluant furnished 20 as a white pow-
der (0.12 g, 12%).
19F NMR (376 MHz, DMSO-d6): d ꢂ110.52 (2F, t, JC–F = 7.5 Hz).
5.2.16. (E)-3,5-Difluoro-40-N-(BOC-glycine)aminostilbene (18)
(E)-3,5-Difluoro-40-aminostilbene (0.8 g, 3.85 mmol) was dis-
solved in dichloromethane (20 ml). N-tert-Butoxycarbonyl-glycine
(0.68 g, 3.85 mmol), 1-hydroxybenzotriazole (0.52 g, 3.85 mmol)
and triethylamine (0.54 ml, 3.85 mmol) were added to stirred solu-
tion. The reaction mixture was cooled to 0 °C, and N-ethyl-N0-(3-
dimethylaminopropyl) carbodiimide (0.74 g, 3.85 mmol) was
added. After 30 min the solution was raised to room temperature
and the reaction was allowed to proceed for 48 h. The solution
was washed with brine, satd potassium hydrogen carbonate, 10%
citric acid and dried over sodium sulfate. The solvent was evapo-
rated in vacuo and purification was achieved by column chroma-
tography with hexane/ethyl acetate. Recrystallisation from ethyl
acetate/hexane furnished 18 as a white powder (0.25 g, 17%).
Mp 189–191 °C.
Mp 213–215 °C.
Anal. Calcd for C22H24N2O3F2: C, 65.66; H, 6.01; N, 6.96. Found:
C, 65.28; H, 6.07; N, 6.77.
IR (KBr):
m 3353, 2985, 1682, 1619, 1588, 1521, 1446, 1411,
1343, 1281, 1248, 1167, 1113, 980, 958, 841, 667 cmꢂ1
.
UV (ACN): kmax 326 nm.
1H NMR (400 MHz, DMSO-d6): d 10.07 (1H, s, –NH), 7.64 (2H, d,
J = 8.4 Hz, –ArH 30 and 50), 7.54 (2H, d, J = 8.4 Hz, –ArH 20 and 60),
7.31–7.38 (3H, m, –ArH 2, 6 and –CH), 7.06–7.17 (2H, m, –CH,
–ArH 4), 6.90 (1H, t, J = 5.6 Hz, –NH), 3.23 (2H, q, J = 6.4 Hz, b-H),
2.47–2.52 (m, a-H), 1.38 (9H, s, t-CH3).
13C NMR (100 MHz, DMSO-d6): d 169.5 (–COCH2), 162.8 (d,
J = 243.0 Hz, –CF), 162.7 (d, J = 243.0 Hz, –CF), 155.5 (–COOt-Butyl),
141.3 (t, J = 10.0 Hz, –ArC 1), 139.3 (–ArC 40), 131.0 (–CH), 131.0
(–ArC 10), 127.3 (–ArC 20 and 60) 124.7 (–CH), 119.1 (–ArC 30 and
50), 109.0 (d, J = 25.0 Hz, –ArC 2 and 6), 102.3 (t, J = 26.0 Hz, –ArC
Anal. Calcd for C21H22N2O3F2: C, 64.94; H, 5.71; N, 7.21. Found:
C, 64.81; H, 5.70; N, 7.12.
4), 77.6 (–C(CH3)3), 36.8 (a-C, –VE DEPT), 36.4 (b-C, –VE DEPT),
IR (KBr):
m 3414, 3277, 3195, 2977, 1679, 1603, 1509, 1447,
28.2 (–C(CH3)3).
1414, 1371, 1313, 1277, 1166, 1117, 1056, 962, 844, 670 cmꢂ1
.
19F NMR (376 MHz, DMSO-d6): d ꢂ110.25 (2F, t, J = 7.5 Hz).
UV (ACN): kmax 321 nm.
1H NMR (400 MHz, DMSO-d6): d 10.05 (1H, s, –NH) 7.63 (2H, d,
J = 8.4 Hz, –ArH 30 and 50), 7.55 (2H, d, J = 8.8 Hz, –ArH 20 and 60),
7.31–7.38 (3H, m, –ArH 2, 6 and –CH), 7.15 (1H, d, J = 16.4 Hz,
–CH), 7.06–7.12 (2H, m, –ArH 4 and –NH), 3.73 (2H, d, J = 6.0 Hz,
–CH2), 1.40 (9H, s, t-CH3).
5.2.19. (E)-3,5-Difluoro-40-N-(BOC-
L-valine)aminostilbene (21)
The experimental procedure is identical to the preparation of
compound 18 except (E)-3,5-difluoro-40-aminostilbene (0.97 g,
4.20 mmol) and N-tert-butoxycarbonyl-L-valine (0.91 g, 4.20
mmol) were used. Purification by column chromatography with
hexane/ethyl acetate as eluant yielded 21 as a white powder
(0.20 g, 11%).
Mp 177–180 °C.
Anal. Calcd for C24H28N2O3F2: C, 66.96; H, 6.56; N, 6.51. Found:
C, 66.71; H, 6.57; N, 6.51.
13C NMR (100 MHz, DMSO-d6): d 168.3 (–COCH2), 162.8 (d,
J = 243.3 Hz, –CF), 162.6 (d, J = 243.6 Hz, –CF), 155.9 (–COOt-Butyl),
141.4 (t, J = 9.9 Hz, –ArC 1), 139.1 (–ArC 40), 131.2 (–CH), 131.1
(–ArC 10), 127.4 (–ArC 20 and 60) 124.8 (–CH), 119.1 (–ArC 30 and
50), 109.0 (d, J = 25.4 Hz, –ArC 2 and 6), 102.0 (t, J = 26.2 Hz, –ArC
4), 78.0 (–C(CH3)3), 43.8 (–CH2, –VE DEPT), 28.2 (–C(CH3)3).
19F NMR (376 MHz, DMSO-d6): d ꢂ110.28 (2F, t, JC–F = 7.5 Hz).
IR (KBr):
m 3337, 2964, 2871, 1666, 1588, 1516, 1447, 1412,
1367, 1310, 1246, 1168, 1116, 982, 961, 844, 668 cmꢂ1
.
UV (ACN): kmax 307 nm.
5.2.17. (E)-3,5-Difluoro-40-N-(BOC-
L-alanine)aminostilbene (19)
1H NMR (400 MHz, DMSO-d6): d 10.06 (1H, s, –NH), 7.65 (2H, d,
J = 8.4 Hz, –ArH 30 and 50), 7.55 (2H, d, J = 8.4 Hz, –ArH 20 and 60),
7.32–7.39 (3H, m, –ArH 2, 6 and –CH), 7.07–7.18 (2H, m, –CH,
The experimental procedure is identical to the preparation of
compound 18 except (E)-3,5-difluoro-40-aminostilbene (1.7 g,
7.36 mmol)
and
N-tert-butoxycarbonyl-
L
-alanine
(1.39 g,
–ArH 4), 6.94 (1H, d, J = 8.8 Hz, –NH), 3.92 (1H, t, J = 7.8 Hz, a-H),

B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
4519
1.96–2.01 (m, –CH(CH3)2), 1.38 (9H, s, t-CH3), 0.90 (6H, d, J = 6.4 Hz,
–CH(CH3)2).
(0.59 g, 5.57 mmol) were used. Recrystallisation from ethanol gave
the trans-isomer 23 as a mustard yellow powder (0.47 g, 35%). The
resulting mother liquor was evaporated to dryness to yield the cis-
isomer 24 as a pale yellow powder (0.62 g, 46%).
Mp 93–96 °C.
13C NMR (100 MHz, DMSO-d6): d 170.8 (–COCH2), 162.8 (d,
J = 243.5 Hz, –CF), 162.6 (d, J = 243.5 Hz, –CF), 155.6 (–COOt–Butyl),
141.3 (t, J = 9.8 Hz, –ArC 1), 139.0 (–ArC 40), 131.3 (–CH), 131.0
(–ArC 10), 127.3 (–ArC 20 and 60) 124.8 (–CH), 119.3 (–ArC 30 and
50), 109.0 (d, J = 25.3 Hz, –ArC 2 and 6), 102.3 (t, J = 26.0 Hz, –ArC
IR (KBr):
m 3102, 2954, 2922, 2869, 2359, 2341, 1903, 1600,
1535, 1506, 1342, 1314, 1218, 1158, 1076, 955, 916, 860, 841,
4), 78.0 (–C(CH3)3), 60.6 (a-C), 30.3 (–C(CH3)2), 28.1 (–C(CH3)3),
826, 816, 752, 730, 644 cmꢂ1
.
19.2 (–CH3), 18.4 (–CH3).
UV (ACN): kmax 262 nm.
19F NMR (376 MHz, DMSO-d6): d ꢂ110.25 (2F, t, J = 7.5 Hz).
1H NMR (400 MHz, DMSO-d6): d 8.67 (1H, t, J = 2.2 Hz, –ArH 4),
8.40, (2H, d, J = 2.0 Hz, –ArH 2 and 6), 7.31–7.34 (2H, m, –ArH 20
and 60), 7.17 (2H, t, J = 8.8 Hz, –ArH 30 and 50), 6.99 (1H, d,
J = 12.0 Hz, –CH), 6.87 (1H, d, J = 12.4 Hz, –CH).
5.2.20. (E)-3,5-Difluoro-40-(aminoglycine)stilbene
trifluoroacetate salt (22)
(E)-3,5-difluoro-40-(amino-BOC-glycine)stilbene (0.22 g, 0.57
mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic
acid (5 ml) was added and the reaction was stirred at room tem-
perature for 1 h. The reaction was monitored by thin layer chroma-
tography. The solvent and excess TFA was evaporated with
nitrogen stream. The crude residue was recrystallised from ethyl
acetate to yield the title product 22 as a white powder (0.21 g, 92%)
Mp 196–199 °C.
13C NMR (100 MHz, DMSO-d6): d 161.6 (d, J = 244.4 Hz, –CF),
147.9 (–ArC 3 and 5), 139.7 (–ArC 1), 133.3 (–CH), 131.5 (d,
J = 3.5 Hz, –ArC 10), 130.5 (d, J = 8.1 Hz, –ArC 20 and 60), 128.6
(–ArC 2 and 6), 126.1 (–CH), 116.7 (–ArC 4), 115.7 (d, J = 21.3 Hz,
–ArC 30 and 50).
19F NMR (376 MHz, DMSO-d6): d ꢂ112.98 to ꢂ113.05 (1F, m).
5.2.23. (E)-3,5-Diamino-40-fluorostilbene (25)
The experimental procedure is identical to the preparation of
compound 13 except (E)-3,5-dinitro-40-fluorostilbene (1.4 g,
4.86 mmol) was used. The title product 25 was purified by column
chromatography with hexane/ethyl acetate as eluant, furnishing in
a brown powder (0.85 g, 77%).
Mp 157–160 °C.
Anal. Calcd for C14H13N2F1: C, 73.66; H, 5.74; N, 12.27. Found: C,
72.93; H, 5.87; N, 11.94.
IR (KBr):
m 3260, 3116, 2360, 1677, 1589, 1546, 1509, 1434,
1315, 1263, 1201, 1139, 1121, 958, 842, 800, 724, 670 cmꢂ1
.
UV (ACN): kmax 318 nm.
1H NMR (400 MHz, DMSO-d6): d 10.70 (1H, s, –NH) 8.25 (3H, s,
–NH3þ), 7.66 (2H, d, J = 8.8 Hz, –ArH 30 and 50), 7.61 (2H, d,
J = 8.8 Hz, –ArH 20 and 60), 7.39 (1H, d, J = 16.4 Hz, –CH), 7.34 (2H,
m, –ArH 2 and 6), 7.19 (1H, d, J = 16.4 Hz, –CH), 7.11 (1H, tt,
J = 2.2 and 9.4 Hz, –ArH 4), 3.83 (2H, s, –CH2).
13C NMR (100 MHz, DMSO-d6):
d 164.9 (–CO), 162.8 (d,
IR (KBr):
1896, 1593, 1507, 1464, 1362, 1333, 1225, 1192, 1159, 1097,
963, 834, 788, 682 cmꢂ1
m 3436, 3397, 3360, 3316, 3198, 3062, 3047, 3021,
J = 243.5 Hz, –CF), 162.6 (d, J = 243.5 Hz, –CF), 158.3 (q,
J = 30.0 Hz, –COCF3), 141.2 (t, J = 9.8 Hz, –ArC 1), 138.3 (–ArC 40),
131.9 (–ArC 10), 130.9 (–CH), 127.6 (–ArC 20 and 60), 125.2 (–CH),
119.2 (–ArC 30 and 50), 117.2 (d, J = 298.0 Hz, –CF3), 109.1 (d,
J = 25.3 Hz, –ArC 2 and 6), 102.4 (t, J = 26.4 Hz, –ArC 4), 41.0
(–CH2, ꢂVE DEPT).
.
UV (ACN): kmax 312 nm; 260 nm.
1H NMR (400 MHz, DMSO-d6): d 7.59 (2H, m, –ArH 20 and 60),
7.17 (2H, t, J = 8.8 Hz, –ArH 30 and 50), 6.90 (2H, d, J = 2.0 Hz,
HC@CH), 6.04 (2H, d, J = 2.0 Hz, –ArH 2 and 6), 5.80 (1H, t,
J = 1.8 Hz, –ArH 4), 4.76 (4H, s, –NH2).
19F NMR (376 MHz, DMSO-d6): d ꢂ73.61 (3F, s), ꢂ110.20
(2F, t, JC–F = 9.4 Hz).
13C NMR (100 MHz, DMSO-d6): d 161.3 (d, J = 242.9 Hz, –CF),
149.3 (–ArC 3 and 5), 137.5 (–ArC 1), 133.9 (d, J = 3.0 Hz, –ArC
10), 130.0 (d, J = 2.1 Hz, –CH), 128.0 (d, J = 7.8 Hz, –ArC 20 and 60),
125.1 (–CH), 115.5 (d, J = 21.2 Hz, –ArC 30 and 50), 101.7 (–ArC 2
and 6), 100.1 (–ArC 4).
5.2.21. (E)-3,5-Dinitro-40-fluorostilbene (23)
The experimental procedure is identical to the preparation of
compound 2 except 3,5-dinitrobenzoyl chloride (1 g, 4.35 mmol)
and 4-fluorostyrene (0.53 g, 4.35 mmol) were used. Recrystallisa-
tion from hexane/ethyl acetate 50:1 gave the title product 23 as
a mustard yellow powder (0.91 g, 65%).
19F NMR (376 MHz, DMSO-d6): d ꢂ114.93 to ꢂ115.01 (1F, m).
Mp 228–230 °C.
Anal. Calcd for C14H9N2O4F1: C, 58.34; H, 3.15; N, 9.72. Found: C,
58.35; H, 3.12; N, 9.83.
5.2.24. (Z)-3,5-Diamino-40-fluorostilbene (26)
The experimental procedure is identical to the preparation of
compound 13 except (Z)-3,5-dinitro-40-fluorostilbene (1.39 g,
4.83 mmol) was used. Purification by column chromatography
with hexane/ethyl acetate as eluant yielded 26 as a brown oil
(0.72 g, 65%).
IR (KBr):
m 3012, 2870, 1789, 1592, 1533, 1506, 1411, 1343,
1233, 1214, 1161, 1075, 962, 860, 815, 783, 731, 704, 652 cmꢂ1
.
UV (ACN): kmax 280 nm.
1H NMR (400 MHz, DMSO-d6): d 8.84 (2H, d, J = 2.0 Hz, –ArH 2
and 6), 8.68 (1H, t, J = 1.8 Hz, –ArH 4), 7.73–7.78 (3H, m, –ArH 20,
60 and –CH), 7.54 (1H, d, J = 16.4 Hz, –CH), 7.29 (2H, t, J = 8.8 Hz,
–ArH 30 and 50).
Bp 190–195 °C.
Anal. Calcd for C14H13N2F1: C, 73.66; H, 5.74; N, 12.27. Found: C,
73.12; H, 5.76; N, 12.05.
IR (KBr):
m 3424, 3339, 3208, 3010, 1614, 1585, 1505, 1460,
13C NMR (100 MHz, DMSO-d6): d 162.31 (d, J = 245.0 Hz, –CF),
148.5 (–ArC 3 and 5), 140.9 (–ArC 1), 132.6 (–CH), 132.6 (d,
J = 3.3 Hz, –ArC 10), 129.1 (d, J = 8.2 Hz, –ArC 20 and 60), 125.9 (–
ArC 2 and 6), 124.4 (d, J = 2.3 Hz, –CH), 116.4 (–ArC 4), 115.8 (d,
J = 21.5 Hz, –ArC 30 and 50).
1420, 1349, 1218, 1190, 1157, 1095, 863, 834, 787, 674 cmꢂ1
.
UV (ACN): kmax 252 nm; 222, 286 nm.
1H NMR (400 MHz, DMSO-d6): d 7.32 (2H, m, –ArH 20 and 60),
7.05 (2H, t, J = 9.0 Hz, –ArH 30 and 50), 6.39 (2H, d, J = 3.2 Hz,
HC@CH), 5.72 (3H, m, –ArH 2, 4 and 6), 4.68 (4H, s, –NH2).
13C NMR (100 MHz, DMSO-d6): d 160.9 (d, J = 242.6 Hz, –CF),
149.3 (–ArC 3 and 5), 137.7 (–ArC 1), 133.5 (d, J = 3.1 Hz, –ArC
10), 131.8 (d, J = 1.0 Hz, –CH), 130.6 (d, J = 7.9 Hz, –ArC 20 and 60),
127.1 (–CH), 114.8 (d, J = 21.1 Hz, –ArC 30 and 50), 102.9 (–ArC 2
and 6), 99.3 (–ArC 4).
19F NMR (376 MHz, DMSO-d6): d ꢂ112.26 to ꢂ112.34 (1F, m).
5.2.22. (Z)-3,5-Dinitro-40-fluorostilbene (24)
The experimental procedure is identical to the preparation of
compounds 11/12 except 3,5-dinitrobenzyl triphenyl phospho-
nium bromide (2.22 g, 4.64 mmol) and 4-fluorobenzaldehyde
19F NMR (376 MHz, DMSO-d6): d ꢂ114.89 to ꢂ114.98 (1F, m).

4520
B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
5.2.25. (E)-3-Nitro-5-amino-40-fluorostilbene (27)
The experimental procedure is identical to the preparation of
compound 13 except (E)-3,5-dinitro-40-fluorostilbene (0.54 g,
1.88 mmol) was used. The title product 27 was purified by column
chromatography with hexane/ethyl acetate as eluant, furnishing an
orange powder (0.08 g, 17%).
5.2.28. (E)-3,5-Di(trifluoroacetylamino)-40-fluorostilbene (30)
The experimental procedure is identical to the preparation of
compound 15 except (E)-3,5-difluoro-40-aminostilbene (0.56 g,
2.46 mmol) was used. Recrystallisation from hexane/ethyl acetate
yielded the title product 30 as a white powder (0.58 g, 56%).
Mp 247–250 °C.
Mp 138–141 °C.
Anal. Calcd for C18H11N2O2F7: C, 51.44; H, 2.64; N, 6.67. Found:
Anal. Calcd for C14H11N2O2F1: C, 65.11; H, 4.29; N, 10.85. Found:
C, 51.85; H, 2.86; N, 6.47.
C, 64.99; H, 4.32; N, 10.86.
IR (KBr):
1568, 1458, 1322, 1216, 1149, 1006, 959, 938, 914, 890, 849,
815, 791, 738, 674, 623 cmꢂ1
m 3410, 3325, 3107, 1888, 1732, 1711, 1598, 1562,
IR (KBr):
1531, 1509, 1447, 1413, 1352, 1333, 1241, 1159, 1091, 964, 856,
841, 778, 742, 666 cmꢂ1
m 3472, 3372, 3224, 3082, 1895, 1620, 1600, 1578,
.
.
UV (ACN): kmax 260 nm; 296, 307 (sh) nm.
UV (ACN): kmax 290 nm.
1H NMR (400 MHz, DMSO-d6): d 11.47 (2H, s, –NH), 8.02 (1H, t,
J = 1.6 Hz, –ArH 4), 7.70–7.74 (4H, m, –ArH 2, 6, 20 and 60), 7.16–
7.28 (4H, m, –ArH 30, 50 and HC@CH).
1H NMR (400 MHz, DMSO-d6): d 7.70 (2H, m, –ArH 20 and 60),
7.58 (1H, s, –ArH 2), 7.17–7.31 (5H, m, –ArH 4, 30, 50 and HC@CH),
7.14 (1H, s, –ArH 6), 5.86 (2H, s, –NH2).
13C NMR (100 MHz, DMSO-d6): d 161.9 (d, J = 243.8 Hz, –CF),
154.7 (q, J = 36.9 Hz, –C@O), 138.3 (–ArC 1), 137.1 (–ArC 3 and 5),
133.0 (d, J = 3.0 Hz, –ArC 10), 128.7 (d, J = 7.9 Hz, –ArC 20 and 60),
128.7 (–CH), 127.3 (–CH), 115.7 (q, J = 287.1 Hz,–CF3), 116.2
(–ArC 2 and 6), 115.6 (d, J = 21.4 Hz, –ArC 30 and 50), 113.1 (–ArC 4).
19F NMR (376 MHz, DMSO-d6): d ꢂ73.87 (6H, s), ꢂ113.49 to
ꢂ113.57 (1F, m).
13C NMR (100 MHz, DMSO-d6): d 161.7 (d, J = 242.9 Hz, –CF),
150.1 (–ArC 3), 149.2 (–ArC 5), 138.9 (–ArC 1), 133.09 (d,
J = 3.0 Hz, –ArC 10), 130.04 (d, J = 2.1 Hz, –CH), 128.0 (d, J = 7.8 Hz,
–ArC 20 and 60), 127.0 (–CH), 117.2 (–ArC 6), 115.6 (–ArC 30 and
50), 107.8 (–ArC 2), 106.3 (–ArC 4).
19F NMR (376 MHz, DMSO-d6): d ꢂ113.55 to ꢂ113.62 (1F, m).
5.2.29. (E)-3,5-Di(N-BOC-glycine)amino-40-fluorostilbene (31)
The experimental procedure is identical to the preparation of
compound 18 except (E)-3,5-diamino-40-fluorostilbene (0.29 g,
1.27 mmol) and N-tert-butoxycarbonyl-glycine (0.67 g, 3.81 mmol)
were used. Purification by column chromatography using hexane/
ethyl acetate as eluant gave a solid. Recrystallisation from ethyl
acetate/hexane furnished 31 as a white powder (0.26 g, 56%).
Mp 138–140 °C.
5.2.26. (Z)-3-Nitro-5-amino-40-fluorostilbene (28)
The experimental procedure is identical to the preparation of
compound 13 except (Z)-3,5-dinitro-40-fluorostilbene (1.39 g,
4.83 mmol) was used. Purification by column chromatography
with hexane/ethyl acetate as eluant furnished compound 28 as
an orange powder (0.11 g, 23%).
Mp 116–118 °C.
IR (KBr):
1508, 1343, 1238, 1221, 1159, 998, 877, 840, 807, 767, 745,
663 cmꢂ1
m 3438, 3356, 3232, 3085, 3017, 1635, 1600, 1526,
Anal. Calcd for C28H35N4O6F1: C, 61.98; H, 6.50; N, 10.33. Found:
C, 61.58; H, 6.66; N, 9.82.
.
IR (KBr):
m 3300, 3103, 2976, 2929, 1675, 1599, 1507, 1452,
UV (ACN): kmax 270 nm.
1366, 1225, 1160, 1052, 959, 847, 791, 681 cmꢂ1
.
1H NMR (400 MHz, DMSO-d6): d 7.26 (3H, m, –ArH 4, 20 and 60),
7.12 (3H, m, –ArH 2, 30 and 50), 6.80 (1H, s, –ArH 6), 6.69 (1H, d,
J = 12.4 Hz, –CH), 6.59 (1H, d, J = 12.0 Hz, –CH), 5.80 (2H, s, –NH2).
13C NMR (100 MHz, DMSO-d6): d 168.4 (d, J = 214.9 Hz, –CF),
150.1 (–ArC 1), 148.8 (–ArC 3), 147.4 (–ArC 5), 138.5 (–ArC 10),
130.6 (d, J = 8.0 Hz, –ArC 20 and 60), 130.3 (–CH), 128.7 (–CH),
119.4 (–ArC 6), 115.3 (d, J = 21.2 Hz, –ArC 30 and 50), 109.7 (–ArC
2), 106.0 (–ArC 4).
UV (ACN): kmax 257 nm; 298, 309 (sh) nm.
1H NMR (400 MHz, DMSO-d6): d 9.99 (2H, s, –NH) 7.80 (1H, s,
–ArH 4), 7.70 (2H, m, –ArH 20 and 60), 7.55 (2H, s, –ArH 2 and 6),
7.15–7.24 (3H, m, –ArH 30, 50 and –CH), 7.04–7.08 (3H, m, –CH
and –NH–), 3.75 (4H, d, J = 6.4 Hz, –CH2), 1.41 (18H, s, t-CH3).
13C NMR (100 MHz, DMSO-d6): d 168.3 (–COCH2), 161.7 (d,
J = 243.6 Hz, –CF), 155.9 (–COOt–Butyl), 139.5 (–ArC 3 and 5),
137.6 (–ArC 1), 133.3 (d, J = 3.1 Hz, –ArC 10), 128.5 (–CH), 128.5
(–ArC 20 and 60), 127.4 (–CH), 115.6 (d, J = 21.4 Hz, –ArC 30 and
50), 112.1 (–ArC 2 and 6), 109.6 (–ArC 4), 78.0 (–C(CH3)3), 43.7
(–CH2, ꢂVE DEPT), 28.2 (–C(CH3)3).
19F NMR (376 MHz, DMSO-d6): d ꢂ113.94 to ꢂ114.02 (1F, m).
5.2.27. (E)-3,5-Diacetylamino-40-fluorostilbene (29)
The experimental procedure is identical to the preparation of
compound 15 except (E)-3,5-difluoro-40-aminostilbene (0.5 g,
2.19 mmol) was used. Recrystallisation from hexane/ethyl acetate
yielded the product 29 as a white powder (0.53 g, 78%).
Mp 213–215 °C.
19F NMR (376 MHz, DMSO-d6): d ꢂ113.98 to ꢂ114.05 (1F, m).
5.2.30. (E)-3,5-Di(N-BOC-L
-alanine)amino-40-fluorostilbene (32)
The experimental procedure is identical to the preparation of
compound 18 except (E)-3,5-diamino-40-fluorostilbene (1.21 g,
Anal. Calcd for C18H17N2O2F1: C, 69.22; H, 5.49; N, 8.97. Found:
5.31 mmol)
and
N-tert-butoxycarbonyl-L-alanine
(3.01 g,
C, 68.85; H, 5.63; N, 8.83.
15.92 mmol) were used. Purification by column chromatography
with hexane/ethyl acetate as eluant furnished the product 32 as
a white powder (1.15 g, 38%).
IR (KBr):
m 3268, 3099, 1667, 1615, 1599, 1556, 1509, 1456,
1420, 1371, 1276, 1227, 1159, 1038, 998, 964, 848, 609 cmꢂ1
.
UV (ACN): kmax 258 nm, 298, 307 (sh) nm.
Mp 139–141 °C.
1H NMR (400 MHz, DMSO-d6): d 9.99 (2H, s, –NH), 7.76 (1H, s,
–ArH 4), 7.69 (2H, m, –ArH 20 and 60), 7.52 (2H, d, J = 1.2 Hz,
–ArH 2 and 6), 7.21 (2H, t, J = 9.0 Hz, –ArH 30 and 50), 7.14 (1H, d,
J = 16.4 Hz, –CH), 7.03 (1H, d, J = 16.4 Hz, –CH), 2.05 (6H, s, –CH3).
13C NMR (100 MHz, DMSO-d6): d 168.4 (–C@O), 161.7 (d,
J = 244.0 Hz, –CF), 139.8 (–ArC 3 and 5), 137.4 (–ArC 1), 133.3 (d,
J = 2.0 Hz, –ArC 10), 128.5 (–ArC 20 and 60), 128.4 (–CH), 127.2
(–CH), 115.5 (d, J = 21.0 Hz, –ArC 30 and 50), 112.0 (–ArC 2 and 6),
109.5 (–ArC 4), 24.0 (–CH3).
Anal. Calcd for C30H39N4O6F1: C, 63.14; H, 6.89; N, 9.82. Found:
C, 63.42; H, 6.72; N, 9.66.
IR (KBr):
m 3292, 2977, 2931, 1672, 1600, 1508, 1452, 1366,
1288, 1164, 1070, 1021, 960, 846, 790, 711, 681 cmꢂ1
.
UV (ACN): kmax 258 nm; 298, 307 (sh) nm.
1H NMR (400 MHz, DMSO-d6): d 9.98 (2H, s, –NH) 7.84 (1H, s,
–ArH 4), 7.69 (2H, m, –ArH 20 and 60), 7.55 (2H, s, –ArH 2 and 6),
7.14–7.23 (3H, m, –ArH 30, 50 and –CH), 7.04–7.08 (3H, m, –CH
and –NH), 4.14 (2H, quin, J = 7.2 Hz,
1.27 (6H, d, J = 7.2 Hz, –CH3).
a-H), 1.39 (18H, s, t-CH3),
19F NMR (376 MHz, DMSO-d6): d ꢂ114.05 to ꢂ114.13 (1F, m).

B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
4521
13C NMR (100 MHz, DMSO-d6): d 172.0 (–COCH2), 161.7 (d,
J = 243.5 Hz, –CF), 155.1 (–COOt-Butyl), 139.6 (–ArC 3 and 5),
137.5 (–ArC 1), 133.3 (–ArC 10), 128.54 (–CH), 128.46 (–ArC 20
and 60) 127.4 (–CH), 115.6 (d, J = 21.3 Hz, –ArC 30 and 50), 112.3
from ethyl acetate to yield the title product 35 as a white powder
(0.22 g, 95%)
Mp 204–206 °C.
IR (KBr):
m 3095, 3002, 1670, 1626, 1560, 1509, 1458, 1199,
(–ArC 2 and 6), 109.9 (–ArC 4), 78.0 (–C(CH3)3), 50.4 (
a-C), 28.2
1136, 847, 798, 722 cmꢂ1
.
(–C(CH3)3), 18.0 (–CH3).
UV (ACN): kmax 254 nm; 298 nm.
19F NMR (376 MHz, DMSO-d6): d ꢂ113.99 to ꢂ114.07 (1F, m).
1H NMR (400 MHz, DMSO-d6): d 10.65 (2H, s, –NH) 8.24 (6H, s,
–NH3þ), 7.88 (1H, s, –ArH 4), 7.71 (2H, m, –ArH 20 and 60), 7.57 (2H,
d, J = 1.2 Hz, –ArH 2 and 6), 7.23 (3H, m, –ArH 30, 50 and –CH), 7.07
(1H, d, J = 16.0 Hz, –CH), 3.28 (4H, s, –CH2).
5.2.31. (E)-3,5-Di(N-BOC-b-alanine)amine-40-fluorostilbene (33)
The experimental procedure is identical to the preparation of
compound 18 except (E)-3,5-diamino-40-fluorostilbene (0.52 g,
13C NMR (100 MHz, DMSO-d6):
d 164.9 (–CO), 161.5 (d,
J = 243.8 Hz, –CF), 158.4 (q, J = 32.0 Hz, –CO), 139.0 (–ArC 3 and
5), 138.0 (–ArC 1), 133.1 (d, J = 3.2 Hz, –ArC 10), 128.6 (d,
J = 7.9 Hz, –ArC 20 and 60), 128.1 (–CH), 127.9 (–CH), 116.9 (d,
J = 297.0 Hz, –CF3), 115.6 (d, J = 21.5 Hz, –ArC 30 and 50), 112.6
(–ArC 2 and 6), 109.6 (–ArC 4), 41.0 (–CH2, –VE DEPT).
19F NMR (376 MHz, DMSO-d6): d ꢂ73.84 (6F, s, ꢂCF3), ꢂ113.72
to ꢂ113.80 (1F, m, 40-F).
2.28 mmol)
and
N-tert-butoxycarbonyl-b-alanine
(1.3 g,
6.84 mmol) were used. Purification by column chromatography
with hexane/ethyl acetate as eluant yielded 33 as a white powder
(0.52 g, 60%).
Mp 113–116 °C.
Anal. Calcd for C30H39N4O6F1: C, 63.14; H, 6.89; N, 9.82. Found:
C, 62.95; H, 7.24; N, 9.64.
IR (KBr):
m 3303, 3095, 2975, 2928, 1680, 1599, 1508, 1450,
1366, 1247, 1165, 1068, 961, 846, 789 cmꢂ1
.
6. Supplementary data
UV (ACN): kmax 257 nm, 298, 308 (sh) nm.
1H NMR (400 MHz, DMSO-d6): d 9.99 (2H, s, –NH) 7.79 (1H, s,
–ArH 4), 7.68 (2H, m, –ArH 20 and 60), 7.56 (2H, s, –ArH 2 and 6),
7.21 (2H, t, J = 8.8 Hz, –ArH 30 and 50), 7.13 (1H, d, J = 16.2 Hz,
–CH), 7.03 (1H, d, J = 16.2 Hz, –CH), 6.86 (2H, t, J = 5.4 Hz, –NH),
3.24 (4H, q, J = 6.4 Hz, –CH2), 2.47–2.50 (m, –CH2), 1.38 (18H, s,
t-CH3).
Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication number 685944 for 11. Copies of the data
can be obtained free of charge from The Director, CCDC, 12, Union
Road, Cambridge, CB2 1 EZ, UK. [fax: +44 (0) 1223 336033 or e-
mail: deposit@ccdc.cam.ac.uk].
13C NMR (100 MHz, DMSO-d6): d 169.5 (–COCH2), 161.7 (d,
J = 243.5 Hz, –CF), 155.5 (–COOt–Butyl), 139.7 (–ArC 3 and 5),
137.4 (–ArC 1), 133.3 (d, J = 3.1 Hz,–ArC 10), 128.5 (–ArC 20 and
60), 128.4 (–CH), 127.2 (–CH), 115.6 (d, J = 21.5 Hz,–ArC 30 and 50),
112.2 (–ArC 2 and 6), 109.7 (–ArC 4), 77.6 (–C(CH3)3), 36.7 (–CH2,
ꢂVE DEPT), 36.5 (–CH2, ꢂVE DEPT), 28.2 (–C(CH3)3).
Acknowledgements
This research was supported by the National Institute for Cellu-
lar Biotechnology under the Programme for Research in Third Level
Institutions (PRTLI, round 3, 2001–2006). The authors are grateful
to Dr. Robert O’Connor for valuable discussions. We are also grate-
ful to the NCI for biological studies.
19F NMR (376 MHz, DMSO-d6): d ꢂ114.03 to ꢂ114.11 (1F, m).
5.2.32. (E)-3,5-Di(N-BOC-L
-valine)amino-40-fluorostilbene (34)
The experimental procedure is identical to the preparation of
compound 18 except (E)-3,5-diamino-40-fluorostilbene (0.62 g,
References and notes
2.72 mmol) and N-tert-butoxycarbonyl-L-valine (1.35 g, 6.21 mmol)
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Boronat, M. C. J. Agric. Food Chem. 2001, 49, 210.
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2004, 248, 2323.
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were used. Purification by column chromatography with hexane/
ethyl acetate as eluant gave the title product 34 as a brown wax
(0.20 g, 12%).
IR (KBr):
m 3305, 3091, 2964, 2924, 2873, 2358, 2336, 1670,
1508, 1451, 1366, 1227, 1164, 1024, 847 cmꢂ1
.
UV (ACN): kmax 258 nm; 296, 310 (sh) nm.
1H NMR (400 MHz, DMSO-d6): d 10.06 (2H, s, –NH) 7.88 (1H, s,
–ArH 4), 7.70 (2H, m, –ArH 20 and 60), 7.60 (2H, s, –ArH 2 and 6),
7.16–7.23 (3H, m, –ArH 30, 50 and –CH), 7.08 (1H, d, J = 16.4 Hz,
–CH), 6.89 (2H, d, J = 8.4 Hz, –NH), 3.99 (2H, t, J = 7.8 Hz,
a-H),
1.94–2.10 (2H, m, –CH), 1.41 (18H, s, t-CH3), 0.94 (12H, d,
J = 6.0 Hz, –CH(CH3)2).
13C NMR (100 MHz, DMSO-d6): d 170.8 (–COCH2), 161.7 (d,
J = 243.0 Hz, –CF), 155.5 (–COOt-Butyl), 139.4 (–ArC 3 and 5),
137.6 (–ArC 1), 133.3 (d, J = 3.0 Hz, –ArC 10), 128.5 (–CH), 128.4
(–ArC 20 and 60) 127.4 (–CH), 115.5 (d, J = 22.0 Hz, –ArC 30 and 50),
112.5 (–ArC 3 and 5), 110.0 (–ArC 4), 78.0 (–C(CH3)3), 60.6 (
a-C),
30.3 (–CH–), 28.1 (–C(CH3)3), 18.4 and 19.2 (–CH(CH3)2).
19F NMR (376 MHz, DMSO-d6): d ꢂ113.98 to ꢂ114.03 (1F, m).
5.2.33. (E)-3,5-Di(aminoglycine)-40-fluorostilbene
trifluoroacetate salt (35)
The experimental procedure is identical to the preparation of
compound 22 except 3,5-di(amino-BOC-glycine)-40-fluorostilbene
(0.22 g, 0.41 mmol) was used. The crude residue was recrystallised
20. Kobayashi, Y.; Furukawa-Hibi, Y.; Chen, C.; Horio, Y.; Isobe, K.; Ikeda, K.;
Motoyama, N. Int. J. Mol. Med. 2005, 2, 237.

4522
B. W. Moran et al. / Bioorg. Med. Chem. 17 (2009) 4510–4522
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