Synthesis of photosynthesis-inhibiting nostoclide analogues

Article abstract of DOI:10.1021/jf072964g

A series of 34 3-benzyl-5-(arylmethylene)furan-2(5H)-ones, designed using the naturally occurring toxins nostoclides as a lead structure, was synthesized as potential inhibitors of the photosynthetic electron transport. All compounds were fully characterized by IR, NMR (¹H and ¹³C), and MS spectrometry. HMBC and HSQC bidimensional experiments allowed ¹³C and ¹H assignments. Their biological activities were evaluated in vitro as the ability to interfere with light-driven reduction of ferricyanide by isolated spinach chloroplasts. About two-thirds of the compounds exhibited inhibitory properties in the micromolar range against the basal electron flow from water to K₃[Fe(CN)₆]. The inhibitory potential of these 3-benzyl-5-(arylmethylene)furan-2(5H)-one lactones is higher than that of other nostoclide analogues previously synthesized in the same laboratories.

Full text of DOI:10.1021/jf072964g

J. Agric. Food Chem. 2008, 56, 2321–2329 2321
Synthesis of Photosynthesis-Inhibiting Nostoclide
Analogues
RÓBSON R. TEIXEIRA,§,† LUIZ C. A. BARBOSA,*,§ GIUSEPPE FORLANI,‡
#
DORILA PILÓ-VELOSO,§ AND JOSÉ WALKIMAR DE MESQUITA CARNEIRO
Department of Chemistry, Federal University of Viçosa, Avenida P. H. Rolfs, CEP 36570-000,
Viçosa, MG, Brazil; Department of Chemistry, Federal University of Minas Gerais, Avenida Antônio
Carlos, 6627, CEP 31270-9001, Belo Horizonte, MG, Brazil; Department of Biology and Evolution,
University of Ferrara, via L. Borsari 46, I-44100 Ferrara, Italy; and Inorganic Chemistry Department,
Chemistry Institute, Federal University Fluminense, Outeiro de São João Batista s/n, Centro,
CEP 24020-150, Niterói, RJ, Brazil
A series of 34 3-benzyl-5-(arylmethylene)furan-2(5H)-ones, designed using the naturally occurring
toxins nostoclides as a lead structure, was synthesized as potential inhibitors of the photosynthetic
electron transport. All compounds were fully characterized by IR, NMR (1H and 13C), and MS
spectrometry. HMBC and HSQC bidimensional experiments allowed 13C and 1H assignments. Their
biological activities were evaluated in vitro as the ability to interfere with light-driven reduction of
ferricyanide by isolated spinach chloroplasts. About two-thirds of the compounds exhibited inhibitory
properties in the micromolar range against the basal electron flow from water to K3[Fe(CN)6]. The
inhibitory potential of these 3-benzyl-5-(arylmethylene)furan-2(5H)-one lactones is higher than that
of other nostoclide analogues previously synthesized in the same laboratories.
KEYWORDS: Herbicides; nostoclide analogues; photosynthetic electron transport inhibitors
INTRODUCTION
mammals, high specificity, low application rates, and fast
soilborne microorganism degradation are thus important char-
acteristics in the development of new herbicides.
In modern agriculture, farmers continually face a battle to
achieve high yields and quality products to feed an ever-
increasing world population. The optimization of agriculture
efficiency demands, along with other requirements, the applica-
tion of crop protection agents to control a variety of diseases
and pests, among which are weeds (1). The use of herbicides
has become the most reliable and least expensive tool for weed
control throughout the world. Since the introduction of 2,4-
dichlorophenoxyacetic acid in 1946 by a British research team
at the Rothamsted Experimental Station, agrochemical compa-
nies have developed and commercialized a plethora of
herbicides (2, 3). Although important advances have been
achieved in the chemical control of weeds, the identification of
novel herbicides is highly desirable to overcome weed resistance,
rapidly raised as a consequence of the severe selective pressure
imposed by the continuous application of products with the same
biochemical mechanism of action (4–6). Moreover, increasing
public concern with regard to environmental pollution deriving
from agricultural practice strictly requires that phytochemicals
would be endowed with low recalcitrance, and thus may be
rapidly mineralized by the soil microflora. Low toxicity to
Nowadays, strategies utilized to identify new chemical agents
for weed control can no longer be distinguished from pharma-
ceutical research and development (7). Three different ap-
proaches are employed. The first one refers to the systematic
screening of large numbers of synthetic compounds. Subse-
quently, lead compounds are optimized. This has been the most
widely used strategy by agrochemical companies (8). The second
one is the rational design of specific inhibitors of key metabolic
processes (9). However, to date such an approach has not been
fully successful. A third strategy is associated with the exploita-
tion of natural products as herbicides or as leads for new
herbicides (10–14). Even though the enormous variety of natural
products has been relatively little explored, several active
principles were discovered in this way (Figure 1). Bialaphos,
originally isolated from various Streptomyces strains, is currently
commercialized in Japan with the name Herbiace (15). Lep-
tospermone, a major component of the essential oil of Lep-
tospermum scoparium (16), was chemically modified to make
mesotrione (17). Mesotrione is the active ingredient of the
commercial herbicide Callisto, which is commercialized by
Syngenta and suitable for use in corn fields. Another example
is sulcotrione, a herbicide marketed in Europe by Bayer
CropScience under the tradename Mikado (18). Sulcotrione is
utilized to control a broad range of annual and perennial
broadleaf weeds in maize and sugar cane. The commercial
* Author to whom correspondence should be addressed [fax (55)
31 3899 3065; e-mail lcab@ufv.br].
§ Federal University of Viçosa.
† Federal University of Minas Gerais.
‡ University of Ferrara.
# Federal University Fluminense.
10.1021/jf072964g CCC: $40.75  2008 American Chemical Society
Published on Web 03/14/2008

2322 J. Agric. Food Chem., Vol. 56, No. 7, 2008
Teixeira et al.
MATERIALS AND METHODS
General Experimental Procedures. All reactions were carried out
under a protective atmosphere of dry nitrogen or utilizing a calcium chloride
tube. Dichloromethane, tetrahydrofuran (THF), diethyl ether, and amines
were purified as described by Perrin and Armarego (39). Commercially
available tert-butyldimethylsilyltrifluoromethanesulfonate (TBDMSOTf),
diisopropylethylamine (DIPEA), 8-diazabyciclo[5.4.0]undec-7-ene (DBU),
and phosphoryl chloride (POCl3) were purchased from Aldrich
(Milwaukee, WI) and utilized without further purification. The com-
pounds 3-bromobenzaldehyde, 4-methylbenzaldehyde, and 2,5-dimethox-
ybenzaldehyde were prepared from the corresponding commercially
available (Aldrich) benzylic alcohols by Swern oxidation (40). The
compound 3-(N,N-dimethylamino)benzaldehyde was prepared via
reduction of the commercially available 3-(N,N-dimethylamino)benzoic
acid with lithium aluminum hydride (LiAlH4), followed by Swern
oxidation of the produced 3-(N,N-dimethylamino)benzylic alcohol.
Other aldehydes were purchased from Aldrich and utilized without
further purification. The preparation of the silyl enol ethers from
2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzalde-
hyde, and 4-hydroxy-3-methoxybenzaldehyde was carried out by
methodology previously described (41). Lactone 3 was synthesized in
43% yield, from furfural, by employing the methodology described by
Näsman (42). Lactone 5 was prepared in 67% yield according to a
procedure described in the literature (43). Commercially available
n-butyllithium hexane solutions (1.4 mol L-1) were titrated prior to
Figure 1. Examples of commercial herbicides developed from natural
templates.
1
use (44). The H and 13C NMR spectra were recorded on a Brucker
AVANCE DRX 400 spectrometer at 400 and 100 MHz using CDCl3
as solvent and TMS as internal standard, unless otherwise stated. Mass
spectra were recorded on a Shimadzu GCMS-QP5050A instrument by
direct insertion, EI mode (70 eV). Infrared spectra were recorded on a
Perkin-Elmer Paragon 1000 FTIR spectrophotometer, using potassium
bromide (1% w/w) disks, scanning from 635 to 4000 cm-1. Melting
points are uncorrected and were obtained from an MQAPF-301 melting
point apparatus (Microquimica, Brazil). Analytical thin layer chroma-
tography analysis was conducted on aluminum-packed precoated silica
gel plates. Column chromatography was performed over silica gel
(60–230 mesh).
Syntheses. (5Z)-3-Benzyl-5-benzylidenefuran-2(5H)-one (6). To a
two-neck round-bottom flask under nitrogen atmosphere were added
3-benzylfuran-2(5H)-one 5 (106 mg, 0.61 mmol), dichloromethane (3
mL), TBDMSOTf (170 µL, 0.74 mmol), DIPEA (310 µL, 1.2 mmol),
and benzaldehyde (75 µL, 1.2 mmol). The resulting mixture was stirred
at room temperature over 1 h. After DBU (120 µL, 1.22 mmol) was
added, the reaction mixture was refluxed for an additional 3 h before
the addition of dichloromethane (70 mL). The resulting organic layer
was washed with 3 mol L-1 HCl aqueous solution (2 × 25 mL) and
brine (25 mL). After separation, the organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure. The resulting
material was purified by column chromatography on silica gel eluted
with hexane/diethyl ether (10:1 v/v). The procedure described afforded
compound 6 in 62% yield (99 mg, 0.38 mmol).
Figure 2. Structures of nostoclides (R ) Cl, nostoclide I; R ) H,
nostoclide II) and cyanobacterin.
herbicide cinmethylin (19, 20) is a 2-benzyl ether derivative of
the natural product 1,4-cineole that was developed to control
annual grasses.
On the other hand, an increasing number of other natural
products have been described in the literature as potential leads
for the development of chemical agents for weed control, among
which are coumarins, benzoquinones, flavonoids, terpenoids, and
lactones, which might be involved in allelopathic effects with
a low efficiency, in contrast with commercial herbicides (21–23).
One example of naturally occurring lactones that could be
considered attractive as model compounds are the nostoclides
(1) (Figure 2). They are produced by a cyanobacterium (Nostoc
sp.), which can live free or in symbiosis, for instance, in the
lichen Peltigera canina (24), and belong to a family of
compounds known as γ-alkylidenebutenolides (25–27). The
nostoclides resemble cyanobacterin (2), a lactone isolated from
the blue-green alga Scytonema hofmanni (28). Compound 2 is
toxic to most cyanobacteria at a concentration as low as 5 µM
and also inhibits the growth of several eukaryotic algae and
mono- and dicotyledonous angiosperms (29, 30). Cyanobacterin
acts by inhibiting the photosynthetic electron transport, leading
to a series of events that result in the disruption of the thylakoid
membrane (31, 32). On the contrary, the biological activity of
nostoclides 1 has not been fully investigated, yet. Nostoclides
I and II have shown moderate cytotoxicity against the mouse
neuroblastoma cell lines Neuro-2a CCL and KB CCL 17. Owing
to the structural similarity of 1 and 2 (both compounds present
a 3-benzyl-5-arylmethylene-4-isopropyldihydrofuran-2-one ring)
and the fact that P. canina cultures are usually not contaminated
with microorganisms, it has been suggested that these chlori-
nated compounds may be allelopathic agents (31).
Compounds 7-35 were prepared by employing a procedure similar
to that described for compound 6, and yields are presented in Table 1.
The synthesized compounds were fully characterized by IR, NMR (1H
and 13C), and MS spectrometry. HMBC and HSQC bidimensional
experiments allowed the 13C and 1H assignments. Structural charac-
terization of compounds 6-8, 11, 13, 21, and 36–38 was already
described (37, 38, 45, 46). The preparation of compounds 36–39 was
carried out as previously reported (46). Structures for the remaining
compounds are supported by the following spectroscopic data.
Data for (5Z)-3-Benzyl-5-[4-(N,N-dimethylamino)benzylidene]furan-
2(5H)-one (9): yellow solid; mp 136.8–137.3 °C; purified by column
chromatography, eluent dichloromethane/hexane (2:1 v/v); IR (KBr,
cm-1), νjmax 3094, 3026, 2915, 2884, 1732, 1642, 1607, 1588, 1524,
1365, 1186, 1037, 813, 699, 641, 523; 1H NMR (400 MHz, CDCl3), δ
3.01 (s, 6H, N(CH3)2), 3.70 (s, 2H, H7), 5.80 (s, 1H, H6), 6.79 (br d,
2H, H3′′/H5′′), 6.91 (s, 1H, H4), 7.25–7.35 (m, 5H, Ph), 7.65 (d, 2H,
H2′′/H6′′, J ) 8.8 Hz); 13C NMR (100 MHz, CDCl3), δ 31.61 (C7);
40.29 (N(CH3)2), 112.24 (C6), 113.80 (C3′′/C5′′), 121.67 (C1′′), 126.75
(C4′), 128.76 (C3′/C5′), 128.92 (C2′/C6′), 129.46 (C3), 132.15 (C2′′/
Aspartofourongoingeffortstodevelopnewherbicides(33–36),
we decided to investigate the potential phytotoxicity of new
nostoclide analogues (37, 38). In this paper, we describe the
preparation of 34 3-benzyl-5-(arylmethylene)furan-2(5H)-ones.
Their ability to inhibit the Hill reaction in isolated spinach
chloroplasts was also assessed.

Photosynthesis-Inhibiting Nostoclide Analogues
J. Agric. Food Chem., Vol. 56, No. 7, 2008 2323
Table 1. Yields Obtained in the Preparation of Compounds 6–39
Data for (5Z)-3-Benzyl-5-(4-methylbenzylidene)furan-2(5H)-one
(14): white solid; mp 111.8–112.3 °C; purified by column chromatog-
raphy, eluent hexane/dicloromethane (2:1 v/v); IR (KBr, cm-1), νjmax
3088, 3072, 3028, 2918, 1763, 1650, 1608, 1595, 1455, 1436, 812,
698, 651, 520; 1H NMR (400 MHz, CDCl3), δ 2.36 (s, 3H, CH3), 3.72
(s, 2H, H7), 5.84 (s, 1H, H6), 6.94 (s, 1H, H4), 7.16 (d, 2H, J ) 8.0
Hz, H3′′/H5′′), 7.25–7.36 (m, 5H, Ph), 7.63 (d, 2H, J ) 8.0 Hz, H2′′/
H6′′); 13C NMR (100 MHz, CDCl3), δ 21.45 (CH3), 31.68 (C7), 112.84
(C6), 126.92 (C4′), 128.84 (C3′/C5′), 128.93 (C2′/C6′), 129.56, 130.39,
and 130.44 (C1′′, C2′′/C6′′, C3′′/C5′′), 131.98 (C3), 137.32 (C1′),
139.28 (C4′′), 139.69 (C4), 146.92 (C5), 170.54 (C2); MS, m/z (%)
276 (M+, C19H16O2, 100), 258 (7), 243 (9), 230 (23), 215 (32), 202
(6), 181 (7), 156 (5), 143 (20), 132 (27), 115 (39), 103 (56), 91 (16),
77 (42), 65 (8), 63 (8), 51 (13).
yielda (%)
compd
arylidene group
benzylidene
6
62 (Z)
83 (Z)
86 (E)
43 (Z)
16 (Z)
68 (Z)
33 (Z)
33 (Z)
32 (Z)
55 (Z)
66 (Z)
68 (Z)
44 (Z)
63 (Z)
67 (Z)
75 (Z)
32 (Z)
55 (Z)
41 (Z)
82 (Z)
38 (Z)
33 (Z)
21 (Z)
41 (Z)
33 (Z)
56 (Z)
25 (Z)
39 (Z)
12 (Z)
47 (Z)
74 (Z)
78 (Z)
91 (Z)
12 (Z)
7
8
9
1,3-dioxalenebenzylidene
2,4,6-trimethoxybenzylidene
4-dimethylaminobenzylidene
2-chloro-4-dimethylaminobenzylidene
2,5-dimethoxybenzylidene
4-nitrobenzylidene
3-bromobenzylidene
4-methylbenzylidene
3-nitrobenzylidene
3-methylbenzylidene
4-chlorobenzylidene
3-chlorobenzylidene
4-methoxybenzylidene
4-fluorobenzylidene
4-bromobenzylidene
3-fluorobenzylidene
2-fluorobenzylidene
2-chlorobenzylidene
2-methylbenzylidene
4-ethylbenzylidene
2-bromobenzylidene
pentafluorobenzylidene
4-cyanobenzylidene
4-trifluoromethylbenzylidene
3-trifluoromethylbenzylidene
2-trifluoromethylbenzylidene
3-cyanobenzylidene
3-dimethylaminobenzylidene
4-phenylbenzylidene
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Data for (5Z)-3-Benzyl-5-(3-nitrobenzylidene)furan-2(5H)-one (15):
pale yellow solid; mp 131.0–131.5 °C; purified by column chroma-
tography, eluent hexane/dichloromethane (3:2 v/v); IR (film, dichlo-
romethane, cm-1), νjmax 3094, 3068, 3028, 1764, 1654, 1608, 1528,
1493, 1453, 1347, 951, 816, 701; 1H NMR (400 MHz, CDCl3), δ 3.75
(s, 2H, H7), 5.91 (s, 1H, H6), 6.99 (s, 1H, H4), 7.26–7.38 (m, 5H, Ph),
7.55 (t, 1H, J ) 8.0 Hz, H3′′), 8.13 (dd, 1H, J ) 8.0 Hz and J ) 1.2
Hz, H4′′), 8.17 (br d, 1H, J ) 8.0 Hz, H2′′), 8.41 (br s, 1H, H6′′); 13
C
NMR (100 MHz, CDCl3), δ 31.83 (C7), 109.45 (C6), 123.05 (C4′′),
124.68 (C6′′), 127.16 (C4′), 128.94 (C3′/C5′), 128.97 (C2′/C6′), 129.79
(C3′′), 134.41 (C1′′), 134.77 (C3), 135.59 (C2′′), 136.71 (C1′), 139.12
(C4), 148.57 (C5), 149.15 (C5′′), 169.52 (C2); MS, m/z (%) 307, (M+,
C18H13NO4, 67), 290 (46), 272 (8), 260 (7), 244 (7), 231 (13), 215
(52), 202 (35), 189 (11), 177 (9), 143 (20), 127 (11), 115 (100), 101
(16), 91 (26), 89 (49), 76 (18), 63 (27), 51 (12).
Data for (5Z)-3-Benzyl-5-(3-methylbenzylidene)furan-2(5H)-one
(16): white solid; mp 102.1–102.5 °C; purified by column chromatog-
raphy, eluent hexane/dichloromethane (2:1 v/v); IR (film, dichlo-
romethane, cm-1), νjmax 3108, 3062, 3032, 3018, 2922, 2860, 1765,
2-hydroxybenzylidene
3-hydroxybenzylidene
4-hydroxybenzylidene
3-hydroxy-4-methoxybenzylidene
1
1645, 1608, 1495, 1454, 1027, 696; H NMR (400 MHz, CDCl3), δ
2.36 (s, 3H, CH3), 3.72 (br s, 2H, H7), 5.83 (s, 1H, H6), 6.93 (t, 1H,
J ) 1.4 Hz, H4), 7.12 (br d, 1H, J ) 7.6 Hz, H4′′), 7.24–7.29 (m, 4H,
H3′′, H2′/H6′, and H4′), 7.33–7.37 (m, 2H, H3′/H5′), 7.53 (br d, 1H,
J ) 8.9 Hz, H2′′), 7.54 (br s, 1H, H6′′); 13C NMR (100 MHz, CDCl3),
δ 21.83 (CH3), 31.66 (C7), 112.87 (C6), 126.91 (C4′), 127.68 (C2′′),
128.64 (C3′′), 128.82 (C3′/C5′), 128.90 (C2′/C6′), 129.80 (C4′′), 130.92
(C6′′), 132.30 (C3), 133.02 (C1′′), 137.21 (C1′), 138.40 (C5′′), 139.68
(C4), 147.30 (C5), 170.46 (C2); MS, m/z (%) 276 (M+, C19H16O2, 100),
258 (9), 243 (9), 231 (26), 215 (21), 202 (9), 184 (8), 144 (15), 132
(25), 115 (46), 104 (35), 91 (38), 78 (43), 77 (33), 65 (20), 51 (28).
a Yields based on compound 5.
C6′′), 137.84 (C1′), 139.65 (C4), 144.97 (C5), 150.34 (C4′′), 171.05
(C2); MS, m/z (%) 305 (M+, C20H19NO2, 100), 161 (17), 133 (16),
132 (18), 115 (9), 91 (10), 77 (5), 69 (7), 65 (6), 57 (9), 51 (4).
Data for (5Z)-3-Benzyl-5-(2-chloro-4-[N,N-dimethylamino)ben-
zylidene]furan-2(5H)-one (10): yellow solid; mp 121.1–122.1 °C;
purified by column chromatography, eluent dichloromethane/hexane
(1:1 v/v); IR (film, dichloromethane, cm-1). νjmax 3087, 3059, 3028,
2905, 2859, 2814, 1747, 1643, 1591, 1514, 1444, 1371, 1290, 1179,
1028, 937, 831, 766, 749, 703, 630, 556; 1H NMR (400 MHz, CDCl3),
δ 3.00 (s, 6H, N(CH3)2), 3.71 (br s, 2H, H7), 6.30 (s, 1H, H6), 6.61
(dd, 1H, J ) 9.0 Hz and J ) 2.7 Hz, H3′′), 6.66 (d, 1H, J ) 2.7 Hz,
H5′′), 6.97 (t, 1H, J ) 1.36 Hz, H4), 7.24–7.36 (m, 5H, Ph), 8.16 (d,
1H, J ) 9.0 Hz, H2′′); 13C NMR (100 MHz, CDCl3), δ 31.64 (C7),
40.10 (N(CH3)2), 108.93 (C6), 111.13 (C3′′), 112.17 (C5′′), 118.75
(C1′′), 126.83 (C4′), 128.80 (C3′/C5′), 128.93 (C2′/C6′);, 130.23 (C3),
132.70 (C2′′), 135.93 (C1′), 137.60 (C6′′), 140.01 (C4), 145.76 (C5),
150.79 (C4′′), 170.82 (C2); MS, m/z (%) 341 (M + 2, 45), 339 (M+,
C20H18ClNO2, 100), 325 (4), 275 (5), 247 (8), 202 (10), 197 (6), 195
(20), 167 (40), 151 (15), 139 (9), 130 (46), 115 (18), 100 (9), 91 (9),
89 (15), 76 (9), 65 (6), 51 (3).
Data for (5Z)-3-Benzyl-5-(4-chlorobenzylidene)furan-2(5H)-one
(17): white solid; mp 138.5–139 °C; purified by column chromatog-
raphy, eluent hexane/dichloromethane (2:1 v/v)’ IR (film, dichlo-
romethane, cm-1), νjmax 3102, 3086, 3060, 3030, 2930, 1765, 1645,
1584, 1492, 857, 814, 696; 1H NMR (400 MHz, CDCl3), δ 3.72 (br s,
2H, H7), 5.81 (s, 1H, H6), 6.94 (t, 1H, J ) 1.44 Hz, H5), 7.25–7.37
(m, 7H, Ph and H3′′/H5′′), 7.66 (d, 2H, J ) 8.6 Hz, H2′′/H6′′); 13C
NMR (100 MHz, CDCl3), δ 31.74 (C7), 111.19 (C6), 127.03 (C4′),
128.86, 128.93, and 129.04 (C2′/C6′, C3′/C5′, C3′′/C5′′), 131.53 (C2′′/
C6′′), 131.64 (C1′′), 132.97 (C3), 134.79 (C4′′), 137.05 (C1′), 139.45
(C4), 147.72 (C5), 170.10 (C2); MS, m/z (%) 298 (M + 2, 22), 296
(C18H13ClO2, M+, 68), 243 (27), 215 (33), 202 (13), 152 (25), 144
(20), 115 (47), 107 (17), 91 (32), 89 (100), 77 (7), 65 (19), 63 (35), 51
(16).
Data for (5Z)-3-Benzyl-5-(4-nitrobenzylidene)furan-2(5H)-one (12):
yellow solid; mp 117.0–117.7 °C; purified by column chromatography,
eluent hexane/dichloromethane (3:2 v/v); IR (KBr, cm-1), νjmax 3108,
3062, 3030, 2928, 1768, 1590, 1509, 1453, 1339, 1110, 1014, 877,
691, 637; 1H NMR (400 MHz, CDCl3), δ 3.75 (br s, 2H, H7), 5.91 (s,
1H, H6), 6.98 (s, 1H, J ) 1.5 Hz, H4), 7.25–7.38 (m, 5H, Ph), 7.86 (d,
2H, J ) 8.9 Hz, H2′′/H6′′), 8.21 (d, 2H, J ) 8.9 Hz, H3′′/H5′′); 13C
NMR (100 MHz, CDCl3), δ 31.86 (C7), 109.55 (C6), 123.97 (C3′′/
C5′′), 127.20 (C4′), 128.93 (C3′/C5′), 128.99 (C2′/C6′), 130.73 (C2′′/
C6′′), 134.87 (C3), 136.60 (C1′), 139.19 (C4), 139.44 (C1′′), 147.09
(C5), 149.85 (C4′′), 169.47 (C2); MS, m/z (%) 307, (M+, C18H13NO4,
81), 262 (13), 231 (13), 215 (60), 202 (37), 165 (9), 143 (18), 133
(16), 115 (100), 91 (26), 89 (46), 76 (22), 65 (12), 63 (28), 51 (14).
Data for (5Z)-3-Benzyl-5-(3-chlorobenzylidene)furan-2(5H)-one
(18): white solid; mp 126–126.4 °C; purified by column chromatog-
raphy, eluent dichloromethane/hexane (3:2 v/v); IR (KBr, cm-1), νjmax
3099, 3060, 3027, 2926, 1769, 1651, 1612, 1586, 1561, 1027, 793,
700, 685; 1H NMR (400 MHZ, CDCl3), δ 3.72 (br s, 2H, H7), 5.78 (s,
1H, H6), 6.94 (t, 1H, J ) 1.4 Hz, H4), 7.25–7.37 (m, 7H, H4′′, H5′′,
and Ph), 7.61 (br d, 1H, J ) 7.2 Hz, H6′′), 7.70 (br s, 1H, H2′′); 13C
NMR (100 MHz, CDCl3), δ 31.71 (C7), 110.87 (C6), 127.03 (C4′),
128.38 and 128.76 (C3′′ and C4′′)*, 128.89 (C3′/C5′), 128.91 (C2′/
C6′), 129.31 (C2′′/C6′′), 133.40 (C3), 134.69 and 134.81 (C1′′ and
C5′′)*, 136.94 (C1′′), 139.37 (C4), 169.96 (C2); MS, m/z (%) 298 (M
+ 2, 19), 296 (M+, C18H13ClO2, 59), 243 (21), 215 (35), 202 (13), 152

2324 J. Agric. Food Chem., Vol. 56, No. 7, 2008
Teixeira et al.
(18), 144 (15), 115 (52), 107 (15), 91 (41), 89 (100), 77 (7), 65 (17),
63 (32), 51 (13). *, these assignments could be reversed.
1.2 Hz, H3′′), 8.20 (dd, 1H, J ) 7.9 and 1.6 Hz, H6′′); 13C NMR (100
MHz, CDCl3), δ 31.74 (C7), 107.76 (C6), 127.05 (C4′), 127.20 (C5′′),
128.91 and 128.95 (C2′/C6′ and C3′/C5′), 129,64 (C3′′), 129,73 (C4′′),
130.94 (C1′′), 131.86 (C6′′), 133.33 (C3), 134.18 (C2′′), 136.92 (C1′),
139,81 (C4), 148.46 (C5), 170.14 (C2); MS, m/z (%) 298, (M + 2,
20), 296 (M+, C18H13ClO2, 58), 243 (21), 233 (16), 215 (34), 202 (15),
152 (18), 144 (16), 115 (51), 107 (14), 91 (33), 89 (100), 77 (8), 65
(15), 63 (25), 51 (12).
Data for (5Z)-3-Benzyl-5-(4-methoxybenzylidene)furan-2(5H)-one
(19): yellow solid; mp 107.2–108.0 °C; purified by column chroma-
tography, eluent dichloromethane/hexane (3:2 v/v); IR (KBr, cm-1),
νjmax 3101, 3058, 3023, 2968, 2930, 2888, 2837, 1743, 1652, 1599,
1510, 1300, 1259, 1028, 936, 825, 750, 699; 1H NMR (400 MHz,
CDCl3), δ 3.71 (s, 2H, H7), 3.82 (s, 3H, -OCH3), 5.82 (s, 1H, H6),
6.89 (d, 2H, J ) 8.8 Hz, H3′′/ H5′′), 6.92 (s, 1H, H4), 7.25–7.36 (m,
5H, Ph), 7.69 (d, 2H, J ) 8.8 Hz, H2′′/H6′′); 13C NMR (100 MHz,
CDCl3), δ 31.61 (C7), 55.31 (-OCH3), 125.95 (C6), 126.84 (C3′′/
C5′′), 128.78 and 128.88 (C2′/C6′ and C3′/C5′), 131.18 (C3), 132.08
(C2′′/C6′′), 137.39 (C1′), 139.64 (C4), 160.17 (C5), 170.62 (C2); MS,
m/z (%) 292 (M+, C19H16O3, 100), 247 (10), 215 (9), 148 (34), 133
(21), 120 (28), 115 (23), 105 (11), 91 (49), 77 (34), 65 (10), 63 (11),
51 (31).
Data for (5Z)-3-Benzyl-5-(2-methylbenzylidene)furan-2(5H)-one (25):
white solid; mp 103.3–103.9 °C; purified by column chromatography,
eluent hexane/dichloromethane (2:1 v/v); IR (film, dichloromethane,
cm-1), νjmax 3061, 3027, 2922, 1766, 1647, 1609, 1485, 1032, 937,
1
823, 756; H NMR (400 MHz, CDCl3), δ 2.36 (s, 3H, CH3), 3.72 (s,
2H, H7), 6.07 (s, 1H, H6), 6.97 (s, 1H, H4), 7.16–7.29 (m, 6H, H2′/
H6′, H4′, H3′′, H4′′, and H5′′), 7.33–7.37 (m, 2H, H3′/H5′), 8.08 (d,
1H, J ) 7.6 Hz, H6′′); 13C NMR (100 MHz, CDCl3), δ 20.09 (CH3),
31.70 (C7), 109.66 (C6), 126.52 (C3′′), 126.96 (C4′), 128.87, 128.97
(C2′/C6′, C3′/C5′, and C4″), 130.35 (C5′′), 130.74 (C6′′), 131.58 (C2′′),
132.47 (C3), 137.07 (C1′′), 137.23 (C1′), 139.80 (C4), 147.57 (C5),
170.54 (C2); MS, m/z (%) 276 (M+, C19H16O2, 100), 215 (15), 185
(24), 157 (26), 129 (23), 116 (26), 115 (56), 104 (34), 91 (35), 78
(38), 77 (32), 65 (20), 51 (22).
Data for (5Z)-3-Benzyl-5-(4-fluorobenzylidene)furan-2(5H)-one (20):
white solid; mp 108.6–108.9 °C; purified by column chromatography,
eluent dichloromethane/hexane (2:1 v/v); IR (film, dichloromethane,
cm-1), νjmax 3111, 3060, 3030, 2906, 2836, 1744, 1654, 1598, 1506,
1
1041, 748, 718; H NMR (400 MHz, CDCl3), δ 3.72 (br s, 2H, H7),
5.83 (s, 1H, H6), 6.94 (t, 1H, J ) 1.5 Hz, H4), 7.05 (t, 2H, J ) 8.7
Hz, H3′′/H5′′), 7.24–7.37 (m, 5H, Ph), 7.72 (dd, 2H, J ) 8.7 Hz and
J ) 5.4 Hz, H2′′/H6′′); 13C NMR (100 MHz, CDCl3), δ 31.70 (s, C7),
111.34 (s, C6), 115.93 (d, JC-F ) 21.7 Hz, C3′′/C5′′), 126.99 (s, C4′),
128.88 (s, C3′/C5′), 128.93 (s, C2′/C6′), 129.43 (d, JC-F ) 3.5 Hz, C1′′),
132.29 (d, JC-F ) 8.1 Hz, C2′′/C6′′), 132.51 (s, C3), 137.15 (s, C1′),
139.54 (s, C4), 147.09 (s, C5), 162.83 (d, JC-F ) 249.5 Hz, C4′′), 170.28
(s, C2); MS, m/z (%) 280 (M+, C18H13FO2, 100), 262 (17), 235 (39),
220 (13), 215 (11), 185 (10), 144 (19), 116 (33), 115 (44), 108 (69),
107 (43), 91 (31), 77 (6), 65 (18), 51 (15).
Data for (5Z)-3-Benzyl-5-(4-ethylbenzylidene)furan-2(5H)-one (26):
white amorphous solid; purified by column chromatography, eluent
hexane/dichloromethane (2:1 v/v); IR (film, dichloromethane, cm-1),
νjmax 3089, 3029, 2961, 2927, 2885, 1759, 1650, 1603, 1036, 937, 698;
1H NMR (400 MHz, CDCl3), δ 1.24 (t, 3H, J ) 7.6 Hz, -CH2CH3),
2.65 (q, 2H, J ) 7.6 Hz, -CH2CH3), 3.72 (s, 2H, H7), 5.85 (s, 1H,
H6), 6.93 (s, 1H, H4), 7.20 (d, 2H, J ) 8.1 Hz, H3′′/H5′′), 7.25–7.36
(m, 5H, Ph), 7.66 (d, 2H, J ) 8.1 Hz, H2′′/H6′′); 13C NMR (100 MHz,
CDCl3), δ 15.31 (-CH2CH3), 28.79 (-CH2CH3), 31.69 (C7), 112.85
(C6), 126.92 (C4′), 128.37 (C3′′/C5′′), 128.85 (C3′/C5′), 128.94 (C2′/
C6′), 130.55 (C2′′/C6′′), 130.64 (C1′′), 131.99 (C3), 137.33 (C1′),
139.68 (C4), 145.59 (C4′′), 146.96 (C5), 170.54 (C2); MS, m/z (%)
290 (M+, C20H18O2, 100), 275 (18), 261 (8), 243 (18), 215 (20), 202
(10), 131 (72), 115 (75), 91 (41), 77 (43), 65 (22), 63 (19), 51 (19).
Data for (5Z)-3-Benzyl-5-(2-bromobenzylidene)furan-2(5H)-one (27):
yellow oil; purified by column chromatography, eluent hexane/
dichloromethane (2:1 v/v); IR (film, NaCl, cm-1), νjmax 3090, 3062,
3028, 2923, 2852, 1769, 1609, 1644, 1585, 1555, 1023, 940, 753, 699;
1H NMR (400 MHz, CDCl3), δ 3.73 (s, 2H, H7), 6.32 (s, 1H, H6),
7.01 (s, 1H, H4), 7.14 (t, 1H, J ) 7.6 Hz, H4′′), 7.19–7.38 (m, 6H,
H5′′ and Ph), 7.58 (d, 1H, J ) 8 Hz, H3′′), 8.19 (d, 1H, J ) 8.0 Hz,
H6′′); 13C NMR (100 MHz, CDCl3), δ 31.77 (C7), 110.51 (C6), 124.96
(C2′′), 127.07 (C4′), 127.81 (C5′′), 128.93 (C3′/C5′), 128.96 (C2′/C6′),
132.03 (C6′′), 132.60 (C1′′), 133.02 (C3′′), 133.37 (C3), 136.93 (C1′),
139.78 (C4), 148.46 (C5), 170.12 (C2); MS, m/z (%) 342 (M + 2, 37),
340 (M+, C18H13BrO2 36), 243 (13), 233 (13), 215 (38), 202 (20), 144
(12), 115 (52), 91 (32), 89 (100), 77 (10), 65 (15), 63 (53), 51 (19).
Data for (5Z)-3-Benzyl-5-(pentafluorobenzylidene)furan-2(5H)-one
(28): pale yellow solid; mp 137.2–137.6 °C; purified by column
chromatography, eluent hexane/dichloromethane (2:1 v/v); IR (KBr,
cm-1), νjmax 3098, 3075, 3026, 2926, 1766, 1671, 1619, 1523, 1495,
Data for (5Z)-3-Benzyl-5-(3-fluorobenzylidene)furan-2(5H)-one (22):
white solid; mp 89.2–89.8 °C; purified by column chromatography,
eluent dichloromethane/hexane (2:1 v/v); IR (KBr, cm-1), νjmax 3099,
3034, 2922, 2826, 1763, 1649, 1603, 1576, 1445, 1017, 933, 878, 784,
758; 1H NMR (400 MHz, CDCl3), δ 3.73 (br s, 2H, H7), 5.83 (s, 1H,
H6), 6.94 (t, 1H, J ) 1.5 Hz, H4), 6.99 (ddd, 1H, J ) 8.3 Hz, J ) 2.6
Hz and J ) 0.9 Hz, H4′′), 7.25–7.37 (m, 6H, H2′/H6′, H3′/H5′, H4′,
and H3′′), 7.45 (br d, 1H, J ) 7.8 Hz, H2′′), 7.49 (m, 1H, H6′′); 13C
NMR (100 MHz, CDCl3), δ 31.78 (s, C7), 111.20 (s, C6), 115.82 (d,
JC-F ) 21.4 Hz, C4′′), 116.77 (d, JC-F ) 22.7 Hz, C6′′), 126.17 (d, JC-F
) 2.8 Hz, C2′′), 127.07 (s, C4′), 128.93 (s, C3′/C5′), 128.96 (s, C2′/
C6′), 130.17 (d, JC-F ) 8.3 Hz, C3′′), 133.40 (s, C3), 135.15 (d, JC-F
)
8.2 Hz, C1′′), 139.42 (s, C4), 148.17 (s, C5), 162.92 (d, JC-F ) 244.3
Hz, C5′′), 170.00 (s, C2); MS, m/z (%) 280 (M+, C18H13FO2, 100),
262 (17), 235 (39), 220 (13), 215 (11), 185 (10), 144 (19), 116 (33),
115 (44), 108 (69), 107 (43), 91 (31), 77 (6), 65 (18), 51 (15).
Data for (5Z)-3-Benzyl-5-(2-fluorobenzylidene)furan-2(5H)-one (23):
white solid; mp 124.7–125.1 °C; purified by column chromatography,
eluent dichloromethane/hexane (2:1 v/v); IR (KBr, cm-1), νjmax 3104,
3062, 3024, 2932, 2848, 1758, 1655, 1614, 1605, 1485, 1457, 1229,
1
1029, 755, 699, 645; H NMR (400 MHz, CDCl3), δ 3.73 (br s, 1H,
H7), 6.18 (t, 1H J ) 1.2 Hz, H6), 7.02–7.07 (m, 1H, H3′′), 7.18 (t,
1H, J ) 7.6 Hz, H5′′), 7.26–7.37 (m, 6H, Ph and H4′′), 8.20 (dt, 1H,
J ) 9.3 Hz, J ) 7.8 Hz, and J ) 1.5 Hz, H6′′); 13C NMR (100 MHz,
CDCl3), δ 31.73 (s, C7), 103.48 (d, JC-F ) 7.9 Hz, C6), 115.25 (d, JC-F
) 21.9, C3′′), 121.23 (d, JC-F ) 11.1 Hz, C1′′), 124.60 (d, JC-F ) 3.7
Hz, C5′′), 127.04 (s, C4′), 128.85 (s, C3′/C5′), 128.90 (s, C2′/C6′),
130.42 (d, JC-F ) 8.6 Hz, C4′′), 131.44 (d, JC-F ) 1.2 Hz, C6′′), 133.19
(s, C3), 136.98 (s, C1′), 139.65 (s, C4), 148.31 (d, JC-F ) 2.2 Hz, C5),
160.56 (d, JC-F ) 250.6 Hz, C2′′), 170.17 (s, C2); MS, m/z (%) 280
(M+, C18H13FO2, 100), 262 (19), 235 (44), 215 (17), 198 (8), 185 (14),
144 (19), 136 (28), 116 (41), 115 (60), 108 (68), 107 (52), 91 (37), 77
(8), 65 (20), 51 (18).
1
1041, 998, 981, 935, 885, 750; H NMR (400 MHz, CDCl3), δ 3.73
(s, 2H, H7), 5.75 (s, 1H, H6), 6.97 (s, 1H, H4), 7.25–7.38 (m, 5H,
Ph); 13C NMR (100 MHz, CDCl3), δ 31.95 (C7), 95.01 (C6), 127.26
(C4′), 128.99 (C3′/C5′), 129.02 (C2′/C6′), 136.38 (C1′), 136.77 (C3),
137.65 (C4), 151.14 (C5), 168.83 (C2); MS, m/z (%) 352 (M+,
C18H9F5O2, 50), 307 (18), 287 (32), 180 (24), 161 (13), 115 (100), 91
(24), 77 (9), 65 (26), 51 (21). Note: Signals for carbons of the
benzylidene ring were not observed.
Data for (5Z)-3-Benzyl-5-(4-cyanobenzylidene)furan-2(5H)-one (29):
white solid; mp 140.1–140.9 °C; purified by column chromatography,
eluent hexane/ethyl acetate (4:1 v/v); IR (KBr, cm-1), νjmax 3061, 3027,
2926, 2856, 2234, 1759, 1651, 1612, 1601, 1033, 938, 838, 750, 697,
555; 1H NMR (400 MHz, CDCl3), δ 3.74 (s, 2H, H7), 5.86 (s, 1H,
H6), 6.97 (s, 1H, H4), 7.25–7.37 (m, 5H, Ph), 7.61 (d, 2H, J ) 8.4 Hz,
H3′′/H5′′), 7.79 (d, 2H, J ) 8.4 Hz, H2′′/H6′′); 13C NMR (100 MHz,
CDCl3), δ 31.79 (C7), 110.03 (C6), 111.63 (C4′′), 118.63 (CN), 127.14
(C4′), 128.91 (C3′/C5′), 128.95 (C2′/C6′), 130.51 (C2′′/C6′′), 132.35
(C3′′/C5′′), 134.45 (C3), 136.67 (C1′), 137.53 (C1′′), 139.23 (C4),
Data for (5Z)-3-Benzyl-5-(2-chlorobenzylidene)furan-2(5H)-one (24):
white solid; mp 68.3–69.5 °C; purified by column chromatography,
eluent hexane/dichloromethane (2:1 v/v); IR (film, dichloromethane,
cm-1), νjmax 3090, 3063, 3029, 2918, 1769, 1646, 1609, 1470, 1023,
1
941, 736, 698; H NMR (400 MHz, CDCl3), δ 3.74 (s, 2H, H7), 6.36
(s, 1H, H6), 7.01 (s, 1H, H4), 7.2 (td, 1H, J ) 7.6 Hz, J ) 1.7 Hz,
H4′′), 7.26–7.36 (m, 6H, Ph and H5′′), 7.38 (dd, 1H, J ) 7.6 Hz and

Photosynthesis-Inhibiting Nostoclide Analogues
J. Agric. Food Chem., Vol. 56, No. 7, 2008 2325
149.48 (C5), 169.52 (C2); MS, m/z (%) 290 (M+, C19H13NO2, 100),
275 (18), 261 (8), 243 (18), 215 (20), 202 (10), 131 (72), 115 (75), 91
(41), 77 (43), 65 (22), 63 (19), 51 (19).
(C7), 40.91 (N(CH3)2), 113.56 (C6), 113.91 (C6′′), 114.46 (C4′′), 119.78
(C2′′), 126.87 (C4′), 128.80 (C3′/C5′), 128.90 (C2′/C6′), 129.44 (C3′′),
132.12 (C3), 133.74 (C1′′), 137.21 (C1′), 139.77 (C4), 147.22 (C5),
150.32 (C5′′), 170.47 (C2); MS, m/z (%) 305 (M+, C20H19NO2, 100),
276 (8), 215 (5), 160 (16), 129 (23), 115 (16), 91 (17), 77(6), 65 (7),
51 (7).
Data for (5Z)-3-Benzyl-5-(4-trifluoromethylbenzylidene)furan-2(5H)-
one (30): white solid; mp 92.7–93.3 °C; purified by column chroma-
tography, eluent hexane/dichloromethane (2:1 v/v); IR (film, dichlo-
romethane, cm-1), νjmax 3088, 3064, 3030, 1773, 1654, 1617, 1325,
1167, 1124, 940, 699; 1H NMR (400 MHz, CDCl3), δ 3.74 (s, 2H,
H7), 5.87 (s, 1H, H6), 6.97 (s, 1H, H4), 7.26–7.38 (m, 5H, Ph), 7.60
(d, 2H, J ) 8.2 Hz, H3′′/H5′′), 7.82 (d, 2H, J ) 8.2 Hz, H2′′/H6′′);
13C NMR (100 MHz, CDCl3), δ 31.78 (s, C7), 110.61 (s, C6), 123.93
(q, JC-F ) 270.4 Hz, CF3), 125.62 (q, JC-F ) 3.7 Hz, C3′′/C5′′), 128.93
(s, C2′/C6′ and C3′/C5′), 130.19 (q, JC-F ) 32.3 Hz, C4′′), 130.37 (s,
C2′′/C6′′), 133.94 (s, C3), 136.46 (s, C1′′), 136.81 (s, C1′), 139.56 (s,
C4), 148.81 (s, C5), 169.87 (s, C2); MS, m/z (%) 330 (M+, C19H13F3O2,
94), 312 (11), 285 (33), 248 (8), 233 (12), 215 (32), 202 (9), 158 (52),
144 (20), 116 (63), 115 (100), 91 (51), 89 (38), 77(11), 63 (26), 51
(27).
Data for (5Z)-3-Benzyl-5-(3-trifluoromethylbenzylidene)furan-2(5H)-
one (31): white solid; mp 95.4–96.5 °C; purified by column chroma-
tography, eluent hexane/dichloromethane (2:1 v/v); IR (film, dichlo-
romethane, cm-1), νjmax 3088, 3062, 3030, 2918, 1770, 1653, 1607,
1330, 1167, 1126, 1025, 942, 907, 882, 800, 695; 1H NMR (400 MHz,
CDCl3), δ 3.74 (br s, 2H, H7), 5.88 (s, 1H, H6), 6.97 (t, 1H, J ) 1.2
Hz, H4), 7.26–7.38 (m, 5H, Ph), 7.48 – 7.56 (m, 2H, H3′′ and H4′′),
7.86 (br s, 1H, H6′′), 7.99 (br d, 1H, J ) 7.6 Hz, H2′′); 13C NMR (100
MHz, CDCl3), δ 31,77 (s, C7), 110.64 (s, C6), 125.17 (q, JC-F ) 270.9
Hz, CF3), 125.17 (q, JC-F ) 3.6 Hz, C4′′), 126.81 (q, JC-F ) 3.8 Hz,
C6′′), 127.08 (s, C4′′), 128.93 (s, C2′/C6′ and C3′/C5′), 129.31 (s, C3′′),
131.20 (q, JC-F ) 32 Hz, C5′′), 133.21 (s, C2′′), 133.77 (s, C3), 133.86
(s, C1′′), 136.88 (s, C1′), 139.33 (s, C4), 148.46 (s, C5), 169.88 (s,
C2); MS, m/z (%) 330, (M+, C19H13F3O2, 91), 312 (11), 285 (40), 243
(15), 233 (13), 215 (33), 202 (12), 158 (52), 144 (19), 116 (60), 115
(100), 91 (52), 89 (43), 77(11), 63 (29), 51 (32).
Data for (5Z)-3-Benzyl-5-(4-phenylbenzylidene)furan-2(5H)-one (35):
pale yellow solid; mp 156.6–156.8 °C; purified by column chroma-
tography, eluent hexane/diethyl ether (6:1 v/v); IR (KBr, cm-1), νjmax
3102, 3058, 3026, 2922, 1759, 1646, 1600, 1943, 1454, 1035, 920,
763, 696; 1H NMR (400 MHz, CDCl3), δ 3.73 (br s, H7), 5.90 (s, H6),
6.96 (t, 1H, J ) 1.4 Hz, H4), 7.25–7.30, 7.33–7.38, 7.42–7.46,
7.60–7.62 (m, 12H, H3′′-H5′′, and 2 × Ph), 7.80 (d, 2H, J ) 8.4 Hz,
H2′′/H6′′); 13C NMR (100 MHz, CDCl3), δ 31.73 (C7), 112.31 (C6),
128.94 and 130.91 (C2′′/C6′′, C3′′/C5′′), 132.19 (C1′′), 132.44 (C3),
139.60 (C4), 141.51 (C4′′), 147.54 (C5), 170.39 (C2), 126.97, 127.02,
127.39, and 140.24 (signals for the phenyl ring attached to the
benzylidene ring); 127.74, 128.88, 137.22 (signals for the benzyl ring)*;
MS, m/z (%) 338 (M+, C24H18O2, 100), 215 (9), 194 (21), 165 (90),
115 (32), 91 (25), 77 (9), 65 (10), 51 (9). *, there was a signal
coincidence for C-2′/C-6′and C-3′/C-5′.
Data for (5Z)-3-Benzyl-5-(4-hydroxy-3-methoxybenzylidene)furan-
2(5H)-one (39): yellow solid; mp 142.9–143.3 °C; purified by column
chromatography, eluent hexane/ethyl acetate (2:1 v/v); IR (KBr, cm-1),
νjmax 3309 (broadband), 3602, 3028, 3002, 2955, 2912, 2836, 1732,
1602, 1651, 1581, 1517, 1293, 1048, 888, 751, 699; 1H NMR (400
MHz, CDCl3), δ 3.71 (s, 2H, H7), 3.94 (s, 3H, OCH3), 5.80 (s, 1H,
H6), 5.86 (s, 1H, OH), 6.89 (d, 1H, J ) 8.3 Hz, H3′′), 6.93 (s, 1H,
H4), 7.12 (dd, 1H, J ) 8.3 Hz and J ) 1.9 Hz, H2′′), 7.25–7.36 (m,
5H, Ph), 7.45 (d, 1H, J ) 1.9 Hz, H6′′); 13C NMR (100 MHz, CDCl3),
δ 31.66 (C7), 56.11 (OCH3), 112.10 (C6′′), 113.02 (C6), 114.59 (C3′′),
125.20 (C2′′), 125.87 (C1′′), 126.88 (C4′′), 128.82 (C3′/C5′), 128.91
(C2′/C6′), 131.15 (C3), 137.44 (C1′), 139.68 (C4), 145.94 (C4), 146.75
(C5′′), 146.90 (C4′′), 170.54 (C2); MS, m/z (%) 308 (M+, C19H16O4,
100), 164 (50), 149 (22), 136 (28), 115 (43), 101 (19), 91 (37), 77
(24), 65 (61), 51 (24).
Biological Tests. The ability of the synthesized compounds to
interfere with the photosynthetic electron transport chain was evaluated
in vitro by the Hill reaction, as previously described (38). Photosyn-
thetically active thylakoid membranes were isolated from market
spinach (Spinacea oleracea L.) leaves. Deveined plant material was
resuspended in 5 mL g-1 of ice-cold 20 mM N-tris(hydroxymethyl)
methylglycine (Tricine)-NaOH buffer (pH 8.0) containing 10 mM
NaCl, 5 mM MgCl2, and 0.4 M sucrose and homogenized for 30 s in
a blender at maximal speed. The homogenate was filtered through
surgical gauze, and the filtrate was centrifuged at 4 °C for 1 min at
500g; the supernatant was further centrifuged for 10 min at 1500g.
Pelleted chloroplasts were osmotically swollen by resuspension in
sucrose-lacking buffer. The suspension was immediately diluted 1:1
with sucrose-containing buffer, kept on ice in the dark, and used within
a few hours from preparation. Following proper dilution with 80% (v/
v) acetone, the absorbance of each sample was determined at 645 and
663 nm, and the chlorophyll content was calculated on the basis of
Arnon’s formula. The basal rate of photosynthetic electron transport
was measured following light-driven ferricyanide reduction. Aliquots
of membrane preparations corresponding to 20 µg of chlorophyll were
incubated at 24 °C in 1- mL cuvettes containing 20 mM Tricine-NaOH
buffer (pH 8.0), 10 mM NaCl, 5 mM MgCl2, 0.2 M sucrose, and 1
mM K3Fe(CN)6. The assay was initiated by exposure to saturating light
(800 µmol m-2 s-1), and the rate of ferricyanide reduction was
measured at 30 s intervals for 10 min against an exact blank at 420
nm. Activity was calculated over the linear portion of the curve from
a molar extinction coefficient of 1000 M-1 cm-1. The mean value for
untreated controls was 59.3 ( 2.2 nmol s-1 (mg of chlorophyll)-1 in
36 independent thylakoid membrane preparations. Nostoclide analogues
were dissolved in DMSO so as to obtain 25 or 50 mM solutions that
were then diluted with water, as appropriate. Their effect upon the Hill
reaction was evaluated in parallel assays in which the compounds were
added to the reaction mixture to concentrations of 5, 10, or 20 µM.
Each dose was carried out at least in triplicate, and results were
expressed as percentage of untreated controls.
Data for (5Z)-3-Benzyl-5-(2-trifluoromethylbenzylidene)furan-2(5H)-
one (32): white amorphous solid; purified by column chromatography,
eluent hexane/dichloromethane (2:1 v/v); IR (KBr, cm-1), νjmax 3089,
3031, 2923, 1770, 1650, 1602, 1574, 1495, 1455, 1315, 1163, 1117,
1035, 943, 765, 699, 657; 1H NMR (400 MHz, CDCl3), δ 3.74 (s, 2H,
H7), 6.21 (s, 1H, H6), 7.00 (s, 1H, H4), 7.16–7.43 (m, 6H, Ph and
H4′′), 7.58 (t, J ) 8.0 Hz, H5′′), 7.67 (d, 1H, J ) 8.0 Hz, H3′′), 8.25
(d, 1H, J ) 8.0 Hz, H6); 13C NMR (100 MHz, CDCl3), δ 31.77 (s,
C7), 106.96 (s, C6), 124.11 (q, JC-F ) 272.3 Hz, CF3), 125.99 (q, JC-F
) 5.8 Hz, C3′′), 127.12 (s, C1′), 128.24 (s, C4′), 128.33 (q, JC-F
)
29.6 Hz, C2′′), 128.95 (s, C3′/C5′), 128.96 (s, C2′/C6′), 130.92 (br s,
C1′′), 132.03 (s, C5′′), 132.24 (s, C6′′), 133.93 (s, C3), 136.75 (s, C1′),
139.77 (s, C4), 148.77 (s, C5), 170.02 (s, C2); MS, m/z (%) (M+,
C19H13F3O2, 100), 285 (44), 215 (36), 158 (54), 144 (21), 115 (100),
91 (53), 89 (39), 77 (12), 65 (28), 63 (29), 51 (44).
Data for (5Z)-3-Benzyl-5-(cyanobenzylidene)furan-2(5H)-one (33):
white solid; mp 120.2–120.8 °C; purified by column chromatography,
eluent hexane/dichloromethane/ethyl acetate (5:1:1 v/v); IR (film,
dichloromethane, cm-1), νjmax 3086, 3060, 3030, 2231, 1769, 1655,
1610, 1495, 1479, 1454, 1429, 1027, 903, 700, 683; 1H NMR (400
MHz, CDCl3), δ 3.74 (s, 2H, H7), 5.82 (s, 1H, H6), 6.96 (s, 1H, H4),
7.25–7.34 (m, 5H, Ph), 7.48 (t, 1H, 8.0 Hz, H3′′), 7.56 (br d, 1H, J )
8.0 Hz, H4′′), 7.95 (br s, 1H, H6′′), 7.98 (br d, 1H, J ) 8.0 Hz, H2′′);
13C NMR (100 MHz, CDCl3), δ 31.81 (C7), 109.53 (C6), 113.19 (C5′′),
118.37 (CN), 127.14 (C4′), 128.94 (C3′/C5′), 128.94 (C2′/C6′), 129.62
(C3′′), 131.69 (C4′′), 133.37 (C6′′), 134.06 (C2′′), 134.24 (C3), 134.39
(C1′′), 136.74 (C1′), 148.92 (C5), 169.57 (C2); MS, m/z (%) 287 (M+,
C19H13NO2, 59), 269 (10), 242 (36), 215 (5), 144 (12), 116 (35), 115
(100), 91 (24), 77(6), 65 (15), 51 (13).
Data for (5Z)-3-Benzyl-5-[3-(N,N-dimethylamino)benzylidene]furan-
2(5H)-one (34): yellow solid; mp 85.1–85.4 °C; purified by column
chromatography, eluent hexane/dichloromethane (1:1 v/v); IR (film,
dichloromethane, cm-1), νjmax 3088, 3029, 2898, 2806, 1761, 1650,
1595, 1571, 1496, 1357, 1031, 935, 699; 1H NMR (400 MHz, CDCl3),
δ 2.98 (s, 6H, N(CH3)2), 3.72 (s, 2H, H7), 5.85 (s, 1H, H5), 6.77 (br
d, 1H, J ) 7.8 Hz, H4′′), 6.94 (t, 1H, J ) 1.4 Hz, H4), 7.25–7.38 (m,
8H, H2′′, H3′′, H6′′, and Ph); 13C NMR (100 MHz, CDCl3), δ 31.64

2326 J. Agric. Food Chem., Vol. 56, No. 7, 2008
Teixeira et al.
Figure 4. Selected long-range HMBC (structure A) and NOESY (structure
B) correlations found in the corresponding contour plots of compound 14.
Figure 3. Synthetic steps involved in the preparation of nostoclide
analogues 6–39.
With the exception of compound 8, all lactones synthesized
exhibited the Z configuration (Table 1). This configuration was
supported by the observation of a NOE cross-peak between H4
and H6, as exemplified for compound 14 in Figure 4 (structure
B). Other correlations found in the NOESY contour plot of 14
are also shown. Regarding compound 8, the exocyclic double
bond presented an E configuration. Because the ortho positions
are both substituted by methoxy groups, the compound attains
the E configuration to alleviate the nonbonding destabilizing
steric interaction between O-1 in the lactone ring and the
methoxy groups. In fact, density functional theory calculations
(B3LYP/6-31+G(d) level) using the Gaussian 03 program
demonstrated that for substance 8 the E configuration is more
stable than the Z configuration (45). The opposite situation is
observed for the other nostoclide analogues synthesized. In these
cases, AM1 calculations revealed that the Z isomer is more
Molecular Modeling. Molecular modeling calculations were carried
out with the AM1 semiempirical method (47) as implemented in the
TITAN (48) molecular orbital package. Calculations were done for both
Z and E stereoisomers. Determination of the most stable conformers
for each Z or E stereoisomer was performed using the conformer
distribution subroutine of the TITAN software. After identification of
the three or four most relevant conformers in each case, these were
further fully optimized with the AM1 method.
RESULTS AND DISCUSSION
Synthesis of Nostoclide Analogues. The synthesis of nostoclide
analogues was accomplished as previously described (37, 38, 45, 46).
Briefly, reaction of lactone (5), prepared as shown in Figure 3,
with pertinent aldehydes in the presence of tert-butyldimethylsi-
lyltrifluoromethanesulfonate and diisopropylethylamine followed
by treatment of the silyl ether generated in situ with DBU (43, 49–53)
afforded compounds 6–39 in yields ranging from 12 to 91% (Table
1). It is important to note that in the preparation of compounds
36-39, tert-butyldimethylsilyloxy aldehydes were employed. After
various attempts, the removal of the tert-butyldimethylsilyl protect-
ing group was achieved with a mixture of MeCN/HF (1:1
v/v) (46, 54).
stable than the E isomer, on average by 0.8 kcal mol-1
.
Although the energy differences between both isomers are
indeed small, it is systematic, always giving the Z stereoisomer
as the more stable. Therefore, experimental preference for the
Z stereoisomer seems to indicate that the isomer selection forces
drive the reaction to the thermodynamically more stable isomer.
Preferential formation of Z stereoisomers was also recently
reported for similar systems (55).
Inhibition of the Photosynthetic Electron Transfer in
Although reaction conditions were not optimized, in general
the reactions were complete 3 h after the addition of DBU under
refluxing. For the preparation of the compounds 12, 15, 29, and
30-33, the reaction mixture was refluxed for 1 h, a procedure
that afforded these compounds in moderate yields. It was
observed that extended refluxing time led to the formation of a
complex mixture. For reasons not well understood, some
compounds were obtained with low yield (Table 1). The
structures of lactones (6-39) were confirmed on the basis of
NMR, IR, and MS analyses. In all cases, the presence of a
molecular ion peak was observed in the MS spectra, which
correlated with the expected molecular formulas. The IR spectra
of these compounds revealed intense absorption bands for
carbonyl groups ranging from 1721 to 1773 cm-1. Interestingly,
the frequency of the carbonyl stretching varies with the
substitution pattern in the benzylidene ring. A combination of
two-dimensional NMR analyses (HSQC and HMBC) of the
lactones synthesized not only confirmed the presence of the five-
membered ring R,ꢀ-unsaturated lactone moiety, substituted by
both the benzyl and benzylidene functionalities, but also allowed
complete hydrogen and carbon assignments. Some of the major
long-range correlations (J2 and J3) observed in the HMBC
contour plot of compound 14 are outlined in structure A
(Figure 4).
Thylakoids. Because of their structural similarity to cyanobac-
terin and to other nostoclide analogues, both of which had been
previously found to inhibit the photosynthetic electron transport
chain (32, 37, 38), the synthesized compounds were expected
to potentially show biological activity against the photosynthetic
process. To verify such a hypothesis, their ability to interfere
with ferricyanide reduction by isolated spinach chloroplasts was
evaluated. Results are summarized in Table 2. At 5 × 10-6 M,
21 of the 34 compounds were indeed able to significantly reduce
the rate of the light-driven electron transport chain, whereas 13
analogues were substantially ineffective. Among the active
compounds, at 10-5 M, 8 analogues (8, 11, 12, 23, 26, 30-32)
caused more than 40% inhibition. It should be noted that
compounds 12 and 30, which present a strong electron-
withdrawing group at the para position, exhibited the highest
percentage of inhibition. The effectiveness even of the most
active derivatives was strikingly lower than that of the com-
mercial herbicide diuron, taken as a comparison term. Notwith-
standing this, the occurrence of a remarkable variability among
the compounds suggests that the presence of various substituents
in the benzylidene moiety, and their position as well, may
strongly influence the ability to interfere with the photosynthetic
apparatus. In particular, the presence of a trifluoromethyl group
at any of the three positions, as in compounds 30-32, was found
to significantly enhance the effect against the Hill reaction.
The stereochemistry of the exocyclic double bond in lactones
6-39 was confirmed by bidimensional NOESY experiment.

Photosynthesis-Inhibiting Nostoclide Analogues
J. Agric. Food Chem., Vol. 56, No. 7, 2008 2327
Table 2. In Vitro Effects of Nostoclide Analogues on Ferricyanide
Reduction by Functionally Intact Chloroplasts Isolated from
Spinacia oleracea Leavesa
compd
arylidene group
benzylidene
5 µM
10 µM
6
7
8
9
12.7 ( 3.2
N
29.2 ( 1.4
N
1,3-dioxalenebenzylidene
2,4,6-trimethoxybenzylidene
4-dimethylaminobenzylidene
2-chloro-4-dimethylaminobenzylidene
2,5-dimethoxybenzylidene
4-nitrobenzylidene
3-bromobenzylidene
4-methylbenzylidene
3-nitrobenzylidene
3-methylbenzylidene
4-chlorobenzylidene
3-chlorobenzylidene
4-methoxybenzylidene
4-fluorobenzylidene
4-bromobenzylidene
3-fluorobenzylidene
2-fluorobenzylidene
2-chlorobenzylidene
2-methylbenzylidene
4-ethylbenzylidene
2-bromobenzylidene
pentafluorobenzylidene
4-cyanobenzylidene
4-trifluoromethylbenzylidene
3-trifluoromethylbenzylidene
2-trifluoromethylbenzylidene
3-cyanobenzylidene
3-dimethylaminobenzylidene
4-phenylbenzylidene
25.2 ( 2.4
5.7 ( 2.7
13.8 ( 1.5
30.3 ( 0.6
49.8 ( 1.6
13.8 ( 3.6
N
30.0 ( 1.0
8.0 ( 2.1
N
5.8 ( 0.7
8.5 ( 0.7
9.2 ( 1.1
N
9.5 ( 2.9
24.5 ( 3.3
19.4 ( 2.3
16.7 ( 0.4
40.6 ( 1.5
N
43.6 ( 2.1
7.1 ( 1.5
25.37 ( 4.2
43.5 ( 2.7
57.8 ( 1.0
22.6 ( 2.9
8.0 ( 1.7
39.5 ( 0.8
16.7 ( 2.6
5.8 ( 1.4
20.3 ( 4.8
15.0 ( 1.4
25.6 ( 1.8
N
28.8 ( 1.2
49.5 ( 1.9
30.8 ( 3.7
26.0 ( 0.1
50.7 ( 4.1
21.8 ( 2.2
6.6 ( 2.8
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
diuron
Figure 5. Comparison between the effectiveness of 3-benzyl-5-(aryl-
methylene)-furan-2(5H)-ones 6-8, 10, 11, 15-17, 20, 21, 29, and 30,
and their (4-bromobenzyl)- counterparts (38). The photosynthetic electron
transport rate was measured either in the absence or in the presence of
each compound at 20 µM. Assays were carried out in triplicate, and values
are expressed as percentage ( SD of untreated controls. The 1:1 line
indicates equipotency. A point above the line shows that the brominated
analogue is less effective than the corresponding nonbrominated
compound, vice versa for a point below the line.
N
N
34.6 ( 2.7
27.3 ( 4.8
23.5 ( 4.5
N
10.9 ( 3.2
N
55.5 ( 1.7
49.9 ( 1.7
44.9 ( 2.6
N
38.6 ( 5.4
N
However, when added at micromolar concentrations none of
the compounds was capable of completely suppressing the Hill
reaction. Nevertheless, their inhibitory potential is higher than
that of other nostoclide analogues previously characterized in
our laboratories (37, 38). Moreover, the strong effect of the
substituents in the benzylidene moiety in varying nostoclide
effectiveness opens the way to the exploitation of their structure
for the design of new substances endowed with biological
activity. On the basis of a structure–activity relationship analysis
of the present data, work is currently under way both to achieve
the synthesis of new nostoclide analogues with better photo-
synthesis-inhibiting properties and to evaluate in vivo effects
of the most active compounds.
2-hydroxybenzylidene
3-hydroxybenzylidene
4-hydroxybenzylidene
3-hydroxy-4-methoxybenzylidene
N
N
N
N
N
6.9 ( 0.8
6.5 ( 2.3
N
93.2 ( 0.5
95.1 ( 0.7
a Basal activity was measured as described under Materials and Methods either
in the absence or in the presence of nostoclide analogues at a concentration of 5
or 10 µM. Each treatment was carried out in triplicate, and values ((SD) were
expressed as percent inhibition of the rate of ferricyanide reduction in untreated
controls. N, no effect (P < 0.05).
As to the scaffold effect, the activity of 12 of the compounds
was compared with that of a group of 3-(4-bromobenzyl)-5-
arylmethylene-5H-furan-2-one lactones, previously synthesized
and characterized (38), that differ only by a bromine substituent
in the benzyl moiety. The effect of each pair on the rate of the
light-driven electron transport chain at 20 µM is shown in
Figure 5. A noteworthy correlation between the corresponding
effects seems to account once more for a pivotal role of the
substituents in the benzylidene moiety as the determinant of
the biological activity. In the case of the active compounds,
the distribution of all dots above the 1:1 line, with the only
exception that of compound 16 versus its brominated counter-
part, suggests a general, slightly higher effectiveness of non-
brominated nostoclide analogues, mainly for compounds 8 and
10. Preliminary data seem to relate such a higher efficacy to a
different water solubility, thus facilitating the access of the
inhibitors to the active site and/or their partition between water
and the lipophilic thylakoid membranes. However, further data
are required to elucidate this point.
ACKNOWLEDGMENT
We acknowledge the technical assistance of Dr. Andrea
Raccagni.
LITERATURE CITED
(1) Stetter, J.; Lieb, F. Innovation in crop protection: trends in
research. Angew. Chem., Int. Ed. 2000, 39, 1724–1744.
(2) Tomlin, C., Ed. The Pesticide Manual; Royal Society of Chem-
istry: Cambridge, U.K., 1994.
(3) Böger, P.; Wakabayashi, K.; Hirai, K. Herbicide Classes in
DeVelopment. Mode of Action, Targets, Genetic Engineering,
Chemistry; Springer-Verlag: Berlin, Germany, 2002.
(4) Devine, M.; Shukla, A. Altered target sites as a mechanism of
herbicide resistance. Crop Prot. 2000, 19, 881–889.
(5) Preston, C. Herbicide resistance in weeds endowed by enhanced
detoxification: complications for management. Weed Sci. 2004,
52, 448–453.
(6) Heap, I. International Survey of Herbicide Resistant Weeds; http://
www.weedscience.org (accessed Sept 1, 2007).
(7) Short, P. L. Growing agrochemical research and development.
Chem. Eng. News 2005, 83, 19–22.
(8) Kropff, M. J.; Walter, H. EWRS and the challenges for weed
research at the start of a new millennium. Weed Res. 2000, 40,
7–10.
A number of new analogues of the naturally occurring toxins
nostoclides were synthesized, purified, and thoroughly charac-
terized from a chemical point of view. Their potential as
inhibitors of photosynthetic electron transfer was investigated.
Several of them were able to various degrees to interfere with
the light-driven ferricyanide reduction by isolated chloroplasts.

2328 J. Agric. Food Chem., Vol. 56, No. 7, 2008
Teixeira et al.
(9) Lein, W.; Börnke, F.; Reindl, A.; Ehrhardt, T.; Stitt, M.;
Sonnewald, U. Target-based discovery of novel herbicides. Curr.
Opin. Plant Biol. 2004, 7, 219–225.
(32) Gleason, F. K. The natural herbicide, cyanobacterin, specifically
disrupts thylakoid membrane structure in Euglena gracilis strain
Z. FEMS Microbiol. Lett. 1990, 68, 77–82.
(33) Demuner, A. J.; Barbosa, L. C. A.; Veloso, D. P.; Howarth, O. W.
Synthesis and plant growth regulatory activity of 6R,7ꢀ-dihy-
droxyvouacapan-17ꢀ-oic acid derivatives. Aust. J. Chem. 1998,
51, 61–66.
(10) Copping, L. G. Crop Protection Agents from Nature; Royal
Society of Chemistry: Cambridge, U.K., 1996.
(11) Godfrey, C. R. A. Agrochemicals from Natural Products; Dekker:
New York, 1994.
(34) Barbosa, L. C. A.; Demuner, A. J.; Maltha, C. R. A.; Silva, P. S.;
Silva, A. A. Synthesis and phytotoxic activity evaluation of new
oxygenated analogues of helminthosporic acid. Quim. NoVa 2003,
26, 655–660.
(35) Barbosa, L. C. A.; Costa, A. V.; Veloso, D. P.; Lopes, J. L. C.;
Terrones, M. G. H.; Diaz, B. K.; Hennsen, B. L. Phytogrowth-
inhibitory lactones derivatives of glaucolide B. Z. Naturforsch.
2004, 59C, 803–810.
(36) Demuner, A. J.; Barbosa, L. C. A.; Veloso, D. P. New
8-oxabicyclo[3.2.1]oct-6-en-3-one derivatives with plant growth
regulatory activity. J. Agric. Food Chem. 1998, 46, 1173–1176.
(37) Barbosa, L. C. A.; Demuner, A. J.; Alvarenga, E. S.; Oliveira,
A.; King-Diaz, B.; Lotina-Hennsen, B. Phytogrowth- and photo-
synthesis-inhibiting properties of nostoclide analogues. Pest
Manag. Sci. 2006, 62, 214–222.
(38) Barbosa, L. C. A.; Rocha, M. E.; Teixeira, R. R.; Maltha, C. R. A.;
Forlani, G. Synthesis of 3-(4-bromobenzyl)-5-(arylmethylene)-
5H-furan-2-ones and their activity as inhibitors of the photosyn-
thetic electron transport chain. J. Agric. Food Chem. 2007, 55,
8562–8569.
(12) Duke, S. O.; Romagni, J. G.; Dayan, F. E. Natural products as
sources for new mechanisms of herbicidal action. Crop Prot. 2000,
19, 583–589.
(13) Duke, S. O.; Dayan, F. E.; Romagni, J. G.; Rimando, A. M.
Natural products as sources of herbicides: current status and future
trends. Weed Res. 2000, 40, 99–111.
(14) Duke, S. O.; Dayan, F. E.; Rimando, A. M.; Schrader, K. K.;
Aliotta, G.; Oliva, A.; Romagni, J. G. Chemicals from nature for
weed management. Weed Sci. 2002, 50, 138–151.
(15) Sanjai, S.; Pandey, A. K. Microbial metabolites as eco-friendly
agrochemicals for the next millenium. Appl. Microbiol. Biotechnol.
2001, 55, 395–403.
(16) Klink, J. V.; Brophy, J. J.; Perry, N. B.; Weavers, R. T.
ꢀ-triketones from Myrtaceae: isoleptospermone from Leptosper-
mum scoparium and Papuanone from Corymbia dallachia. J. Nat.
Prod. 1999, 62, 487–489.
(17) Mitchell, G.; Bartlett, D. W.; Fraser, T. E. M.; Hawkes, T. R.;
Holt, D. C.; Townson, J. K.; Wichert, R. A. Mesotrione: a new
selective herbicide for use in maize. Pest Manag. Sci. 2001, 57,
120–128.
(18) Chaabaiane, H.; Cooper, J. F.; Azouzi, L.; Coste, C. M. Influence
of soil properties on the adsorption-desorption of sulcotrione and
its hydrolysis metabolites on various soils. J. Agric. Food Chem.
2005, 53, 4091–4095.
(19) Romagni, J. G.; Allen, S. N.; Dayan, F. E. Allelopathic effects of
volatile cineoles on two weedy plant species. J. Chem. Ecol. 2000,
26, 303–313.
(20) Romagni, J. G.; Duke, S. O.; Dayan, F. E. Inhibition of asparagine
synthetase by 1,4-cineole, the key to mode of action of cin-
methylin. Plant Physiol. 2000, 123, 725–732.
(21) Vyvyan, J. R. Allelochemicals as leads for new herbicides and
agrochemicals. Tetrahedron 2002, 58, 1631–1646.
(22) Macías, F. A.; Molinillo, J. M. G.; Varela, R. M.; Galindo, J. C. G.
Allelopathysa natural alternative for weed control. Pest Manag.
Sci. 2007, 63, 327–348.
(23) Xuan, T. D.; Elzaawely, A. A.; Fukuta, M.; Tawata, S. Herbicidal
and fungicidal activities of lactones in kava (Piper methyusticum).
J. Agric. Food Chem. 2006, 54, 720–725.
(24) Yang, X.; Shimizu, Y.; Steiner, J. R.; Clardy, J. Nostoclide I and
II, extracellular metabolites from a symbiotic cyanobacterium,
Nostoc sp., from the lichen Peltigera canina. Tetrahedron Lett.
1993, 5, 761–764.
(25) Negishi, E.; Kotora, M. Regio- and stereoselective synthesis of
γ-alkylidenebutenolides and related compounds. Tetrahedron
1997, 53, 6707–6738.
(39) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, U.K., 1988.
(40) Mancuso, A. J.; Huang, S. L.; Swern, D. Oxidation of long-chain
and related alcohols to carbonyls by dimethyl sulfoxide ‘activated’
by oxalyl chloride. J. Org. Chem. 1978, 43, 2480–2482.
(41) Pettit, G. R.; Grealish, M. P.; Jung, K.; Harmel, E.; Pettit, R. K.;
Chaput, J. C.; Schmidt, J. M. Antineoplastic agents. 465. Structural
modificaction of resveratrol: sodium reverastatin phosphate.
J. Med. Chem. 2002, 45, 2534–2542.
(42) Näsman, J. H. 3-Methyl-2(5H)-furanone-(2(5H)-furanone, 3-methyl).
Org. Synth. 1990, 6, 162–174.
(43) Boukouvalas, J.; Maltais, F.; Lachance, N. Furanolate-based
strategy for sequential 2,3,4-trisubstitution of butenolide: total
synthesis of nostoclides I and II. Tetrahedron Lett. 1994, 35, 7897–
7900.
(44) Lipton, M. F.; Sorensen, C. M.; Sadler, A. C.; Shapiro, R. H. A
convenient method for the accurate estimation of concentrations of
alkyllithium reagents. J. Organomet. Chem. 1980, 186, 155–158 .
(45) Teixeira, R. R.; Barbosa, L. C. A.; Santana, J. O.; Veloso, D. P.;
Ellena, J.; Doriguetto, A. C.; Drew, M. G. B.; Ismail, F. M. D.
Synthesis and structural characterization of two nostoclides
analogues. J. Mol. Struct. 2006, 837, 197–205.
(46) Teixeira, R. R.; Barbosa, L. C. A.; Maltha, C. R. A.; Rocha, M. E.;
Bezerra, D. P.; Costa-Lotufo, L. V.; Pessoa, C.; Moraes, M. O.
Synthesis and cytotoxic activity of some 3-benzyl-5-arylidene-
furan-2(5H)-ones. Molecules 2007, 12, 1101–1116.
(26) Brückner, R. The ꢀ-elimination route to stereodefined γ-alky-
lidenebutenolides. Chem. Commun. 2001, 2001, 141–152.
(27) Brückner, R. The synthesis of γ-alkylidenebutenolides. Curr. Org.
Chem. 2001, 5, 679–718.
(28) Pignatello, J. J.; Porwoll, J. J.; Carlson, R. E.; Xavier, A.; Gleason,
F. K.; Wood, J. M. Structure of the antibiotic cyanobacterin, a
chlorine-containing γ-lactone from the freshwater cyanobacterium
Scytonema hofmanni. J. Org. Chem. 1983, 48, 4035–4038.
(29) Gleason, F. K.; Baxa, C. A. Activity of the natural algicide,
cyanobacterin, on eukaryotic microorganisms. FEMS Microbiol.
Lett. 1986, 33, 85–88.
(47) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P.
AM1: a new quantum chemical molecular model. J. Am. Chem.
Soc. 1985, 107, 3902.
(48) Titan, version 1; Wavefunction: Irvine, CA, 2000.
(49) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. The
vinylogous aldol reaction: a valuable, yet understated carbon-carbon
bond-forming maneuver. Chem. ReV. 2000, 100, 1929–1972.
(50) Boukouvalas, J.; Lachance, N.; Ouellet, M.; Trudeu, M. Facile
access 4-aryl-2(5H)-furanones by Suzuki cross coupling: efficient
synthesis of rubrolides C and E. Tetrahedron Lett. 1998, 39, 7665–
7668.
(30) Gleason, F. K.; Case, D. E. Activity of the natural algicide,
cyanobacterin, on angiosperms. Plant Physiol. 1986, 80, 834–
838.
(31) Gleason, F. K.; Paulson, J. L. Site of action of the natural algicide,
cyanobacterin, in the blue-green alga. Synechococcus sp. Arch.
Microbiol. 1984, 138, 273–277.
(51) Bellina, F.; Anselmi, C.; Stéphane, V.; Mannina, L.; Rossi, R.
Selective synthesis of (Z)-4-aryl-5-[1-(aryl)methylidene]-3-
bromo-2(5H)-furanones. Tetrahedron 2001, 57, 9997–10007.
(52) Bellina, F.; Anselmi, C.; Rossi, R. Total synthesis of rubrolide
M and some of its unnatural congeners. Tetrahedron Lett. 2002,
43, 2023–2027.

Photosynthesis-Inhibiting Nostoclide Analogues
J. Agric. Food Chem., Vol. 56, No. 7, 2008 2329
(53) Boukouvalas, J.; Beltrán, P. P.; Lachance, N.; Côte, S.; Maltais,
M.; Pouliot, M.
of ꢀ-unsubstituted (Z)-γ-alkylidenebutenolides using bromine
as removable stereocontrol element. Synlett 2007,
219–222.
A new, highly stereoselective synthesis
Received for review October 8, 2007. Revised manuscript received
January 25, 2008. Accepted January 25, 2008. We are grateful to the
following Brazilian agencies: Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq) for research fellowships (L.C.A.B.,
R.R.T., J.W.M.C.) and financial support and Fundação de Amparo à
Pesquisa de Minas Gerais (FAPEMIG) and FINEP for financial
support. We are also grateful for partial support from the University
of Ferrara (Fondo d’Ateneo 2006 and 2007).
a
(54) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1990.
(55) Wei, H.; Wang, J. F.; Liu, G. Z.; Hong, G. F.; Liu, H. M. Facile
synthesis of γ-alkylidenobutenolides. Org. Biomol. Chem. 2007,
5, 1247–1250.
JF072964G