Synthesis of methoxylated goniothalamin, aza-goniothalamin and γ-pyrones and their in vitro evaluation against human cancer cells

Article abstract of DOI:10.1016/j.bmc.2012.03.059

The present work describes the preparation of three novel series of compounds based on the structure of goniothalamin, a natural styryl lactone which has been found to display cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 29 novel goniothalamin analogues was prepared and evaluated against seven human cancer cell lines. While the γ-pyrones and the aza-goniothalamin analogues were less potent than the lead compound, 2,4-dimethoxy analogue 88 has shown to be more potent in vitro than goniothalamin against all cancer cell lines evaluated. Furthermore, it was more potent than doxorubicin against NCI-ADR/RES, OVCAR-03 and HT-29 while being less toxic to human keratinocytes (HaCat). The 3,5-dimethoxy analogue 90 and 2,4,5-trimethoxy analogue 92 also displayed promising antiproliferative activity when compared to goniothalamin (1). These results provide new elements for the design and synthesis of novel representatives of this family of natural compounds.

Full text of DOI:10.1016/j.bmc.2012.03.059

Bioorganic & Medicinal Chemistry 20 (2012) 3635–3651
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of methoxylated goniothalamin, aza-goniothalamin and
and their in vitro evaluation against human cancer cells
c-pyrones
Rosimeire Coura Barcelos a, Julio Cezar Pastre a, Vanessa Caixeta a, Débora Barbosa Vendramini-Costa b,c
,
João Ernesto de Carvalho b,c, Ronaldo Aloise Pilli a,b,
⇑
a Departamento de Química Orgânica, Instituto de Química, UNICAMP, CP 6154, 13083-970 Campinas, SP, Brazil
b Programa de Pós-graduação em Biologia Celular e Estrutural, Instituto de Biologia, UNICAMP, CP 6109, 13083-970 Campinas, SP, Brazil
c Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), UNICAMP, CP 6171, 13083-970 Campinas, SP, 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 three novel series of compounds based on the structure of
goniothalamin, a natural styryl lactone which has been found to display cytotoxic and antiproliferative
activities against a variety of cancer cell lines. A focused library of 29 novel goniothalamin analogues
Received 18 January 2012
Revised 16 March 2012
Accepted 23 March 2012
Available online 1 April 2012
was prepared and evaluated against seven human cancer cell lines. While the c-pyrones and the aza-
goniothalamin analogues were less potent than the lead compound, 2,4-dimethoxy analogue 88 has
shown to be more potent in vitro than goniothalamin against all cancer cell lines evaluated. Furthermore,
it was more potent than doxorubicin against NCI-ADR/RES, OVCAR-03 and HT-29 while being less toxic to
human keratinocytes (HaCat). The 3,5-dimethoxy analogue 90 and 2,4,5-trimethoxy analogue 92 also dis-
played promising antiproliferative activity when compared to goniothalamin (1). These results provide
new elements for the design and synthesis of novel representatives of this family of natural compounds.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Goniothalamin
Cancer cells
Antiproliferative activity
c
-Pyrones
Dihydro-
c
-pyrones
Aza-goniothalamin
1. Introduction
properties displayed by goniothalamin and analogues. Some stud-
ies indicate the apoptotic activity of goniothalamin in cancer cell
Cancer treatment includes many strategies and chemotherapy
plays a central role in curing the disease or considerably prolong-
ing and improving the patient’s quality of life. However, resistance
of tumor cells to multiple structurally unrelated cytotoxic drugs
(multidrug resistance) is nowadays the major limitation to the suc-
cessful chemotherapeutic treatment of disseminated neoplasms. In
this regard, natural products remain a privileged source for the dis-
covery and the development of new compounds for cancer
treatment.1
lines through different pathways, including the increase in the
expression of caspases 3, 7 and 9,10 increase in the expression of
pro-apoptotic protein Bax,11 inhibition of constitutive NOS12 and
inhibition of nucleus-cytoplasm transport mediated by CRM1.13
Recently, in vivo studies performed by our group with goniothal-
amin in a solid tumor experimental model in mice confirmed its
low acute toxicity and suggested a relationship between anticancer
and anti-inflammatory activities, with the anti-inflammatory
activity favoring the antiproliferative activity itself.14
During an ongoing program to identify new candidates for can-
cer treatment, goniothalamin (1) (Fig. 1) was recognized as a good
lead compound with significant cytotoxic and antiproliferative
activities against a variety of cancer cell lines, including kidney,
prostate, breast carcinoma, leukemia, lung and liver.2,3 Originally
isolated from various species of the genus Goniothalamus,4 this sty-
ryl lactone also presents other important biological activities
including antimicrobial,5 antifungal,6 larvicidal,7 insecticidal8 and
trypanocidal.9
In order to fine tune the cytotoxic activity and to better under-
stand its mode of action, the synthesis of new goniothalamin deriv-
atives continues to attract interest. Such analogues could be useful
for the elucidation of structure–activity relationships (SARs) and
could result in the development of compounds with higher activity
and selectivity.
A limited number of structure–activity relationship studies of
goniothalamin and synthetic analogues established some of the
relevant structural requirements for the cytotoxic activity
(Fig. 2).15
Mu and co-workers described the semi-synthesis of 19 deriva-
tives of the natural isomer (R)-goniothalamin (only most active
compounds were shown) and found that 2- and 4-nitro analogues
2 and 3, respectively, were the most active against promyelocytic
leukemia (HL-60) and human lung carcinoma (A549) cells. On
Several efforts have been made in an attempt to elucidate the
mechanism responsible for the cytotoxic and antiproliferative
⇑
Corresponding author. Tel.: +55 19 3521 4739; fax: +55 19 3521 4892.
E-mail address: pilli@iqm.unicamp.br (R.A. Pilli).
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2012.03.059

3636
R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
O
to higher conformational restriction or steric hindrance due to
the 2-naphtyl and 3-quinolyl substituents. Interestingly, 1-naph-
thyl substitution in the lactone ring dramatically enhanced the
cytotoxic activity, especially when it posses a methyl group in
the 2 or 3 position. For example, analogue 31 was 80- and 40-fold
more potent against PC-3 and MCF-7 cells, respectively, in compar-
ison with goniothalamin (1).
O
Figure 1. Chemical structure of (R)-goniothalamin (1).
Gademann and co-workers designed a series of goniothalamin
analogues aiming to evaluate the impact of the distance of the phe-
nyl group to the lactone in the biological activity.13 In the event,
truncated goniothalamin analogues 32, 34 and 35 were prepared.
Additionally, extended analogues containing a phenyl 36 or a triple
bond 33 spacer were obtained. These compounds were investi-
gated in the inhibition of CRM1-dependente nuclear export of
the protein kinase Rio2 in HeLa cells, which could be associated
to potent antiproliferative effects. Of all the analogues tested, only
32 showed activity similar to goniothalamin and analogues 33–36
did not display significant inhibition of nuclear export.
Recently, Pilli et al. evaluated racemic goniothalamin against sev-
eral human cancer cell lines and it was observed that the racemate
exhibited similar antiproliferative activity profile compared to both
enantiomers against glioma(U251), breast expressing themultidrug
resistance phenotype (NCI-ADR/RES), kidney (786-0), lung (NCI-
H460) and prostate (PC-3) cancer cells. However, in analogy to (R)-
goniothalamin (1), the racemic form displayed higher potency
against melanoma (UACC-62), breast (MCF-7), ovarian (OVCAR-03)
and colon (HT-29) cancer cells than (S)-goniothalamin.14
the other hand, most of the amino acid derivatives of goniothalam-
in expressed poor antitumor activities.16
Later, Pilli and co-workers prepared both enantiomers of gonio-
thalamin and it was found that (S)-goniothalamin (15) was 1,600-
fold more potent than (R)-goniothalamin (1) against kidney cancer
cells (786-0), possessing IC50 in the nanomolar range. Synthesis of
analogues 16–23 also allowed the identification of the pharmaco-
phoric groups responsible for the high antiproliferative activity
and selectivity displayed by (S)-goniothalamin against the cancer
cell line 786-0. Analogues 21–23 lacking one or two double bonds
were marginally active or inactive, showing that the endo and exo
double bond related to the pyrone ring are essential for the activity
against kidney cancer (786-0) cell line.2 From this study and others
performed with fostriecin and cytostatin,17 the
a,b-unsaturated d-
lactone moiety seems to be a key feature for activity as a result of
its ability to act as a Michael acceptor in the presence of biomole-
cules containing nucleophilic amino acid (e.g. cysteine, lysine, ser-
ine and threonine) or guanine residues.
In the same study, goniothalamin analogue 14 displaying Z-con-
figured double bond in the styryl moiety, was 2-fold less active
against most of the cell lines evaluated. Having this in mind, Çag˘ır
and co-workers prepared and evaluated a series of 2-naphtyl and
3-quinolyl derivatives in order to better understand the role of
the exo double bond in the antiproliferative activity.18 It was ob-
served that analogues 24 and 25 had slightly better antiprolifera-
tive activities against prostate (PC-3) and breast (MCF-7) cancer
cell lines compared to goniothalamin (1), which may be related
In our previus work, 4-methoxy substitution afforded the highly
active and selective derivative 18 against breast cancer cells
expressing the multidrug resistance phenotype (NCI-ADR/RES),
with IC50 in the nanomolar range. In addition, a recent work per-
formed to evaluate the bioactivity of stilbenes demonstrated that
those having methoxy groups exhibited stronger inhibition of tu-
mor growth in roundworms when compared to the hydroxylated
ones.19 Methoxylation can increase bioactivity in vivo since stilb-
Mu 2005
Pilli 2006
2; R1 = NO2; R2 = H
3; R1 = H; R2 = NO2
O
O
O
R
R
R
1 = H; R2 = NH2
O
4;
5;
6;
1 = H; R2 = NHCOCH3
1 = H; R2 = NH(NHBoc-
R
O
L
L
L
L
-Gly)
-Ala)
-Val)
-Phe)
14
15;
16;
17;
18;
19;
R = Ph; ( )-goniothalamin
S
7; R1 = H; R2 = NH(NHBoc-
R = piperonyl
R = cyclohexyl
R = 4-OMeC6H4
R = 4-FC6H4
R2
O
8; R1 = H; R2 = NH(NHBoc-
9;
10;
11;
R
R
1 = H; R2 = NH(NHBoc-
1
= H; R2 = [NH(
= H; R2 = [NH(
L
L
L
L
-Ala)+][CF3CO2
]
]
-
20; R = 4-NO2C6H4
R1
1
-
R
-Leu)+][CF3CO2
-
12; R1 = H; R2 = [NH(
13; R1 = H; R2 = [NH(
-Ile)+][CF3CO2
]
O
O
O
O
-Phe)+][CF3CO2
]
-
O
O
Çagir 2009
O
O
O
21
22
23
O
O
O
O
Gademann 2010
X
O
24;
26
27
X = C
O
25; X = N
O
O
O
O
R
O
O
R
32; R = Ph
34; R = Ph
35;
R = Bn
36; R = C6H4Ph
X
R2
R1
33; R = -CH=CHPh
30; R1 = Me; R2 = H
28; X = C
29;
X = N
1
= H; R2 = Me
31;
R
Figure 2. Analogues of goniothalamin (1) reported in the literature.

R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
3637
O
TMSO
O
O
O
a
c
+
R1
R2
+
H
O
OMe
37
MeO HO
O
40
38
39
R3
b
1
; R = R2 = R3 = H
41
42
; R = R3 = H; R2 = CF3
1
43; R1 = R3 = H; R2 = OMe
44; R1 = H; R2 = R3 = OMe
45; R1 = R2 = R3 = OMe
; R = H; R2,R3 = OCH2O
1
46
Scheme 1. Synthesis of compounds 40–46. Reagents and conditions: (a) BF3ÁOEt2, Et2O, À78 °C, 3 h; (b) TFA (1.3 equiv), CH2Cl2, 0 °C to rt, 40 min (59–70%, over 2 steps); (c)
Styrene (3–5 equiv), Grubbs’ second generation catalyst (2 mol %), CuI (3 mol %), CH2Cl2, reflux, 3–6 h (56–79%).
c
-pyrone structural motifs and their in vitro evaluation against se-
O
O
O
O
ven human cancer cell lines: U251 (glioma), MCF-7 (breast), NCI-
ADR/RES (breast expressing the multidrug resistance phenotype),
786-0 (kidney), NCI-H460 (lung non-small cells), OVCAR-03 (ovar-
ian) and HT-29 (colon).
a
R1
R2
R1
R2
; R1 = R2 = H
; R1 = R2 = H
41
43
47
48
; R1 = H; R2 = OMe
; R1 = H; R2 = OMe
2. Results and discussion
2.1. Chemistry
44; R1 = R2 = OMe
49; R1 = R2 = OMe
Scheme 2. Synthesis of compounds 47–49. Reagents and conditions: (a) DDQ
(1.7 equiv), benzene, reflux, 3 h (78–85% yield).
The synthetic strategy aiming the preparation of dihydro-c-pyr-
enes that have methoxyl groups are metabolized and excreted
slower than those with hydroxyl groups. Therefore, the synthesis
of poly-methoxylated goniothalamin analogues stands as a prom-
ising approach to improve the potency and selectivity of this family
of compounds as well as the incorporation of fluorine into the
structure of the lead compound which has become a common tool
in medicinal chemistry for improving the pharmacological profile
of bioactive compounds.20
Additionally, the synthesis of aza-analogues is another strategy
employed to prepare compounds with better bioavailability. Sev-
eral reports in the literature have validated this approach,21 the
most representative case being ixabepilone, an epothilone B ana-
logue with increased stability due to isosteric replacement of the
lactone ring by a lactam one,22 which has been approved by U.S.
Food and Drug Administration (FDA) for the treatment of patients
with metastatic or locally advanced breast cancer resistant to
treatment with an anthracycline and a taxane.23 The synthesis of
aza-analogues of goniothalamin would also enable further evalua-
tion of the importance of the Michael acceptor site for the cytotoxic
and antiproliferative activities of this family of compounds since
ones is outlined in Scheme 1. Olefin 40 was prepared using opti-
mized conditions of the reported procedure.25 The boron
trifluoride catalyzed hetero Diels–Alder reaction (HDA) of Dani-
shefsky´s diene 37 with acrolein 38 afforded a mixture of 39/40
(1:2 molar ratio), due to the competitive Mukaiyama aldol reac-
tion. Adduct 39 was cyclized after treatment with trifluoroacetic
acid, allowing to obtain dihydro-c-pyrone 40 in 59–70% yield, over
two steps. Next, an olefin cross metathesis reaction with various
styrenes in the presence of Grubbs’ second generation catalyst
(2 mol %) and CuI (3 mol %) as additive, in refluxing CH2Cl2, affor-
ded the desired dihydro-c-pyrones 41–46 in moderate to good
yields (56–79%). The exclusive formation of the E isomer (>95:05
by 1H NMR) was confirmed by NMR analysis of the coupling con-
stants of the double bond (J = 16.0 Hz).
The synthesis of
tion of the corresponding dihydro-
c
-pyrones 47–49 was performed using oxida-
-pyrones 41, 43 and 44 with
c
DDQ in refluxing benzene as shown in Scheme 2 (78–85% yield).
In order to evaluate the importance of the styryl moiety of the
dihydro-
50 was prepared according to the methodology described by Rawal
and Huang.26 Next, the synthesis of the
-pyrone 51 was per-
formed using the previously reported DDQ oxidation (Scheme 3),
albeit in longer reaction time (15 h), in 87% yield. Finally, the
bromo and -iodo-dihydro- -pyrones 52 and 53, respectively,
c-pyrones to the antiproliferative activity, aryl derivative
a
,b-unsaturated d-lactams are less electron deficient than
unsaturated d-lactones thus impacting their biological profile.
Along this line of reasoning, the synthesis of dihydro- -pyrones
a
,b-
c
c
a-
analogues of goniothalamin seemed to be of interest as vinylogous
a
c
lactones are expected to display electron acceptor properties in the
were prepared according to the protocol developed by Evans
et al.27 Thus, treatment of compound 50 with iodosobenzene diac-
etate and trimethylsilyl bromide, in the presence of pyridine, fur-
range of
as changing the oxygen atom from alpha (lactones) to gamma po-
sition ( -pyrones) is expected to change the electron deficiency of
the ,b-unsaturated system. -Pyrones are considered to be an
a,b-unsaturated d-lactones and a,b-unsaturated d-lactams
c
nished the
in Scheme 3. Iodination of the dihydro-
using molecular iodine under essentially identical reaction condi-
tions, giving -iodo-dihydro- -pyrone 53 in excellent yield (92%).
a
-bromo-dihydro-
c
-pyrone 52 in 81% yield, as shown
a
c
c
-pyrone 50 was performed
important class of natural products isolated mainly from marine
organisms and displaying structural diversity.24 Most biological
a
c
studies with
c
-pyrones were performed in marine ecosystem and
The synthesis of the racemic form of the trifluoromethylated
and methoxylated analogues of goniothalamin (compounds 85–
92) was carried out using the reaction sequence depicted below
(Scheme 4). Triethyl phosphonoacetate was used to homologate
commercially available aldehydes 54–60 by the Horner–Wads-
worth–Emmons reaction, followed by reduction with DIBAL-H
less attention has been devoted to their potential as prototypes
for the development of new drug candidates. Furthermore, despite
the considerable number of synthetic methodologies, to our
knowledge no evaluation of the cytotoxic activity of simple dihy-
dro-c-pyrones against cancer cell lines have been reported.
Herein, we report the design and synthesis of a focused library
and oxidation with IBX, leading to the corresponding
a,b-unsatu-
of goniothalamin analogues displaying the d-lactone, d-lactam and
rated aldehydes 61–62, 64–68 in 50–90% yields. The final steps in

3638
R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
the preparation of goniothalamin analogues 85–92 involved the
addition of the allyl Grignard reagent to the corresponding alde-
hyde, followed by esterification of the resulting alcohol with acry-
loyl chloride and ring-closing metathesis reaction employing
Grubbs’ first generation catalyst. Overall yields ranged from 15–
70% and the goniothalamin analogues 85–92, as well as the cor-
responding intermediates, were purified by column chromatogra-
phy on silica gel and characterized by IR, NMR and HRMS
analyses.
Finally, the aza-goniothalamin analogues 103–111 were achieved
by reacting the amides 94–102 with Grubbs’ second generation
catalyst (2 mol %). Overall yields for 103–111 ranged from 20–
70%. The aza-goniothalamin derivatives, as well as the correspond-
ing intermediates, were purified by column chromatography on
silica gel and characterized by IR, NMR and HRMS analyses.
2.2. Biological activities
The aza-goniothalamin series (compounds 103–111) were
achieved from the corresponding amides (Scheme 5) obtained
according to the methodology described by Hart et al.28 This scaf-
fold was derived from reaction between the unsaturated aldehyde
and a solution of lithium hexamethyldisilazide (LHMDS) in THF at
0 °C, followed by the addition of an allylmagnesium bromide solu-
tion leading to a primary amine. This crude product was dissolved
in dichloromethane and treated with acryloyl chloride in the pres-
ence of triethylamine to afford amides 94–102, in 50–87% yields.
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—gli-
oma; MCF-7—breast; NCI-ADR/RES—breast expressing the multi-
drug resistance phenotype; 786-0—kidney; NCI-H460—lung non-
small cells; OVCAR-03—ovary and HT-29—colon). The cytotoxic
activity of each compound was also evaluated in vitro against
spontaneously transformed keratinocytes from histologically
O
O
O
O
O
X
a
b or c
O
OMe
OMe
OMe
51
50
52;
X = Br
53; X = I
Scheme 3. Synthesis of compounds 51–53. Reagents and conditions: (a) DDQ (1.7 equiv), benzene, reflux, 15 h (87% yield). (b) Iodosobenzene diacetate (2.2 equiv),
trimethylsilyl bromide (4.4 equiv), pyridine (5.0 equiv), CH2Cl2, 0 °C, 30 min (81% yield). (c) Molecular iodine (2.25 equiv), pyridine (5.0 equiv), CH2Cl2, 0 °C, 30 min, then rt,
2.5 h (92% yield).
OH
R4
R3
CHO
R1
R4
R3
R4
R3
CHO
a, b, c
d
R1
R1
R2
R2
R2
54-60
61-68
69-76
1 = CF3; R2 = R3 = R4 = H
1 = R2 = R4 = H; R3 = CF3
R
R
1 = CF3; R2 = R3 = R4 = H
1 = R2 = R4 = H; R3 = CF3
69;
70;
R
R
1 = CF3; R2 = R3 = R4 = H
54;
55;
61;
62;
R
R
1 = R2 = R4 = H; R3 = CF3
71; R1 = R2 = R4 = H; R3 = OMe
56; R1 = R3 = OMe; R2 = R4 = H
63; R1 = R2 = R4 = H; R3 = OMe
72; R1 = R3 = OMe; R2 = R4 = H
57; R1 = R4 = H; R2 = R3 = OMe
58;
59;
60;
64; R1 = R3 = OMe; R2 = R4 = H
1 = R3 = H; R2 = R4 = OMe
1 = H; R2 = R3 = R4 = OMe
1 = R3 = R4 = OMe; R2 = H
R
R
R
1 = R4 = H; R2 = R3 = OMe
1 = R3 = H; R2 = R4 = OMe
1 = H; R2 = R3 = R4 = OMe
73;
74;
75;
R
R
R
1 = R4 = H; R2 = R3 = OMe
1 = R3 = H; R2 = R4 = OMe
1 = H; R2 = R3 = R4 = OMe
65;
66;
67;
R
R
R
76; R1 = R3 = R4 = OMe; R2 = H
68; R1 = R3= R4 = OMe; R2 = H
O
O
O
O
R4
R3
R4
R3
f
e
R1
R1
R2
R2
77-84
85-92
77; R1 = CF3; R2 = R3 = R4 = H
85; R1 = CF3; R2 = R3 = R4 = H
R
R
1 = R2 = R4 = H; R3 = CF3
1 = R2 = R4 = H; R3 = OMe
R
R
1 = R2 = R4 = H; R3 = CF3
1 = R2 = R4 = H; R3 = OMe
78;
79;
86;
87;
80; R1 = R3 = OMe; R2 = R4 = H
81; R1 = R4 = H; R2 = R3 = OMe
82; R1 = R3 = H; R2 = R4 = OMe
88; R1 = R3 = OMe; R2 = R4 = H
89; R1 = R4 = H; R2 = R3 = OMe
90; R1 = R3 = H; R2 = R4 = OMe
1 = H; R2 = R3 = R4 = OMe
1 = R3 = R4 = OMe; R2 = H
83;
84;
91;
92;
R
R
R
R
1 = H; R2 = R3 = R4 = OMe
1 = R3 = R4 = OMe; R2 = H
Scheme 4. Synthesis of compounds 85–92. Reagents and conditions: (a) NaH (1.5 equiv), THF, DMF, 0 °C, triethyl phosphonoacetate (1.3 equiv), 15 min, then rt, aldehydes
54–60, (b) CH2Cl2, À78 °C, DIBAL-H (2.5 equiv), 30 min, (c) IBX (3.0 equiv), 80 °C, 3.5 h, (d) aldehydes 61–68, THF, À78 °C, allylmagnesium bromide (1.2 equiv), 30 min, (e)
alcohols 69–76, CH2Cl2, 0 °C, Et3N (2.0 equiv), acryloyl chloride (1.5 equiv), then rt, 1 h. (f) esters 77–84, CH2Cl2, reflux, Grubbs’ first generation catalyst (10 mol %), 8 h.

R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
3639
O
O
HN
HN
R4
R3
CHO
R4
R3
R4
R3
a, b
c
R1
R1
R1
R2
R2
R2
61-68, 93
94-102
103-111
103; R1 = R2 = R3 = R4 = H
93; R1 = R2 = R3 = R4 = H
94; R1 = R2 = R3 = R4 = H
104; R1 = CF3; R2 = R3 = R4 = H
61; R1 = CF3; R2 = R3 = R4 = H
95; R1 = CF3; R2 = R3 = R4 = H
R
R
R
1 = R2 = R4 = H; R3 = CF3
1 = R2 = R4 = H; R3 = OMe
1 = R3 = OMe; R2 = R4 = H
R
R
R
1 = R2 = R4 = H; R3 = CF3
1 = R2 = R4 = H; R3 = OMe
1 = R3 = OMe; R2 = R4 = H
R
R
R
1 = R2 = R4 = H; R3 = CF3
1 = R2 = R4 = H; R3 = OMe
1 = R3 = OMe; R2 = R4 = H
105;
106;
107;
62;
63;
64;
96;
97;
98;
108; R1 = R4 = H; R2 = R3 = OMe
65; R1 = R4 = H; R2 = R3 = OMe
99; R1 = R4 = H; R2 = R3 = OMe
109; R1 = R3 = H; R2 = R4 = OMe
66; R1 = R3 = H; R2 = R4 = OMe
100; R1 = R3 = H; R2 = R4 = OMe
R
R
1 = H; R2 = R3 = R4 = OMe
1 = R3= R4 = OMe; R2 = H
R
R
1 = H; R2 = R3 = R4 = OMe
1 = R3 = R4 = OMe; R2= H
R
R
1 = H; R2 = R3 = R4 = OMe
1 = R3= R4 = OMe; R2= H
110;
111;
67;
68;
101;
102;
Scheme 5. Synthesis of compounds 103–111. Reagents and conditions: (a) LHMDS (1.2 equiv), THF, 0 °C, aldehydes 61–68, 93, then allylmagnesium bromide (1.2 equiv),
30 min, (b) CH2Cl2, 0 °C, Et3N (2.0 equiv), acryloyl chloride (1.5 equiv), then rt, 1 h, (c) amides 94–102, CH2Cl2, reflux, Grubbs’ second generation catalyst (2 mol %), 6 h.
normal skin (HaCat cells). Doxorubicin was employed as the posi-
tive control and goniothalamin was included as the reference
compound.
the Michael acceptor nature of the heterocyclic ring, particularly
when the aromatic ring is substituted with electron donating
methoxyl groups.
Cell proliferation 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 tumour
cell line anticancer drug screen (NCI60).29 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).29a
On the other hand, noteworthy are the superior antiprolifera-
tive properties of the halogenated dihydro-c-pyrones 42, 52 and
53 when compared to the other representatives in this series, a
behavior which is in line with the reasoning that electron with-
drawing groups are beneficial to the antiproliferative activities of
goniothalamin analogues, a pattern that may be worthy to explore
further.
Table 2 features the total growth inhibition values for gonio-
thalamin (1), aza-goniothalamin (103) and their analogues 85–92
and 104–111 (Fig. 4), as well as for doxorubicin.
It is evident from the data shown that the introduction of the
lactam ring significantly reduces the antiproliferative activity for
all cancer cell lines evaluated. In fact, aza-goniothalamin (103)
did not display any cytotoxic activity against several cancer cell
lines and human keratinocytes (HaCat) cells. This pattern is even
more pronounced when we compare the cytotoxic activity of the
methoxy derivatives in both series: all aza-goniothalamin
analogues investigated were not cytotoxic against the cell lines
evaluated except for the 3,5-dimethoxy derivative 109 which only
displayed cytotoxic activity at the largest concentration employed
in the assay. The only aza-goniothalamin derivative deserving fur-
ther investigation seems to be the trifluoromethylated analogue
104 wihich displayed promising TGI values for breast cancer
expressing the multidrug resistance phenotype (NCI-ADR/RES)
Goniothalamin (1) and its analogues were employed at concen-
trations between 0.25 and 250
lg/mL and doxorubicin at 0.025–
25 g/mL. Concentration that elicits total growth inhibition (TGI)
l
was determined after 48 h of cell treatment. The initial in vitro
screening evaluations were planned to select the best candidates
for anticancer drug development in animal models and, eventually,
in clinical trials. To identify compounds with growth-inhibitory or
toxic effects on particular tumour types, it is important to charac-
terize the disease-oriented concept.29b
The biological evaluation of dihydro-
c-pyrones 41–46, 50, 52
and 53 and -pyrones 47–49 and 51 (Fig. 3) are summarized in Ta-
c
ble 1, which displays the total growth inhibition concentration
(TGI) value for each compound.
In general, the dihydro-c-pyrones and
c-pyrones evaluated
and glioma (U251) cells (40.6 and 69.9 lM, respectively).
were shown to be less potent than goniothalamin (1) with
ones being less cytotoxic than the corresponding dihydro-
c
c
-pyr-
-pyr-
In contrast to the aza-goniothalamin series, the methoxylation
of the aromatic ring proved to be beneficial for the in vitro antipro-
liferative activity of the goniothalamin analogues. While the 3,4,5-
trimethoxy goniothalamin 91 was less potent than goniothalamin
(1) for all the cell lines evaluated, the 3,5-dimethoxy and the 2,4,5-
trimethoxy analogues 90 and 92, respectively, displayed lower TGI
values for most of the cell lines tested while 2,4-dimethoxy gonio-
thalamin 88 proved to be more potent than goniothalamin against
all cancer cell lines. Lower TGI values than doxorubicin were ob-
served for 2,4-dimethoxy goniothalamin 88 against breast cancer
expressing the multidrug resistance phenotype (NCI-ADR/RES),
ovary (OVCAR-03) and colon (HT-29) in addition to be less toxic
to human keratinocytes (HaCat).
ones. In particular,
effect against the cancer cell lines over the range of concentration
employed and -pyrones 47–49 displayed a clear correlation be-
c-pyrone 51 did not display any cytotoxic
c
tween their total growth inhibition (TGI) values and the degree
of methoxylation of the aromatic ring with the dimethoxylated
derivative 49 being the less cytotoxic in this series of compounds.
For the dihydro-c-pyrones series (43–46), there is no clearcut cor-
relation between the degree of oxygenation of the aromatic ring
and the antiproliferative potency of these compounds, the 4-meth-
oxy derivative 43 displaying the largest TGI value in this series.
The reduced antiproliferative activity of dihydro-c-pyrones and
c
-pyrones as compared to goniothalamin (1) can be correlated to
3. Conclusions
the diminished electron acceptor nature of the vinylogous lactone
moiety present in these goniothalamin analogues while the lack of
As compared to our previous study,2b the present work shed
new light on the SAR for goniothalamin analogues regarding the
potency of
c-pyrones can be ascribed to the extensive electronic
conjugation with the aromatic ring which is expected to reduce

3640
R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
O
O
O
O
O
O
O
O
CF3
OMe
41
42
1
43
O
O
O
O
O
O
OMe
OMe
OMe
OMe
O
O
44
45
46
OMe
O
O
O
O
O
OMe
OMe
O
OMe
47
48
49
O
O
O
O
O
O
Br
I
O
O
OMe
OMe
OMe
OMe
50
51
52
53
Figure 3. Structures of dihydro-
c
-pyrones 41–46, 50, 52 and 53,
c
-pyrones 47–49 and 51 and the lead compound goniothalamin (1).
Table 1
TGI values, given in
l
M, for compounds 1, 41–53 and doxorubicin (DOX) necessary for total inhibition of tumor cell proliferationa
TGI
U251
2.4
13.7
121.8
38.6
151.9
86.9
101.8
77.0
285.4
278.4
338.9
226.1
>1236.3
46.4
MCF7
3.7
12.7
152.6
41.2
155.5
130.2
149.4
81.4
691.1
395.9
953.6
172.9
>1236.3
42.2
NCI-ADR
786-0
NCI-H460
OVCAR-03
HT-29
7.1
13.9
123.6
33.3
203.9
123.2
134.5
126.9
344.1
379.2
806.7
203.4
>1236.3
69.0
HaCat
0.8
DOXb
1
13.5
8.0
105.3
51.6
2.1
14.8
138.2
39.6
1.3
13.6
82.4
95.6
149.4
89.6
127.3
147.4
508.5
606.1
545.5
192.8
>1236.3
117.7
74.6
6.3
14.2
58.2
58.2
87.4
27.7
126.5
122.8
144.5
133.5
154.7
144.9
710.8
710.0
689.7
264.4
>1236.3
164.0
53.3
41
42
43
44
45
46
47
48
49
50
51
52
53
239.3
145.8
223.2
186.8
514.2
309.9
407.9
419.6
>1236.3
52.9
191.5
145.1
125.0
104.1
409.9
376.8
635.4
197.0
>1236.3
33.4
74.3
85.4
101.7
545.5
327.9
540.2
248.6
>1236.3
113.5
38.2
24.4
43.2
39.7
27.0
24.4
a
Concentration that elicits total growth inhibition (TGI) was determined from non-linear regression analysis using the ORIGIN 7.5Ò (OriginLab Corporation).
Doxorubicin (DOX) was the positive control.
b
prevalence of the
phoric motif for the in vitro antiproliferative activity as compared
to the ,b-unsaturated d-lactam, dihydro- -pyrone and the -pyr-
one motifs.
a
,b-unsaturated d-lactone ring as the pharmaco-
It seems that the beneficial effect of the methoxy groups at-
tached to the aromatic ring in goniothalamin derivatives investi-
gated could be judiciously explored in the future design of novel
series of analogues as well it can be coupled to the effect of halogen
a
c
c
When compared to the 4-methoxy analogue 87, the 2,4-dime-
thoxy derivative 88 displayed higher potency against all the seven
human cancer cell lines investigated, as well as the 3,5-dimethoxy
analogue 90. As to the trimethoxylated series of compounds, the
2,4,5-trimethoxy analogue 92 proved to be more potent than the
monosubstituted derivative 87 and displayed higher antiprolifera-
tive activity than the 3,4,5-trimethoxy analogue 91. Additionally,
the 2,4-dimethoxy goniothalamin 88 was shown to be more potent
than goniothalamin (1) against all cancer cell lines evaluated and
more potent than doxorubicin against NCI-ADR/RES, OVCAR-03
and HT-29 while being less toxic to human keratinocytes (HaCat).
The 3,5-dimethoxy and the 2,4,5-trimethoxy analogues 90 and 92
also displayed promising antiproliferative activity when compared
to goniothalamin (1).
substituents at C-
the results observed for dihydro-
sign of novel and more potent analogues for further studies.
a
of the
a
,b-unsaturated d-lactone ring, following
-pyrones 52 and 53, in the de-
c
4. General procedures
Reagents and solvents were commercial grade and were used as
supplied, except when specified in the experimental procedure.
Grubbs’ first generation catalyst (Lot#MKBF1581 V) and Grubbs’
second generation catalyst (Lot#MKBG2090 V) were purchased
from Aldrich. Doxorubicin was purchased from Europharma.
Racemic goniothalamin (1) was prepared according to previously
described methodology, except for the utilization of allylmagne-
sium bromide in substitution to the enantioselective allylation

R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
3641
Table 2
TGI values, given in
l
M, for compounds 1, 85–92, 104–111 and doxorubicin (DOX) necessary for total inhibition of tumor cell proliferationa
TGI
U251
2.4
13.7
797.6
43.4
69.9
36.8
130.3
20.6
MCF7
3.7
12.7
607.4
50.4
120.2
51.0
149.5
25.5
NCI-ADR
786-0
2.1
14.8
>1254.8
52.3
123.4
44.5
127.8
21.6
NCI-H460
OVCAR-03
HT-29
7.1
13.9
1195.8
71.7
195.4
36.2
139.2
33.7
HaCat
0.8
27.7
>1254.8
82.7
249.1
69.7
173.7
58.8
Doxb
1
103
85
104
86
105
87
13.5
8.0
966.6
75.5
40.6
54.8
1.3
13.6
6.3
14.2
928.5
241.5
194.7
476.9
150.4
28.3
>1254.8
295.6
329.3
167.2
126.0
61.5
71.8
17.3
106
88
981.3
4.6
>1090.4
5.4
841.7
8.8
>1090.4
4.1
>1090.4
6.0
786.8
5.6
>1090.4
6.6
>1090.4
15.8
107
89
>964.1
23.9
>964.1
7.8
>964.1
11.6
>964.1
10.9
>964.1
14.6
>964.1
16.8
>964.1
17.2
>964.1
63.0
108
90
>964.1
8.1
>964.1
9.5
>964.1
8.9
>964.1
10.6
>964.1
9.0
>964.1
19.1
>964.1
8.2
>964.1
8.8
109
91
169.9
25.1
146.4
15.3
203.2
35.1
173.4
18.5
145.5
28.8
232.1
44.9
196.6
18.8
211.9
21.6
110
92
>864.1
11.5
>864.1
3.8
>864.1
9.4
>864.1
6.0
>864.1
9.8
>864.1
7.2
>864.1
15.9
>864.1
46.9
111
>864.1
>864.1
>864.1
>864.1
>864.1
>864.1
>864.1
>864.1
a
Concentration that elicits total growth inhibition (TGI) was determined from non-linear regression analysis using the ORIGIN 7.5Ò (OriginLab Corporation).
Doxorubicin (DOX) was the positive control.
b
O
O
O
O
O
HN
O
HN
CF3
CF3
1
103
85
104
O
O
O
O
O
HN
O
HN
F3C
F3C
MeO
MeO
86
105
87
106
O
O
O
O
O
HN
O
HN
MeO
MeO
MeO
MeO
MeO
OMe
MeO
MeO
OMe
107
89
108
88
O
O
O
O
O
HN
O
HN
MeO
MeO
MeO
MeO
MeO
OMe
OMe
OMe
OMe
110
90
109
91
O
O
O
HN
MeO
MeO
MeO
MeO
OMe
92
Figure 4. Structures of methoxylated and trifluoromethylated goniothalamin 85–92 and aza-goniothalamin 104–111 analogues.
OMe
111
step.2a,b Et3N and CH2Cl2 were distilled from calcium hydride and
THF, ether and benzene were distilled from Na/benzophenone.
Reactions were monitored by TLC analysis using Merck Silica Gel
60 F-254 thin layer plates. Flash column chromatography was per-
formed on Acros silica gel 60, 0.040–0.063 mm. 1H NMR and 13C
NMR data were recorded on a Varian Inova (500 MHz for 1H and

3642
R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
125 MHz for 13C NMR) or Bruker Avance (250 MHz for 1H and
62.5 MHz for 13C NMR) spectrometer using as internal standard
the residual nondeuterated solvent (CHCl3) or TMS (1H NMR). Data
are reported as follows: chemical shift in ppm (d), multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet,
m = multiplet, br = broad signal, app = apparent signal), coupling
constant (Hz), integration. High resolution mass spectra (HRMS)
for novel compounds were measured on a Waters XEVO Q-TOF spec-
trometer (ESI) or in a Waters GCT Premier (EI). Infrared spectra (IR)
were obtained on a ABB Bomem MB Series B102, Thermo-Nicolet IR-
200 or iS5 spectrometer and absorptions are reported in reciprocal
centimeters. Melting points were recorded on an Electrothermal
9100 melting point apparatus and were uncorrected.
1594, 1452, 1406, 1268, 1219, 1038, 969, 741; 1H NMR
(250 MHz, CDCl3): d 7.47–7.25 (m, 6H), 6.73 (d, J = 16.0 Hz, 1H),
6.31 (dd, J = 16.0 and 6.5 Hz, 1H), 5.46 (d, J = 6.0 Hz, 1H), 5.11–
5.02 (m, 1H), 2.73 (dd, J = 16.8 and 12.4 Hz, 1H), 2.60 (dd, J = 16.8
and 4.4 Hz, 1H); 13C NMR (62.5 MHz, CDCl3): d 191.8 (C0), 162.9
(CH), 135.5 (C0), 133.7 (CH), 128.6 (2 Â CH), 128.5 (CH), 126.7
(2 Â CH), 125.0 (CH), 107.2 (CH), 79.6 (CH), 41.9 (CH2); HRMS
(ESI+) m/z: Calcd for C13H13O2 [M+H+] 201.0916, found 201.0903.
4.1.2.2. (E)-2-(4-(Trifluoromethyl)styryl)-2H-pyran-4(3H)-one
(42).
fin cross-metathesis reaction in 58% yield (light yellow solid). Elu-
ent: hexanes/ethyl acetate 1:1 v/v. Mp: 43.0–44.4 °C; IR (cmÀ1
Prepared according to the general procedure for the ole-
,
thin film): 1678, 1596, 1408, 1325, 1269, 1220, 1165, 1121,
1067, 1039, 973; 1H NMR (250 MHz, CDCl3): d 7.60 (d, J = 8.3 Hz,
2H), 7.50 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 6.0 Hz, 1H), 6.76 (d,
J = 16.0 Hz, 1H), 6.39 (dd, J = 16.0 and 6.1 Hz, 1H), 5.49 (dd, J = 6.0
and 0.6 Hz, 1H), 5.15–5.06 (m, 1H), 2.81–2.56 (m, 2H); 13C NMR
(62.5 MHz, CDCl3): d 191.4 (C0), 162.7 (CH), 139.1 (C0), 131.9
(CH), 130.2 (q, J = 32.4 Hz, C0), 127.7 (CH), 126.9 (2 Â CH), 125.7
(q, J = 15.1 Hz, 2 Â CH), 124.0 (q, J, = 270.0 Hz, C0), 107.5 (CH),
79.1 (CH), 41.7 (CH2); HRMS (ESI+) m/z: Calcd for C14H12F3O2
[M+H+] 269.0789, found 269.0838.
4.1. Experimental procedures
4.1.1. 2-Vinyl-2H-pyran-4(3H)-one (40)
To a solution of acrolein (38, 42.4 mmol, 2.83 mL) in anhydrous
diethyl ether (160 mL) under nitrogen atmosphere at À78 °C was
added
trans-1-methoxy-3-trimethylsiloxy-1,3-butadiene
(37,
15.3 mmol, 2.64 g), followed by 1.3 equiv of boron trifluoride
etherate (20.3 mmol; 2.51 mL). After 3.0 h, a saturated aqueous
solution of sodium bicarbonate (100 mL) was added, the layers
were separated and the aqueous layer was extracted with diethyl
ether (3 Â 100 mL). The combined organic layers were dried over
anhydrous magnesium sulfate, filtered and concentrated under re-
duced pressure. The crude product was dissolved in CH2Cl2
(250 mL) and the resulting solution was cooled to 0 °C. Trifluoro-
acetic acid (22.0 mmol; 1.7 mL; 1.3 equiv) was added and the
resulting solution was maintained under magnetic stirring and at
room temperature for 40 min. The solvent was removed under re-
duced pressure and the residue was dissolved in diethyl ether
(100 mL) and washed with a saturated aqueous solution of sodium
hydrogen carbonate (100 mL). The aqueous layer was extracted
with diethyl ether (2 Â 100 mL) and the combined organic layers
were dried over magnesium sulfate, filtered and concentrated un-
der vacuum. The residue was purified by flash column chromatog-
4.1.2.3.
(E)-2-(4-Methoxystyryl)-2H-pyran-4(3H)-one
(43).
Prepared according to the general procedure for the olefin cross-
metathesis reaction in 73% yield (light yellow solid). Eluent: hex-
anes/ethyl acetate 2:1 v/v. Mp: 79.0–80.0 °C; IR (cmÀ1, thin film):
2928, 1673, 1594, 1513, 1463, 1405, 1251, 1219, 1177, 1034,
970, 835, 792; 1H NMR (250 MHz, CDCl3): d 7.39 (d, J = 6.0 Hz,
1H), 7.34 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.65 (d,
J = 16.0 Hz, 1H), 6.15 (dd, J = 16.0 and 6.8 Hz, 1H), 5.45 (d,
J = 6.0 Hz, 1H), 5.08–4.98 (m, 1H), 3.80 (s, 3H), 2.72 (dd, J = 16.8
and 12.6 Hz, 1H), 2.59 (dd, J = 16.8 and 4.1 Hz, 1H); 13C NMR
(62.5 MHz, CDCl3): d 192.0 (C0), 163.0 (CH), 159.9 (C0), 133.5
(CH), 128.2 (C0), 128.0 (2 Â CH), 122.7 (CH), 114.1 (2 Â CH), 107.2
(CH), 80.0 (CH), 55.2 (OCH3), 42.0 (CH2); HRMS (ESI+) m/z: Calcd
for C14H15O3 [M+H+] 231.1021, found 231.1062.
raphy (hexanes/ethyl acetate 2:1 v/v) giving the desired dihydro-c-
pyrone 40 in 70% yield (1.33 g), as a light yellow oil. IR (cmÀ1, thin
film): 1678, 1594, 1405, 1273, 1225, 1039, 993, 937, 895, 795; 1H
NMR (250 MHz, CDCl3): d 7.38 (d, J = 6.0 Hz, 1H), 5.95 (ddd,
J = 16.6, 10.6 and 5.8 Hz, 1H), 5.45 (s, 1H), 5.38 (dd, J = 16.6 and
12.2 Hz, 2H), 4.98–4.85 (m, 1H), 2.71–2.49 (m, 2H); 13C NMR
(62.5 MHz, CDCl3): d 191.3 (C0), 162.5 (CH), 134.1 (CH), 117.9
(CH2), 106.9 (CH), 79.1 (CH), 41.1 (CH2).
4.1.2.4. (E)-2-(3,4-Dimethoxystyryl)-2H-pyran-4(3H)-one (44).
Prepared according to the general procedure for the olefin cross-
metathesis reaction in 56% yield (light yellow viscous oil). Eluent:
CH2Cl2/ethyl acetate 95:05 v/v, then hexanes/ethyl acetate 1:1 v/v.
IR (cmÀ1, thin film): 1671, 1593, 1515, 1463, 1406, 1263, 1140,
1027, 970, 794; 1H NMR (250 MHz, CDCl3): d 7.40 (d, J = 6.0 Hz,
1H), 6.95–6.81 (m, 3H), 6.65 (d, J = 15.9 Hz, 1H), 6.16 (dd, J = 15.9
and 6.8 Hz, 1H), 5.46 (d, J = 6.0 Hz, 1H), 5.09–5.00 (m, 1H), 3.90
(s, 3H), 3.88 (s, 3H), 2.74 (dd, J = 16.7 and 12.5 Hz, 1H), 2.59 (dd,
J = 16.7 and 4.2 Hz, 1H); 13C NMR (62.5 MHz, CDCl3): d 191.9 (C0),
162.9 (CH), 149.5 (C0), 149.1 (C0), 133.7 (CH), 128.5 (C0), 122.9
(CH), 120.3 (CH), 111.0 (CH), 108.9 (CH), 107.2 (CH), 79.8 (CH),
55.8 (2 Â OCH3), 42.0 (CH2); HRMS (ESI+) m/z: Calcd for C15H17O4
[M+H+] 261.1127, found 261.1207.
4.1.2. General procedure for the olefin cross-metathesis reaction
A typical procedure for the preparation of dihydro-
c-pyrones
41–46 follows: to a solution of dihydro- -pyrone 40 (0.5 mmol;
c
62.0 mg) in anhydrous CH2Cl2 (9 mL) was added the corresponding
styrene (3–5 equiv), Grubbs’ second generation catalyst (8.5 mg;
2 mol %) and copper iodide (2.9 mg; 3 mol %), under nitrogen
atmosphere. The reaction mixture was immersed in an oil bath
and heated at reflux until TLC analysis indicated complete con-
sumption of the starting material (3–6 h). After cooling to room
temperature, 50 equiv of DMSO (relative to the catalyst) were
added and the mixture was maintained under magnetic stirring
overnight. The solvent was then removed under reduced pressure
and the residue was purified by flash column chromatography
(using the eluent indicated) to afford the corresponding cross-
metathesis adducts 41–46.
4.1.2.5. (E)-2-(3,4,5-Trimethoxystyryl)-2H-pyran-4(3H)-one (45).
Prepared according to the general procedure for the olefin cross-
metathesis reaction in 67% yield (light yellow solid). Eluent:
CH2Cl2/ethyl acetate 95:05 v/v, then hexanes/ethyl acetate 1:1 v/
v. Mp: 128.0–130.0 °C; IR (cmÀ1, thin film): 2928, 1663, 1592,
1507, 1423, 1402, 1334, 1248, 1237, 1124, 1038, 1008, 982, 795;
1H NMR (500 MHz, CDCl3): d 7.41 (d, J = 6.0 Hz, 1H), 6.65 (d,
J = 15.7 Hz, 1H), 6.64 (s, 2H), 6.22 (dd, J = 15.9 and 6.5 Hz, 1H),
5.47 (d, J = 6.0 Hz, 1H), 5.12–5.02 (m, 1H), 3.88 (s, 6H), 3.86 (s,
3H), 2.75 (dd, J = 16.8 and 12.2 Hz, 1H), 2.62 (dd, J = 16.8 and
4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 191.7 (C0), 162.8 (CH),
153.3 (C0), 138.5 (C0), 133.7 (2 Â CH), 131.2 (C0), 124.4 (CH),
4.1.2.1. (E)-2-Styryl-2H-pyran-4(3H)-one (41).
Prepared
according to the general procedure for the olefin cross-metathesis
reaction in 79% yield (light brown viscous oil). Eluent: hexanes/
ethyl acetate 2:1, 1:1 v/v. IR (cmÀ1, thin film): 2925, 2855, 1676,

R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
3643
107.2 (CH), 103.8 (CH), 79.5 (CH), 60.8 (OCH3), 56.1 (2 Â OCH3),
41.9 (CH2); HRMS (ESI+) m/z: Calcd for C16H19O5 [M+H+]
291.1232, found 291.1327.
800, 769; 1H NMR (250 MHz, CDCl3): d 7.71 (d, J = 5.5 Hz, 1H),
7.32 (d, J = 16.0 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.03 (s, 1H), 6.86
(d, J = 8.2 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.30–6.20 (m, 2H),
3.92 (s, 3H), 3.90 (s, 3H); 13C NMR (62.5 MHz, CDCl3): d 179.2
(C0), 162.5 (C0), 154.2 (CH), 150.7 (C0), 149.2 (C0), 136.1 (CH),
127.8 (C0), 121.9 (CH), 117.2 (CH), 116.6 (CH), 114.2 (CH), 111.2
(CH), 109.2 (CH), 55.9 (2 Â OCH3); HRMS (ESI+) m/z: Calcd for
4.1.2.6.
4(3H)-one (46).
(E)-2-(2-(Benzo[d][1,3]dioxol-5-yl)vinyl)-2H-pyran-
Prepared according to the general procedure
for the olefin cross-metathesis reaction in 64% yield (light yellow
solid). Eluent: CH2Cl2/ethyl acetate 95:05 v/v, then hexanes/ethyl
acetate 1:1 v/v. Mp: 111.2–112.2 °C; IR (cmÀ1, thin film): 2917,
1666, 1592, 1503, 1449, 1257, 1225, 1191, 1037, 974, 927, 906,
791; 1H NMR (250 MHz, CDCl3): d 7.40 (d, J = 6.0 Hz, 1H), 6.94 (d,
J = 1.5 Hz, 1H), 6.85 (dd, J = 8.0 and 1.5 Hz, 1H), 6.77 (d, J = 8.0 Hz,
1H), 6.62 (d, J = 15.9 Hz, 1H), 6.12 (dd, J = 15.9 and 6.7 Hz, 1H),
5.97 (s, 2H), 5.46 (d, J = 6.0 Hz, 1H), 5.09–4.97 (m, 1H), 2.72 (dd,
J = 16.8 and 12.5 Hz, 1H), 2.59 (dd, J = 16.8 and 4.4 Hz, 1H); 13C
NMR (62.5 MHz, CDCl3): d 191.8 (C0), 162.9 (CH), 148.1 (C0),
148.0 (C0), 133.5 (CH), 129.9 (C0), 123.1 (CH), 121.8 (CH), 108.3
(CH), 107.2 (CH), 105.8 (CH), 101.2 (CH2), 79.8 (CH), 42.0 (CH2);
HRMS (ESI+) m/z: Calcd for C14H13O4 [M+H+] 245.0808, found
245.0817.
C
15H15O4 [M+H+] 259.0970, found 259.1017.
4.1.3.4. 2-(4-Methoxyphenyl)-4H-pyran-4-one (51).
Pre-
pared according to the general procedure for oxidation with DDQ
in 87% yield (light yellow solid). Eluent: CH2Cl2/ethyl acetate 1:2
v/v). Mp: 123.0–125.0 °C; IR (cmÀ1, thin film): 2919, 2838, 1644,
1594, 1512, 1430, 1365, 1307, 1262, 1233, 1181, 1017, 930, 815,
645; 1H NMR (250 MHz, CDCl3): d 7.78 (d, J = 5.8 Hz, 1H), 7.67 (d,
J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 6.66 (d, J = 2.4 Hz, 1H),
6.31 (dd, J = 5.8 and 2.4 Hz, 1H), 3.84 (s, 3H); 13C NMR
(62.5 MHz, CDCl3): d 179.1 (C0), 163.9 (C0), 162.1 (C0), 154.5
(CH), 127.3 (2 Â CH), 123.3 (C0), 116.7 (CH), 114.3 (2 Â CH),
110.7 (CH), 55.3 (OCH3); HRMS (ESI+) m/z: Calcd for C12H11O3
[M+H+] 203.0708, found 203.0797.
4.1.3. General procedure for the DDQ oxidation of dihydro-
c
-pyrones
4.1.4. 5-Bromo-2-(4-methoxyphenyl)-2H-pyran-4(3H)-one (52)
Iodosobenzene diacetate (2.2 equiv; 1.14 mmol; 368 mg) was
suspended in anhydrous CH2Cl2 (2.6 mL) and cooled under mag-
netic stirring to 0 °C, under nitrogen atmosphere. Trimethylsilyl
bromide (4.4 equiv; 2.29 mmol; 302 lL) was then added dropwise
and the resulting orange colored solution stirred at this tempera-
ture for 45 min. Freshly distilled pyridine (5.0 equiv; 2.6 mmol;
210 lL) was added, followed by a solution of dihydro-c-pyrone
50 (0.52 mmol; 106 mg) in anhydrous CH2Cl2 (2.6 mL). The resul-
tant reaction mixture was maintained under these conditions for
ca. 30 min. After this period, the reaction was quenched with a sat-
urated aqueous solution of sodium thiosulfate (2.0 mL) and parti-
To a solution of the dihydro-c-pyrone 41, 43, 44 or 50
(0.25 mmol) in dry benzene (3.0 mL), under nitrogen atmosphere
and magnetic stirring, was added DDQ (1.7 equiv; 0.43 mmol;
96.5 mg) and the reaction mixture was heated to reflux for 3–
15 h. After cooling to room temperature, the reaction mixture
was diluted with CH2Cl2 (30 mL), washed with a saturated aqueous
solution of sodium hydrogen carbonate (20 mL). The aqueous layer
was extracted with CH2Cl2 (2 Â 30 mL) and the combined organic
layers were dried over magnesium sulfate, filtered and concen-
trated under reduced pressure. The crude was purified by flash col-
umn chromatography (using the eluent indicated) to provide the
corresponding
c
-pyrones 47–49 or 51 .
tioned between a saturated solution of aqueous sodium
hydrogen carbonate (20 mL) and CH2Cl2 (3 Â 20 mL). The com-
bined organic layers were dried over magnesium sulfate, filtered
and concentrated under reduced pressure. The residue was puri-
fied by flash column chromatography (hexanes/ethyl acetate 4:1,
4.1.3.1. (E)-2-Styryl-4H-pyran-4-one (47).
Prepared accord-
ing to the general procedure for oxidation with DDQ in 85% yield
(white solid). Eluent: hexanes/ethyl acetate 2:1, 1:1, 1:3 v/v. Mp:
83.8–85.0 °C; IR (cmÀ1, thin film): 2927, 1646, 1596, 1411, 1381,
1260, 1171, 973, 945, 874, 851, 759, 695; 1H NMR (500 MHz,
CDCl3): d 7.73 (d, J = 3.0 Hz, 1H), 6.66 (dd, J = 4.1 and 0.8 Hz, 2H),
7.42–7.33 (m, 4H), 6.66 (d, J = 8.1 Hz, 1H), 6.31–6.27 (m, 2H); 13C
NMR (62.5 MHz, CDCl3): d 179.2 (C0), 162.2 (C0), 154.4 (CH),
136.2 (CH), 134.8 (C0), 129.7 (CH), 128.9 (2 Â CH), 127.5
(2 Â CH), 119.4 (CH), 116.8 (CH), 114.9 (CH); HRMS (ESI+) m/z:
Calcd for C13H11O2 [M+H+] 199.0759, found 199.0820.
3:1 v/v) to afford the desired 3-bromo-dihydro-c-pyrone 52 in
81% yield (119 mg), as a light yellow solid. Mp: 108.2–108.9 °C;
IR (cmÀ1, thin film): 3039, 2919, 1667, 1617, 1567, 1519, 1357,
1260, 1181, 1128, 1029, 996, 818; 1H NMR (250 MHz, CDCl3, d):
7.79 (s, 1H), 7.33 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 5.49
(dd, J = 14.1 and 3.6 Hz, 1H), 3.84 (s, 3H), 3.09 (dd, J = 16.9 and
14.1 Hz, 1H), 2.90 (dd, J = 16.9 and 3.6 Hz, 1H); 13C NMR
(62.5 MHz, CDCl3): d 185.0 (C0), 161.9 (CH), 160.3 (C0), 128.6 (C0),
127.8 (2 Â CH), 114.2 (2 Â CH), 102.4 (C0), 81.7 (CH), 55.3 (OCH3),
43.0 (CH2); HRMS (ESI+) m/z: Calcd for C12H12BrO3 [M+H+]
282.9964, found 283.0009.
4.1.3.2. (E)-2-(4-Methoxystyryl)-4H-pyran-4-one (48).
Pre-
pared according to the general procedure for oxidation with DDQ
in 78% yield (off-white solid). Eluent: ethyl acetate. Mp: 123.4–
124.0 °C; IR (cmÀ1, thin film): 3060, 2919, 2848, 1652, 1599,
1515, 1411, 1383, 1264, 1252, 1165, 1018, 970, 949, 859, 847,
810; 1H NMR (250 MHz, CDCl3): d 7.70 (d, J = 5.7 Hz, 1H), 7.44 (d,
J = 8.7 Hz, 2H), 7.32 (d, J = 16.0 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H),
6.51 (d, J = 16.0 Hz, 1H), 6.31–6.19 (m, 2H), 3.82 (s, 3H); 13C NMR
(62.5 MHz, CDCl3): d 179.2 (C0), 162.6 (C0), 160.9 (C0), 154.2 (CH),
135.8 (CH), 129.0 (2 Â CH), 127.5 (C0), 117.0 (CH), 116.6 (CH),
114.3 (2 Â CH), 114.1 (CH), 55.3 (OCH3); HRMS (ESI+) m/z: Calcd
for C14H13O3 [M+H+] 229.0865, found 229.0879.
4.1.5. 5-Iodo-2-(4-methoxyphenyl)-2H-pyran-4(3H)-one (53)
To a solution of molecular iodine (2.25 equiv; 4.73 mmol; 1.2 g)
in anhydrous CH2Cl2 (11 mL) at 0 °C, under magnetic stirring and
nitrogen atmosphere, was added freshly distilled pyridine
(5.0 equiv; 23.7 mmol; 0.8 mL). A solution of dihydro-c-pyrone
50 (2.10 mmol; 430 mg) in anhydrous CH2Cl2 (11 mL) was then
added dropwise. The resultant reaction mixture was maintained
under magnetic stirring at 0 °C for 30 min and then at room tem-
perature for ca. 2.5 h. After this period, the reaction was quenched
with a saturated aqueous solution of sodium thiosulfate (20 mL)
and partitioned between a saturated solution of aqueous sodium
hydrogen carbonate (50 mL) and CH2Cl2 (3 Â 70 mL). The com-
bined organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified
by flash column chromatography (hexanes/ethyl acetate 2:1 v/v)
4.1.3.3.
(E)-2-(3,4-Dimethoxystyryl)-4H-pyran-4-one
(49).
Prepared according to the general procedure for oxidation with
DDQ in 85% yield (off-white solid). Eluent: ethyl acetate + 2%
MeOH v/v. Mp: 133.5–134.6 °C; IR (cmÀ1, thin film): 2918, 1647,
1596, 1508, 1412, 1380, 1263, 1156, 1140, 1019, 966, 942, 862,

3644
R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
to afford the desired 3-iodo-dihydro-
c
-pyrone 53 in 92% yield
homologations in 80% yield (yellow solid). Mp: 59.0–61.0 °C; IR
(0.64 g), as a light yellow solid. Mp: 113.6–114.2 °C; IR (cmÀ1, thin
film): 1660, 1612, 1552, 1516, 1342, 1273, 1250, 1175, 1119, 1102,
1022, 987, 951, 815; 1H NMR (250 MHz, CDCl3): d 7.88 (s, 1H), 7.32
(d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 5.51 (dd, J = 13.7 and
4.0 Hz, 1H), 3.83 (s, 3H), 3.11 (dd, J = 16.8 and 13.7 Hz, 1H), 2.97
(dd, J = 16.8 and 4.0 Hz, 1H); 13C NMR (62.5 MHz, CDCl3): d 186.2
(C0), 166.0 (CH), 160.3 (C0), 128.7 (C0), 127.8 (2 Â CH), 114.3
(2 Â CH), 81.7 (CH), 76.8 (C0), 55.3 (OCH3), 42.5 (CH2); HRMS
(ESI+) m/z: Calcd for C12H12IO3 [M+H+] 330.9826, found 330.9882.
(cmÀ1, thin film): 2819, 2721, 1680, 1629, 1574, 1421, 1322,
1171, 1122, 1065, 981, 821, 760; 1H NMR (250 MHz, CDCl3): d
9.75 (d, J = 7.6 Hz, 1H), 7.70–7.67 (m, 4H), 7.51 (d, J = 16.0 Hz,
1H), 6.77 (dd, J = 16.0 and 7.6 Hz, 1H); 13C NMR (62.5 MHz, CDCl3):
d 193.0 (CH), 150.0 (CH), 137.2 (C0), 132.0 (q, J = 32.9 Hz, C0), 130.2
(CH), 128.3 (2 Â CH), 125.7 (q, J = 3.9 Hz, 2 Â CH), 123.5 (q,
J = 272.5 Hz, C0); HRMS (ESI+) m/z: Calcd for C10H8F3O [M+H+]
201.0527, found 201.0619.
4.1.6.3.
(E)-3-(2,4-Dimethoxyphenyl)acrylaldehyde
(64).
4.1.6. General procedure for the aldehyde homologations
Prepared according to the general procedure for the aldehyde
homologations in 61% yield (yellow solid). Mp: 99.0–100.0 °C; IR
(cmÀ1, thin film): 2970, 2922, 2845, 2767, 1668, 1610, 1573,
1503, 1469, 1455, 1427, 1327, 1278, 1168, 1110, 971, 843, 785;
1H NMR (250 MHz, CDCl3): d 9.59 (d, J = 7.9 Hz, 1H), 7.71 (d,
J = 15.9 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 6.67 (dd, J = 15.9 and
7.9 Hz, 1H), 6.51 (dd, J = 8.6 and 2.3 Hz, 1H), 6.44 (d, J = 2.3 Hz,
1H), 3.86 (s, 3H), 3.83 (s, 3H); 13C NMR (62.5 MHz, CDCl3): d
194.5 (CH), 163.7 (C0), 159.9 (C0), 148.3 (CH), 130.4 (CH), 126.7
(CH), 116.1 (C0), 105.6 (CH), 98.3 (CH), 55.5 (OCH3), 55.4 (OCH3);
HRMS (ESI+) m/z: Calcd for C11H13O3 [M+H+] 193.0865, found
193.0950.
To
a suspension of sodium hydride 60% in mineral oil
(1.5 equiv; 18.1 mmol) in a mixture of anhydrous THF (50 mL)
and anhydrous DMF (4 mL), under nitrogen atmosphere and cooled
at 0 °C, was added triethyl phosphonoacetate (1.3 equiv;
15.6 mmol). The reaction mixture was maintained under magnetic
stirring under these conditions for 15 min. A solution of aldehyde
54–60 (12.0 mmol) in anhydrous THF (10 mL) was then added
dropwise and the cooling bath was removed. After total consump-
tion of the starting material (TLC analysis), the reaction mixture
was filtered on silica under reduced pressure and the filter cake
washed with ethyl acetate. The solution was concentrated to dry-
ness under vacuum and the residue was subjected to flash column
chromatography (hexanes/ethyl acetate 2:1, 1:1 v/v or 10:1 v/v in
the case of the CF3-derivatives). The ester intermediate obtained
(10.7 mmol) was dissolved in anhydrous CH2Cl2 (107 mL) and the
resulting solution was cooled to À78 °C, under nitrogen atmo-
sphere and magnetic stirring. DIBAL-H (2.5 equiv; 26.8 mmol)
was added dropwise and the reaction mixture was maintained un-
der these conditions until completion, ca. 30 min. After this period,
the temperature was raised to 0 °C and ethyl acetate (15 mL) was
added carefully, followed by 1 M HCl (90 mL). The emulsion re-
mained under strong stirring until complete phase separation.
The aqueous layer was extracted with CH2Cl2 (3 Â 50 mL) and
the combined organic layer was dried with anhydrous MgSO4, fil-
tered and concentrated to dryness under reduced pressure. The
residue was purified by flash column chromatography (hexanes/
ethyl acetate 1:1 v/v or 2:1 v/v in the case of the CF3-derivatives)
and the allylic alcohol obtained (10.7 mmol) was dissolved in ethyl
acetate (77 mL). Next, IBX was added (3.0 equiv; 32.1 mmol) and
the resulting suspension was immersed in an oil bath at 80 °C.
After, vigorous stirring under open atmosphere for approximately
3.5 h, the reaction mixture was cooled to room temperature, fil-
tered over Celite under vacuum and the filter cake washed with
ethyl acetate (3 Â 20 mL). The filtrates were combined and the sol-
vent was removed under reduced pressure. The residue obtained
was purified by flash column chromatography (hexanes/ethyl ace-
tate 2:1, 1:1 v/v or 3:1 v/v in the case of the CF3-derivatives) to give
the homologated aldehydes 61–62, 64–68.
4.1.6.4.
(E)-3-(3,4-Dimethoxyphenyl)acrylaldehyde
(65).
Prepared according to the general procedure for the aldehyde
homologations in 81% yield (yellow solid). Mp: 80.0–81.5 °C; IR
(cmÀ1, thin film): 3014, 2974, 2923, 2841, 2806, 2749, 1673,
1621, 1596, 1513, 1421, 1266, 1226, 1138, 1131, 1017, 878, 800,
742; 1H NMR (250 MHz, CDCl3): d 9.66 (d, J = 7.7 Hz, 1H), 7.41 (d,
J = 15.8 Hz, 1H), 7.16 (dd, J = 8.3 and 1.8 Hz, 1H), 7.08 (d,
J = 1.8 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.61 (dd, J = 15.8 and
7.7 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H); 13C NMR (62.5 MHz, CDCl3):
d 193.3 (CH), 152.7 (CH), 151.8 (C0), 149.2 (C0), 126.9 (C0), 126.5
(CH), 123.3 (CH), 111.0 (CH), 109.8 (CH), 55.8 (OCH3), 55.7
(OCH3); HRMS (ESI+) m/z: Calcd for C11H13O3 [M+H+] 193.0865,
found 193.0866.
4.1.6.5.
(E)-3-(3,5-Dimethoxyphenyl)acrylaldehyde
(66).
Prepared according to the general procedure for the aldehyde
homologations in 87% yield (yellow solid). Mp: 78.5–80.0 °C; IR
(cmÀ1, thin film): 3090, 2994, 2968, 2846, 2814, 2730, 1674,
1590, 1446, 1424, 1349, 1299, 1264, 1209, 1193, 1152, 1126,
1058, 970, 832, 819; 1H NMR (250 MHz, CDCl3): d 9.67 (d,
J = 7.7 Hz, 1H), 7.37 (d, J = 15.9 Hz, 1H), 6.68 (d, J = 2.2 Hz, 2H),
6.65 (dd, J = 15.9 and 7.7 Hz, 1H), 6.53 (t, J = 2.2 Hz, 1H), 3.80 (s,
6H); 13C NMR (62.5 MHz, CDCl3): d 193.5 (CH), 161.1 (2 Â C0),
152.6 (CH), 135.8 (C0), 128.9 (CH), 106.3 (2 Â CH), 103.3 (CH),
55.4 (2 Â OCH3); HRMS (ESI+) m/z: Calcd for C11H13O3 [M+H+]
193.0865, found 193.0950.
4.1.6.1. (E)-3-(2-(Trifluoromethyl)phenyl)acrylaldehyde (61).
Prepared according to the general procedure for the aldehyde
homologations in 61% yield (yellow solid). Mp: 39.0–41.0 °C; IR
(cmÀ1, thin film): 3079, 1689, 1631, 1603, 1577, 1489, 1315,
1166, 1122, 1061, 1037, 974, 768; 1H NMR (250 MHz, CDCl3): d
9.68 (d, J = 7.6 Hz, 1H), 7.80 (dd, J = 15.8 and 1.8 Hz, 1H), 7.68 (t,
J = 7.5 Hz, 2H), 7.60–7.40 (m, 2H), 6.62 (dd, J = 15.8 and 7.6 Hz,
4.1.6.6.
(E)-3-(3,4,5-Trimethoxyphenyl)acrylaldehyde
(67).
Prepared according to the general procedure for the aldehyde
homologations in 90% yield (yellow solid). Mp: 110.0–111.0 °C;
IR (cmÀ1, thin film): 3013, 3002, 2979, 2948, 2840, 2749, 1699,
1677, 1621, 1581, 1504, 1470, 1422, 1335, 1123, 998, 973, 817,
736; 1H NMR (250 MHz, CDCl3): d 9.66 (d, J = 7.7 Hz, 1H), 7.37 (d,
J = 15.8 Hz, 1H), 6.78 (s, 2H), 6.61 (dd, J = 15.8 and 7.7 Hz, 1H),
3.88 (s, 9H); 13C NMR (62.5 MHz, CDCl3): d 193.3 (CH), 153.5
(2 Â C0), 152.6 (CH), 140.9 (C0), 129.4 (C0), 127.9 (CH), 105.7
(2 Â CH), 60.9 (OCH3), 56.1 (2 Â OCH3); HRMS (ESI+) m/z: Calcd
for C12H15O4 [M+H+] 223.0970, found 223.0979.
1H); 13C NMR (62.5 MHz, CDCl3):
d 193.0 (CH), 147.1 (q,
J = 2.0 Hz, CH), 132.5 (q, J = 1.4 Hz, C0), 132.1 (CH), 131.8 (CH),
130.3 (CH), 128.6 (q, J = 30.4 Hz, C0), 127.8 (CH), 126.1 (q,
J = 5.7 Hz, CH), 123.7 (q, J = 274.2 Hz, C0); HRMS (ESI+) m/z: Calcd
for C10H8F3O [M+H+] 201.0527, found 201.0619.
4.1.6.7.
(E)-3-(2,4,5-Trimethoxyphenyl)acrylaldehyde
(68).
4.1.6.2. (E)-3-(4-(Trifluoromethyl)phenyl)acrylaldehyde (62).
Prepared according to the general procedure for the aldehyde
Prepared according to the general procedure for the aldehyde
homologations in 50% yield (yellow solid). Mp: 129.0–130.5 °C;

R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
3645
IR (cmÀ1, thin film): 3056, 2989, 2934, 2843, 1658, 1604, 1505,
1468, 1310, 1277, 1210, 1120, 1025, 876, 828, 751; 1H NMR
(250 MHz, CDCl3): d 9.43 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 15.9 Hz,
1H), 6.82 (s, 1H), 6.44 (dd, J = 15.9 and 7.8 Hz, 1H), 6.33 (s, 1H),
3.75 (s, 3H), 3.71 (s, 3H), 3.67 (s, 3H); 13C NMR (62.5 MHz, CDCl3):
d 193.6 (CH), 153.7 (C0), 152.9 (C0), 147.3 (CH), 142.8 (C0), 125.7
(CH), 113.9 (C0), 110.2 (CH), 96.0 (CH), 55.9 (OCH3), 55.7 (OCH3),
55.5 (OCH3); HRMS (ESI+) m/z: Calcd for C12H15O4 [M+H+]
223.0970, found 223.1012.
HRMS (ESI+) m/z: Calcd for C13H15O [M+H+À18] 187.1123, found
187.1203.
4.1.7.4. (E)-1-(2,4-Dimethoxyphenyl)hexa-1,5-dien-3-ol (72).
Prepared according to the general procedure for the allylation reac-
tions in quantitative yield (yellow oil). Eluent: hexanes/ethyl ace-
tate 2:1 v/v. IR (cmÀ1, thin film): 3442, 3072, 3002, 2938, 2838,
1638, 1609, 1505, 1465, 1209, 1159, 1034, 921, 834; 1H NMR
(250 MHz, CDCl3): d 7.33 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 16.0 Hz,
1H), 6.47 (d, J = 2.3 Hz, 1H), 6.45–6.41 (m, 1H), 6.13 (dd, J = 16.0
and 6.8 Hz, 1H), 5.87 (dtd, J = 17.2, 10.2, 6.8 and 6.8 Hz, 1H),
5.21–5.08 (m, 2H), 4.32 (q, J = 6.8 Hz, 1H), 3.80 (s, 3H), 3.79 (s,
3H), 2.40 (app t, J = 6.8 Hz, 2H), 2.06 (br s, 1H); 13C NMR
(62.5 MHz, CDCl3): d 160.4 (C0), 157.8 (C0), 134.4 (CH), 130.1
(CH), 127.5 (CH), 125.0 (CH), 118.6 (C0), 117.8 (CH2), 104.7 (CH),
98.3 (CH), 72.4 (CH), 55.3 (OCH3), 55.2 (OCH3), 42.0 (CH2); HRMS
(ESI+) m/z: Calcd for C14H17O2 [M+H+À18] 217.1228, found
217.1205.
4.1.7. General procedure for the allylation reactions
To a stirred solution of the homologated aldehyde 61–68
(4.94 mmol) in anhydrous THF (25 mL), at À78 °C under nitrogen
atmosphere, was added dropwise a solution of allylmagnesium
bromide in diethyl ether (1.2 equiv; 5.93 mmol). The reaction mix-
ture was maintained under these conditions for 30 min. After this
period, a saturated aqueous solution of ammonium chloride
(10 mL) was added and the layers were separated. The aqueous
layer was extracted with diethyl ether (3 Â 10 mL) and the com-
bined organic layers were dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure. The crude was purified
by flash column chromatography (using the eluent indicated) to
give the corresponding homoallylic alcohols 69–76.
4.1.7.5. (E)-1-(3,4-Dimethoxyphenyl)hexa-1,5-dien-3-ol (73).
Prepared according to the general procedure for the allylation reac-
tions in 94% yield (yellow oil). Eluent: hexanes/ethyl acetate 1:1 v/
v. IR (cmÀ1, thin film): 3479, 3075, 3002, 2936, 2909, 2837, 1678,
1641, 1600, 1586, 1515, 1464, 1265, 1139, 1026, 969, 918, 863;
1H NMR (250 MHz, CDCl3): d 6.95–6.87 (m, 2H), 6.79 (app d,
J = 8.0 Hz, 1H), 6.52 (d, J = 15.9 Hz, 1H), 6.09 (dd, J = 15.9 and
6.5 Hz, 1H), 5.85 (dtd, J = 17.2, 10.2, 6.5 and 6.5 Hz, 1H), 5.22–
5.10 (m, 2H), 4.32 (q, J = 6.5 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H),
2.44–2.34 (m, 2H), 1.92 (br s, 1H); 13C NMR (62.5 MHz, CDCl3): d
149.0 (C0), 148.8 (C0), 134.1 (CH), 130.1 (CH), 129.7 (C0), 129.6
(CH), 119.6 (CH), 118.2 (CH2), 111.1 (CH), 108.9 (CH), 71.8 (CH),
55.8 (2 Â OCH3), 42.0 (CH2); HRMS (ESI+) m/z: Calcd for C14H17O2
[M+H+À18] 217.1228, found 217.1205.
4.1.7.1.
(69).
(E)-1-(2-(Trifluoromethyl)phenyl)hexa-1,5-dien-3-ol
Prepared according to the general procedure for the ally-
lation reactions in 90% yield (yellow oil). Eluent: hexanes/ethyl
acetate 4:1 v/v. IR (cmÀ1, thin film): 3418, 3078, 2931, 1640,
1614, 1576, 1488, 1455, 1315, 1165, 1123, 1036, 974, 921, 768;
1H NMR (250 MHz, CDCl3):
d 7.66–7.57 (m, 2H), 7.50 (t,
J = 7.5 Hz, 1H), 7.39–7.29 (m, 1H), 6.99 (d, J = 15.7 Hz, 1H), 6.21
(dd, J = 15.7 and 6.5 Hz, 1H), 5.95–5.77 (m, 1H), 5.26–5.13 (m,
2H), 4.46–4.35 (m, 1H), 2.54–2.32 (m, 2H), 1.83 (d, J = 4.1 Hz,
1H); 13C NMR (62.5 MHz, CDCl3): d 136.0 (CH), 135.9 (C0), 133.7
(CH), 131.8 (CH), 127.5 (CH), 127.4 (q, J = 30.0 Hz, C0), 127.3 (CH),
126.3 (q, J = 1.8 Hz, CH), 125.7 (q, J = 5.7 Hz, CH), 124.3 (q,
J = 273.9 Hz, C0), 118.7 (CH2), 71.5 (CH), 41.8 (CH2); HRMS (ESI+)
m/z: Calcd for C13H12F3 [M+H+À18] 225.0891, found 225.0911.
4.1.7.6. (E)-1-(3,5-Dimethoxyphenyl)hexa-1,5-dien-3-ol (74).
Prepared according to the general procedure for the allylation reac-
tions in quantitative yield (light brown viscous oil). Eluent: hex-
anes/ethyl acetate 1:1 v/v. IR (cmÀ1, thin film): 3418, 3076, 3002,
2937, 2838, 1640, 1593, 1459, 1427, 1205, 1154, 1064, 969, 923,
828; 1H NMR (250 MHz, CDCl3): d 6.52 (d, J = 2.1 Hz, 2H), 6.49 (d,
J = 15.9 Hz, 1H), 6.36 (t, J = 2.1 Hz, 1H), 6.20 (dd, J = 15.9 and
6.3 Hz, 1H), 5.84 (dtd, J = 17.2, 10.2, 6.3 and 6.3 Hz, 1H), 5.20–
5.07 (m, 2H), 4.30 (q, J = 6.3 Hz, 1H), 3.75 (s, 6H), 2.45 (br s, 1H),
2.38 (app t, J = 6.3 Hz, 2H); 13C NMR (62.5 MHz, CDCl3): d 160.7
(2 Â C0), 138.6 (C0), 134.0 (CH), 132.1 (CH), 129.9 (CH), 118.0
(CH2), 104.4 (2 Â CH), 99.7 (CH), 71.4 (CH), 55.1 (2 Â OCH3), 41.7
(CH2); HRMS (ESI+) m/z: Calcd for C14H19O3 [M+H+] 235.1334,
found 235.1407.
4.1.7.2.
(70).
(E)-1-(4-(Trifluoromethyl)phenyl)hexa-1,5-dien-3-ol
Prepared according to the general procedure for the ally-
lation reactions in 99% yield (yellow oil). Eluent: hexanes/ethyl
acetate 4:1 v/v. IR (cmÀ1, thin film): 3411, 3079, 2981, 2933,
1642, 1616, 1579, 1514, 1415, 1326, 1166, 1125, 1067, 1017,
971, 921, 863, 838, 819; 1H NMR (250 MHz, CDCl3,): d 7.54 (d,
J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 15.9 Hz, 1H),
6.33 (dd, J = 15.9 and 5.9 Hz, 1H), 5.95–5.75 (m, 1H), 5.25–5.11
(m, 2H), 4.38 (q, J = 5.9 Hz, 1H), 2.52–2.31 (m, 3H); 13C NMR
(62.5 MHz, CDCl3): d 140.2 (C0), 134.3 (CH), 133.7 (CH), 129.3 (q,
J = 32.3 Hz, C0), 128.7 (CH), 126.6 (2 Â CH), 125.5 (q, J = 3.9 Hz,
2 Â CH), 124.2 (q, J = 271.3 Hz, C0), 118.6 (CH2), 71.3 (CH), 41.9
(CH2); HRMS (ESI+) m/z: Calcd for C13H12F3 [M+H+À18] 225.0891,
found 225.0962.
4.1.7.7. (E)-1-(3,4,5-Trimethoxyphenyl)hexa-1,5-dien-3-ol (75).
Prepared according to the general procedure for the allylation reac-
tions in 92% yield (yellow oil). Eluent: hexanes/ethyl acetate 3:2 v/
v. IR (cmÀ1, thin film): 3439, 3074, 2999, 2938, 2838, 1640, 1584,
1507, 1463, 1420, 1329, 1241, 1127, 1004, 969, 919, 814; 1H
NMR (250 MHz, CDCl3): d 6.55 (s, 2H), 6.47 (d, J = 15.9 Hz, 1H),
6.11 (dd, J = 15.9 and 6.5 Hz, 1H), 5.82 (dtd, J = 17.2, 10.2, 6.5 and
6.5 Hz, 1H), 5.18–5.06 (m, 2H), 4.30 (q, J = 6.5 Hz, 1H), 3.82 (s,
6H), 3.80 (s, 3H), 2.42–2.32 (m, 2H), 2.23 (br s, 1H); 13C NMR
(62.5 MHz, CDCl3): d 153.1 (2 Â C0), 137.7 (C0), 134.0 (CH), 132.3
(C0), 131.0 (CH), 130.0 (CH), 118.1 (CH2), 103.5 (2 Â CH), 71.5
(CH), 60.7 (OCH3), 55.9 (2 Â OCH3), 41.8 (CH2); HRMS (ESI+) m/z:
Calcd for C15H21O4 [M+H+] 265.1440, found 265.1553.
4.1.7.3.
(E)-1-(4-Methoxyphenyl)hexa-1,5-dien-3-ol
(71).
Prepared according to the general procedure for the allylation reac-
tions in quantitative yield (yellow oil). Eluent: hexanes/ethyl ace-
tate 3:2 v/v. IR (cmÀ1, thin film): 3409, 3075, 3004, 2934, 2904,
2837, 1641, 1607, 1578, 1512, 1465, 1302, 1250, 1175, 1033,
969, 917, 816; 1H NMR (250 MHz, CDCl3): d 7.26 (d, J = 8.7 Hz,
2H), 6.81 (d, J = 8.7 Hz, 2H), 6.50 (d, J = 15.9 Hz, 1H), 6.09 (dd,
J = 15.9 and 6.6 Hz, 1H), 5.87 (dtd, J = 17.2, 10.2, 6.6 and 6.6 Hz,
1H), 5.20–5.07 (m, 2H), 4.29 (q, J = 6.6 Hz, 1H), 3.72 (s, 3H), 3.26
(br s, 1H), 2.39 (t, J = 6.6 Hz, 2H); 13C NMR (62.5 MHz, CDCl3): d
158.7 (C0), 134.1 (CH), 129.3 (2 Â CH), 129.1 (C0), 127.2 (2 Â CH),
117.2 (CH2), 113.5 (2 Â CH), 71.6 (CH), 54.7 (OCH3), 41.6 (CH2);
4.1.7.8. (E)-1-(2,4,5-Trimethoxyphenyl)hexa-1,5-dien-3-ol (76).
Prepared according to the general procedure for the allylation reac-
tions in 80% yield (yellow oil). Eluent: hexanes/ethyl acetate 1:1 v/

3646
R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
v. IR (cmÀ1, thin film): 3422, 3074, 3000, 2936, 2834, 1641, 1609,
1511, 1466, 1208, 1034, 973, 916, 874, 732; 1H NMR (250 MHz,
CDCl3): d 6.83 (s, 1H), 6.17 (d, J = 16.0 Hz, 1H), 6.34 (s, 1H), 5.99
(dd, J = 16.0 and 6.7 Hz, 1H), 5.86–5.64 (m, 1H), 5.12–4.91 (m,
2H), 4.26–4.11 (m, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.65 (s, 3H),
2.67 (br s, 1H), 2.28 (t, J = 6.7 Hz, 2H); 13C NMR (62.5 MHz, CDCl3):
d 151.3 (C0), 149.4 (C0), 143.2 (C0), 134.3 (CH), 129.9 (CH), 124.7
(CH), 117.8 (CH2), 117.3 (C0), 109.9 (CH), 97.6 (CH), 72.3 (CH),
56.4 (2 Â OCH3), 55.9 (OCH3), 41.9 (CH2); HRMS (ESI+) m/z: Calcd
for C15H19O3 [M+H+À18] 247.1334, found 247.1358.
CDCl3): d 164.8 (C0), 159.2 (C0), 132.8 (CH), 132.0 (CH), 130.1
(CH2), 128.5 (C0), 128.4 (CH), 127.4 (2 Â CH), 124.3 (CH), 117.6
(CH2), 113.6 (2 Â CH), 73.7 (CH), 54.6 (OCH3), 38.7 (CH2); HRMS
(ESI+) m/z: Calcd for
C13H15
O
[M+H+À72] 187.1123, found
187.1203.
4.1.8.4. (E)-1-(2,4-Dimethoxyphenyl)hexa-1,5-dien-3-yl acrylate
(80). Prepared according to the general procedure for the
esterification reactions in 60% yield (yellow oil). Eluent: hexanes/
ethyl acetate 3:1 v/v. IR (cmÀ1, thin film): 3004, 2936, 2837,
1723, 1609, 1580, 1505, 1465, 1289, 1264, 1208, 1159, 1036,
974, 834; 1H NMR (250 MHz, CDCl3,): d 7.33 (d, J = 8.3 Hz, 1H),
6.88 (d, J = 16.0 Hz, 1H), 6.51–6.35 (m, 3H), 6.22–6.04 (m, 2H),
5.90–5.70 (m, 2H), 5.54 (q, J = 6.8 Hz, 1H), 5.18–5.04 (m, 2H),
3.82 (s, 3H), 3.81 (s, 3H), 2.52 (t, J = 6.8 Hz, 2H); 13C NMR
(62.5 MHz, CDCl3): d 165.5 (C0), 160.7 (C0), 158.1 (C0), 133.4 (CH),
130.4 (CH2), 128.9 (CH), 127.9 (CH), 127.7 (CH), 125.2 (CH), 118.3
(C0), 117.9 (CH2), 104.8 (CH), 98.4 (CH), 74.8 (CH), 55.4 (2 Â OCH3),
39.3 (CH2); HRMS (ESI+) m/z: Calcd for C14H17O2 [M+H+À72]
217.1228, found 217.1308.
4.1.8. General procedure for the esterification reactions
To a solution of the homoallylic alcohols 69–76 (3.40 mmol) in
anhydrous CH2Cl2 (70 mL), at 0 °C under magnetic stirring and
nitrogen atmosphere, was added triethylamine (2.0 equiv;
6.80 mmol), followed by acryloyl chloride (1.5 equiv; 5.10 mmol).
The cooling bath was removed and the reaction mixture was stir-
red for 1 h at room temperature. After this period, the volatiles
were removed under reduced pressure and the crude was purified
by flash column chromatography (using the eluent indicated) to af-
ford the corresponding esters 77–84.
4.1.8.5. (E)-1-(3,4-Dimethoxyphenyl)hexa-1,5-dien-3-yl acrylate
4.1.8.1.
acrylate (77).
(E)-1-(2-(Trifluoromethyl)phenyl)hexa-1,5-dien-3-yl
Prepared according to the general procedure
(81).
Prepared according to the general procedure for the
esterification reactions in 60% yield (yellow oil). Eluent: hexanes/
ethyl acetate 2:1 v/v. IR (cmÀ1, thin film): 3077, 3002, 2956,
2937, 2837, 1722, 1639, 1602, 1586, 1515, 1465, 1406, 1266,
1192, 1027, 967, 809; 1H NMR (250 MHz, CDCl3): d 6.93–6.84 (m,
2H), 6.76 (d, J = 8.7 Hz, 1H), 6.55 (d, J = 15.9 Hz, 1H), 6.39 (d,
J = 17.3 Hz, 1H), 6.11 (dd, J = 17.3 and 10.3 Hz, 1H), 6.02 (dd,
J = 15.9 and 6.7 Hz, 1H), 5.87–5.67 (m, 1H), 5.78 (d, J = 10.3 Hz,
1H), 5.51 (q, J = 6.7 Hz, 1H), 5.17–5.01 (m, 2H), 3.85 (s, 3H), 3.82
(s, 3H), 2.50 (t, J = 6.7 Hz, 2H); 13C NMR (62.5 MHz, CDCl3): d
165.2 (C0), 149.0 (C0), 148.8 (C0), 132.9 (CH), 132.5 (CH), 130.5
(CH2), 129.1 (C0), 128.5 (CH), 124.7 (CH), 119.7 (CH), 117.9 (CH2),
110.9 (CH), 108.9 (CH), 73.9 (CH), 55.7 (OCH3), 55.6 (OCH3), 38.9
(CH2); HRMS (ESI+) m/z: Calcd for C17H21O4 [M+H+] 289.1440,
found 289.1489.
for the esterification reactions in 61% yield (yellow oil). Eluent:
hexanes/ethyl acetate 9:1 v/v. IR (cmÀ1, thin film): 3078, 2928,
2855, 1726, 1638, 1576, 1406, 1315, 1189, 1165, 1124, 1036,
967, 809, 765; 1H NMR (250 MHz, CDCl3): d 7.65–7.55 (m, 2H),
7.48 (t, J = 7.6 Hz, 1H), 7.38–7.29 (m, 1H), 7.02 (d, J = 16.0 Hz,
1H), 6.46 (dd, J = 17.3 and 1.3 Hz, 1H), 6.23–6.10 (m, 2H), 5.91–
5.72 (m, 2H), 5.60 (q, J = 6.5 Hz, 1H), 5.22–5.07 (m, 2H), 2.55 (t,
J = 6.5 Hz, 2H); 13C NMR (62.5 MHz, CDCl3): d 165.2 (C0), 135.5
(q, J = 1.8 Hz, C0), 132.7 (CH), 131.8 (CH), 131.4 (CH), 130.9 (CH2),
128.5 (CH), 128.1 (q, J = 1.8 Hz, CH), 127.6 (q, J = 29.9 Hz, C0),
127.5 (2 Â CH), 125.7 (q, J = 5.8 Hz, CH), 124.2 (q, J = 274.0 Hz,
C0), 118.4 (CH2), 73.2 (CH), 38.9 (CH2); HRMS (ESI+) m/z: Calcd
for C16H16F3O2 [M+H+] 297.1102, found 297.1135.
4.1.8.2.
acrylate (78).
(E)-1-(4-(Trifluoromethyl)phenyl)hexa-1,5-dien-3-yl
Prepared according to the general procedure
4.1.8.6. (E)-1-(3,5-Dimethoxyphenyl)hexa-1,5-dien-3-yl acrylate
(82).
Prepared according to the general procedure for the
for the esterification reactions in 41% yield (yellow oil). Eluent:
hexanes/ethyl acetate 9:1 v/v. IR (cmÀ1, thin film): 3081, 2927,
2855, 1727, 1640, 1617, 1407, 1326, 1189, 1167, 1125, 1068,
970, 810; 1H NMR (250 MHz, CDCl3): d 7.56 (d, J = 8.4 Hz, 2H),
7.46 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 16.0 Hz, 1H), 6.45 (dd, J = 17.3
and 1.5 Hz, 1H), 6.28 (dd, J = 16.0 and 7.0 Hz, 1H), 6.16 (dd,
J = 17.3 and 10.4 Hz, 1H), 5.86 (dd, J = 10.4 and 1.5 Hz, 1H), 5.81
(dtd, J = 17.4, 10.2, 7.0 and 7.0 Hz, 1H), 5.58 (q, J = 7.0 Hz, 1H),
5.19–5.08 (m, 2H), 2.55 (t, J = 7.0 Hz, 2H); 13C NMR (62.5 MHz,
CDCl3): d 165.3 (C0), 139.7 (C0), 132.7 (CH), 131.1 (CH), 131.0
(CH2), 129.7 (q, J = 32.3 Hz, C0), 129.7 (CH), 128.5 (CH), 126.7
(2 Â CH), 125.5 (q, J = 3.9 Hz, 2 Â CH), 124.3 (q, J = 272.2 Hz, C0),
118.4 (CH2), 73.5 (CH), 38.9 (CH2); HRMS (EI) m/z: Calcd for
esterification reactions in 92% yield (yellow oil). Eluent: hexanes/
ethyl acetate 2:1 v/v. IR (cmÀ1, thin film): 3078, 3002, 2939,
2838, 1723, 1636, 1593, 1457, 1428, 1405, 1295, 1268, 1205,
1193, 1154, 1066, 967, 809; 1H NMR (250 MHz, CDCl3): d 6.62–
6.35 (m, 5H), 6.24–6.06 (m, 2H), 5.90–5.70 (m, 2H), 5.55 (q,
J = 6.6 Hz, 1H), 5.19–5.06 (m, 2H), 3.77 (s, 6H), 2.52 (t, J = 6.6 Hz,
2H); 13C NMR (62.5 MHz, CDCl3): d 165.1 (C0), 160.8 (2 Â C0),
138.1 (C0), 132.8 (CH), 132.6 (CH), 130.6 (CH2), 128.5 (CH), 127.4
(CH), 118.1 (CH2), 104.5 (2 Â CH), 100.2 (CH), 73.6 (CH), 55.1
(2 Â OCH3), 38.9 (CH2); HRMS (ESI+) m/z: Calcd for C17H21O4
[M+H+] 289.1440, found 289.1381.
4.1.8.7. (E)-1-(3,4,5-Trimethoxyphenyl)hexa-1,5-dien-3-yl acry-
C
16H15F3O2 [M+] 296.1024, found 296.1039.
late (83).
Prepared according to the general procedure for the
esterification reactions in 82% yield (yellow oil). Eluent: hexanes/
ethyl acetate 2:1 v/v. IR (cmÀ1, thin film): 3077, 2998, 2940,
2840, 1722, 1638, 1619, 1583, 1507, 1463, 1455, 1420, 1405,
1330, 1241, 1190, 1127, 967, 810; 1H NMR (250 MHz, CDCl3): d
6.61–6.56 (m, 2H), 6.56 (d, J = 16.0 Hz, 1H), 6.43 (d, J = 17.3 Hz,
1H), 6.20–6.00 (m, 2H), 5.89–5.69 (m, 2H), 5.53 (q, J = 6.6 Hz,
1H), 5.19–5.09 (m, 2H), 3.85 (s, 6H), 3.82 (s, 3H), 2.52 (t,
J = 6.6 Hz, 2H); 13C NMR (62.5 MHz, CDCl3): d 165.3 (C0), 153.2
(2 Â C0), 138.1 (C0), 132.9 (CH), 132.8 (CH), 131.8 (C0), 130.7
(CH2), 128.6 (CH), 126.3 (CH), 118.1 (CH2), 103.7 (2 Â CH), 73.8
(CH), 60.8 (OCH3), 56.0 (2 Â OCH3), 39.0 (CH2); HRMS (ESI+) m/z:
Calcd for C15H19O3 [M+H+À72] 247.1334, found 247.1389.
4.1.8.3. (E)-1-(4-methoxyphenyl)hexa-1,5-dien-3-yl acrylate
(79). Prepared according to the general procedure for the
esterification reactions in 86% yield (yellow oil). Eluent: hexanes/
ethyl acetate 2:1 v/v. IR (cmÀ1, thin film): 3077, 3036, 3005,
2959, 2934, 2837, 1722, 1638, 1608, 1513, 1405, 1250, 1190,
1176, 1036, 966, 808; 1H NMR (250 MHz, CDCl3): d 7.27 (d,
J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 6.58 (d, J = 15.9 Hz, 1H),
6.40 (dd, J = 17.3 and 1.3 Hz, 1H), 6.12 (dd, J = 17.3 and 10.3 Hz,
1H), 6.03 (dd, J = 15.9 and 6.7 Hz, 1H), 5.88–5.69 (m, 1H), 5.75
(dd, J = 10.3 and 1.3 Hz, 1H), 5.54 (q, J = 6.7 Hz, 1H), 5.18–5.02
(m, 2H), 3.69 (s, 3H), 2.49 (t, J = 6.7 Hz, 2H); 13C NMR (62.5 MHz,

R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
3647
4.1.8.8. (E)-1-(2,4,5-Trimethoxyphenyl)hexa-1,5-dien-3-yl acry-
late (84). Prepared according to the general procedure for the
3.79 (s, 3H), 2.53–2.49 (m, 2H); 13C NMR (62.5 MHz, CDCl3): d
163.9 (C0), 159.6 (C0), 144.7 (CH), 132.6 (CH), 128.3 (C0), 127.8
(2 Â CH), 123.3 (CH), 121.3 (CH), 113.9 (2 Â CH), 78.1 (CH), 55.1
(OCH3), 29.8 (CH2); HRMS (ESI+) m/z: Calcd for C14H15O3 [M+H+]
231.1021, found 231.1013.
esterification reactions in 83% yield (yellow oil). Eluent: hexanes/
ethyl acetate 2:1 v/v. IR (cmÀ1, thin film): 2995, 2922, 2831,
1724, 1607, 1511, 1464, 1402, 1206, 1123, 1033, 985, 869; 1H
NMR (250 MHz, CDCl3): d 6.96–6.83 (m, 2H), 6.50–6.32 (m, 2H),
6.19–5.98 (m, 2H), 5.89–5.68 (m, 2H), 5.53 (q, J = 6.4 Hz, 1H),
5.17–5.00 (m, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 2.51 (t,
J = 6.4 Hz, 2H); 13C NMR (62.5 MHz, CDCl3): d 165.3 (C0), 151.6
(C0), 149.7 (C0), 143.1 (C0), 133.2 (CH), 130.4 (CH2), 128.7 (CH),
127.3 (CH), 124.9 (CH), 117.8 (CH2), 116.8 (C0), 110.0 (CH), 97.5
(CH), 74.6 (CH), 56.4 (2 Â OCH3), 55.9 (OCH3), 39.1 (CH2); HRMS
4.1.9.4.
(E)-6-(2,4-Dimethoxystyryl)-5,6-dihydro-2H-pyran-2-
one (88).
Prepared according to the general procedure for
the preparation of lactones in 50% yield (yellow solid). Eluent: hex-
anes/ethyl acetate 1:1 v/v. Mp: 72.4–74.6 °C; IR (cmÀ1, thin film):
3003, 2940, 2838, 1719, 1608, 1505, 1465, 1384, 1247, 1209,
1160, 1031, 972, 815, 734; 1H NMR (500 MHz, CDCl3): d 7.33 (d,
J = 8.5 Hz, 1H), 6.91 (d, J = 16.0 Hz, 1H), 6.90 (dt, J = 9.8 and
4.5 Hz, 1H), 6.47 (dd, J = 8.5 and 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz,
1H), 6.21 (dd, J = 16.0 and 6.9 Hz, 1H), 6.06 (dt, J = 9.8 and 1.8 Hz,
1H), 5.08–5.02 (m, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 2.55–2.50 (m,
2H); 13C NMR (62.5 MHz, CDCl3): d 164.0 (C0), 160.7 (C0), 157.9
(C0), 144.9 (CH), 128.0 (CH), 127.8 (CH), 123.7 (CH), 121.0 (CH),
117.4 (C0), 104.7 (CH), 98.0 (CH), 78.8 (CH), 55.1 (2 Â OCH3), 29.7
(CH2); HRMS (ESI+) m/z: Calcd for C15H17O4 [M+H+] 261.1127,
found 261.1112.
(ESI+) m/z: Calcd for
247.1389.
C
15H19O3 [M+H+À72] 247.1334, found
4.1.9. General Procedure for the Preparation of Lactones
To a solution of esters 77–84 (1.80 mmol) in CH2Cl2 (180 mL),
under reflux and magnetic stirring, was added Grubbs’ first gener-
ation catalyst (10 mol %; 0.18 mmol). After 8.0 h under these con-
ditions, the reaction was allowed to cool to room temperature,
DMSO (50 equiv relative to the catalyst) was added and the mix-
ture was maintained under magnetic stirring overnight. After this
period, the solvent was removed under reduced pressure and the
residue was subjected to flash column chromatography (using
the eluent indicated) to afford the corresponding lactones 85–92.
4.1.9.5.
(E)-6-(3,4-Dimethoxystyryl)-5,6-dihydro-2H-pyran-2-
one (89).
Prepared according to the general procedure for
the preparation of lactones in 45% yield (yellow solid). Eluent: hex-
anes/ethyl acetate 1:1 v/v. Mp: 116.0–118.0 °C; IR (cmÀ1, thin
film): 3001, 2934, 2843, 1715, 1602, 1585, 1515, 1464, 1421,
1383, 1266, 1251, 1141, 1023, 968, 817; 1H NMR (500 MHz,
CDCl3): d 6.95–6.89 (m, 3H), 6.82 (d, J = 8.5 Hz, 1H), 6.64 (d,
J = 15.9 Hz, 1H), 6.13 (dd, J = 15.9 and 6.5 Hz, 1H), 6.07 (dt, J = 9.8
and 1.6 Hz, 1H), 5.10–5.04 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H),
2.57–2.50 (m, 2H); 13C NMR (62.5 MHz, CDCl3): d 163.7 (C0),
149.1 (C0), 148.8 (C0), 144.7 (CH), 132.7 (CH), 128.5 (C0), 123.4
(CH), 121.2 (CH), 119.9 (CH), 110.9 (CH), 108.7 (CH), 77.9 (CH),
55.6 (2 Â OCH3), 29.6 (CH2); HRMS (ESI+) m/z: Calcd for C15H17O4
[M+H+] 261.1127, found 261.1207.
4.1.9.1. (E)-6-(2-(Trifluoromethyl)styryl)-5,6-dihydro-2H-pyran-
2-one (85).
Prepared according to the general procedure for
the preparation of lactones in 70% yield (yellow oil). Eluent: hex-
anes/ethyl acetate 2:1 v/v. IR (cmÀ1, thin film): 3074, 2925, 1725,
1605, 1577, 1488, 1384, 1314, 1246, 1164, 1120, 1058, 1036,
968, 832, 815, 743; 1H NMR (500 MHz, CDCl3):
d 7.66 (d,
J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.40
(t, J = 7.8 Hz, 1H), 7.08 (d, J = 15.9 Hz, 1H), 6.94 (ddd, J = 9.7, 4.8
and 3.8 Hz, 1H), 6.28 (dd, J = 15.9 and 6.5 Hz, 1H), 6.11 (dt, J = 9.7
and 1.7 Hz, 1H), 5.17–5.12 (m, 1H), 2.60–2.56 (m, 2H); 13C NMR
(62.5 MHz, CDCl3): d 163.6 (C0), 144.5 (CH), 134.9 (q, J = 1.5 Hz,
C0), 132.0 (CH), 130.2 (CH), 129.2 (q, J = 1.6 Hz, CH), 128.0 (CH),
127.7 (q, J = 30.0 Hz, C0), 127.6 (CH), 125.8 (q, J = 5.7 Hz, CH),
124.1 (q, J = 273.7 Hz, C0), 121.6 (CH), 77.7 (CH), 29.6 (CH2); HRMS
(ESI+) m/z: Calcd for C14H12F3O2 [M+H+] 269.0789, found 269.0835.
4.1.9.6.
(E)-6-(3,5-Dimethoxystyryl)-5,6-dihydro-2H-pyran-2-
one (90).
Prepared according to the general procedure for
the preparation of lactones in 88% yield (yellow oil). Eluent: hex-
anes/ethyl acetate 1:1 v/v. IR (cmÀ1, thin film): 3002, 2940, 2840,
1721, 1661, 1592, 1459, 1428, 1383, 1246, 1205, 1154, 1060,
967, 818, 734; 1H NMR (500 MHz, CDCl3): d 6.91 (ddd, J = 9.7, 5.0
and 3.5 Hz, 1H), 6.64 (d, J = 15.8 Hz, 1H), 6.53 (d, J = 2.2 Hz, 2H),
6.39 (t, J = 2.2 Hz, 1H), 6.24 (dd, J = 15.9 and 6.3 Hz, 1H), 6.07 (dt,
J = 9.7 and 1.4 Hz, 1H), 5.11–5.05 (m, 1H), 3.79 (s, 6H), 2.58–2.47
(m, 2H); 13C NMR (62.5 MHz, CDCl3): d 163.4 (C0), 160.5 (2 Â C0),
144.8 (CH), 137.4 (C0), 132.4 (CH), 125.9 (CH), 120.8 (CH), 104.3
(2 Â CH), 100.0 (CH), 77.4 (CH), 54.8 (2 Â OCH3), 29.3 (CH2); HRMS
(ESI+) m/z: Calcd for C15H17O4 [M+H+] 261.1127, found 261.1112.
4.1.9.2. (E)-6-(4-(Trifluoromethyl)styryl)-5,6-dihydro-2H-pyran-
2-one (86).
Prepared according to the general procedure for
the preparation of lactones in 73% yield (yellow solid). Eluent: hex-
anes/ethyl acetate 2:1 v/v. Mp: 72.3–74.2 °C; IR (cmÀ1, thin
film): 2922, 1714, 1615, 1428, 1418, 1384, 1328, 1245, 1162,
1120, 1069, 1017, 971, 861, 814; 1H NMR (500 MHz, CDCl3): d
7.59 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 6.93 (ddd, J = 9.7,
5.3 and 3.2 Hz, 1H), 6.78 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 16.0 and
5.9 Hz, 1H), 6.11 (ddd, J = 9.7, 2.3 and 1.3 Hz, 1H), 5.16–5.11 (m,
1H), 2.63–2.50 (m, 2H); 13C NMR (62.5 MHz, CDCl3): d 163.6 (C0),
144.7 (CH), 139.3 (C0), 131.4 (CH), 130.0 (q, J = 32.3 Hz, C0), 128.3
(CH), 126.9 (2 Â CH), 125.6 (q, J = 3.8 Hz, 2 Â CH), 124.0 (q,
J = 271.9 Hz, C0), 121.5 (CH), 77.4 (CH), 29.7 (CH2); HRMS (ESI+)
m/z: Calcd for C14H12F3O2 [M+H+] 269.0789, found 269.0730.
4.1.9.7. (E)-6-(3,4,5-Trimethoxystyryl)-5,6-dihydro-2H-pyran-2-
one (91).
Prepared according to the general procedure for the
preparation of lactones in 70% yield (yellow solid). Eluent: hex-
anes/ethyl acetate 1:2 v/v. Mp: 117.6–119.0 °C; IR (cmÀ1, thin
film): 2940, 2840, 1721, 1658, 1583, 1508, 1463, 1455, 1421,
1244, 1125, 1018, 967, 817; 1H NMR (500 MHz, CDCl3): d 6.91
(ddd, J = 13.3, 4.9 and 3.5 Hz, 1H), 6.62 (d, J = 15.9 Hz, 1H), 6.64–
6.62 (m, 2H), 6.17 (dd, J = 15.9 and 6.3 Hz, 1H), 6.06 (dt, J = 9.8
and 1.5 Hz, 1H), 5.14–5.06 (m, 1H), 3.85 (s, 6H), 3.82 (s, 3H),
2.62–2.50 (m, 2H); 13C NMR (62.5 MHz, CDCl3): d 163.3 (C0),
152.8 (2 Â C0), 144.7 (CH), 137.8 (C0), 132.4 (CH), 131.0 (C0),
124.8 (CH), 120.7 (CH), 103.3 (2 Â CH), 77.4 (CH), 60.3 (OCH3),
55.5 (2 Â OCH3), 29.2 (CH2); HRMS (ESI+) m/z: Calcd for C16H19O5
[M+H+] 291.1233, found 291.1263.
4.1.9.3.
(87).
(E)-6-(4-Methoxystyryl)-5,6-dihydro-2H-pyran-2-one
Prepared according to the general procedure for the
preparation of lactones in 74% yield (white solid). Eluent: hex-
anes/ethyl acetate 1:1 v/v. Mp: 110.6–112.5 °C; IR (cmÀ1, thin
film): 3045, 2936, 2839, 1712, 1651, 1605, 1513, 1455, 1420,
1245, 1145, 1025, 968, 849, 809, 771; 1H NMR (500 MHz, CDCl3):
d 7.32 (d, J = 8.7 Hz, 2H), 6.90 (dt, J = 9.7 and 4.3 Hz, 1H), 6.85 (d,
J = 8.7 Hz, 2H), 6.64 (d, J = 15.9 Hz, 1H), 6.12 (dd, J = 15.9 and
6.6 Hz, 1H), 6.06 (dt, J = 9.7 and 1.8 Hz, 1H), 5.08–5.02 (m, 1H),

3648
R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
4.1.9.8. (E)-6-(2,4,5-Trimethoxystyryl)-5,6-dihydro-2H-pyran-2-
one (92). Prepared according to the general procedure for the
118.7 (CH2), 49.9 (CH), 39.0 (CH2); HRMS (ESI+) m/z: Calcd for
16H17F3NO [M+H+] 296.1262, found 296.1331.
C
preparation of lactones in 45% yield (yellow solid). Eluent: hex-
anes/ethyl acetate 1:1 v/v. Mp: 101.4–102.8 °C; IR (cmÀ1, thin
film): 2995, 2934, 2825, 1714, 1586, 1513, 1464, 1404, 1208,
1030, 873, 816; 1H NMR (250 MHz, CDCl3): d 7.00–6.86 (m, 3H),
6.49 (s, 1H), 6.18 (dd, J = 16.1 and 6.9 Hz, 1H), 6.07 (dt, J = 9.7
and 1.7 Hz, 1H), 5.13–5.02 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.82
(s, 3H), 2.58–2.50 (m, 2H); 13C NMR (62.5 MHz, CDCl3): d 163.9
(C0), 151.7 (C0), 150.0 (C0), 144.8 (CH), 143.1 (C0), 127.8 (CH),
123.7 (CH), 121.3 (CH), 116.1 (C0), 109.9 (CH), 97.2 (CH), 78.7
(CH), 56.3 (2 Â OCH3), 55.9 (OCH3), 29.8 (CH2) ; HRMS (ESI+) m/z:
Calcd for C16H19O5 [M+H+] 291.1233, found 291.1232.
4.1.10.3. (E)-N-(1-(4-(Trifluoromethyl)phenyl)hexa-1,5-dien-3-
yl)acrylamide (96). Prepared according to the general proce-
dure for the preparation of the amides in 50% yield (white solid).
Eluent: hexanes/ethyl acetate 2:1 v/v. Mp: 113.6–115.3 °C; IR
(cmÀ1, thin film): 3280, 3069, 2981, 2934, 1660, 1631, 1548,
1409, 1330, 1245, 1164, 1122, 1069, 958, 925, 811; 1H NMR
(250 MHz, CDCl3): d 7.54 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz,
2H), 6.55 (d, J = 16.1 Hz, 1H), 6.32 (dd, J = 17.0 and 1.6 Hz, 1H),
6.25 (dd, J = 16.1 and 6.5 Hz, 1H), 6.15 (dd, J = 17.0 and 10.0 Hz,
1H), 5.90–5.70 (m, 2H), 5.67 (dd, J = 10.0 and 1.6 Hz, 1H), 5.21–
5.10 (m, 2H), 4.84 (quint, J = 6.5 Hz, 1H), 2.46 (t, J = 6.5 Hz, 2H);
13C NMR (62.5 MHz, CDCl3): d 165.2 (C0), 140.1 (C0), 133.5 (CH),
131.9 (CH), 130.9 (CH), 129.3 (q, J = 32.7 Hz, C0), 129.2 (CH),
126.7 (CH2), 126.5 (2 Â CH), 125.4 (q, J = 3.8 Hz, 2 Â CH), 124.1
(q, J = 271.6 Hz, C0), 118.5 (CH2), 50.3 (CH), 39.2 (CH2); HRMS
(ESI+) m/z: Calcd for C16H17F3NO [M+H+] 296.1262, found
296.1364.
4.1.10. General Procedure for the Preparation of the Amides
To a stirred solution of lithium hexamethyldisilazide (1.2 equiv;
5.93 mmol) in anhydrous THF (20 mL), at 0 °C under nitrogen
atmosphere, was added a solution of the homologated aldehyde
61–68, 93 (4,94 mmol) in anhydrous THF (5 mL). After 15 min un-
der these conditions, a solution of allylmagnesium bromide in
diethyl ether (1.2 equiv; 5.93 mmol) was added dropwise and the
resulting solution was stirred at room temperature for 30 min.
After this period, a saturated aqueous solution of ammonium chlo-
ride (35 mL) was added and the layers were separated. The aque-
ous layer was extracted with CH2Cl2 (3 Â 15 mL) and the
combined organic layers were dried over anhydrous MgSO4, fil-
tered and concentrated under reduced pressure. The crude was dis-
solved in anhydrous CH2Cl2 (50 mL), triethylamine (2.0 equiv;
9.88 mmol) was added and the resulting solution was cooled to
0 °C. Acryloyl chloride (1.5 equiv; 7.41 mmol) was then added
dropwise and the reaction mixture was stirred for 1 h at room tem-
perature. After completion (indicated by TLC analysis), the volatiles
were removed under reduced pressure and the crude was purified
by flash column chromatography (using the eluent indicated), giv-
ing the corresponding amides 94–102.
4.1.10.4. (E)-N-(1-(4-Methoxyphenyl)hexa-1,5-dien-3-yl)acryl-
amide (97).
Prepared according to the general procedure for
the preparation of the amides in 84% yield (white solid). Eluent:
hexanes/ethyl acetate 2:1 v/v. Mp: 128.0–130.0 °C; IR (cmÀ1, thin
film): 3276, 3075, 3005, 2979, 2954, 2932, 2905, 2834, 1658,
1627, 1606, 1545, 1512, 1248, 1178, 1033, 971, 915, 803; 1H
NMR (250 MHz, CDCl3):
d 7.25 (d, J = 8.6 Hz, 2H), 6.81 (d,
J = 8.6 Hz, 2H), 6.46 (d, J = 15.9 Hz, 1H), 6.29 (dd, J = 16.9 and
1.9 Hz, 1H), 6.22–6.08 (m, 2H), 6.00 (dd, J = 15.9 and 6.2 Hz, 1H),
5.79 (dtd, J = 17.2, 10.2, 6.2 and 6.2 Hz, 1H), 5.61 (dd, J = 9.8 and
1.9 Hz, 1H), 5.18–5.04 (m, 2H), 4.78 (quint, J = 6.2 Hz, 1H), 3.77
(s, 3H), 2.42 (t, J = 6.2 Hz, 2H); 13C NMR (62.5 MHz, CDCl3): d
164.8 (C0), 159.1 (C0), 133.8 (CH), 130.9 (CH), 130.1 (CH), 129.3
(C0), 127.5 (2 Â CH), 126.7 (CH), 126.4 (CH2), 118.1 (CH2), 113.8
(2 Â CH), 55.2 (OCH3), 50.2 (CH), 39.4 (CH2); HRMS (ESI+) m/z:
Calcd for C16H20NO2 [M+H+] 258.1494, found 258.1542.
4.1.10.1. (E)-N-(1-Phenylhexa-1,5-dien-3-yl)acrylamide (94).
Prepared according to the general procedure for the preparation
of the amides in 85% yield (white solid). Eluent: hexanes/ethyl ace-
tate 1:2 v/v. Mp: 94.2–96.0 °C; IR (cmÀ1, thin film): 3277, 3079,
3028, 2979, 2927, 1657, 1627, 1553, 1406, 1250, 1070, 992, 967,
926, 745; 1H NMR (250 MHz, CDCl3): d 7.38–7.18 (m, 5H), 6.53
(d, J = 16.1 Hz, 1H), 6.31 (dd, J = 17.0 and 1.6 Hz, 1H), 6.22–6.08
(m, 2H), 5.93 (br s, 1H), 5.81 (dtd, J = 17.0, 10.0, 7.0 and 7.0 Hz,
1H), 5.65 (dd, J = 10.0 and 1.6 Hz, 1H), 5.20–5.08 (m, 2H), 4.90–
4.76 (m, 1H), 2.45 (t, J = 7.0 Hz, 2H); 13C NMR (62.5 MHz, CDCl3):
d 164.8 (C0), 136.5 (C0), 133.7 (CH), 130.9 (CH), 130.7 (CH), 128.9
(CH), 128.5 (2 Â CH), 127.6 (CH), 126.6 (CH2), 126.4 (2 Â CH),
118.4 (CH2), 50.1 (CH), 39.3 (CH2); HRMS (ESI+) m/z: Calcd for
4.1.10.5.
acrylamide (98).
for the preparation of the amides in 50% yield (yellow solid). Elu-
ent: hexanes/ethyl acetate 2:1 v/v. Mp: 79.1–81.0 °C; IR (cmÀ1
(E)-N-(1-(2,4-Dimethoxyphenyl)hexa-1,5-dien-3-yl)-
Prepared according to the general procedure
,
thin film): 3276, 3074, 3002, 2938, 2837, 1658, 1609, 1504, 1465,
1439, 1209, 1159, 1035, 972, 835; 1H NMR (250 MHz, CDCl3, d):
7.25 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 16.0 Hz, 1H), 6.45 (d, J = 8.4 Hz,
1H), 6.42–6.35 (m, 2H), 6.27 (dd, J = 17.0 and 2.6 Hz, 1H), 6.16
(dd, J = 17.0 and 9.2 Hz, 1H), 6.04 (dd, J = 16.0 and 7.0 Hz, 1H),
5.78 (dtd, J = 17.2, 10.2, 7.0 and 7.0 Hz, 1H), 5.55 (dd, J = 9.2 and
2.6 Hz, 1H), 5.13–5.00 (m, 2H), 4.83–4.68 (m, 1H), 3.74 (s, 3H),
3.73 (s, 3H), 2.40 (t, J = 7.0 Hz, 2H); 13C NMR (62.5 MHz, CDCl3): d
164.7 (C0), 160.2 (C0), 157.6 (C0), 134.0 (CH), 131.0 (CH), 127.4
(CH), 127.1 (CH), 126.0 (CH2), 125.1 (CH), 118.5 (C0), 117.7 (CH2),
104.6 (CH), 98.1 (CH), 55.2 (OCH3), 55.1 (OCH3), 50.7 (CH), 39.4
(CH2); HRMS (ESI+) m/z: Calcd for C17H22NO3 [M+H+] 288.1600,
found 288.1629.
C
15H18NO [M+H+] 228.1388, found 228.1422.
4.1.10.2. (E)-N-(1-(2-(Trifluoromethyl)phenyl)hexa-1,5-dien-3-
yl)acrylamide (95). Prepared according to the general proce-
dure for the preparation of the amides in 60% yield (yellow oil).
Eluent: hexanes/ethyl acetate 2:1 v/v. IR (cmÀ1, thin film): 3271,
3075, 2982, 2933, 1658, 1628, 1544, 1488, 1409, 1315, 1164,
1124, 1060, 1036, 966, 921, 765; 1H NMR (250 MHz, CDCl3): d
7.61 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.51–7.42 (m, 1H),
7.38–7.28 (m, 1H), 6.88 (d, J = 15.8 Hz, 1H), 6.31 (dd, J = 17.0 and
1.6 Hz, 1H), 6.22–6.07 (m, 2H), 5.90–5.70 (m, 2H), 5.67 (dd,
J = 10.0 and 1.6 Hz, 1H), 5.22–5.10 (m, 2H), 4.92–4.78 (m, 1H),
2.45 (t, J = 6.4 Hz, 2H); 13C NMR (62.5 MHz, CDCl3): d 164.9 (C0),
135.8 (C0), 133.5 (CH), 133.4 (CH), 131.8 (CH), 130.7 (CH), 127.6
(CH), 127.4 (q, J = 29.9 Hz, C0), 127.3 (CH), 126.7 (CH2), 126.5 (q,
J = 1.6 Hz, CH), 125.7 (q, J = 5.7 Hz, CH), 124.3 (q, J = 273.4 Hz, C0),
4.1.10.6.
yl)acrylamide (99).
(E)-N-(1-(3,4-Dimethoxyphenyl)hexa-1,5-dien-3-
Prepared according to the general proce-
dure for the preparation of the amides in 60% yield (yellow oil).
Eluent: hexanes/ethyl acetate 2:1 v/v. IR (cmÀ1, thin film): 3280,
3074, 3002, 2936, 2911, 2836, 1659, 1627, 1603, 1515, 1464,
1264, 1238, 1139, 1026, 965, 803; 1H NMR (250 MHz, CDCl3): d
7.14 (d, J = 8.5 Hz, 1H), 6.75–6.58 (m, 3H), 6.33 (d, J = 16.0 Hz,
1H), 6.22–6.16 (m, 2H), 5.90 (dd, J = 16.0 and 6.4 Hz, 1H), 5.77–
5.57 (m, 1H), 5.51–5.41 (m, 1H), 5.05–4.88 (m, 2H), 4.73–4.58
(m, 1H), 3.68 (s, 6H), 2.40 (t, J = 6.4 Hz, 2H); 13C NMR (62.5 MHz,

R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
3649
CDCl3): d 164.7 (C0), 148.5 (C0), 148.3 (C0), 133.7 (CH), 130.8 (CH),
4.1.11.1.
(E)-6-Styryl-5,6-dihydropyridin-2(1H)-one
(103).
130.0 (CH), 129.4 (C0), 126.8 (CH), 126.0 (CH2), 119.1 (CH), 117.5
(CH2), 110.8 (CH), 108.6 (CH), 55.4 (OCH3), 55.3 (OCH3), 50.2
(CH), 39.0 (CH2); HRMS (ESI+) m/z: Calcd for C17H22NO3 [M+H+]
288.1600, found 288.1629.
Prepared according to the general procedure for the preparation
of lactams in 82% yield (white solid). Eluent: hexanes/ethyl acetate
1:1, 1:2 v/v. Mp: 152.8–154.2 °C; IR (cmÀ1, thin film): 3211, 1676,
1610, 1415, 1327, 1275, 1126, 965, 816, 754; 1H NMR (250 MHz,
CDCl3): d 7.40–7.21 (m, 5H), 6.64–6.53 (m, 2H), 6.19 (dd, J = 15.8
and 7.3 Hz, 1H), 6.03 (br s, 1H), 5.95 (dd, J = 9.9 and 2.0 Hz, 1H),
4.36–4.24 (m, 1H), 2.54 (dt, J = 17.8 and 5.3 Hz, 1H), 2.36 (dddd,
J = 17.8, 9.5, 3.4 and 2.0 Hz, 1H); 13C NMR (62.5 MHz, CDCl3): d
166.2 (C0), 139.9 (CH), 135.9 (C0), 131.8 (CH), 128.5 (2 Â CH),
128.4 (CH), 127.9 (CH), 126.4 (2 Â CH), 124.4 (CH), 53.1 (CH),
30.2 (CH2); HRMS (ESI+) m/z: Calcd for C13H14NO [M+H+]
200.1075, found 200.1077.
4.1.10.7.
yl)acrylamide (100).
(E)-N-(1-(3,5-Dimethoxyphenyl)hexa-1,5-dien-3-
Prepared according to the general pro-
cedure for the preparation of the amides in 50% yield (yellow
oil). Eluent: hexanes/ethyl acetate 2:1 v/v. IR (cmÀ1, thin film):
3283, 3075, 3002, 2938, 2838, 1659, 1627, 1593, 1538, 1461,
1427, 1205, 1154, 1064, 967, 923, 828; 1H NMR (250 MHz, CDCl3):
d 6.67 (d, J = 8.5 Hz, 1H), 6.44 (d, J = 2.2 Hz, 2H), 6.39–6.18 (m, 4H),
6.10 (dd, J = 15.9 and 6.5 Hz, 1H), 5.75 (dtd, J = 17.1, 10.3, 6.5 and
6.5 Hz, 1H), 5.57 (dd, J = 8.9 and 2.9 Hz, 1H), 5.13–5.00 (m, 2H),
4.75 (quint, J = 6.5 Hz, 1H), 3.71 (s, 6H), 2.37 (t, J = 6.5 Hz, 2H);
13C NMR (62.5 MHz, CDCl3): d 164.8 (C0), 160.6 (2 Â C0), 138.5
(C0), 133.7 (CH), 130.8 (CH), 130.3 (CH), 129.4 (CH), 126.2 (CH2),
117.9 (CH2), 104.3 (2 Â CH), 99.6 (CH), 55.0 (2 Â OCH3), 50.1
(CH), 39.0 (CH2); HRMS (ESI+) m/z: Calcd for C17H22NO3 [M+H+]
288.1600, found 288.1629.
4.1.11.2. (E)-6-(2-(Trifluoromethyl)styryl)-5,6-dihydropyridin-
2(1H)-one (104).
Prepared according to the general proce-
dure for the preparation of lactams in 64% yield (white solid).
Eluent: hexanes/ethyl acetate 1:1, 1:2 v/v. Mp: 98.1–100.0 °C;
IR (cmÀ1, thin film): 3384, 3044, 1681, 1609, 1429, 1316, 1158,
1117, 1105, 1036, 967, 809, 766; 1H NMR (500 MHz, CDCl3): d
7.64 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.52 (t,
J = 7.8 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 6.97 (dd, J = 15.7 and
1.7 Hz, 1H), 6.63 (ddd, J = 10.0, 5.0 and 3.5 Hz, 1H), 6.18 (dd,
J = 15.7 and 7.7 Hz, 1H), 5.97 (dq, J = 10.0 and 2.0 Hz, 1H), 5.50
(br s, 1H), 4.39–4.33 (m, 1H), 2.59 (dt, J = 17.8 and 5.0 Hz, 1H),
2.41 (dddd, J = 17.8, 9.7, 3.5 and 2.0 Hz, 1H); 13C NMR
(62.5 MHz, CDCl3): d 166.0 (C0), 139.9 (CH), 135.1 (q, J = 1.6 Hz,
C0), 132.8 (CH), 131.9 (CH), 128.5 (q, J = 1.7 Hz, CH), 127.8 (CH),
127.6 (q, J = 30.0 Hz, C0), 127.6 (CH), 125.8 (q, J = 5.7 Hz, CH),
124.6 (CH), 124.2 (q, J = 274.0 Hz, C0), 53.5 (CH), 30.3 (CH2);
HRMS (ESI+) m/z: Calcd for C14H13F3NO [M+H+] 268.0949, found
268.1034.
4.1.10.8.
yl)acrylamide (101).
(E)-N-(1-(3,4,5-Trimethoxyphenyl)hexa-1,5-dien-3-
Prepared according to the general pro-
cedure for the preparation of the amides in 75% yield (yellow so-
lid). Eluent: hexanes/ethyl acetate 2:1 v/v. Mp: 104.2–106.0 °C;
IR (cmÀ1, thin film): 3284, 2938, 2839, 1658, 1627, 1583, 1508,
1420, 1240, 1127, 1004, 964, 920, 807; 1H NMR (250 MHz, CDCl3):
d 6.58–6.45 (m, 3H), 6.37 (d, J = 15.8 Hz, 1H), 6.30–6.09 (m, 2H),
6.00 (dd, J = 15.8 and 6.5 Hz, 1H), 5.73 (dtd, J = 17.2, 10.2, 6.5 and
6.5 Hz, 1H), 5.55 (dd, J = 9.0 and 2.8 Hz, 1H), 5.12–4.98 (m, 2H),
4.72 (quint, J = 6.5 Hz, 1H), 3.76 (s, 9H), 2.37 (t, J = 6.5 Hz, 2H);
13C NMR (62.5 MHz, CDCl3): d 164.7 (C0), 152.8 (2 Â C0), 137.3
(C0), 133.7 (CH), 132.2 (C0), 130.8 (CH), 130.2 (CH), 128.4 (CH),
126.0 (CH2), 117.6 (CH2), 103.1 (2 Â CH), 60.4 (OCH3), 55.6
(2 Â OCH3), 50.1 (CH), 38.9 (CH2); HRMS (ESI+) m/z: Calcd for
4.1.11.3. (E)-6-(4-(Trifluoromethyl)styryl)-5,6-dihydropyridin-
2(1H)-one (105).
Prepared according to the general proce-
18H24NO4 [M+H+] 318.1705, found 318.1799.
dure for the preparation of lactams in 60% yield (white solid). Elu-
ent: hexanes/ethyl acetate 1:1, 1:2 v/v. Mp: 129.6–131.0 °C; IR
(cmÀ1, thin film): 3218, 3053, 1681, 1611, 1415, 1324, 1172,
1117, 1067, 1016, 973, 818, 734; 1H NMR (500 MHz, CDCl3): d
7.59 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 6.65–6.60 (m, 2H),
6.30 (dd, J = 15.9 and 7.2 Hz, 1H), 5.98 (dq, J = 10.0 and 2.0 Hz,
1H), 5.53 (br s, 1H), 4.38–4.32 (m, 1H), 2.61 (dt, J = 17.8 and
5.3 Hz, 1H), 2.41 (dddd, J = 17.8, 9.3, 3.5 and 2.0 Hz, 1H); 13C
NMR (62.5 MHz, CDCl3): d 166.3 (C0), 139.8 (CH), 139.5 (C0),
131.3 (CH), 130.5 (CH), 129.8 (q, J = 32.4 Hz, C0), 126.7 (2 Â CH),
125.6 (q, J = 4.0 Hz, 2 Â CH), 124.6 (CH), 124.1 (q, J = 272.1 Hz,
C0), 53.0 (CH), 30.1 (CH2); HRMS (ESI+) m/z: Calcd for C14H13F3NO
[M+H+] 268.0949, found 268.1065.
C
4.1.10.9.
yl)acrylamide (102).
(E)-N-(1-(2,4,5-Trimethoxyphenyl)hexa-1,5-dien-3-
Prepared according to the general pro-
cedure for the preparation of the amides in 87% yield (yellow so-
lid). Eluent: hexanes/ethyl acetate 1:5 v/v. Mp: 103.0–105.0 °C;
IR (cmÀ1, thin film): 3259, 3070, 2999, 2956, 2935, 2836, 1655,
1627, 1514, 1463, 1210, 1063, 1044, 1031, 968, 869, 734; 1H
NMR (250 MHz, CDCl3): d 6.90 (s, 1H), 6.77 (d, J = 16.1 Hz, 1H),
6.46 (s, 1H), 6.29–5.97 (m, 3H), 5.91–5.70 (m, 2H), 5.61 (d,
J = 9.8 Hz, 1H), 5.18–5.03 (m, 2H), 4.87–4.72 (m, 1H), 3.86 (s, 3H),
3.85 (s, 3H), 3.78 (s, 3H), 2.50–2.39 (m, 2H); 13C NMR (62.5 MHz,
CDCl3): d 164.7 (C0), 151.4 (C0), 149.5 (C0), 143.2 (C0), 134.0 (CH),
130.9 (CH), 127.2 (CH), 126.3 (CH2), 125.0 (CH), 118.1 (CH2),
117.3 (C0), 110.0 (CH), 97.6 (CH), 56.5 (2 Â OCH3), 56.0 (OCH3),
50.5 (CH), 39.4 (CH2); HRMS (ESI+) m/z: Calcd for C18H24NO4
[M+H+] 318.1705, found 318.1635.
4.1.11.4. (E)-6-(4-Methoxystyryl)-5,6-dihydropyridin-2(1H)-one
(106).
Prepared according to the general procedure for the
preparation of lactams in 76% yield (white solid). Eluent: hex-
anes/ethyl acetate 1:2 v/v. Mp: 157.0–158.0 °C; IR (cmÀ1, thin
film): 3184, 2928, 2835, 1673, 1655, 1608, 1514, 1306, 1241,
1177, 1031, 969, 850, 822, 811; 1H NMR (500 MHz, CDCl3): d
7.29 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.60 (ddd, J = 9.9,
5.0 and 3.0 Hz, 1H), 6.51 (d, J = 15.8 Hz, 1H), 6.04 (dd, J = 15.8 and
7.4 Hz, 1H), 5.94 (dd, J = 9.9 and 1.4 Hz, 1H), 5.80 (br s, 1H),
4.30–4.23 (m, 1H), 3.80 (s, 3H), 2.51 (dt, J = 17.8 and 5.0 Hz, 1H),
2.35 (ddt, J = 17.8, 9.9 and 3.0 Hz, 1H); 13C NMR (62.5 MHz, CDCl3):
d 166.2 (C0), 159.4 (C0), 140.0 (CH), 131.3 (CH), 128.6 (C0), 127.6
(2 Â CH), 126.1 (CH), 124.3 (CH), 113.9 (2 Â CH), 55.1 (OCH3),
53.3 (CH), 30.4 (CH2); HRMS (ESI+) m/z: Calcd for C14H17NO2
[M+H+] 230.1181, found 230.1200.
4.1.11. General procedure for the preparation of lactams
To a solution of the amides 94–102 (1.52 mmol) in CH2Cl2
(152 mL), under reflux and magnetic stirring, was added second
generation Grubbs catalyst (2 mol %; 0.03 mmol). After 6.0 h un-
der these conditions, the reaction was allowed to cool to room
temperature, DMSO (50 equiv relative to the catalyst) was added
and the mixture was maintained overnight under magnetic stir-
ring. After this period, the solvent was removed under reduced
pressure and the residue was subjected to flash column chroma-
tography (using the eluent indicated) to afford the corresponding
lactams 103–111.

3650
R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
4.1.11.5. (E)-6-(2,4-Dimethoxystyryl)-5,6-dihydropyridin-2(1H)-
one (107). Prepared according to the general procedure for
the preparation of lactams in 64% yield (white solid). Eluent: hex-
anes/ethyl acetate 1:1, 1:5, 1:10 v/v. Mp: 165.6–166.7 °C; IR (cmÀ1
dure for the preparation of lactams in 60% yield white solid). Elu-
ent: hexanes/ethyl acetate 1:1, 1:5, 1:10 v/v. Mp: 136.8–138.6 °C;
IR (cmÀ1, thin film): 3238, 3001, 2938, 2835, 1673, 1608, 1513,
1464, 1440, 1208, 1125, 1031, 973, 813; 1H NMR (500 MHz,
CDCl3): d 6.91 (s, 1H), 6.83 (d, J = 15.9 Hz, 1H), 6.60 (ddd, J = 9.9,
5.0 and 3.0 Hz, 1H), 6.47 (s, 1H), 6.06 (dd, J = 15.9 and 7.7 Hz,
1H), 5.93 (dd, J = 9.9 and 1.1 Hz, 1H), 5.71 (br s, 1H), 4.31–4.24
(m, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 2.51 (dt, J = 17.7
and 5.0 Hz, 1H), 2.36 (ddt, J = 17.7, 10.3 and 3.0 Hz, 1H); 13C NMR
(62.5 MHz, CDCl3): d 166.0 (C0), 151.3 (C0), 149.7 (C0), 143.0 (C0),
140.0 (CH), 126.4 (CH), 126.2 (CH), 124.2 (CH), 116.3 (C0), 109.8
(CH), 97.3 (CH), 56.3 (OCH3), 56.2 (OCH3), 55.8 (OCH3), 53.8 (CH),
30.5 (CH2); HRMS (ESI+) m/z: Calcd for C16H20NO4 [M+H+]
290.1392, found 290.1404.
,
thin film): 3193, 3104, 3049, 2964, 2846, 1673, 1607, 1504, 1417,
1308, 1282, 1208, 1026, 975, 825, 813; 1H NMR (500 MHz, CDCl3):
d 7.30 (d, J = 8.5 Hz, 1H), 6.79 (d, J = 15.9 Hz, 1H), 6.60 (ddd, J = 9.8,
5.1 and 3.0 Hz, 1H), 6.46 (dd, J = 8.5 and 2.3 Hz, 1H), 6.42 (d,
J = 2.3 Hz, 1H), 6.08 (dd, J = 15.9 and 7.7 Hz, 1H), 5.93 (d,
J = 9.9 Hz, 1H), 5.64 (br s, 1H), 4.30–4.22 (m, 1H), 3.81 (s, 3H),
3.80 (s, 3H), 2.49 (dt, J = 17.8 and 5.1 Hz, 1H), 2.35 (ddt, J = 17.8,
10.5 and 3.0 Hz, 1H); 13C NMR (62.5 MHz, CDCl3): d 166.1 (C0),
160.8 (C0), 157.8 (C0), 140.2 (CH), 127.7 (CH), 126.8 (CH), 126.5
(CH), 124.3 (CH), 117.7 (C0), 104.8 (CH), 98.3 (CH), 55.3 (OCH3),
55.2 (OCH3), 54.1 (CH), 30.7 (CH2); HRMS (ESI+) m/z: Calcd for
C
15H18NO3 [M+H+] 260.1287, found 260.1298.
4.2. In vitro antiproliferative assay
4.1.11.6. (E)-6-(3,4-Dimethoxystyryl)-5,6-dihydropyridin-2(1H)-
one (108). Prepared according to the general procedure for
the preparation of lactams in 60% yield (white solid). Eluent: hex-
anes/ethyl acetate 1:1, 1:5, 1:10 v/v. Mp: 162.7–164.3 °C; IR (cmÀ1
4.2.1. Cell lines
Human tumor cell lines U251 (glioma), MCF-7 (breast), NCI-
H460 (lung, non-small cells), OVCAR-03 (ovarian), HT-29 (colon),
786-0 (kidney), and NCI-ADR/RES (ovarian expressing phenotype
multiple drugs resistance) were obtained from National Cancer
Institute at Frederick MA-USA.
,
thin film): 3187, 3045, 2929, 2846, 1674, 1609, 1517, 1417, 1265,
1141, 1017, 965, 822, 807; 1H NMR (500 MHz, CDCl3): d 6.92–
6.88 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.60 (ddd, J = 9.9, 4.9 and
3.0 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H), 6.05 (dd, J = 15.8 and 7.5 Hz,
1H), 5.94 (d, J = 9.9 Hz, 1H), 5.77 (br s, 1H), 4.31–4.24 (m, 1H),
3.89 (s, 3H), 3.87 (s, 3H), 2.54 (dt, J = 17.8 and 4.9 Hz, 1H), 2.37
(ddt, J = 17.8, 9.7 and 3.0 Hz, 1H); 13C NMR (62.5 MHz, CDCl3): d
166.1 (C0), 148.9 (C0), 148.8 (C0), 139.9 (CH), 131.5 (CH), 128.9
(C0), 126.3 (CH), 124.3 (CH), 119.6 (CH), 110.9 (CH), 108.7 (CH),
55.7 (OCH3), 55.6 (OCH3), 53.1 (CH), 30.3 (CH2); HRMS (ESI+) m/
z: Calcd for C15H18NO3 [M+H+] 260.1287, found 260.1298.
4.2.2. Cell culture
Stock cultures were grown in medium containing 5 mL RPMI
1640 (GIBCO BRL) supplemented with 5% fetal bovine serum
(FBS, GIBCO) at 37 °C with 5% CO2. Penicillin: streptomicyne
(1000 lg/L:1000 U/L, 1 mL/L) were added to the experimental
cultures.
4.2.3. Antiproliferative assay
Cells in 96 well plates (100 lL cells/well) were exposed to
4.1.11.7. (E)-6-(3,5-Dimethoxystyryl)-5,6-dihydropyridin-2(1H)-
goniothalamin and its analogues in concentrations 0.25, 2.5, 25
and 250 g/mL in DMSO (Merck)/RPMI at 37 °C, 5% of CO2 in air
for 48 h. Doxorubicin was used as positive control (0.025, 0.25,
2.5 and 25 g/mL). Final DMSO concentration did not affect cell
viability. Afterwards cells were fixed with 50% trichloroacetic acid
(Merck) and cell proliferation determined by spectrophotometric
quantification (540 nm) of cellular protein content using sulforho-
damine B assay.30a Using the concentration-response curve for
each cell line, the TGI (concentration that produces total growth
inhibition or cytostatic effect) were determined through non-linear
regression analysis (Table 1 and 2) using software ORIGIN 7.5Ò
(OriginLab Corporation).30b
one (109).
the preparation of lactams in 70% yield (white solid). Eluent: hex-
anes/ethyl acetate 1:1, 1:5, 1:10 v/v. Mp: 101.9–103.6 °C; IR (cmÀ1
Prepared according to the general procedure for
l
,
l
thin film): 3227, 2939, 2839, 1677, 1592, 1457, 1427, 1205, 1153,
1064, 969, 814; 1H NMR (250 MHz, CDCl3): d 6.60 (ddd, J = 9.9,
5.0 and 3.6 Hz, 1H), 6.61 (d, J = 2.2 Hz, 2H), 6.50 (d, J = 15.7 Hz,
1H), 6.38 (app t, J = 2.2 Hz, 1H), 6.16 (dd, J = 15.7 and 7.3 Hz, 1H),
5.95 (dd, J = 9.9 and 2.0 Hz, 1H), 5.81 (br s, 1H), 4.36–4.22 (m,
1H), 3.79 (s, 6H), 2.56 (dt, J = 17.7 and 5.0 Hz, 1H), 2.36 (dddd,
J = 17.7, 9.4, 3.6 and 2.0 Hz, 1H); 13C NMR (62.5 MHz, CDCl3,): d
166.1 (C0), 160.6 (2 Â C0), 139.8 (CH), 137.8 (C0), 131.5 (CH),
128.9 (CH), 124.3 (CH), 104.4 (2 Â CH), 100.0 (CH), 55.0 (2 Â OCH3),
52.8 (CH), 30.0 (CH2); HRMS (ESI+) m/z: Calcd for C15H18NO3
[M+H+] 260.1287, found 260.1298.
Acknowledgments
4.1.11.8.
2(1H)-one (110).
(E)-6-(3,4,5-Trimethoxystyryl)-5,6-dihydropyridin-
Prepared according to the general proce-
The authors thank FAPESP (10/16990–1 and 2009/51602–5),
CNPq and Capes for financial support and the National Cancer
Institute-Frederick, MA, USA for granting the human tumor cell
lines.
dure for the preparation of lactams in 97% yield (white solid). Elu-
ent: hexanes/ethyl acetate 1:1, 1:5, 1:10 v/v. Mp: 138.2–139.2 °C;
IR (cmÀ1, thin film): 3219, 3012, 2996, 2968, 2934, 2839, 1673,
1608, 1583, 1462, 1423, 1127, 1006, 971, 815, 736; 1H NMR
(500 MHz, CDCl3): d 6.64–6, 65 (m, 3H), 6.49 (d, J = 15.7 Hz, 1H),
6.10 (dd, J = 15.7 and 7.3 Hz, 1H), 5.95 (d, J = 9.9 Hz, 1H), 6.80 (br
s, 1H), 4.29 (q, J = 7.3 Hz, 1H), 3.86 (s, 6H), 3.83 (s, 3H), 2.56 (dt,
J = 17.8 and 5.4 Hz, 1H), 2.43–2.34 (m, 1H); 13C NMR (62.5 MHz,
CDCl3): d 166.0 (C0), 153.0 (2 Â C0), 139.7 (CH), 137.7 (C0), 131.5
(CH), 131.4 (C0), 127.8 (CH), 124.2 (CH), 103.4 (2 Â CH), 60.5
(OCH3), 55.8 (2 Â OCH3), 52.7 (CH), 30.0 (CH2); HRMS (ESI+) m/z:
Calcd for C16H20NO4 [M+H+] 290.1392, found 290.1408.
Supplementary data
Supplementary data (1H and 13C NMR spectra and concentra-
tion–response curve) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2012.03.059.
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2(1H)-one (111).
(E)-6-(2,4,5-Trimethoxystyryl)-5,6-dihydropyridin-
Prepared according to the general proce-

R. C. Barcelos et al. / Bioorg. Med. Chem. 20 (2012) 3635–3651
3651
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