Enantioselective syntheses of (R)- and (S)-argentilactone and their cytotoxic activities against cancer cell lines

Article abstract of DOI:10.1016/j.bmc.2004.07.044

Concise total syntheses of (R)- and (S)-argentilactone have been developed via enantioselective catalytic allylation (ECA) and ring-closing metathesis pathways. Both enantiomers were obtained in four steps and 39% overall yield and 82-84% ee from 2-octynal. In addition, we present the results of in vitro activity of (R)- and (S)-argentilactone against cancer cell line. Concise total syntheses of (R)- and (S)-argentilactone have been developed via enantioselective catalytic allylation (ECA) and ring-closing metathesis pathways (four steps, 39% overall yield and 82-84% ee) from 2-octynal and their in vitro activity against cancer cells is described.

Full text of DOI:10.1016/j.bmc.2004.07.044

Bioorganic & Medicinal Chemistry 12 (2004) 5437–5442
Enantioselective syntheses of (R)- and (S)-argentilactone
and their cytotoxic activities against cancer cell lines
a
Angelo de Fatima, Luciana Konecny Kohn, Marcia Aparecida Antonio,
b,c
b
^
´
ˆ
Joa˜o Ernesto de Carvalhob,c and Ronaldo Aloise Pillia,
*
a
´
Instituto de Quımica, Unicamp, CP 6154, 13084-971, Campinas, Sa˜o Paulo, Brazil
´
b
´ ´ ´
Centro Pluridisciplinar de Pesquisas Quımica, Biologicas e Agrıcolas, Unicamp, CP 6171, 13083-970, Paulınia, Sa˜o Paulo, Brazil
cInstituto de Biologia, Unicamp, CP 6109, 13084-971, Campinas, Sa˜o Paulo, Brazil
Received 18 June 2004; revised 15 July 2004; accepted 20 July 2004
Available online 11 September 2004
Abstract—Concise total syntheses of (R)- and (S)-argentilactone have been developed via enantioselective catalytic allylation (ECA)
and ring-closing metathesis pathways (four steps, 39% overall yield and 82–84% ee) from 2-octynal and their in vitro activity against
cancer cells is described.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
A (2)6,7 and spicigerolide (3),8 to induce the apoptotic
process such as goniothalamin (4)9–11 or to be an anti-
cancer agent such as fostriecin (5) (Fig. 1).12–15
Natural, synthetic or semi-synthetic compounds may be
used to block, reverse, or prevent the development of
invasive cancers.1,2 6-Substituted derivatives of 5,6-di-
hydro-a-pyrones such as pironetin (1)3–5 have been
found to inhibit the cell cycle progression in the M
phase, to exhibit cytotoxic activity such as callystatin
Argentilactone (6) (Fig. 1) is a natural compound
5,6-dihydro-2H-pyran-2-one moi-
that displays
a
ety and bears the (R)-configuration in its natural
form. It was isolated from Aristolochia argentina
O
OH
O
O
O
OMe OH
O
O
OAc OAc
O
OAc OAc
Callystatin A (2)
Pironetin (1)
Spicigerolide (3)
O
O
O
O
HO
OH OPO3HNa O
O
HO
Fostriecin (5)
Figure 1. Some examples of 6-substituted natural 5,6-dihydro-pyrones.
Goniothalamin (4)
Argentilactone (6)
Keywords: Argentilactone; Asymmetric synthesis; Cytotoxic activity; Cancer cell.
*
Corresponding author. Tel.: +55-1937883083; fax: +55-1937883023; e-mail: pilli@iqm.unicamp.br
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.07.044

^
5438
A. de Fatima et al. / Bioorg. Med. Chem. 12 (2004) 5437–5442
(Aristolochiaceae),16 Chorisia crispflora (Bombaceae)17
and Annona haematantha (Annonaceae).18 This natural
pyranone was shown to have in vitro antiprotozoa activ-
ity against Plasmodium falciparum (ED50 = 0.5lM),19
Leishmania panamensis (ED50 = 51.5lM),19, and
Leishmania amazonensis (ED50 = 51.5lM),18 as well as
cytotoxic activity against leukemia cells (P-388,
IC50 = 21.4lM).17
Enantioselective catalytic allylation (ECA) is one of the
fundamental powerful C–C bond-forming reactions that
has attracted considerable attention in asymmetric
synthesis.35 This work provides a full account of our
previously reported total synthesis of (R)-argentilactone
[(R)-6], in four steps and 39% overall yield and 82–84%
ee, featuring enantioselective catalytic allylation of 2-
octynal (8)36 and ring-closing metathesis as the key
steps.37 Moreover, we present for the first time the in
vitro biological activity of (S)-argentilactone [(S)-(6)]
against cancer cells and compare these results with
those exhibited by its enantiomer, (R)-argentilactone
[(R)-(6)].
A wide variety of biological functions that emerges
through molecular recognition requires strict matching
of chirality. Enzymes and receptors sites in biological
systems have the ability to distinguish between two
enantiomers compounds through differential binding
thus eliciting different biological response. The most
dramatic example reported is thalidomide, where one
enantiomer is a useful drug for prevention of morning
sickness, whereas its antipode is highly teratogenic.20
Inspired by the cytotoxic activity against P-388 leukemia
cells reported for natural (R)-argentilactone [(R)-(6)], we
decided to extend the evaluation of the cytotoxic activity
of (R)- and (S)-argentilactone [(R)- and (S)-(6)] to other
cancer cell lines. In order to successfully implement the
study proposed, it was mandatory to provide a short
and efficient access to chiral nonracemic argentilactone
(6). In spite of the biological activities exhibited by
(R)-argentilactone [(R)-(6)], the biological profile of its
enantiomer, (S)-argentilactone [(S)-6], still remains
unknown, particularly, regarding its antiproliferative
activity.
2. Results and discussion
2.1. Chemistry
Maruoka and co-workers have developed a new class of
highly reactive and selective titanium complexes for the
allylation of aldehydes38–40 featuring the l-oxo bis(bina-
phthoxy)(isopropoxy)-titanium complex [(R, R)-7] (Fig.
2), which displays excellent enantioselectivity and yield
for the addition of allyltributyltin to aldehydes.40 The
efficiency of this catalyst is proposed to be due to its
simultaneous coordination and double activation abil-
ity.
Several syntheses of (R)-argentilactone [(R)-(6)]21–27 and
its nonnatural enantiomer are reported.28,29 Usually, the
(R)-stereogenic center has been introduced from chiral
starting material21–24,26–28 or from asymmetric reduction
using enzymes.29 A noteworthy exception is the asymmet-
ric allylboration of aldehydes with B-allyldiisopinocam-
pheylborane developed by Brown and co-workers.30–32
While high yield and enantiomeric excess are generally
achieved, the use of a stoichiometric amount of the chiral
allylborane is not the more efficient solution for the
transfer of chirality. Catalytic asymmetric protocols are
certainly the more attractive alternative to chiral non-
racemic 6-substituted 5,6-dihydro-2H-pyran-2-ones.33,34
O
O
OiPr
Ti
O
O
O
Ti
iPrO
(R,R)-7
Figure 2. l-Oxo bis(binaphthoxy)(isopropoxy)titanium complex
(R,R)-7 developed by Maruoka and co-workers.40
Our approach (Scheme 1) to (R)-argentilactone [(R)-(6)]
centered on the enantioselective addition of allyltributyl-
OH
CHO
a
(R)-9
(8)
b
O
O
O
O
OH
c
d
(R)-Argentilactone (6)
(R)-11
(R)-10
Scheme 1. (a) (R)-BINOL (10mol%), Ti(OiPr)4 (15mol%), TiCl4 (5mol%), Ag2O (10mol%), allyltributyltin (1.1equiv), CH2Cl2, ꢀ20ꢁC, 24h (89%;
84% ee); (b) quinoline (2.0equiv), Lindlar catalyst (10mol%), EtOAc–1-octene (1:1) (74%); (c) acryloyl chloride (1.8equiv), Et3N (3.6equiv), CH2Cl2,
0ꢁC (86%); (d) Grubbsꢀ catalyst [(PCy3)2Cl2Ru@CHPh] (10mol%), CH2Cl2 (70%).

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A. de Fatima et al. / Bioorg. Med. Chem. 12 (2004) 5437–5442
5439
tin to 2-octynal (8) in CH2Cl2, which under the influence
100
75
A
of in situ generated chiral (R,R)-7 complex afforded 9 in
89% yield and 84% ee (see Section 4 for determination of
enantiomeric excess). Despite the recent developments in
the catalytic asymmetric allylation promoted by chiral
Lewis acids, no successful example with propargylic
aldehydes had been reported previously.35 The conver-
sion of propargylic alcohol 9 to (Z)-allylic alcohol 10
was accomplished by treatment of 9 with Lindlar cata-
lyst and quinoline, in the presence of 1-octene as a cosol-
vent (1:1 v/v of EtOAc–1-octene), and H2 (1atm) for
30min at room temperature, in 74% yield.41 The absence
of 1-octene in this step furnished a complex mixture of
byproducts, containing mostly the saturated alcohol
formed from reduction of allylic alcohol 10. Acylation
of 10 with acryloyl chloride provided ester 11 in 86%
yield after purification by chromatography on silica
gel. Finally, ring-closing metathesis of acrylate 11 took
50
25
0
UACC.62
MCF.7
-25
-50
-75
-100
NCI.460
OVCAR
PC0.3
HT.29
786-0
NCI.ADR
10-3
10-2
10-1
0.25
Concentration (µg/mL)
100
101
102
103
2.5
0
25
250
100
75
B
place with good yield under the catalysis of Grubbꢀs
50
42–44
ruthenium complex PhCH@RuCl2(PCy3)2
and did
25
not require the addition of Ti(OiPr)4, as in other
instances,45,46 to afford (R)-argentilactone [(R)-(6)] in
70% yield. In summary, (R)-argentilactone [(R)-(6)]
was efficiently obtained in 39% overall yield and 84%
ee from 2-octynal providing sufficient amounts for
biological evaluation. The same approach afforded
(S)-argentilactone [(S)-6] when (S,S)-7 was used as
catalyst in the catalytic asymmetric allylation step.
0
UACC.62
MCF.7
-25
-50
-75
-100
NCI.460
OVCAR
PC0.3
HT.29
786-0
NCI.ADR
10-3
10-2
10-1
0.25
Concentration (µg/mL)
100
101
102
103
2.5
0
25
250
2.2. Biological activities
Antiproliferative activity of (R)- and (S)-argentilactone
[(R)- and (S)-(6)] was evaluated in the following human
cancer cell lines: MCF-7 (breast), NCI-ADR(breast
expressing the multidrug resistance phenotype), NCI
460 (lung, nonsmall cells), UACC62 (melanoma),
786-0 (kidney), OVCAR03 (ovarian), PCO 3 (prostate),
and HT-29 (colon), which were grown in vitro (cell lines
were kindly provided by Frederick Cancer Research &
Development Center––National Cancer Institute––
Frederick, MA, USA). Chemotherapic doxorubicin
(DOX) was used as positive control.
Figure 3. Percent growth of cancer cells for 48h with different
concentrations of (R)- or (S)-argentilactone. A, (R)-argentilactone; B,
(S)-argentilactone. Positive values in relation to y axis correspond to
cytostatic activity while the others refer to cytotoxic activity of
compounds analyzed. Data were obtained from a representative
experiment carried out in triplicate.
Table 1. Comparison of antiproliferative activity of (R)- and
(S)-argentilactone against cancer cell linesa
Cell line
IC50 (lM)
(S)-(6)
Both enantiomers of argentilactone (6) displayed anti-
proliferative activity against the cancer cells tested in a
concentration-dependent way. At 0.25lg/mL, only (S)-
(6) inhibited the growing of the cells tested according
to the following increasing order: UACC62 (41%),
MCF-7 (51%), NCI 460 (60%), HT-29 (63%), PCO 3
(68%), NCI-ADR(78%), and OVCAR03 (85%) ( Fig.
3). On the other hand, at this concentration (S)-(6)
showed to be cytotoxic against 786–0 cell line reducing
in 34% the initial cell number after 48h of treatment.
In addition to this, (S)-(6) at 0.25lg/mL was more effi-
cient than doxorubicin (DOX) in inhibiting the growing
of all cell lines studied (data not shown).
(R)-(6)
Doxorubicinb
3.3
MCF-7
14.7
13.9
NCI-ADR11.0
NCI 460
UACC62
786–0
>100
48.7
14.3
55.0
73.6
33.8
29.0
42.3
17.9
17.8
48.5
25.3
30.4
1.8
9.8
>100
11.7
18.6
5.3
OVCAR03
PCO 3
HT-29
>100
a IC50 values (concentration that elicits 50% inhibition) were determi-
nated from nonlinear regression analysis by GraphPad Prism soft-
ware (r2 > 0.9).
b Doxorubicin (DOX) was employed as positive control.
It is noteworthy that, although both enantiomers [(R)-
and (S)-(6)] display roughly the same IC50 (lM) values
for MCF-7, NCI 460, and PCO 3, (R)-(6) was consider-
ably more potent toward NCI-ADRand ( S)-(6) for
UACC62 cancer cells (Table 1). Besides this, (R)-(6)
showed to be four times more powerful than reference
drug DOX on NCI-ADRcell line. In fact, both enanti-
omers of argentilactone (6) represent a promising car-
bon–carbon backbone for the development of drugs to
be used as chemotherapics.

^
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A. de Fatima et al. / Bioorg. Med. Chem. 12 (2004) 5437–5442
3. Conclusion
tin (1.37g, 4.16mmol). The whole mixture was allowed
to warm to 0ꢁC and stirred for 24h. The reaction mix-
ture was quenched with saturated NaHCO3 and ex-
tracted with ether. The organic extracts were dried
over MgSO4. Evaporation of solvents and purification
of this residue by column chromatography on silica
(hexane–ethyl acetate, 9:1) furnished (R)-1-undec-5-yn-
4-ol (9) in 89% yield (357mg). The enantiomeric purity
of both enantiomers of 9 was determined to be 82–
84% ee by chiral GC analysis (column: CP-Chiralsil-
DEX CB fused silica WCOT, 25m · 0.25mm · 0.25lm;
conditions––initial temperature/time: 60ꢁC/1min, rate:
0.5ꢁC/min, final temperature/time: 180ꢁC/70min, H2
as the carrier gas and FID detector) and comparing with
racemic standard. IR(film): 3356, 3078, 2956, 2933,
2860, 2227, 1641, 1462, 1433, 1379, 1331, 1144, 1036,
The approach presented here for the synthesis of both
enantiomers of argentilactone (6) represents a short
route to these pyranones amenable to provide these
compounds in sufficient amounts for biological assays.
Both enantiomers displayed antiproliferative activity
against the cancer cell lines tested. For MCF-7 (breast),
NCI 460 (lung, nonsmall cells), and PCO 3 (prostate)
cell lines, similar potency was observed for (R)- and
(S)-(6). The natural form of argentilactone [(R)-(6)]
proved to be more potent for breast cancer cells that ex-
press multidrug resistance phenotype (NCI-ADR),
whereas melanoma cells (UACC62) were more sensitive
to (S)-(6).
The versatility of our synthetic route allows its applica-
tion to the preparation of both enantiomers of argenti-
lactone analogues to be screened against cancer cell
lines in order to improve their antiproliferative activity.
995, 914cmꢀ1 1H NMR(300MHz, CDCl 3): d 5.96–
.
5.82 (m, 1 H), 5.21–5.15 (m, 2 H), 4.44–4.37 (m, 1 H),
2.45 (t, 2 H, J = 6.6Hz), 2.21 (dt, 2 H, J = 7.1 e
1.8Hz), 1.96 (d, 1 H, J = 5.9Hz), 1.53–1.30 (m, 6 H),
0.92–0.88 (m, 3 H). 13C NMR(75MHz, CDCl 3): d
133.2, 118.5, 85.9, 80.5, 61.8, 42.6, 31.0, 28.4, 22.2,
18.7, 14.0. HRMS (EI) m/z calculated for
4. Experimental section
4.1. Chemistry
M+Å = 166.13576; found: 166.13148. For (R)-9
25
D
for the use of (S)-BINOL instead of (R)-BINOL, af-
½aŠ þ 30:0 (c 2.0, CHCl3). The same procedure except
25
4.1.1. General procedures. Reagents and solvents are
commercial grade and were used as supplied, except
for dichloromethane and triethylamine that were dis-
tilled from calcium hydride. Chromatographic separa-
tions were performed using 70–230 mesh silica gel.
Thin layer chromatography was carried out on Mache-
rey–Nagel precoated silica plates (0.25mm layer thick-
ness). IRspectra were obtained on Nicolet Impact 410
FT (film or KBr). 1H NMRand 13C NMRdata were re-
corded on a Varian Gemini 2000 (7.0T) or Varian Inova
(11.7T) spectrometer. Chemical shifts are reported in d
forded (S)-(9). For (S)-9 ½aŠ ꢀ 30:0 (c 2.0, CHCl3).
D
4.1.3. Preparation of (4R,5Z)- and (4S,5Z)-1, 5-undeca-
dien-4-ol (10). To a stirred solution of (R)-1-undec-5-yn-
4-ol (9) (150mg, 0.89mmol) in a (1:1, v/v) mixture of
EtOAc and 1-octene at room temperature and 1atm
H2 was added quinoline (210lL, 1,78mmol) and Lind-
lar catalyst (191mg, 0.09mmol). The mixture was stirred
for 30min and after TLC indicated only a trace amount
of starting material, the mixture was filtered through a
pad of Celite using EtOAc as eluent, and then dried over
MgSO4. Evaporation of solvents and purification of this
residue by column chromatography on silica (hexane–
ethyl acetate, 9:1) furnished (4R, 5Z)-1,5-undecadien-
4-ol (10) in 74% yield (113mg). IR(film): 3350, 3076,
3006, 2956, 2925, 2856, 1641, 1466, 1030, 912,
1
[ppm relative to (CH3)4Si] for H and CDCl3 for 13C
1
NMR. For H NMR, the chemical shifts were followed
by multiplicity (s, singlet; d, doublet; dd, double dou-
blet; ddd, double double doublet; t, triplet; q, quartet;
m, multiplet) and coupling constant J reported in hertz
(Hz). High resolution mass spectra (HRMS) were meas-
ured on a VG Autospec-Micromass spectrometer.
Chiral GC analyses were performed with capillary
column CP-Chirasil-DEX CB fused silica WCOT
(25m · 0.25mm · 0.25lm) on Agilent 6890 series GC
system. Optical rotations were measured at 25ꢁC with
Perkin-Elmer 241 instrument.
748cmꢀ1 1H NMR(300MHz, CDCl 3): d 5.89–5.75
.
(m, 1 H), 5.55–5.36 (m, 2 H), 5.18–5.11 (m, 2 H), 4.49
(q, 1 H, J = 6.8Hz), 2.32–2.27 (m, 2 H); 2.15–2.02 (m,
2 H), 1.66–1.61 (m, 1 H), 1.42–1.29 (m, 6 H), 0.90 (t, 1
H, J = 6.8Hz). 13C NMR(75MHz, CDCl ): d 134.1,
3
132.5, 131.4, 117.9, 66.8, 42.2, 31.5, 29.4, 27.8, 22.6,
14.1. HRMS (EI) m/z calculated for M+Å = 168.15141;
25
D
The same procedure except for the use of (S)-1-undec-5-
found: 168.15560. For (R)-10 ½aŠ þ 25:9 (c 1.5, CHCl3).
4.1.2. Preparation of (R)- and (S)-1-undec-5-yn-4-ol (9).
To a stirred solution of TiCl4 (13lL, 0.12mmol) in
CH2Cl2 (2.4mL) was added dried Ti(OiPr)4 (110lL,
0.36mmol) at 0ꢁC under argon. The solution was al-
lowed to warm to room temperature. After 1h, silver(I)
oxide (56mg, 0.24mmol), recently prepared,47 was
added at room temperature, and the whole mixture
was stirred 5h under exclusion of direct light. The mix-
ture was diluted with CH2Cl2 (4mL) and treated with
(R)-BINOL (138mg, 0.48mmol) at room temperature
for 2h to furnish chiral bis-Ti(IV) oxide (R,R)-7. After
cooling this mixture to ꢀ15ꢁC, it was treated sequential-
ly with 2-octynal (300mg, 2.41mmol) and allyltributyl-
yn-4-ol (9) instead of (R)-1-undec-5-yn-4-ol (9), afforded
25
D
(S)-(10). For (S)-10 ½aŠ ꢀ 26:0 (c 1.5, CHCl3).
4.1.4. Preparation of (4R,5Z)- and (4S,5Z)-1,5-undeca-
dien-4-yl propenoate (11). To (4R, 5Z)-1, 5-undecadien-
4-ol (10) (110mg, 0.65mmol) dissolved in CH2Cl2
(15mL) and cooled to 0ꢁC, were added acryloyl chloride
(950lL, 1.17mmol) and Et3N (330lL, 2.34mmol). The
mixture was warmed to room temperature and stirred
for 2h. The resulting mixture was filtered through a
short pad of Celite to remove solid Et3NÆHCl, poured
into water, and the product was extracted with CH2Cl2.

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A. de Fatima et al. / Bioorg. Med. Chem. 12 (2004) 5437–5442
5441
Evaporation of solvents and purification of this residue
by column chromatography on silica (hexane–ethyl ace-
tate, 9:1) furnished (4R, 5Z)-1,5-undecadien-4-yl pro-
penoate (11) in 86% yield (125mg). IR(film): 3080,
3014, 2958, 2927, 2858, 1726, 1637, 1404, 1267, 1190,
serum. Gentamicine (50lg/mL) was added to the exper-
imental cultures. Cells in 96 well plates (100lL cells/
well) were exposed to various concentrations of samples
in DMSO (0.25, 2.5, 25, and 250lg/mL) at 37ꢁC, 5% of
CO2 in air for 48h. The final concentration of DMSO
did not affect the cell viability. Then, a 50% of trichloro-
acetic acid solution was added and after incubation for
30min at 4ꢁC, washing, and drying, the cell prolifera-
tion was determined by spectrophotometric quantifica-
tion (540nm) of the cellular protein content using
sulforhodamine B assay described by Skehan et al.48
1043, 984, 808cmꢀ1 1H NMR(300MHz, CDCl 3): d
.
6.39 (dd, 1 H, J = 17.2, 1.5Hz), 6.10 (dd, 1 H,
J = 17.2, 10.2Hz), 5.80 (dd, 1 H, J = 10.2, 1.5Hz),
5.80–5.54 (m, 2 H), 5.40–5.33 (m, 1 H), 5.14–5.06 (m,
2 H), 2.50–2.31 (m, 2 H), 2.19–2.09 (m, 2 H), 1.39–
1.26 (m, 6 H), 0.93–0.87 (m, 3 H). 13C NMR(75MHz,
CDCl3): d 165.1, 134.5, 133.0, 130.2, 128.7, 127.0,
117.7, 69.7, 39.4, 31.5, 29.2, 27.9, 22.6, 14.1. HRMS
(EI) m/z calculated for M+Å = 222.16198; found:
Acknowledgements
25
D
222.16354. For (R)-11, ½aŠ ꢀ 32:7 (c 1.0, CHCl3).
The authors would like to thank FAPESP (Fundac¸a˜o de
Amparo a Pesquisa no Estado de Sa˜o Paulo) for finan-
cial support and fellowship (A.F.) and CNPq (Conselho
The same procedure except for the use of (4S,5Z)-1,
5-undecadien-4-ol (10) instead of (4R, 5Z)-1,5-undecadi-
en-4-ol (10), afforded (4S, 5Z)-1,5-undecadien-4-yl pro-
25
´
Nacional de Desenvolvimento Cientıfico e Tecnologico)
for fellowship (R.A.P.). We are grateful to Luzia Valen-
´
penoate (11). For (4S, 5Z)-11 ½aŠ þ 33:0 (c 1.0, CHCl3).
D
´
tina Modolo (Depto. Bioquımica, Instituto de Biologia,
4.1.5. Preparation of (R)- and (S)-argentilactone (6). To a
stirred solution of bis(tricyclohexylphosphine)benzyl-
idine ruthenium(IV) dichloride (Grubbꢀs catalyst,
22mg, 10mol%) in CH2Cl2 (7mL) at 55–60ꢁC was
added (4R, 5Z)-1,5-undecadien-4-yl propenoate (11)
(60mg, 0.27 mmol) dissolved in CH2Cl2 (27mL).The
resulting mixture was heated for 4h. After this period,
the mixture was cooled at room temperature and evap-
orated under reduced pressure, and purification of this
residue by column chromatography on silica (hexane–
ethyl acetate, 9:2) furnished (R)-argentilactone in 70%
yield (37mg). IR(film): 3020, 2956, 2927, 2858, 1722,
Unicamp, Campinas/SP, Brazil) for the critical reading
of the manuscript. Professor Timothy J. Brocksom
(UFSCar) for optical rotation measurements.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmc.2004.07.044. This consists of spectra of com-
pounds 6, 9, 10, and 11.
1466, 1381, 1244, 1149, 1055, 1022, 816cmꢀ1 1H
.
References and notes
NMR(300MHz, CDCl 3): d 6.90 (ddd, 1 H, J = 9.7,
5.5, 3.1Hz), 6.05 (ddd, 1 H, J = 9.7, 2.2, 1.4Hz), 5.71–
5.52 (m, 2 H), 5.22 (ddd, 1 H, J = 10.2, 8.4, 4.9Hz),
2.49–2.30 (m, 2 H), 2.17–2.03 (m, 2 H), 1.46–1.26 (m,
6 H), 0.90 (t, 3 H, J = 7.0Hz). 13C NMR(75MHz,
CDCl3): d 163.9, 144.6, 135.5, 126.3, 121.5, 73.9, 31.5,
29.9, 29.1, 27.8, 22.5, 14.1. HRMS (EI) m/z calculated
for M+Å = 194.13068; found: 194.12733. For natural
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