Design, synthesis and in vitro evaluation against human cancer cells of 5-methyl-5-styryl-2,5-dihydrofuran-2-ones, a new series of goniothalamin analogues

Article abstract of DOI:10.1016/j.bmc.2013.06.044

The present work describes the preparation of a novel series of compounds based on the structure of goniothalamin (1), a natural styryl lactone with known cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 17 goniothalamin analogues displaying the 5-methyl-2,5-dihydrofuran-2-one motif were prepared, and their cytotoxicity evaluated. While the analogues bearing methoxy and/or hydroxy groups on the aromatic moiety usually were at least three times less potent than the lead compound (1), ortho and para-trifluoromethyl analogues 10 and 11 exhibited levels of cytotoxicity similar to goniothalamin (1) against most cancer cell lines evaluated. One could suggest that the electronic effect of the trifluoromethyl group activates the inhibitor's electrophilic site via reduction of the electron density of the α,β-unsaturated ester oxygen atom. These results provide new information on the structure activity relationship of these α,β-unsaturated styryl lactones, thereby further focusing the design of novel candidates.

Full text of DOI:10.1016/j.bmc.2013.06.044

Bioorganic & Medicinal Chemistry 21 (2013) 5107–5117
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis and in vitro evaluation against human cancer cells
of 5-methyl-5-styryl-2,5-dihydrofuran-2-ones, a new series
of goniothalamin analogues
Marjorie Bruder a, Débora Barbosa Vendramini-Costa a,b,c, João Ernesto de Carvalho b,c
,
Ronaldo Aloise Pilli a,
⇑
a Departamento de Química Orgânica, Instituto de Química, UNICAMP, CP 6154, Campinas, SP 13083-970, Brazil
b Instituto de Biologia, UNICAMP, CP 6109, Campinas, SP 13083-970, Brazil
c Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), UNICAMP, CP 6171, Campinas, SP 13083-970, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The present work describes the preparation of a novel series of compounds based on the structure of
goniothalamin (1), a natural styryl lactone with known cytotoxic and antiproliferative activities against
a variety of cancer cell lines. A focused library of 17 goniothalamin analogues displaying the 5-methyl-
2,5-dihydrofuran-2-one motif were prepared, and their cytotoxicity evaluated. While the analogues bear-
ing methoxy and/or hydroxy groups on the aromatic moiety usually were at least three times less potent
than the lead compound (1), ortho and para-trifluoromethyl analogues 10 and 11 exhibited levels of cyto-
toxicity similar to goniothalamin (1) against most cancer cell lines evaluated. One could suggest that the
electronic effect of the trifluoromethyl group activates the inhibitor’s electrophilic site via reduction of
Received 20 April 2013
Revised 12 June 2013
Accepted 19 June 2013
Available online 27 June 2013
Keywords:
Goniothalamin
Cancer cells
Antiproliferative activity
2,5-Dihydrofuran-2-ones
the electron density of the
a,b-unsaturated ester oxygen atom. These results provide new information
on the structure activity relationship of these
the design of novel candidates.
a
,b-unsaturated styryl lactones, thereby further focusing
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
anti-inflammatory activities, with the anti-inflammatory activity
favoring the antiproliferative activity itself.13
Natural products are a privileged source of molecular diversity
that have shown to exhibit numerous biological activities. It is esti-
mated that half of current drugs used in cancer chemotherapy
are—or are based on—natural products. Goniothalamin (GNT, 1)
(Fig. 1) is a naturally occurring styryl lactone originally isolated
from various species of the genus Goniothalamus,1 displaying sig-
nificant cytotoxic and anti-proliferative activities against a variety
of cancer cell lines, including kidney, prostate, breast carcinoma,
leukemia, lung and liver.2,3 Other important biological properties
such as antimicrobial,4 antifungal,5 larvicidal,6 insecticidal7 and
trypanocidal activities,8 have also been reported.
Because of the broad spectrum of biological properties, gonio-
thalamin has caught the attention of several research groups, thus
triggering a number of studies on the possible mechanism of action
for its cytotoxic and antiproliferative activity.9–12 Recently, in vivo
studies performed by our research group with goniothalamin in a
solid tumor experimental model in mice confirmed its low acute
toxicity and suggested a relationship between anticancer and
In order to better understand the mode of action of
goniothalamin (1) and design more active and selective analogues,
several structure–activity relationship (SAR) studies have been
conducted.14–16 These studies established the
a,b-unsaturated
d-lactone moiety as the key feature for activity as a result of its
ability to act as a Michael acceptor in the presence of nucleophilic
biomolecules such as cysteine and glutathione. As demonstrated
by Çag˘ır and co-workers, the styryl moiety with E double bond
geometry could be replaced by 2- and 1-naphthyl group, the latter
dramatically enhancing the cytotoxic activity.17
Based on these preliminary results, our research group has
recently reported the design of three new series of goniothalamin
analogues (Fig. 1).18 The influence of hydroxy and methoxy
groups,19,20 as well as fluorinated substituents21 on the aromatic
ring, such as in 2 was examined; the effect of the electronic nature
of the Michael acceptor on the cytotoxic activity was investigated
with the synthesis of azagoniothalamin (3),22,23 as well as dihydro-
c
-pyrones analogues (4).24 The study concluded on the prevalence
of the ,b-unsaturated lactone ring as the pharmacophoric motif
a
for the in vitro antiproliferative activity, with the highest cytotox-
icity being observed for the di- and trimethoxy goniothalamin
analogues.
⇑
Corresponding author. Tel.: +55 19 35213422; fax: +55 19 35213023.
E-mail address: pilli@iqm.unicamp.br (R.A. Pilli).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.06.044

5108
M. Bruder et al. / Bioorg. Med. Chem. 21 (2013) 5107–5117
O
O
O
O
O
O
X
O
R
R
5
1
2 = O
3 = NH
4
Figure 1. Chemical structure of (R)-goniothalamin 1, and analogues: with modified aromatic moiety (2), azagoniothalamin (3), dihydro-
c-pyrones (4), and homogonio-
thalamin (5, HGNT).
In a continuous effort to enhance the cytotoxic profile of gonio-
thalamin, and to complement previous studies from our research
group, we envisioned to prepare analogues with a reduced size of
under such conditions.28 Obtaining analogue lactones with substi-
tuted aromatic rings in high purity was also an issue, and therefore,
these could not be evaluated in cytotoxic bioassys.29
the lactone ring, for example, styryl
c
-butyrolactones 5. In fact,
In order to overcome the instability of compound 5, we thought
that replacing this acidic proton with a methyl group, for example,
should render the structure more robust. Reassuringly, two antibi-
otics, OH-3984 K1 and K2, isolated from a Streptomyces species and
bearing the methyl vinyl furanone unit, as well as a synthetic
intermediate are reported in the literature, thus suggesting that
this motif is relatively stable.30,31 Only one synthesis of 5-
methyl-5-styrylbutenolide 7 has been reported by Saberi and
Thomas.32 To our knowledge, there are no reports of other synthe-
ses and no biological evaluation of 5-methylated styryl furanones
such as 7 in the literature. The synthetic approach for furanones
7 was based on literature precedents for the formation of buteno-
lides, and is exemplified in Scheme 2.33,34 Commercially available
benzylideneacetone 8 was treated with lithium ethylpropiolate
formed in situ at low temperature, to generate the tertiary alcohol
9 in excellent yield. The triple bond was subjected to a semi-hydro-
genation following a Lindlar protocol, and yielded the desired Z-al-
kene, as verified by 1H NMR. The crude acrylic ester was treated
with acidic DOWEX resin to deliver the coveted 5-methylfuranone
7, in 79% yield over two steps.
some natural products possess the furan-2(5H)-one motif, and
are reported to display various biological activities including
cytotoxicity.25 Therefore, the synthesis of goniothalamin analogues
such as styryl furan-2(5H)-one 5 stands as a promising approach to
improve the potency and selectivity of this family of compounds.
Although compound 5 has been described in the literature, it ap-
pears that there are no other reports of such styryl furanones.26
We herein report the design and synthesis of a focused library
of goniothalamin analogues displaying the
c-butyrolactone
structural motif, and their evaluation in vitro against eight human
cancer cell lines: U251 (glioma), UACC-62 (melanoma), MCF-7
(breast), NCI-ADR/RES (multidrug resistant ovary carcinoma),
786-0 (renal), PC-3 (prostate), HT-29 (colon), and K-562
(leukemia).
2. Results and discussion
2.1. Chemistry
For the preparation of analogues of lactone 7, we needed access
to substituted benzylideneacetones, which are relatively scarce on
the market, and we decided to prepare them from readily available
benzaldehydes, employing an aldol condensation reaction with
acetone. From the plethora of methodologies available in the liter-
ature, we chose the recent work of List and colleagues, where a
variety of substrates were obtained in excellent yields with simple
purifications required.35,36 List’s protocol involved a mixture of
benzaldehyde in excess acetone, the latter also acting as the sol-
vent, in the presence of a morpholinium-trifluoroacetate salt
(25 mol %) acting as the catalyst (Scheme 3). The whole mixture
was heated at reflux in a sealed tube for several hours. Once the
reaction was complete, the salt was removed through filtration
and impurities separated by chromatography to afford clean
benzylideneacetones (8a–i). The desired E-stereochemistry of the
newly created double bonds was confirmed on the basis of the
Initial attempts to prepare styryl lactone 5 following the meth-
odology usually applied to the synthesis of goniothalamin ana-
logues in our laboratory failed.4c Only mild conditions using a
tandem ring-closing/cross-coupling metathesis reaction led to
the production of five analogues (Scheme 1).27 Pentadienyl ester
6 was readily prepared from pentadienyl-3-ol and crotonoyl chlo-
ride upon treatment with sodium hydride at room temperature.
Reacting a mixture of 6 and excess styrene with Grubbs’ second-
generation catalyst (GII) under diluted conditions at reflux, deliv-
ered the desired styryl butenolide 5 after 4 h, albeit in poor yield.
The latter was attributed to the sensitivity of the lactone toward
purification conditions, probably due to the proton at C5, which
could easily eliminate to produce a highly conjugated system
O
R
O
OH
O
Me
NaH
(5 eq.)
+
CO2Et
O
OH
Me
9
Cl
Me
THF, 0 ºC
(72%)
GII (5 mol%)
CH2Cl2,
LDA
Me
50 ºC, 4 h
6
-78 ºC
THF
CO2Et
8
O
O
O
O
H
O
O
Lindlar (4%wt)
H2, Quinolin
+
R
Me
5
rt, 2 h
MeOH
then H+
R
7
Scheme 1. Synthesis of styryl lactones using a tandem ring-closing/cross-coupling
metathesis reaction.
Scheme 2. Synthesis of 5-methyl-5-styryl butenolide 7.

M. Bruder et al. / Bioorg. Med. Chem. 21 (2013) 5107–5117
5109
O
N
O
O
(25 mol%)
a
b
ArCHO
Me
Me
H•TFA
O
O
R
R
sealed tube
Me
R
R
8j (4-OH-2,3-OMe)
8k (2-OH)
19a (4-OTBS-2,3-OMe)
19b (2-OTBS)
75 ºC
24-96h
Acetone
8l (3-OH)
19c (3-OTBS)
Benzilideneacetones
8m (4-OH)
19d (4-OTBS)
Benzaldehydes
Scheme 3. List’s preparation of benzylideneacetones via an ammonium salt
catalyzed aldol condensation of substituted benzaldehydes with acetone.
O
OH
O
Me
c
d
coupling constant values in the vicinity of 16 Hz, as determined by
1H NMR analysis.
Me
CO2Et
R
R
Based on previous work in our research group, we opted for the
preparation of mono-, di- and trimethoxylated, as well as fluori-
nated substrates.18 Following the reaction sequence shown in
Scheme 2, alcohols 9a–i were obtained in good to excellent yields
(73–97%). The final Lindlar reduction and cyclization steps deliv-
ered the desired substituted MeHGNTs (10–18) in modest to good
yields (55–88%) (Scheme 4).
9j (4-OTBS-2,3-OMe)
9k (2-OTBS)
20 (4-OH-2,3-OMe)
21 (2-OH)
9l (3-OTBS)
22 (3-OH)
9m (4-OTBS)
23 (4-OH)
Scheme 5. Reagents and conditions: (a) morpholinium-trifluoroacetate salt
(25 mol %), acetone (excess), 75 °C in sealed tube, 24–48 h (48–81%); (b)
imidazole, TBSCl, DMF, rt, 16 h (90–99%); (c) ethylpropiolate lithium salt, THF,
ꢀ78 °C, 30 min (61–94%); (d) (i) Lindlar catalyst (4% wt), H2, quinoline, MeOH, rt,
3 h; (ii) HFÅ pyr, THF, rt, 16 h (57–84%).
a
We also chose to include substrates bearing free hydroxy
groups, and it was therefore necessary to protect this functionality
prior to the alkyne addition step, the aldol condensation tolerating
the presence of unprotected alcohols. The tert-butyldimethylsilyl
protecting group was selected and it was planned to be removed
simultaneously in the last step while enabling the ring closure un-
der acidic conditions, however using hydrogen fluoride (Scheme 5).
After obtaining the corresponding benzylideneacetones 8j–m (48–
81% yield), their TBS-protected forms (19a–d) were prepared in
excellent yields. The alkyne addition proceeded reasonably well
(9j–m, 61-94%), although both ortho and para-substituted sub-
strates appeared less reactive. The Lindlar reduction and cycliza-
tion went smoothly and the final TBS-group removal using
hydrogen fluoride in pyridine gave the desired MeHGNTs (20–23)
in overall good yields (57–84%) (Scheme 5). Additionally, we took
advantage of the three monohydroxylated subtrates to convert
them into their corresponding methyl ethers using trimethylsilyl-
diazomethane in the presence of base in moderate yields
(42–61%), giving three new monomethoxylated MeGNTs (24–26)
(Scheme 6).
O
O
O
O
a
Me
Me
R
R
21 2-OH
24 2-OMe
22 3-OH
23 4-OH
25 3-OMe
26 4-OMe
Scheme 6. Reagents and conditions: (a) TMSCHN2, iPr2NEt, MeCN, rt, 16 h
(42–61%).
2.2. Biological activities
Considering that different cell lines display different sensitivi-
ties toward the same cytotoxic compound, the antiproliferative
activity of all the goniothalamin analogues were evaluated
in vitro against seven different human cancer cell lines: U251
(glioma), UACC-62 (melanoma), MCF-7 (breast), NCI-ADR/RES
(multidrug resistant ovary carcinoma), 786-0 (renal), PC-3 (pros-
tate), HT-29 (colon), and K-562 (leukemia). The antiproliferative
activity of each compound was also evaluated in vitro against
Finally, in order to complete the series of methylated lactones,
we decided to prepare the analogous 6-methylgoniothalamin 27.
Although lactone 27 is reported in the literature as a synthetic
intermediate,37 the usual laboratory methodology was applied
using benzylideneacetone 8 as starting material, as shown in
Scheme 7.
O
O
OH
Me
O
a
c
b
ArCHO
Me
Me
CO2Et
R
R
R
8a R = 2-CF3
9a R = 2-CF3
9b R = 4-CF3
9c R = 4-F
10 R = 2-CF3
8b R = 4-CF3
8c R = 4-F
11 R = 4-CF3
12 R = 4-F
8d R = 2,4-OMe
8e R = 3,4-OMe
8f R = 2,3,4-OMe
8g R = 2,4,5-OMe
8h R = 3,4,5-OMe
8i R = 2,4,6-OMe
9d R = 2,4-OMe
9e R = 3,4-OMe
13 R = 2,4-OMe
14 R = 3,4-OMe
15 R = 2,3,4-OMe
16 R = 2,4,5-OMe
17 R = 3,4,5-OMe
18 R = 2,4,6-OMe
9f R = 2,3,4-OMe
9g R = 2,4,5-OMe
9h R = 3,4,5-OMe
9i R = 2,4,6-OMe
Scheme 4. Reagents and conditions: (a) morpholinium-trifluoroacetate salt (25 mol %), acetone (excess), 75 °C in a sealed tube, 24–96 h (51–89%); (b) ethylpropiolate lithium
salt, THF, ꢀ78 °C, 30 min (73–97%); (c) (i) Lindlar catalyst (4% wt), H2, quinoline, MeOH, rt, 3 h; (ii) DOWEX H+, MeOH, rt, 2 h (55–88%).

5110
M. Bruder et al. / Bioorg. Med. Chem. 21 (2013) 5107–5117
Table 1
TGI values, given in
l
M, for compounds goniothalamin (1), compounds 7, 10–18, 20–27 and doxorubicin (DOX), concentration necessary for total inhibition of tumor cell
growtha,b
TGI
U251
UAAC-62
MCF-7
NCI-ADR/RES
786-0
PC-3
2.5
9.6
86.9
17.9
13.1
46.5
63.5
175.5
90.0
183.5
131.2
239.0
130.9
111.8
98.8
137.7
34.2
31.6
HT-29
K-562
HaCat
DOX
1
7
2.1
9.8
89.8
14.1
15.7
0.2
17.4
97.2
17.7
15.5
55.3
80.1
84.1
71.5
127.0
178.5
207.7
24.6
92.5
108.2
55.3
31.0
55.8
147.3
37.2
4.9
11.2
95.3
13.5
20.4
38.5
43.5
78.9
109.5
144.2
56.6
102.4
45.3
46.2
123.6
69.1
27.0
25.3
182.7
48.0
10.3
14.5
414.3
12.2
9.4
25.7
150.7
110.9
349.4
158.2
123.0
229.1
51.6
1.0
13.9
170.0
27.9
3.6
10.0
122.6
15.8
12.3
34.9
45.5
926.8
>1000
573.4
651.8
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
860.1
>1000
>1000
>1000
0.4
13.4
118.8
12.7
12.1
47.5
10
11
12
13
14
15
16
17
18
20
21
22
23
24
25
26
27
34.0
60.8
62.8
101.2
107.9
22.91
132.0
205.0
116.4
458.9
108.5
136.2
196.
143.3
35.4
70.0
>1000
68.7
57.5
53.6
192.5
87.2
159.6
124.6
192.8
40.7
927.2
132.6
126.7
390.0
126.8
19.1
31.3
97.4
122.2
30.8
17.0
838.1
217.1
179.8
175.3
458.0
64.4
57.3
88.1
81.2
30.8
70.9
78.0
117.8
106.9
41.1
37.6
127.0
27.5
646.9
111.3
64.5
48.6
>1000
106.8
5.7
316.2
50.7
145.1
31.7
92.9
41.1
a
Concentration that elicits total growth inhibition (TGI) was determined from nonlinear regression analysis using the ORIGIN 7.5Ò (OriginLab Corporation).
Doxorubicin (DOX) was the positive control.
b
less than GNT (1) itself, the loss of antiproliferative activity being
assigned to the steric hindrance introduced by the methyl group,
much more severe in 7 than in the goniothalamin analogue 27
(Table 1). Despite that, potency was recovered by the introduction
of a trifluoromethyl group in the ortho and para positions of the
aromatic ring. In fact, compounds 10 and 11 displayed similar
TGI values to GNT (1) for melanoma (UACC-62) and slightly better
cytotoxic activity for ovary resistant to adriamycin cancer cells
(NCI-ADR/RES). Derivatives 10 and 11 were as toxic as GNT (1)
towards spontaneously transformed keratinocytes from histologi-
cally normal skin (HaCat cells). The higher toxicity of compounds
10 and 11 could be attributed to the highly electron-withdrawing
nature of the trifluoromethyl groups, which could reduce the elec-
O
O
O
a,b
Me
Me
28
8
O
O
c
Me
27
tron density of the a,b-unsaturated lactone oxygen atom by means
Scheme 7. Reagents and conditions: (a) allylmagnesium bromide, THF, ꢀ78 °C,
30 min (95%); (b) acryloyl chloride, Et3N, CH2Cl2, rt, 20 min (40%); (c) GII (4 mol %),
CH2Cl2, 45 °C, 4 h (74%).
of an inductive effect along the styryl moiety. Consequently the
reactivity of the Michael acceptor would be increased, leading to
higher cytotoxicity. One could also speculate that the lipophilic
nature of the trifluoromethyl group could have a privileged inter-
action with a putative hydrophobic binding site of the biological
target of these compounds.On the other hand, the p-fluor analogue
12 showed only a minor improvement in cytotoxicity when
compared to analogue 7.40
Except for substituents in the para position of the aromatic ring,
the presence of a methoxy group at ortho- and meta-positions in
the aromatic ring (compounds 24 and 25, respectively) led to more
potent analogues than 5-methyl furan-2(5H)-one 7 and the corre-
sponding hydroxy derivatives (21 and 22, respectively). Surpris-
ingly, the presence of two and three methoxy groups led to less
potent analogues (compounds 13–18). 3,5-Dimethoxy-4-hydroxy
derivative 20 was only twice less active than GNT (1) against colon
cancer cells (HT-29), but five times less toxic to spontaneously
transformed keratinocytes from histologically normal skin (HaCat
cells).
spontaneously transformed keratinocytes from histologically nor-
mal skin (HaCat cells). Doxorubicin was employed as the positive
control and goniothalamin (1) was included as the reference
compound.38
Cell growth was determined spectrophotometrically using
sulforhodamine B (SRB) as protein-binding dye and analyses were
based on the U.S. National Cancer Institute (NCI) 60 human tumor
cell line anticancer drug screen (NCI60).39 Differently from other
methods, in the SRB assay measurement of the cell population den-
sity at time zero (the time at which drugs are added) is possible,
which allows the calculation of the cellular responses for total
growth inhibition. The drug concentration resulting in total growth
inhibition (TGI) is calculated from T = T0, where the amount of pro-
tein at the end of drug incubation (T) is equal to the amount at the
beginning (T0).
Goniothalamin (GNT, 1) and its analogues were employed at
concentrations between 0.25–250
l
g/mL and doxorubicin at
Analogue 25 displayed lower (MCF-7, NCI-ADR/RES and HT-29)
or similar (786-0 and PC-3) TGI values when compared to the 6-
methyl analogue of goniothalamin 27, while the 2-methoxy deriv-
ative 24 was shown to be as potent as for UACC-62 and PC-03 and
more potent than 27 for MCF-7, NCI-ADR/RES, 786-0 and HT-29
cancer cell lines. Additionally, the 2-methoxy derivative 24 was
shown to be three times less toxic to (HaCat cells) than the corre-
sponding 3-methoxy derivative 25.
0.025–25 g/mL. Concentration that elicits total growth inhibition
l
(TGI) was determined after 48 h of cell treatment. The initial
in vitro screening evaluations were planned to select the best can-
didates for anticancer drug development in animal models and,
eventually, in clinical trials.
The 5-methyl furan-2(5H)-one analogue 7 proved to be less
potent than the 6-methyl analogue of goniothalamin 27 and much

M. Bruder et al. / Bioorg. Med. Chem. 21 (2013) 5107–5117
5111
416 mg, 10.40 mmol) at 0 °C under nitrogen. After 30 min, croto-
noyl chloride (1.11 mL, 10.40 mmol) was added dropwise. After
15 min, the reaction mixture was carefully quenched with a satu-
rated ammonium chloride solution (40 mL) and extracted into
ethyl acetate (60 mL). The organic fraction was washed with brine
(40 mL), dried over magnesium sulfate and evaporated in vacuo,
with the water bath being left at room temperature. The resulting
oil was purified by chromatography, eluting with hexane/dichloro-
methane (7:3) to give the title compound (580 mg, 64%) as a col-
ourless and volatile oil (leaving the compound under high
vacuum for a few hours lead to its complete evaporation); dH
(250 MHz; CDCl3) 7.05 (1H, dq, J 15.6, 6.9, H-30), 5.93–5.74 (4H,
m, H-20, H-2, H-3, H-4), 5.31 (2H, d, J 16.9, H-1trans, H-5trans), 5.22
(2H, d, J 10.2, H-1cis, H-5cis), 1.89 (3H, dd, J 6.9, 1.6, Me); dC
(62.5 MHz; CDCl3) 165.3 (CO), 145.0 (CH), 135.2 (CH), 122.7 (CH),
117.2 (CH2), 74.6 (CH), 17.9 (Me).
3. Conclusions
A synthetic route to styryl furan-2(5H)-one 5 has been imple-
mented via a tandem ring-closing/cross-coupling metathesis reac-
tion, but its chemical liability precluded the evaluation of its
cytotoxic profile. In order to circumvent this problem, 17 methyl-
ated furanone analogues of goniothalamin (MeHGNTs 7, 10–18,
20–26) and 6-methylgoniothalamin (27) were prepared and sub-
jected to bioassays for evaluation of their antiproliferative profile
against a panel of seven human cancer cell lines. Although the
introduction of a methyl group at the quaternary center of the lac-
tones had a negative effect on the biological activity of 5-methyl
furan-2(5H)-one (7) and the 6-methyl analogue (27) of goniothal-
amin (1), ortho- and para-trifluoromethylated analogues 10 and 11
displayed significant antiproliferative activity, particularly for
melanoma (UACC-62) and multidrug resistant ovary carcinoma
cells (NCI-ADR/RES), when compared to goniothalamin (1). This
observation suggests that the trifluoromethyl groups could be
responsible for the recovery of potency due to their highly elec-
tron-withdrawing and inductive effect via activation of the electro-
philic site of the inhibitor. Indeed, analogs bearing hydroxyl or
methoxyl substituents generally gave inhibitory values at least
three times higher than the reference compound (1). These results
provide new information on the structure activity relationship of
4.1.2. (E)-5-Styrylfuran-2(5H)-one (5)
A mixture of triene 6 (1 equiv), styrene (5 equiv) and Grubbs’
second generation catalyst (5 mol %) in dichloromethane (50 mM)
was heated at reflux for 4 h. Upon cooling, DMSO (50 equiv relative
to the catalyst) was added and the mixture was stirred overnight at
room temperature. The solvent was removed and the crude residue
was purified by chromatography eluting with hexane/ethyl acetate
(65:33) to afford the title compound (28 mg, 38%) as an off-white
powder: mp 88–100 °C; mmax (film) 2922, 1760, 1601, 1496,
1334, 1132; dH (250 MHz; CDCl3) 7.46 (1H, d, J 5.6, H-4), 7.36–
7.23 (5H, m, ArH), 6.77 (1H, d, J 15.8, H-20), 6.18 (1H, d, J 5.6, H-
3), 5.99 (1H, dd, J 15.8, 7.4, H-10), 5.62 (1H, d, J 7.4, H-5); dC
(62.5 MHz; CDCl3) 172.8 (CO), 155.0 (CH), 135.3 (C), 135.0 (CH),
128.7 (CH), 126.9 (CH), 126.8 (CH), 122.0 (CH), 121.5 (CH), 83.6
(CH); (found: [M+H]+, 187.0847. C12H10O2+H+ requires 187.0759).
these
a,b-unsaturated styryl lactones, thereby further focusing
the design of novel candidates.
4. Procedures
Reagents and solvents were commercial grade and were used as
supplied, except when specified in the experimental procedure.
Grubbs’ second generation catalyst (Lot#MKBG2090 V) was
purchased from Aldrich. Doxorubicin was purchased from
Europharma. Racemic goniothalamin (1) was prepared according
to previously described methodology. For reactions requiring
anhydrous conditions, flame dried glassware and nitrogen atmo-
sphere were used. THF was distilled from calcium hydride and
redistilled from sodium/benzophenone, and dichloromethane,
diisopropylamine and triethylamine were distilled from calcium
hydride immediately prior to use. Reactions were monitored by
thin-layer chromatography (TLC) on Silica gel 60 F254 aluminium
sheets and exposed to UV radiation, followed by treatment with
adequate stains and heating. Chromatographic separations were
carried out on Merck 60 silica gel (230–400 mesh). Melting points
were recorded on an Electrothermal IA9000 Series digital melting
point apparatus and are not corrected. IR spectra were registered
on a Nicolet Impact 410 (Film) or on a Nicolet iS5/iD3 (ATR), with
the observed absorptions expressed in cmꢀ1. 1H NMR and 13C NMR
data were recorded on a Varian Inova (500 MHz for 1H and
125 MHz for 13C NMR) or Bruker Avance (250 MHz for 1H and
62.5 MHz for 13C NMR) spectrometer using as internal standard
TMS, or the residual non deuterated solvent MeOH. Chemical shifts
(d) were expressed in ppm and multiplicities were reported as sin-
glet (s), doublet (d), double doublet (dd), triplet (t), double triplet
(dt), quartet (q), apparent quartet (q (dt)), quintuplet (quint), mul-
tiplet (m). Coupling constants (J) are expressed in Hertz (Hz). High
resolution mass spectra (HRMS) for novel compounds were mea-
sured on a Waters XEVO Q-TOF spectrometer (ESI) or on a Waters
GCT Premier (EI).
4.1.3. General procedure for the preparation of
36
benzilideneacetones (8a–m)
A mixture of benzaldehyde (12.0 mmol) and morpholinium tri-
fluoroacetate (3.0 mmol) in acetone (30 mL) was heated at 80 °C in
a sealed tube for 24–96 h. After cooling to room temperature, the
reaction mixture was diluted with ether (30 mL) and washed with
a saturated aqueous sodium hydrogen carbonate solution (30 mL).
The organic layer was washed with brine (30 mL), dried over mag-
nesium sulfate, filtered and evaporated under reduced pressure.
The crude was purified by chromatography, eluting with hexane
and ethyl acetate (see analytical details).
4.1.3.1.
(3E)-4-(2-Trifluoromethylphenyl)but-3-en-2-one
(8a). Yield: 1.61 g, 63%, as a yellow oil; Rf = 0.33, hexane/ethyl
acetate (9:1); mmax (ATR) 1677, 1617, 1487, 1361, 1313, 1290,
116, 1037, 765; dH (250 MHz; CDCl3) 7.89 (1H, d, J 16.1, H-4),
7.73 (1H, d, J 6.8, ArH), 7.72 (1H, d, J 6.8, ArH), 7.59 (1H, t, J 7.7,
ArH), 7.50 (1H, t, J 7.7, ArH), 6.65 (1H, d, J 16.1, H-3), 2.41 (3H, s,
H-1); dC (62.5 MHz; CDCl3) 198.0 (C), 138.8 (CH), 133.3 (C), 132.1
(CH), 131.1 (CH), 129.2 (CH), 128.8 (C, q, 2J 30.2), 127.8 (CH),
126.1 (CH, q, 3J 5.5), 123.9 (CF3, q, 1J 273.9), 27.0 (Me); (Found:
[M+H]+, 215.0785. C11H9F3O+H+ requires 215.0684).
4.1.3.2.
(3E)-4-(2,3,4-Trimethoxyphenyl)but-3-en-2-one
(8f). Yield: 2.48 g, 88%, as a yellow oil; Rf = 0.33, hexane/ethyl
acetate (7:3); mmax (ATR) 2942, 1667, 1590, 1494, 1253, 1094; dH
(250 MHz; CDCl3) 7.76 (1H, d, J 16.4, H-4), 7.31 (1H, d, J 8.8,
ArH), 6.71 (1H, d, J 8.8, ArH), 6.68 (1H, d, J 16.4, H-3), 3.94 (3H, s,
ArOMe), 3.90 (3H, s, ArOMe), 3.88 (3H, s, ArOMe), 2.38 (3H, s, H-
1); dC (62.5 MHz; CDCl3) 198.8 (C), 155.7 (C), 153.2 (C), 142.2 (C),
138.3 (CH), 126.3 (CH), 122.8 (CH), 121.3 (C), 107.7 (CH), 61.4
4.1. Experimental procedures
4.1.1. (E)-Penta-1,4-dien-3-yl but-2-enoate (6)
To a solution of pentadienyl-3-ol (500 mg, 5.95 mmol) in THF
(20 mL) was added sodium hydride (60% dispersion in grease;

5112
M. Bruder et al. / Bioorg. Med. Chem. 21 (2013) 5107–5117
(OMe), 60.8 (OMe), 56.0 (OMe), 27.0 (Me); (found: [M+H]+,
237.1135. C13H16O4+H+ requires 237.1127).
added ethyl propiolate (1.8 equiv) dropwise. After 10 min, a solu-
tion of the ketone in THF (0.5 M; 1.0 equiv) at ꢀ78 °C was added
via cannula. After 30 min, a saturated aqueous ammonium chloride
solution was slowly poured onto the reaction mixture and the lat-
ter was extracted into ether twice. The combined organic layers
were washed with brine, dried over magnesium sulfate, filtered
and evaporated under reduced pressure. The crude was purified
by chromatography, eluting with hexane and ethyl acetate (see
analytical details).
4.1.4. General procedure for the preparation of TBS-protected
phenols (19a–d)
A mixture of phenol (1.0 equiv), imidazole (1.5 equiv) and
tert-butyldimethylsilyl chloride (1.3 equiv) in dry DMF (0.2 M)
was stirred for 4 h at room temperature under a nitrogen atmo-
sphere. The reaction mixture was then diluted with an equal
amount of ether and washed three times with brine. The organic
layer was dried over magnesium sulfate, filtered and evaporated
under reduced pressure. The crude was purified by chromatogra-
phy, eluting with hexane and ethyl acetate (see analytical
details).
4.1.5.1. Ethyl (5E)-4-hydroxy-4-methyl-6-phenylhex-5-en-2-
ynoate (9). Yield: 810 mg, 97%, as an orange oil; Rf = 0.33, hex-
ane/ethyl acetate (4:1); mmax (ATR) 3406, 2984, 2239, 1712, 1590,
1246, 968; dH (250 MHz; CDCl3) 7.42-7.26 (5H, m, ArH), 6.85 (1H,
d, J 16.0, H-6), 6.27 (1H, d, J 16.0, H-5), 4.26 (2H, q, J 7.1, CH2(Et)),
2.66 (1H, s, OH-4), 1.71 (3H, s, Me-4), 1.32 (3H, t, J 7.1, CH3(Et)); dC
(62.5 MHz; CDCl3) 153.4 (C), 135.7 (C), 131.3 (CH), 130.0 (CH),
128.6 (CH), 128.2 (CH), 126.8 (CH), 88.3 (C), 76.5 (C), 67.8 (C),
62.2 (CH2), 29.7 (Me), 13.9 (Me); (found: [MꢀOH]+, 227.1094. [C15-
H16O3ꢀOH]+ requires 227.1072).
4.1.4.1. (3E)-4-{4-[(tert-Butyldimethylsilyl)oxy]-3,5-dimethoxy-
phenyl}but-3-en-2-one (19a). Yield: 0.68 g, 99%, as a colourless
oil; Rf = 0.33, hexane/ethyl acetate (9:1); mmax (ATR) 2994, 2856,
1685, 1577, 1456, 1346, 1281, 1178, 908; dH (250 MHz; CDCl3)
7.43 (1H, d, J 16.2, H-4), 6.75 (2H, s, ArH), 6.60 (1H, d, J 16.2, H-
3), 3.83 (6H, s, 2ꢁ ArOMe), 2.37 (3H, s, H-1), 1.01 (9H, s, SitBu),
0.15 (6H, s, SiMe2); dC (62.5 MHz; CDCl3) 198.2 (C), 151.8 (C),
144.0 (CH), 137.2 (C), 126.9 (C), 125.4 (CH), 105.5 (CH), 55.7
(OMe), 27.2 (Me), 25.7 (Me), 18.7 (C), ꢀ4.6 (Me); (found: [M+H]+,
337.1873. C18H28O4Si+H+ requires 337.1835).
4.1.5.2. Ethyl (5E)-4-hydroxy-4-methyl-6-[2-(trifluoromethyl)-
phenyl]hex-5-en-2-ynoate (9a). Yield: 341 mg, 78%, as an orange
oil; Rf = 0.33, hexane/ethyl acetate (85:15); mmax (ATR) 3419, 2987,
2241, 1713, 1576, 1314, 1248, 1161, 1122, 1034; dH (250 MHz;
CDCl3) 7.64 (1H, d, J 7.8, ArH), 7.61 (1H, d, J 7.8, ArH), 7.51 (1H, t,
J 7.6, ArH), 7.38 (1H, t, J 7.6, ArH), 7.26 (1H, dq, J 15.7, 2.1, H-6),
6.26 (1H, d, J 15.7, H-5), 4.26 (2H, q, J 7.1, CH2(Et)), 2.85 (1H, s,
4.1.4.2. (3E)-4-{2-[(tert-Butyldimethylsilyl)oxy]phenyl}but-3-en-
2-one (19b). Yield: 0.68 g, 99%, as a colourless oil; Rf = 0.33, hex-
ane/ethyl acetate (9:1); mmax (ATR) 2956, 2859, 1670, 1599, 1482,
1253, 919, 836; dH (250 MHz; CDCl3) 7.94 (1H, d, J 16.7, H-4),
7.57 (1H, d, J 8.2, ArH), 7.27 (1H, dd, J 9.7, 7.2, ArH), 6.97 (1H, dd,
J 7.5, 7.4, ArH), 6.85 (1H, d, J 8.2, ArH), 6.65 (1H, d, J 16.7, H-3),
2.37 (3H, s, H-1), 1.05 (9H, s, SitBu), 0.25 (6H, s, SiMe2); dC
(62.5 MHz; CDCl3) 202.1 (C), 158.6 (C), 141.8 (CH), 133.2 (CH),
129.9 (CH), 127.6 (CH), 122.7 (C), 121.0 (CH), 117.2 (CH), 26.6
(Me), 25.7 (Me), 18.3 (C), ꢀ4.3 (Me); (found: [M+H]+, 277.1649.
OH-4), 1.72 (3H, s, Me-4), 1.32 (3H, t,
J 7.1, CH3(Et)); dC
(62.5 MHz; CDCl3) 153.4 (C), 135.6 (CH), 135.0 (C), 131.9 (CH),
127.82 (C, q, 2J 30.0), 127.8 (CH), 127.6 (CH), 126.2 (CH), 125.8
(CH, q, 3J 5.7), 124.1 (CF3, q, 1J 273.9), 87.8 (C), 76.6 (C), 67.7 (C),
62.2 (CH2), 29.5 (Me), 13.9 (Me); (found: [MꢀOH]+, 295.0956. [C16-
H15F3O3ꢀOH]+ requires 295.0946).
4.1.5.3. Ethyl (5E)-4-hydroxy-4-methyl-6-[4-(trifluoromethyl)-
phenyl]hex-5-en-2-ynoate (9b). Yield: 332 mg, 76%, as an or-
ange oil; Rf = 0.33, hexane/ethyl acetate (85:15); mmax (ATR)
3420, 2991, 2241, 1714, 1617, 1325, 1249, 1123, 1067; dH
(250 MHz; CDCl3) 7.58 (2H, d, J 8.3, ArH), 7.49 (2H, d, J 8.3, ArH),
6.89 (1H, d, J 16.0, H-6), 6.36 (1H, d, J 16.0, H-5), 4.27 (2H, q, J
7.1, CH2(Et)), 2.82 (1H, s, OH-4), 1.72 (3H, s, Me-4), 1.33 (3H, t, J
7.1, CH3(Et)); dC (62.5 MHz; CDCl3) 153.4 (C), 139.3 (C), 133.8
(CH), 129.9 (C, q, 2J 32.5), 128.7 (CH), 127.0 (CH), 125.8 (CH, q, 3J
3.6), 124.1 (CF3, q, 1J 273.5), 87.9 (C), 76.7 (C), 67.7 (C), 62.3
(CH2), 29.7 (Me), 13.9 (Me); (found: [MꢀOH]+, 295.0956. [C16H15F3-
O3ꢀOH]+ requires 295.0946).
C
16H24O2Si+H+ requires 277.1624).
4.1.4.3. (3E)-4-{3-[(tert-Butyldimethylsilyl)oxy]phenyl}but-3-en-
2-one (19c). Yield: 0.68 g, 99%, as a colourless oil; Rf = 0.33, hex-
ane/ethyl acetate (3:2); mmax (ATR) 2956, 2859, 1671, 1597, 1480,
1255, 979, 840; dH (250 MHz; CDCl3) 7.46 (1H, d, J 16.3, H-4),
7.26 (1H, dd, J 8.0, 7.7, ArH), 7.15 (1H, d, J 7.7, ArH), 7.02 (1H, s,
ArH), 6.89 (1H, d, J 8.0, ArH), 6.68 (1H, d, J 16.3, H-3), 2.39 (3H, s,
H-1), 1.01 (9H, s, SitBu), 0.22 (6H, s, SiMe2); dC (62.5 MHz; CDCl3)
198.3 (C), 156.1 (C), 143.3 (CH), 135.8 (C), 129.9 (CH), 127.2 (CH),
122.3 (CH), 121.5 (CH), 119.4 (CH), 27.4 (Me), 25.6 (Me), 18.1 (C),
ꢀ4.5 (Me); (found: [M+H]+, 277.1649. C16H24O2Si+H+ requires
277.1624).
4.1.5.4. Ethyl (5E)-4-hydroxy-4-methyl-6-(4-fluorophenyl)hex-
5-en-2-ynoate (9c). Yield: 466 mg, 97%, as a dark orange oil;
Rf = 0.33, hexane/ethyl acetate (4:1); mmax (ATR) 2986, 2240, 1712,
4.1.4.4. (3E)-4-{4-[(tert-Butyldimethylsilyl)oxy]phenyl}but-3-
en-2-one (19d). Yield: 0.68 g, 99%, as a colourless oil; Rf = 0.33,
hexane/ethyl acetate (9:1); mmax (ATR) 2929, 2858, 1681, 1596,
1510, 1270, 1180, 910, 838; dH (250 MHz; CDCl3) 7.47 (1H, d, J
16.4, H-4), 7.44 (2H, d, J 8.6, ArH), 6.85 (2H, d, J 8.6, ArH), 6.60
(1H, d, J 16.4, H-3), 2.35 (3H, s, H-1), 0.99 (9H, s, SitBu), 0.22 (6H,
s, SiMe2); dC (62.5 MHz; CDCl3) 198.3 (C), 158.1 (C), 143.3 (CH),
129.9 (CH), 127.6 (C), 125.2 (CH), 120.6 (CH), 27.3 (Me), 25.6
(Me), 18.2 (C), ꢀ4.4 (Me); (found: [M+H]+, 277.1649. C16H24O2-
Si+H+ requires 277.1624).
1602, 1510, 1368, 1247, 1159, 817; dH (250 MHz; CDCl3) 7.37 (2H,
dd, J 8.4, 8.4, ArH), 7.02 (2H, dd, J 8.6, 8.6, ArH), 6.82 (1H, d, J 15.9,
H-6), 6.19 (1H, d, J 15.9, H-5), 4.26 (2H, q, J 7.1, CH2(Et)), 2.67 (1H,
s, OH-4), 1.70 (3H, s, Me-4), 1.33 (3H, t, J 7.1, CH3(Et)); dC
(62.5 MHz; CDCl3) 162.7 (CF, d, 1J 247.8), 153.5 (C), 131.9 (C, d, 4J
3.2), 131.0 (CH), 128.9 (CH), 128.5 (CH, 3J 8.2), 115.6 (CH, 2J 21.7),
88.2 (C), 76.5 (C), 67.8 (C), 62.2 (CH2), 29.8 (Me), 14.0 (Me); (found:
[MꢀOH]+, 245.0929. [C15H15FO3ꢀOH]+ requires 245.0978).
4.1.5.5. Ethyl (5E)-4-hydroxy-4-methyl-6-(2,4-dimethoxyphenyl)-
hex-5-en-2-ynoate (9d). Yield: 406 mg, 92%, as an orange oil;
Rf = 0.33, hexane/ethyl acetate (7:3); mmax (ATR) 3452, 2939,
2238, 1710, 1609, 1504, 1245, 1209, 1159, 1030; dH (250 MHz;
CDCl3) 7.32 (1H, d, J 8.2, ArH), 7.05 (1H, d, J 16.0, H-6), 6.47 (1H,
dd, J 8.2, 2.4, ArH), 6.46 (1H, d, J 2.4, ArH), 6.24 (1H, d, J 16.0, H-
4.1.5. General procedure for the preparation of ethyl phenylhex-
5-en-2-ynoates (9a-m)
To a freshly prepared solution of lithium diisopropylamine in
THF (0.5 M; 1.8 equiv) at ꢀ78 °C under nitrogen atmosphere, was

M. Bruder et al. / Bioorg. Med. Chem. 21 (2013) 5107–5117
5113
5), 4.25 (2H, q, J 7.1, CH2(Et)), 3.83 (3H, s, ArOMe), 3.81 (3H, s,
ArOMe), 2.44 (1H, s, OH-4), 1.70 (3H, s, Me-4), 1.32 (3H, t, J 7.1,
CH3(Et)); dC (62.5 MHz; CDCl3) 160.9 (C), 158.3 (C), 153.3 (C),
129.8 (CH), 128.4 (CH), 125.0 (CH), 117.7 (C), 104.8 (CH), 98.4
(CH), 88.9 (C), 76.3 (C), 68.2 (C), 62.1 (CH2), 55.4 (OMe), 55.3
(OMe), 29.7 (Me), 14.0 (Me); (found: [MꢀOH]+, 287.1246. [C17H20-
O6ꢀOH]+ requires 287.1283).
7.1, CH3(Et)); dC (62.5 MHz; CDCl3) 160.7 (C), 159.6 (CH), 153.7
(C), 132.0 (CH), 120.4 (CH), 106.2 (C), 90.5 (CH), 89.4 (C), 76.3
(C), 68.9 (C), 62.0 (CH2), 55.6 (OMe), 55.2 (OMe), 29.7 (Me), 14.0
(Me); (found: [MꢀOH]+, 317.1343. [C18H22O6ꢀOH]+ requires
317.1389).
4.1.5.11. Ethyl (5E)-6-{4-[(tert-Butyldimethylsilyl)oxy]-3,5-
dimethoxyphenyl]-4-hydroxy-4-methyl-hex-5-en-2-ynoate
(9j). Yield: 528 mg, 80%, as an off-white solid; Rf = 0.33, hexane/
ethyl acetate (4:1); mp 139-140 °C; mmax (ATR) 3433, 2930, 2239,
1697, 1584, 1510, 1240, 1110, 892, 785; dH (250 MHz; CDCl3)
6.75 (1H, d, J 15.9, H-6), 6.60 (2H, s, ArH), 6.14 (1H, d, J 15.9, H-
5), 4.26 (2H, q, J 7.1, CH2(Et)), 3.81 (6H, s, ArOMe), 2.50 (1H, s,
OH-4), 1.70 (3H, s, Me-4), 1.33 (3H, t, J 7.1, CH3(Et)), 1.01 (9H, s, Sit-
Bu), 0.13 (6H, s, SiMe2); dC (62.5 MHz; CDCl3) 153.5 (C), 151.7 (C),
134.9 (C), 130.4 (C), 129.4 (CH), 128.4 (C), 104.0 (CH), 88.5 (C), 76.5
(C), 67.9 (C), 62.2 (CH2), 55.7 (OMe), 29.8 (Me), 25.7 (Me), 18.7 (C),
14.0 (Me), ꢀ4.7 (Me); (found: [MꢀOH]+, 417.2172. [C23H34O6-
SiꢀOH]+ requires 417.2097).
4.1.5.6. Ethyl (5E)-4-hydroxy-4-methyl-6-(3,4-dimethoxyphenyl)-
hex-5-en-2-ynoate (9e). Yield: 563 mg, 80%, as a dark orange oil;
Rf = 0.33, hexane/ethyl acetate (65:35); mmax (ATR) 3481, 2931,
2237, 1709, 1515, 1247, 1139, 1025; dH (250 MHz; CDCl3) 6.95
(1H, d, J 8.6, ArH), 6.94 (1H, s, ArH), 6.82 (1H, d, J 8.6, ArH), 6.79
(1H, d, J 15.9, H-6), 6.15 (1H, d, J 15.9, H-5), 4.27 (2H, q, J 7.1, CH2(-
Et)), 3.90 (3H, s, ArOMe), 3.88 (3H, s, ArOMe), 2.59 (1H, s, OH-4),
1.71 (3H, s, Me-4), 1.33 (3H, t, J 7.1, CH3(Et)); dC (62.5 MHz; CDCl3)
153.5 (C), 149.3 (C), 149.0 (C), 129.9 (CH), 129.3 (CH), 128.7 (C),
120.2 (CH), 111.1 (CH), 109.0 (CH), 88.5 (C), 76.5 (C), 67.9 (C),
62.2 (CH2), 55.9 (OMe), 55.8 (OMe), 29.8 (Me), 14.0 (Me); (found:
[MꢀOH]+, 287.1293. [C17H20O5ꢀOH]+ requires 287.1283).
4.1.5.12. Ethyl (5E)-6-{2-[(tert-Butyldimethylsilyl)oxy]phenyl}-
4-hydroxy-4-methylhex-5-en-2-ynoate (9k). Yield: 544 mg,
61%, as an orange oil; Rf = 0.33, hexane/ethyl acetate (9:1); mmax
(ATR) 3450, 2931, 2239, 1714, 1598, 1485, 1250, 1028, 919, 878;
dH (250 MHz; CDCl3) 7.44 (1H, d, J 7.6, ArH), 7.21 (1H, d, J 16.0, H-
6), 7.15 (1H, t, J 8.0, ArH), 6.92 (1H, t, J 7.6, ArH), 6.80 (1H, d, J 8.0,
ArH), 6.22 (1H, d, J 16.0, H-5), 4.25 (2H, q, J 7.1, CH2(Et)), 2.42
(1H, s, OH-4), 1.70 (3H, s, Me-4), 1.32 (3H, t, J 7.1, CH3(Et)), 1.02
(9H, s, SitBu), 0.22 (6H, s, SiMe2); dC (62.5 MHz; CDCl3) 153.4 (C),
153.3 (C), 131.1 (CH), 129.1 (CH), 127.1 (C), 126.7 (CH), 125.7
(CH), 121.4 (CH), 119.6 (CH), 88.4 (C), 76.6 (C), 68.3 (C), 62.1
(CH2), 29.7 (Me), 25.7 (Me), 18.2 (C), 14.0 (Me), ꢀ4.2 (Me); (found:
[MꢀOH]+, 357.1881. [C21H30O4SiꢀOH]+ requires 357.1886).
4.1.5.7. Ethyl (5E)-4-hydroxy-4-methyl-6-(2,3,4-trimethoxy-
phenyl)hex-5-en-2-ynoate (9f). Yield: 360 mg, 85%, as an orange
oil; Rf = 0.33, hexane/ethyl acetate (7:3); mmax (ATR) 3450, 2985,
2238, 1712, 1597, 1495, 1437, 1244, 1095; dH (250 MHz; CDCl3)
7.14 (1H, d, J 8.7, ArH), 7.05 (1H, d, J 16.1, H-6), 6.66 (1H, d, J 8.7,
ArH), 6.24 (1H, d, J 16.1, H-5), 4.26 (2H, q, J 7.1, CH2(Et)), 3.874
(3H, s, ArOMe), 3.869 (6H, s, ArOMe), 2.55 (1H, s, OH-4), 1.71
(3H, s, Me-4), 1.32 (3H, t, J 7.1, CH3(Et)); dC (62.5 MHz; CDCl3)
153.7 (C), 153.5 (C), 151.9 (C), 142.3 (C), 130.7 (CH), 124.6 (CH),
122.7 (C), 121.5 (CH), 107.6 (CH), 88.6 (C), 76.4 (C), 68.1 (C), 62.1
(CH2), 61.1 (OMe), 60.8 (OMe), 56.0 (OMe), 29.7 (Me), 13.9 (Me);
(found: [MꢀOH]+, 317.1368. [C18H22O6ꢀOH]+ requires 317.1389).
4.1.5.8. Ethyl (5E)-4-hydroxy-4-methyl-6-(2,4,5-trimethoxy-
phenyl)hex-5-en-2-ynoate (9g). Yield: 387 mg, 91%, as a red oil;
Rf = 0.33, hexane/ethyl acetate (3:2); mmax (ATR) 3470, 2937, 2213,
4.1.5.13. Ethyl (5E)-6-{3-[(tert-Butyldimethylsilyl)oxy]phenyl}-
4-hydroxy-4-methylhex-5-en-2-ynoate(9l). Yield: 812 mg, 94%,
as a yellow oil; Rf = 0.33, hexane/ethyl acetate (95:5); mmax (ATR)
3408, 2956, 2239, 1715, 1580, 1486, 1253, 1173, 974, 855; dH
(250 MHz; CDCl3) 7.18 (1H, at, J 7.8, ArH), 7.00 (1H, d, J 7.6, ArH),
6.87 (1H, s, ArH), 6.79 (1H, d, J 15.9, H-6), 6.76-6.74 (1H, m, ArH),
6.22 (1H, d, J 15.9, H-5), 4.26 (2H, q, J 7.1, CH2(Et)), 2.57 (1H, s,
OH-4), 1.70 (3H, s, Me-4), 1.32 (3H, t, J 7.1, CH3(Et)), 0.99 (9H, s, Sit-
Bu), 0.20 (6H, s, SiMe2); dC (62.5 MHz; CDCl3) 155.9 (C), 153.5 (C),
137.2 (C), 131.3 (CH), 130.0 (CH), 129.5 (CH), 120.00 (CH), 119.96
(CH), 118.5 (CH), 88.3 (C), 76.5 (C), 67.8 (C), 62.2 (CH2), 29.7
(Me), 25.7 (Me), 18.2 (C), 14.0 (Me), ꢀ4.4 (Me); (found: [MꢀOH]+,
357.1881. [C21H30O4SiꢀOH]+ requires 357.1886).
1708, 1609, 1511, 1465, 1244, 1032; dH (250 MHz; CDCl3) 7.09
(1H, d, J 15.9, H-6), 6.94 (1H, s, ArH), 6.50 (1H, s, ArH), 6.21 (1H,
d, J 15.9, H-5), 4.26 (2H, q, J 7.1, CH2(Et)), 3.90 (3H, s, ArOMe),
3.86 (3H, s, ArOMe), 3.83 (3H, s, ArOMe), 2.55 (1H, s, OH-4), 1.72
(3H, s, Me-4), 1.32 (3H, t, J 7.1, CH3(Et)); dC (62.5 MHz; CDCl3)
153.5 (C), 151.9 (C), 150.0 (C), 143.2 (C), 129.6 (CH), 124.6 (CH),
116.3 (C), 110.3 (CH), 97.5 (CH), 88.9 (C), 76.2 (C), 68.1 (C), 62.1
(CH2), 56.5 (OMe), 56.0 (OMe), 29.7 (Me), 14.0 (Me); (found:
[MꢀOH]+, 317.1368. [C18H22O6ꢀOH]+ requires 317.1389).
4.1.5.9. Ethyl (5E)-4-hydroxy-4-methyl-6-(3,4,5-trimethoxy-
phenyl)hex-5-en-2-ynoate (9h). Yield: 178 mg, 42%, as light or-
ange oil; Rf = 0.33, hexane/ethyl acetate (3:2); mmax (ATR) 3457,
2942, 2238, 1711, 1584, 1508, 1419, 1242, 1127; dH (250 MHz;
CDCl3) 6.77 (1H, d, J 15.9, H-6), 6.62 (2H, s, ArH), 6.19 (1H, d, J
15.9, H-5), 4.27 (2H, q, J 7.1, CH2(Et)), 3.88 (6H, s, ArOMe), 3.85
(3H, s, ArOMe), 2.59 (1H, s, OH-4), 1.71 (3H, s, Me-4), 1.33 (3H, t, J
7.1, CH3(Et)); dC (62.5 MHz; CDCl3) 153.5 (C), 153.3 (C), 138.3 (C),
131.4 (C), 130.7 (CH), 130.0 (CH), 104.0 (CH), 88.3 (C), 76.5 (C),
67.8 (C), 62.2 (CH2), 60.9 (OMe), 56.1 (OMe), 29.8 (Me), 14.0 (Me);
(found: [MꢀOH]+, 317.1368. [C18H22O6ꢀOH]+ requires 317.1389).
4.1.5.14. Ethyl (5E)-6-{4-[(tert-Butyldimethylsilyl)oxy]phenyl}-
4-hydroxy-4-methylhex-5-en-2-ynoate (9m). Yield: 619 mg,
69%, as an orange oil; Rf = 0.33, hexane/ethyl acetate (9:1); mmax
(ATR) 3440, 2931, 2240, 1714, 1604, 1509, 1253, 912, 840; dH
(250 MHz; CDCl3) 7.28 (2H, d, J 8.6, ArH), 6.80 (2H, d, J 8.6, ArH),
6.78 (1H, d, J 15.9, H-6), 6.13 (1H, d, J 15.9, H-5), 4.26 (2H, q, J
7.1, CH2(Et)), 2.54 (1H, s, OH-4), 1.69 (3H, s, Me-4), 1.32 (3H, t, J
7.1, CH3(Et)), 0.98 (9H, s, SitBu), 0.20 (6H, s, SiMe2); dC
(62.5 MHz; CDCl3) 155.9 (C), 153.5 (C), 129.7 (CH), 129.3 (CH),
129.0 (C), 128.0 (CH), 120.3 (CH), 88.5 (C), 76.4 (C), 67.9 (C), 62.2
(CH2), 29.8 (Me), 25.6 (Me), 18.2 (C), 14.0 (Me), ꢀ4.4 (Me); (found:
[MꢀOH]+, 357.1881. [C21H30O4SiꢀOH]+ requires 357.1886).
4.1.5.10. Ethyl (5E)-4-hydroxy-4-methyl-6-(2,4,6-trimethoxy-
phenyl)hex-5-en-2-ynoate (9i). Yield: 311 mg, 73%, as a dark or-
ange oil; Rf = 0.33, hexane/ethyl acetate (65:35); mmax (ATR) 2939,
2210, 1707, 1605, 1456, 1245, 1205, 1119, 736; dH (250 MHz;
CDCl3) 7.15 (1H, d, J 16.2, H-6), 6.65 (1H, d, J 16.2, H-5), 6.12 (2H,
s, ArH), 4.25 (2H, q, J 7.1, CH2(Et)), 3.83 (6H, s, ArOMe), 3.82 (3H,
s, ArOMe), 2.41 (1H, s, OH-4), 1.70 (3H, s, Me-4), 1.32 (3H, t, J
4.1.6. General procedure for the preparation of 5-methyl-5-[(E)-
2-phenylethenyl]-2,5-dihydrofuran-2-ones (7, 10-18, 20-26)
A mixture of alkyne (1.0 equiv), quinoline (1.0 equiv) and Lind-
lar’s catalyst (4 wt %) in methanol (0.1 M) was stirred for 3 h at
room temperature under a hydrogen atmosphere. The reaction

5114
M. Bruder et al. / Bioorg. Med. Chem. 21 (2013) 5107–5117
mixture was then filtered through CeliteÒ and the filter cake
washed several times with ethyl acetate. The filtrate was washed
with an equal amount a hydrochloric acid solution (1 M), brine,
dried over magnesium sulfate, filtered and evaporated under re-
duced pressure. If necessary, the crude was taken up in a mixture
of methanol and dichloromethane (1:1) and stirred for another 2 h
at room temperature. The reaction mixture was filtered and evap-
orated under reduced pressure. The crude was purified by chroma-
tography, eluting with hexane and ethyl acetate (see analytical
details).
(CH), 158.1 (C), 128.1 (CH), 126.0 (CH), 125.1 (CH), 119.7 (CH),
117.5 (C), 104.9 (CH), 98.4 (CH), 88.5 (C), 55.3 (2ꢁ OMe), 24.1
(Me); (found: [M+H]+, 261.1238. C15H16O4+H+ requires 261.1127).
4.1.6.6. 5-Methyl-5-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-2,5-
dihydrofuran-2-one (14). Yield: 215 mg, 72%, as a white solid;
Rf = 0.33, hexane/ethyl acetate (1:1); mp 113-114 °C; mmax (ATR)
2938, 1747, 1601, 1515, 1268, 1106, 1026, 946, 820; dH
(250 MHz; CDCl3) 7.47 (1H, d, J 5.6, H-4), 6.93-6.91 (2H, m, ArH),
6.82 (1H, d, J 8.7, ArH), 6.58 (1H, d, J 16.1, H-20), 6.05 (1H, d, J
16.1, H-20), 6.05 (1H, d, J 5.6, H-3), 3.89 (3H, s, ArOMe), 3.88 (3H,
s, ArOMe), 1.68 (3H, s, Me); dC (62.5 MHz; CDCl3) 172.3 (C), 159.4
(CH), 149.3 (C), 149.0 (C), 130.7 (CH), 128.5 (C), 124.7 (CH), 120.0
(CH), 119.6 (CH), 111.0 (CH), 108.7 (CH), 87.9 (C), 55.8 (OMe),
55.7 (OMe), 24.0 (Me); (found: [M+H]+, 261.1138. C15H16O4+H+ re-
quires 261.1127).
4.1.6.1. 5-Methyl-5-[(E)-2-phenylethenyl]-2,5-dihydrofuran-2-
one (7). Yield: 0.51 g, 79%, as a light orange solid; Rf = 0.33, hex-
ane/ethyl acetate (7:3); mp 90-91 °C; mmax (ATR) 2982, 1754, 1602,
1449, 1233, 1104, 943, 751; dH (250 MHz; CDCl3) 7.46 (1H, d, J 5.5,
H-4), 7.37-7.26 (5H, m, ArH), 6.65 (1H, d, J 15.9, H-20), 6.18 (1H, d, J
16.4, H-10), 6.05 (1H, d, J 5.5, H-3), 1.67 (3H, s, Me); dC (62.5 MHz;
CDCl3) 172.3 (C), 159.3 (CH), 135.5 (C), 130.9 (CH), 128.6 (CH),
128.4 (CH), 126.8 (CH), 126.6 (CH), 119.8 (CH), 87.8 (C), 24.1
(Me); (found: [M+H]+, 201.0914. C13H12O2+H+ requires 201.0910).
4.1.6.7.
5-Methyl-5-[(E)-2-(2,3,4-trimethoxyphenyl)ethenyl]-
2,5-dihydrofuran-2-one (15). Yield: 154 mg, 55%, as an orange
oil; Rf = 0.33, hexane/ethyl acetate (3:2); mmax (ATR) 2939, 1751,
1597, 1495, 1464, 1295, 1095, 942, 820; dH (250 MHz; CDCl3)
7.47 (1H, d, J 5.5, H-4), 7.11 (1H, d, J 8.7, ArH), 6.82 (1H, d, J 16.3,
H-20), 6.66 (1H, d, J 8.7, ArH), 6.14 (1H, d, J 16.3, H-10), 6.06 (1H,
d, J 5.5, H-3), 3.86 (9H, s, 3ꢁ ArOMe), 1.68 (3H, s, Me); dC
(62.5 MHz; CDCl3) 172.4 (C), 159.5 (CH), 153.8 (C), 151.8 (C),
142.2 (C), 126.2 (CH), 125.7 (CH), 122.5 (C), 121.3 (CH), 119.9
(CH), 107.6 (CH), 88.2 (C), 61.1 (OMe), 60.8 (OMe), 56.0 (OMe),
24.0 (Me); (found: [M+H]+, 291.1220. C16H18O5+H+ requires
291.1233).
4.1.6.2. 5-Methyl-5-[(E)-4-(2-trifluoromethylphenyl)ethenyl]-
2,5-dihydrofuran-2-one (10). Yield: 225 mg, 90%, as a light yel-
low oil; Rf = 0.33, hexane/ethyl acetate (4:1); mmax (ATR) 1759,
1605, 1314, 1276, 1161, 1036, 916, 813, 766; dH (250 MHz; CDCl3)
7.64 (1H, d, J 7.9, ArH), 7.55 (1H, at, J 7.9, ArH), 7.51 (1H, d, J 7.5,
ArH), 7.48 (1H, d, J 5.6, H-4), 7.39 (1H, at, J 7.5, ArH), 7.01 (1H,
dq, J 16.0, 2.1, H-20), 6.15 (1H, d, J 16.0, H-10), 6.10 (1H, d, J 5.6,
H-3), 1.70 (3H, s, Me); dC (62.5 MHz; CDCl3) 172.0 (C), 158.8
(CH), 134.8 (C), 132.0 (CH), 131.6 (CH), 128.0 (CH), 127.7 (C, q, 2J
30.0), 127.6 (CH), 127.5 (CH), 125.8 (CH, q, 3J 5.6), 124.1 (CF3, q,
1J 273.5), 120.4 (CH), 87.6 (C), 23.8 (Me); (found: [M+H]+,
269.0797. C14H11F3O2+H+ requires 269.0789).
4.1.6.8.
5-Methyl-5-[(E)-2-(2,4,5-trimethoxyphenyl)ethenyl]-
2,5-dihydrofuran-2-one (16). Yield: 164 mg, 55%, as an orange
oil; Rf = 0.33, hexane/ethyl acetate (3:2); mmax (ATR) 2936, 1749,
1609, 1511, 1465, 1208, 1103, 1031, 941, 819; dH (250 MHz; CDCl3)
7.47 (1H, d, J 5.5, H-4), 6.91 (1H, s, ArH), 6.89 (1H, d, J 16.3, H-20),
6.49 (1H, s, ArH), 6.09 (1H, d, J 16.3, H-10), 6.05 (1H, d, J 5.5, H-3),
3.90 (3H, s, ArOMe), 3.85 (3H, s, ArOMe), 3.83 (3H, s, ArOMe),
1.69 (3H, s, Me); dC (62.5 MHz; CDCl3) 172.5 (C), 159.7 (CH),
151.8 (C), 150.2 (C), 143.2 (C), 125.8 (CH), 125.0 (CH), 119.8 (CH),
116.1 (C), 110.0 (CH), 97.3 (CH), 88.4 (C), 56.5 (OMe), 56.3
(OMe), 56.0 (OMe), 24.0 (Me); (found: [M+H]+, 291.1239.
4.1.6.3. 5-Methyl-5-[(E)-2-(4-trifluoromethylphenyl)ethenyl]-
2,5-dihydrofuran-2-one (11). Yield: 222 mg, 88%, as a light yel-
low oil; Rf = 0.33, hexane/ethyl acetate (4:1); mmax (ATR) 2933,
1757, 1617, 1324, 1234, 1104, 1067, 944, 816; dH (250 MHz; CDCl3)
7.58 (2H, d, J 8.3, ArH), 7.49 (1H, d, J 5.6, H-4), 6.46 (2H, d, J 8.3,
ArH), 6.71 (1H, d, J 16.1, H-20), 6.29 (1H, d, J 16.1, H-10), 6.08 (1H,
d, J 5.6, H-3), 1.69 (3H, s, Me); dC (62.5 MHz; CDCl3) 172.1 (C),
158.9 (CH), 139.1 (C), 130.1 (C, q, 2J 32.6), 129.5 (CH), 129.4 (CH),
126.8 (CH), 125.6 (CH, q, 3J 3.8), 124.0 (CF3, q, 1J 272.0), 120.0
(CH), 87.5 (C), 24.1 (Me); (found: [M+H]+, 269.0797. C14H11O3F2+-
H+ requires 269.0789).
C
16H18O5+H+ requires 291.1233).
4.1.6.9. 5-Methyl-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]-
2,5-dihydrofuran-2-one (17). Yield: 64 mg, 50%, as a yellow so-
lid; Rf = 0.33, hexane/ethyl acetate (3:2); mp 125-126 °C; mmax
(ATR) 2970, 1739, 1581, 1510, 1421, 1247, 1105, 936, 815,; dH
(250 MHz; CDCl3) 7.48 (1H, d, J 5.5, H-4), 6.59 (3H, s+d, J 16.0,
ArH, H-20), 6.10 (1H, d, J 16.0, H-10), 6.07 (1H, d, J 5.5, H-3), 3.87
(6H, s, 2ꢁ ArOMe), 3.85 (3H, s, ArOMe), 1.69 (3H, s, Me); dC
(62.5 MHz; CDCl3) 172.3 (C), 159.3 (C), 153.3 (C), 138.3 (C), 131.2
(C), 130.9 (CH), 126.2 (CH), 119.8 (CH), 103.7 (CH), 87.8 (C), 60.8
(OMe), 56.0 (OMe), 24.0 (Me); (found: [M+H]+, 291.1212.
4.1.6.4.
5-Methyl-5-[(E)-4-(4-fluorophenyl)ethenyl]-2,5-dihy-
drofuran-2-one (12). Yield: 299 mg, 82%, as a colourless oil;
Rf = 0.33, hexane/ethyl acetate (7:3); mmax (ATR) 2984, 1756,
1602, 1510, 1231, 1104, 944, 819; dH (250 MHz; CDCl3) 7.47 (1H,
d, J 5.5, H-4), 7.34 (1H, d, J 8.6, ArH), 7.33 (1H, d, J 8.6, ArH), 7.01
(2H, at, J 8.6, ArH), 6.62 (1H, d, J 16.1, H-20), 6.10 (1H, d, J 16.1,
H-10), 6.06 (1H, d, J 5.5, H-3), 1.67 (3H, s, Me); dC (62.5 MHz; CDCl3)
172.2 (C), 162.2 (CF, d, 1J 248.2), 159.2 (CH), 131.8 (C, d, 4J 3.3),
129.7 (CH), 128.3 (CH, d, 3J 8.1), 126.6 (CH), 119.8 (CH), 115.6
(CH, d, 2J 21.7), 87.7 (C), 24.1 (Me); (found: [M+H]+, 219.0791. C13-
H11FO2+H+ requires 219.0821).
C
16H18O5+H+ requires 291.1233).
4.1.6.10. 5-Methyl-5-[(E)-2-(2,4,6-trimethoxyphenyl)ethenyl]-
2,5-dihydrofuran-2-one (18). Yield: 190 mg, 79%, as a light yel-
low oil; Rf = 0.33, hexane/ethyl acetate (3:2); mmax (ATR) 2939,
1749, 1604, 1456, 1205, 1156, 1119, 941, 816; dH (250 MHz; CDCl3)
7.47 (1H, d, J 5.5, H-4), 6.88 (1H, d, J 16.5, H-20), 6.54 (1H, d, J 16.5,
H-10), 6.11 (2H, s, ArH), 6.01 (1H, d, J 5.5, H-3), 3.82 (6H, s, 2ꢁ
ArOMe), 3.81 (3H, s, ArOMe), 1.66 (3H, s, Me); dC (62.5 MHz; CDCl3)
172.8 (C), 160.8 (C), 160.2 (CH), 159.6 (C), 127.5 (CH), 121.6 (CH),
119.4 (CH), 106.1 (C), 90.5 (CH), 89.4 (C), 55.6 (OMe), 55.2
(OMe), 24.2 (Me); (found: [M+H]+, 291.1259. C16H18O5+H+ requires
291.1233).
4.1.6.5. 5-Methyl-5-[(E)-2-(2,4-dimethoxyphenyl)ethenyl]-2,5-
dihydrofuran-2-one (13). Yield: 224 mg, 70%, as a light yellow
oil; Rf = 0.33, hexane/ethyl acetate (7:3); mmax (ATR) 2938, 1750,
1608, 1505, 1288, 1209, 1160, 1103, 941, 819; dH (250 MHz; CDCl3)
7.46 (1H, d, J 5.6, H-4), 7.30 (1H, d, J 8.3, ArH), 6.84 (1H, d, J 16.3, H-
20), 6.45 (1H, d, J 8.3, ArH), 6.43 (1H, s, ArH), 6.11 (1H, d, J 16.3, H-
10), 6.03 (1H, d, J 5.6, H-3), 3.82 (3H, s, ArOMe), 3.81 (3H, s, ArOMe),
1.67 (3H, s, Me); dC (62.5 MHz; CDCl3) 172.5 (C), 161.0 (C), 159.7

M. Bruder et al. / Bioorg. Med. Chem. 21 (2013) 5107–5117
5115
4.1.7. General procedure for the preparation of hydroxylated 5-
methyl-5-[(E)-2-phenylethenyl]-2,5-dihydrofuran-2-ones (20-
23)
88.7 (C), 24.0 (Me); (found: [M+H]+, 217.0933. C13H12O3+H+ re-
quires 217.0865).
A mixture of alkyne (1.0 equiv), quinoline (1.0 equiv) and Lind-
lar’s catalyst (4 wt %) in methanol (0.1 M) was stirred for 3 h at
room temperature under a hydrogen atmosphere. The reaction
mixture was then filtered through CeliteÒ and the filter cake
washed several times with ethyl acetate. The filtrate was washed
with an equal amount a hydrochloric acid solution (1 M), brine,
dried over magnesium sulfate, filtered and evaporated under re-
duced pressure. The crude was then taken up in THF (50 mM) un-
der a nitrogen atmosphere and a solution of HFÅ pyridine (70%;
50 equiv) was added dropwise. After stirring for 16 h at room tem-
perature, the reaction mixture was poured onto ice water and di-
luted with ether. This mixture was then washed twice with a
saturated aqueous sodium hydrogen carbonate solution (!!!vigor-
ous reaction!!!). The organic later was washed with brine, dried
over magnesium sulfate, filtered and evaporated under reduces
pressure. The crude was purified by chromatography, eluting with
hexane and ethyl acetate (see analytical details).
4.1.8. General procedure for the methylation of phenols (24-26)
To a solution of phenol (1.0 equiv) and diisopropylethylamine
(1.5 equiv) in acetonitrile and methanol (9:1) (0.25 M) was added
trimethylsilyl diazomethane (1.3 equiv) at room temperature.
The reaction mixture was stirred for 16 h upon which time an
equal amount of saturated aqueous ammonium chloride solution
and ether were poured. The organic layer was washed with brine,
dried over magnesium sulfate, filtered and evaporated under re-
duced pressure. The crude was purified by chromatography, elut-
ing with hexane and ethyl acetate (see analytical details).
4.1.8.1. 5-[(E)-2-(2-Methoxyphenyl)ethenyl]-5-methyl-2,5-dihy-
drofuran-2-one (24). Yield: 65 mg, 61%, as a colourless oil;
Rf = 0.33, hexane/ethyl acetate (4:1); mmax (ATR) 2925, 1755,
1602, 1464, 1246, 1102, 943, 818, 753; dH (250 MHz; CDCl3) 7.47
(1H, d, J 5.6, H-4), 7.37 (1H, d, J 7.6, ArH), 7.25 (1H, at, J 7.4, ArH),
6.95 (1H, d, J 16.6, H-20), 6.94 (1H, t, J 7.5, ArH), 6.88 (1H, d, J 8.3,
ArH), 6.22 (1H, d, J 16.3, H-10), 6.03 (1H, d, J 5.6, H-3), 3.83 (3H,
s, ArOMe), 1.67 (3H, s, Me); dC (62.5 MHz; CDCl3) 172.4 (C), 159.5
(CH), 156.9 (C), 129.4 (CH), 127.3 (CH), 127.1 (CH), 126.1 (CH),
124.4 (C), 120.5 (CH), 119.7 (CH), 110.8 (CH), 88.2 (C), 55.3
(OMe), 24.0 (Me); (found: [M+H]+, 231.1091. C14H14O3+H+ requires
231.1021).
4.1.7.1. 5-[(E)-2-(4-Hydroxy-3,5-dimethoxyphenyl)ethenyl]-5-
methyl-2,5-dihydrofuran-2-one (20). Yield: 177 mg, 57%, as a
light orange powder; Rf = 0.33, hexane/ethyl acetate (3:2); mp
150-151 °C; mmax (ATR) 3446, 2960, 1743, 1607, 1515, 1214,
1105, 971, 829; dH (250 MHz; CDCl3) 7.47 (1H, d, J 5.6, H-4), 6.60
(2H, s, ArH), 6.55 (1H, d, J 16.2, H-20), 6.06 (1H, d, J 5.6, H-3), 6.02
(1H, d, J 16.2, H-10), 5.69 (1H, bs, ArOH) 3.89 (6H, s, 2ꢁ ArOMe),
1.68 (3H, s, Me); dC (62.5 MHz; CDCl3) 172.3 (C), 159.4 (CH),
147.1 (C), 135.2 (C), 131.1 (CH), 127.0 (C), 124.7 (CH), 119.7 (CH),
103.5 (CH), 87.9 (C), 56.2 (OMe), 24.0 (Me); (found: [M+H]+,
277.1103. C15H16O5+H+ requires 277.1076).
4.1.8.2. 5-[(E)-2-(3-Methoxyphenyl)ethenyl]-5-methyl-2,5-dihy-
drofuran-2-one (25). Yield: 45 mg, 42%, as a colourless oil;
Rf = 0.33, hexane/ethyl acetate (4:1); mmax (ATR) 2982, 1757,
1581, 1489, 1232, 1104, 943, 818, 778; dH (250 MHz; CDCl3) 7.46
(1H, d, J 5.6, H-4), 7.24 (1H, at, J 7.8, ArH), 6.96 (1H, d, J 7.7, ArH),
6.89 (1H, s, ArH), 6.83 (1H, dd, J 8.2, 1.6, ArH), 6.53 (1H, d, J 16.1,
H-20), 6.17 (1H, d, J 16.1, H-10), 6.05 (1H, d, J 5.6, H-3), 3.80 (3H,
s, ArOMe), 1.67 (3H, s, Me); dC (62.5 MHz; CDCl3) 172.2 (C), 159.8
(C), 159.2 (CH), 136.9 (C), 130.8 (CH), 129.6 (CH), 127.1 (CH),
119.8 (CH), 119.2 (CH), 114.1 (CH), 111.8 (CH), 87.8 (C), 55.2
(OMe), 24.1 (Me); (found: [M+H]+, 231.1091. C14H14O3+H+ requires
231.1021).
4.1.7.2. 5-[(E)-2-(2-Hydroxyphenyl)ethenyl]-5-methyl-2,5-dihy-
drofuran-2-one (21). Yield: 246 mg, 77%, as a colourless oil;
Rf = 0.33, hexane/ethyl acetate (3:2); mmax (ATR) 3341, 2978,
1731, 1603, 1457, 1254, 1103, 947, 819, 754; dH (250 MHz; CDCl3)
7.49 (1H, d, J 5.5, H-4), 7.32 (1H, d, J 7.6, ArH), 7.13 (1H, at, J 8.4,
ArH), 6.92 (1H, d, J 16.1, H-20), 6.89-6.81 (2H, m, ArH), 6.58 (1H,
bs, ArOH), 6.25 (1H, d, J 16.1, H-10), 6.04 (1H, d, J 5.5, H-3), 1.67
(3H, s, Me); dC (62.5 MHz; CDCl3) 173.3 (C), 160.1 (CH), 153.8 (C),
129.4 (CH), 127.5 (CH), 127.2 (CH), 126.4 (CH), 122.7 (C), 120.6
(CH), 119.7 (CH), 116.1 (CH), 88.9 (C), 24.0 (Me); (found: [M+H]+,
217.0933. C13H12O3+H+ requires 217.0865).
4.1.8.3. 5-[(E)-2-(4-Methoxyphenyl)ethenyl]-5-methyl-2,5-dihy-
drofuran-2-one (26). Yield: 40 mg, 52%, as
a white solid;
Rf = 0.33, hexane/ethyl acetate (7:3); mp 118-120 °C; mmax (ATR)
2925, 1732, 1605, 1512, 1257, 1116, 1030, 835; dH (250 MHz;
CDCl3) 7.45 (1H, d, J 5.6, H-4), 7.30 (2H, d, J 8.6, ArH), 6.85 (2H,
d, J 8.6, ArH), 6.58 (1H, d, J 16.1, H-20), 6.04 (1H, d, J 5.6, H-3),
6.03 (1H, d, J 16.1, H-10), 3.80 (3H, s, ArOMe), 1.66 (3H, s, Me); dC
(62.5 MHz; CDCl3) 172.4 (C), 159.8 (C), 159.5 (CH), 130.5 (CH),
128.3 (C), 127.9 (CH), 124.5 (CH), 119.7 (CH), 114.1 (CH), 88.0
(C), 55.2 (OMe), 24.1 (Me); (found: [M+H]+, 231.1091.
4.1.7.3. 5-[(E)-2-(3-Hydroxyphenyl)ethenyl]-5-methyl-2,5-dihy-
drofuran-2-one (22). Yield: 358 mg, 82%, as a colourless oil;
Rf = 0.33, hexane/ethyl acetate (1:1); mmax (ATR) 3353, 1732,
1584, 1450, 1236, 1105, 948, 819, 779 dH (250 MHz; CDCl3) 7.46
(1H, d, J 5.6, H-4), 7.17 (1H, at, J 8.0, ArH), 6.89-6.87 (2H, m,
ArH), 6.80 (1H, dd, J 8.0, 1.4, ArH), 6.56 (1H, d, J 16.1, H-20), 6.11
(1H, d, J 16.1, H-10), 6.05 (1H, d, J 5.6, H-3), 1.64 (3H, s, Me); dC
(62.5 MHz; CDCl3) 173.2 (C), 159.9 (CH), 156.3 (C), 137.0 (C),
131.0 (CH), 129.8 (CH), 126.6 (CH), 119.7 (CH), 119.1 (CH), 115.7
CH), 113.3 (CH), 88.5 (C), 24.0 (Me), (OH not observed); (found:
[M+H]+, 217.0933. C13H12O3+H+ requires 217.0865).
C
14H14O3+H+ requires 231.1021).
4.1.9. (1E)-3-Methyl-1-phenylhexa-1,5-dien-3-yl prop-2-enoate
(28)
To a solution of benzilideneacetone 8 (2.0 g, 13.6 mmol) in
anhydrous THF (27 mL), was added a solution of allylmagnesium
bromide (1.0 M; 33 mL, 16.32 mmol) at 0 °C under nitrogen
4.1.7.4. 5-[(E)-2-(4-Hydroxyphenyl)ethenyl]-5-methyl-2,5-dihy-
atmosphere. After 30 min,
a saturated aqueous ammonium
drofuran-2-one (23). Yield: 277 mg, 82%, as
a beige solid;
chloride solution (50 mL) was poured and this mixture was
extracted into ethyl acetate (2 ꢁ 100 mL). The organic layer was
washed with brine (2 ꢁ 100 mL), dried over magnesium sulfate,
filtered and evaporated under reduced pressure. To a solution
of the resulting crude allylic alcohol (1.0 g, 5.31 mmol) in
anhydrous THF (18 mL) at ꢀ78 °C was added triethylamine
(1.64 mL, 11.68 mmol), followed by acryloyl chloride (0.90 mL,
Rf = 0.33, hexane/ethyl acetate (3:2); mp 105-106 °C; mmax (ATR)
3354, 2983, 1729, 1609, 1515, 1266, 1101, 947, 820, 736; dH
(250 MHz; CDCl3) 7.48 (1H, d, J 5.6, H-4), 7.20 (2H, d, J 8.5, ArH),
6.80 (2H, d, J 8.5, ArH), 6.72 (1H, bs, ArOH), 6.53 (1H, d, J 16.1, H-
20), 6.06 (1H, d, J 5.6, H-3), 5.98 (1H, d, J 16.1, H-10), 1.66 (3H, s,
Me); dC (62.5 MHz; CDCl3) 173.3 (C), 160.2 (CH), 156.6 (C), 130.9
(CH), 128.1 (CH), 127.8 (C), 123.8 (CH), 119.6 (CH), 115.7 (CH),

5116
M. Bruder et al. / Bioorg. Med. Chem. 21 (2013) 5107–5117
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11.16 mmol) at 0 °C under a nitrogen atmosphere. After 45 min, a
saturated aqueous ammonium chloride solution (40 mL) was
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(50 mL). The organic layer was washed with brine (30 mL), dried
over magnesium sulfate, filtered and evaporated under reduced
pressure. The crude oil was purified by chromatography, eluting
with hexane and ethyl acetate (4:1), to afford the title compound
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1362, 1222, 973; dH (400 MHz; CDCl3) 7.40-7.22 (5H, m, ArH),
6.56 (1H, d, J 16.3, H-1), 6.43 (1H, d, J 16.3, H-2), 6.35 (1H, dd,
J 17.3, 1.5, H-30trans), 6.09 (1H, dd, J 17.3, 10.4, H-20), 5.81 (1H,
ddt, J 16.9, 10.3, 7.3, H-5), 5.77 (1H, dd, J 10.4, 1.5, H-3cis), 5.12
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dd, J 13.0, 7.3, H-4), 1.68 (3H, s, Me); dC (100 MHz; CDCl3)
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129.75 (CH), 128.9 (CH), 128.5 (CH), 127.6 (CH), 126.5 (CH),
118.7 (CH2), 82.3 (C), 44.4 (CH2), 23.9 (Me); (found: [M+K]+,
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l
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Acknowledgments
The authors thank FAPESP (2010/06178-8 and 2009/51602-5)
for financial support and the National Cancer Institute-Frederick,
MA, USA for granting the human tumor cell lines.
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