N-Phthaloylglycine-Derived Strigol Analogues. Influence of the D-Ring on Seed Germination Activity of the Parasitic Weeds Striga hermonthica and Orobanche crenata

Article abstract of DOI:10.1021/jf9604652

Several strigol analogues with modifications in the D-ring were synthesized and assayed for germination stimulatory activity of seeds of Striga hermonthica and Orobanche crenata. All of these D-ring analogues are derived from N-phthaloylglycine as the common ABC-fragment. It was concluded that the correct structure of the 2(5H)-furanone D-ring is essential to retain full biological activity.

Full text of DOI:10.1021/jf9604652

2284
J. Agric. Food Chem. 1997, 45, 2284−2290
N-P h th a loylglycin e-Der ived Str igol An a logu es. In flu en ce of th e
D-Rin g on Seed Ger m in a tion Activity of th e P a r a sitic Weed s Str iga
h er m on th ica a n d Or oba n ch e cr en a ta
J an Willem J . F. Thuring, Harry H. Bitter, Margreet M. de Kok, Ge´rard H. L. Nefkens,
Annemiek M. D. A. van Riel, and Binne Zwanenburg*
NSR-Center for Molecular Structure, Design and Synthesis, Department of Organic Chemistry,
University of Nijmegen, Toernooiveld, 6525 ED Nijmegen, The Netherlands
Several strigol analogues with modifications in the D-ring were synthesized and assayed for
germination stimulatory activity of seeds of Striga hermonthica and Orobanche crenata. All of these
D-ring analogues are derived from N-phthaloylglycine as the common ABC-fragment. It was
concluded that the correct structure of the 2(5H)-furanone D-ring is essential to retain full biological
activity.
Keyw or d s: Striga; Orobanche; germination; strigol analogue
INTRODUCTION
The extremely devastating parasitic weeds Striga and
Orobanche cause severe reductions in food crop yield of
several graminaceous and leguminous crops in tropical
and semitropical areas of the eastern hemisphere (Mus-
selman, 1987; Parker and Riches, 1993). An absolute
requirement for the seeds of these parasitic weeds to
germinate is exposure to a chemical substance, which
is usually present in the root exudate of a potential host
plant (Press et al., 1990; Butler, 1995). The first known
naturally occurring germination stimulant, (+)-strigol
(1; Figure 1), was isolated from the root exudate of the
false host cotton (Gossypium hirsutum L.) (Cook et al.,
1966, 1972). Recently, (+)-strigol (1) was also identified
in the root exudates of the Striga host plants maize (Zea
mays L.) and proso millet (Panicum miliaceum L.)
(Siame et al., 1993). In addition, some structurally
closely related “strigolactones” (Butler, 1995) have been
identified in the root exudates of other Striga hosts, viz.
sorgolactone (2) (Hauck et al., 1992) and alectrol (3)
(Mu¨ller et al., 1992). An attractive control strategy for
the eradication of infested fields is the concept of
F igu r e 1. Strigolactones 1-3 and some active analogues.
suicidal germination, i.e. introduction of a germination-
stimulating agent into the soil to induce germination
of the parasitic seeds in the absence of a host plant
(Eplee, 1975).
Sch em e 1. Molecu la r Mech a n ism for Ger m in a tion
However, strigolactones 1-3 are not suitable for weed
control purposes, because their structures are too
complicated to allow synthesis in an economically
feasible manner. During the past 15 years several
studies have been conducted to design synthetic ana-
logues with the aim to obtain relatively simple com-
pounds possessing high germination stimulatory activ-
ity being suitable as potential herbicides and to locate
the bioactiphore, i.e. the part of the molecule, which is
primarily responsible for the biological activity (J ohnson
et al., 1976, 1981; Vail et al., 1990; Bergmann et al.,
1993; Zwanenburg et al., 1994). These studies have
mainly been focused on the ABC-part of the strigolac-
tones. It was concluded that there exists a relatively
large degree of structural freedom in this part of the
molecule to retain full biological activity. One of the
most potent synthetic strigol analogues is GR24 (4),
containing an aromatic A-ring (J ohnson et al., 1976,
1981), the preparation of which is much easier than that
of strigol (1) (Mangnus et al., 1992a). Further structure-
bioactivity relationship studies revealed that the con-
necting enol ether unit is essential for stimulatory
activity. This finding has led to the proposal of a
molecular mechanism for germination (Scheme 1) in
which the bioactiphoric CD-part plays a key role (Mang-
nus and Zwanenburg, 1992).
* Author to whom correspondence should be ad-
dressed (fax +31.24.3652929; e-mail zwanenb@
sci.kun.nl).
S0021-8561(96)00465-7 CCC: $14.00
© 1997 American Chemical Society

N-Phthaloylglycine-Derived Strigol Analogue
J. Agric. Food Chem., Vol. 45, No. 6, 1997 2285
of MacAlpine et al. (1976). The crude product was purified by
flash chromatography (SiO2, hexane/ethyl acetate 2:1) to give
9 as a yellow oil in 80% yield: 1H NMR (CDCl3, 90 MHz) δ 6.2
(d, 1H, J ) 6 Hz, dCHR), 6.8 (d, 1H, J ) 1 Hz, CHBr), 7.62
(dd, 1H, J ) 6 Hz, J ) 1 Hz, dCHâ).
5-Bromo-4-methoxy-3-methyl-2(5H)-furanone (12). 4-Meth-
oxy-3-methyl-2(5H)-furanone (12a ) (6.04 g, 47 mmol) was
brominated according to the procedure of MacAlpine et al.
(1976). The crude product was purified by distillation to give
12 as a yellow oil in 55% yield: bp 110-120 °C (3 mmHg); 1H
NMR (CDCl3, 90 MHz) δ 2.0 (s, 3H, CH3), 4.1 (s, 3H, OCH3),
6.6 (s, 1H, CHBr).
5-Bromo-4-phenyl-2(5H)-furanone (15). Precursor 15a was
prepared in 21% yield by reduction of phenylmaleic anhydride
34a with lithium aluminum hydride according to the procedure
of Kayser and Morand (1980). Bromination of 15a with
N-bromosuccinimide (NBS) following the procedure of Mac-
Alpine et al. (1976) afforded 15 (Steyn et al., 1965) in quanti-
tative yield and was used in the coupling reaction without
further purification: 1H NMR (CDCl3, 90 MHz) δ 6.4 (s, 1H,
dCH), 7.2 (s, 1H, CHBr), 7.5 (m, 5H, arom H) (see Scheme 4).
3-Phenyl-2(5H)-furanone (14a ). Phenylmaleic anhydride
34a was prepared according to the method of Miller et al.
(1949). To a solution of 34a (3.24 g, 19.0 mmol) in methanol
(15 mL) was gradually added dicyclohexylamine (DCA; 3.78
g, 21.0 mmol) with stirring at 0 °C. After 1 h, the precipitate
of the DCA-salt 35a was removed by filtration and washed
with small portions of cold methanol to give 5.44 g (76%) of
35a as one single regioisomer according to 1H-NMR analysis:
1H NMR (CDCl3 + few drops of D2O, 100 MHz) δ 1.21-2.12
(m, 20H, 20 cyclohexyl H), 2.98 (m, 2H, 2 CHN), 3.82 (s, 3H,
OCH3), 6.41 (s, 1H, dCH), 7.36 (m, 5H, 5 arom H).
Thus far, relatively little attention has been paid to
the influence of the structure of the D-ring. It was
demonstrated that replacement of this 2(5H)-furanone
moiety by other substituents leads to complete loss of
bioactivity (Mangnus and Zwanenburg, 1992; Bergmann
et al., 1993).
The present paper describes the influence of the
structure of the D-ring on the germination stimulatory
activity of Striga hermonthica (Del.) Benth. and
Orobanche crenata Forsk. seeds. To make such an
evaluation feasible, several five-membered ring ana-
logues of the 3-methyl-2(5H)-furanone moiety, as is
present in the strigolactones 1-3 and GR24 (4), were
synthesized and subsequently coupled with a common
ABC-fragment. We have selected Nijmegen 1 (5),
derived from N-phthalimidoglycine, as the reference
compound, the preparation of which has been reported
recently (Nefkens et al., 1997a). It was demonstrated
that 5 exhibits considerable activity as a germination
stimulant. An important benefit of using 5 as the
reference compound is that it contains an achiral ABC-
fragment, which precludes the formation of a diaster-
eomeric mixture after its coupling with a D-ring.
Moreover, the preparation of 5 is simple, because readily
available aldehyde 6 (Scheme 1) is used as the ABC-
precursor.
MATERIALS AND METHODS
Nom en cla tu r e. The AUTONOM 1.0 program, provided by
the Beilstein Institute and Springer Verlag, Weinheim, Ger-
many, was used.
A solution of DCA-salt 35a (5.44 g, 14.0 mmol) in THF (10
mL) was treated with trifluoroacetic acid (TFA; 1.71 g, 15.0
mmol) at 0 °C. The TFA-DCA salt was removed by filtration.
Triethylamine (1.4 g, 14 mmol) at 0 °C was gradually added
to the filtrate. The temperature was lowered to -30 °C, and
then ethyl chloroformate (1.6 g, 14 mmol) was added. The
temperature was kept at -30 °C for 1 h, after which time the
precipitate of Et3N‚HCl was filtered off. A solution of NaBH4
(0.98 g, 26 mmol) in water (10 mL) was slowly added to the
filtrate at 0 °C under vigorous stirring. The reaction mixture
was stirred overnight at room temperature. The salts were
removed by filtration and washed with diethyl ether. The
filtrate was dried (MgSO4) and concentrated in vacuo to give
14a as a greenish solid. Purification by recrystallization (two
times) from hexane/benzene gave 14a (0.54 g, 24%) as colorless
plates: mp 85 °C (lit. 89 °C; Swain et al., 1944). 1H-NMR data
were in agreement with those reported previously (Kayser and
Morand, 1980).
5-Bromo-3-phenyl-2(5H)-furanone (14). Compound 14a was
brominated with NBS following the procedure of MacAlpine
et al. (1976). The reaction was stopped after 80% conversion
(unfortunately, the reaction did not go to completion) to give
a mixture of 14/14a (4:1), which was used in the coupling
reaction without further purification. 1H-NMR data of 14 were
in complete agreement with those reported previously (Edgar
et al., 1978).
3-Ethyl-3-phenylsulfanyldihydrofuran-2-one (31). To a cooled
solution (-78 °C) of freshly prepared lithium diisopropylamide
(5.7 mmol) in tetrahydrofuran (THF; 20 mL) was gradually
added a solution of 3-phenylsulfanyldihydrofuran-2-one (30)
(1.0 g, 5.2 mmol), prepared according to the procedure of Iwai
et al. (1977), in THF (10 mL) (see Scheme 3). After 15 min of
stirring at -78 °C, ethyl iodide (2.0 g, 14 mmol) was added
and the reaction mixture was stirred overnight at room
temperature. Saturated NH4Cl was added and THF was
removed in vacuo. The residue was extracted with ethyl
acetate (three times). The combined extracts were washed
with water (two times), dried (MgSO4), and concentrated in
vacuo to give 31 (0.68 g, 60%) as an oil, which was used in the
next reaction without further purification: purity 95% accord-
ing to GC; 1H NMR (CDCl3, 90 MHz) δ 1.1 (t, J ) 7.5 Hz, 3H,
CH3), 1.9 (m, 2H, CH2), 2.2 (q, J ) 7.5 Hz, 2H, CH2CH3), 4.2
(m, 2H, CH2O), 7.2 (m, 5H, 5 arom H).
Syn th esis. General Remarks. IR spectra were recorded
on Perkin-Elmer 298 infrared spectrophotometer. 1H-NMR
spectra (90 MHz) were recorded on a Varian EM 390 spec-
trometer, Varian Analytical Instruments (Houten, The Neth-
erlands); 100 MHz and 400 MHz 1H-NMR spectra were
recorded on a Bruker AC 100 spectrometer and a Bruker AM-
400 spectrometer, respectively (Me4Si as internal standard),
both from Brucker (Wissembourg, France). All coupling
3
constants are given as J in hertz, unless indicated otherwise.
For mass spectra a double-focusing VG7070E mass spectrom-
eter was used. GC/MS spectra were run on a Varian Saturn
2 GC/MS ion-trap system. Separation was carried out on a
fused-silica capillary column (DB-5, 0.25 µm film thickness,
30 m × 0.25 mm). Helium was used as carrier gas, and
electron impact (EI) was used as ionization mode. GLC was
conducted with a Hewlett-Packard (Avondale, PA) HP 5890
gas chromatograph, using a capillary column (25 m) of HP-1
and nitrogen (2 mL/min, 0.5 atm) as the carrier gas. Melting
points were measured with a Reichert Thermopan microscope
and are uncorrected. Elemental analyses were performed at
the Department of Micro-analysis of this laboratory.
Solvents were dried using the following methods: Dichlo-
romethane was distilled from P2O5. Diethyl ether was distilled
from NaH. Hexane was distilled from CaH2. Tetrahydrofuran
was distilled from lithium aluminum hydride just before use.
All other solvents were of analytical grade. Thin layer
chromatography (TLC) was carried out on Merck precoated
silica gel 60 F254 plates (0.25 mm) using the eluents indicated.
Spots were visualized with UV or using a molybdate spray.
“Flash” chromatography was carried out at a pressure of ca.
1.5 atm, using Merck Kieselgel 60H. Column chromatography
at atmospheric pressure was carried out, using Merck Kiesel-
gel 60.
Nijmegen 1 (5) was prepared as reported previously (Nefkens
et al., 1997a). 2(5H)-Furanone (9a ) (Takano and Ogasawara,
1973), 3-bromophthalide (8) (Koten and Sauer, 1973), 5-bromo-
4-methyl-2(5H)-furanone (10) (J ohnson et al., 1981), and
5-chloro-3,5-dimethyl-2(5H)-furanone (11) (Cane´vet and Graff,
1978) were prepared following literature procedures (see
Scheme 2).
5-Bromo-2(5H)-furanone (9). 2(5H)-Furanone (9a ) was bro-
minated with N-bromosuccinimide according to the procedure
3-Ethyl-2(5H)-furanone (13a ). A solution of 31 (8.3 g, 37.4
mmol) in dichloromethane (50 mL) at 0 °C was treated with

2286 J. Agric. Food Chem., Vol. 45, No. 6, 1997
Thuring et al.
80% m-chloroperbenzoic acid (mCPBA; 7.7 g, 45 mmol) in
dichloromethane (30 mL). The reaction mixture was stirred
at 0 °C for 1 h. Then a saturated solution of Na2SO3 (50 mL)
was added, and the organic phase was successively washed
with saturated NaHCO3, water, and brine. Drying (MgSO4)
and concentration in vacuo afforded the crude sulfoxide in
nearly quantitative yield. The residue was heated at reflux
temperature in CCl4 (50 mL) for 1 h. The solvent was removed
under reduced pressure, and the residue was purified by
distillation to give 13a (1.5 g, 40%) as a colorless oil: bp 42 °C
(0.1 mmHg); 1H NMR (CDCl3, 90 MHz) δ 1.1 (t, J ) 6 Hz, 3H,
CH3), 2.2 (m, 2H, CH2CH3), 4.7 (m, 2H, CH2), 7.0 (m, 1H,
dCH).
Bromination of 3-Ethyl-2(5H)-furanone (13a ). Compound
13a (1.0 g, 8.9 mmol) was brominated with NBS according to
the procedure of MacAlpine et al. (1976). A mixture of mainly
13 and 32 in an equimolar ratio was isolated in quantitative
yield, which could not be separated. This mixture was used
in the coupling reaction (vide infra).
dCHO). Anal. Calcd for C17H13NO7: C, 59.48; H, 3.82; N, 4.08.
Found: C, 59.32; H, 3.83; N, 4.04.
Methyl 3-(3,4-Dimethyl-5-oxo-2,5-dihydrofuran-2-yloxy)-2-
(1,3-dioxo-1,3-dihydroisoindol-2-yl)acrylate (22). Coupling of
5-chloro-3,4-dimethyl-2(5H)-furanone (11) with Sheehan al-
dehyde 6 (1.24 g, 5.00 mmol) was carried out as described in
the general procedure. The crude product was purified by
flash chromatography (SiO2, hexane/ethyl acetate 1:2) to give
22 (1.75 g, 95%) as a slightly yellow solid. An analytical
sample was obtained by crystallization from diisopropyl ether/
1
ethyl acetate: mp 155-157 °C; H NMR (CDCl3, 100 MHz) δ
1.85 (m, 3H, CH3), 1.99 (m, 3H, CH3), 3.78 (s, 3H, OCH3), 6.02
(br s, 1H, OCHO), 7.92 (m, 5H, 4 arom H + dCHO); MS [EI,
m/z, rel intensity (%)] 357 ([M]+, 1.8), 246 ([C12H8NO5]+, 57.9),
111 ([C6H7O2]+, 100). Anal. Calcd for C18H15NO7: C, 60.51;
H, 4.23; N, 3.92. Found: C, 60.55; H, 4.16; N, 3.85.
Methyl 2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(3-methoxy-
4-methyl-5-oxo-2,5-dihydrofuran-2-yloxy)acrylate (23). Cou-
pling of 5-bromo-4-methoxy-3-methyl-2(5H)-furanone (12) with
Sheehan aldehyde 6 (1.20 g, 4.90 mmol) was carried out as
described in the general procedure. The crude product (1.55
4-Bromo-2-methylcyclopent-2-enone (18). 2-Methylcyclopent-
2-enone (18a ) was prepared as described by Gassman and
Pascone (1973). The bromination reaction was performed
similarly as reported by DePuy et al. (1964) starting from 18a
(4.20 g, 43.8 mmol): yield 5.51 g (72%) of 18 after distillation;
bp 52-55 °C (0.25 mmHg); 1H NMR (CDCl3, 100 MHz) δ 1.85
1
g, 85%, purity according to H-NMR > 90%) was crystallized
from 2-propanol to give 23 (1.16 g, 63%) as colorless crystals:
1
4
mp 173 °C; H NMR (CDCl3, 100 MHz) δ 1.89 (d, J < 1 Hz,
3H, CH3), 3.78 (s, 3H, OCH3), 4.05 (s, 3H, dCOCH3), 6.00 (d,
4J < 1 Hz, 1H, OCHO), 7.78 (s, 1H, dCHO), 7.73-7.97 (m,
4H, 4 arom H); MS [EI, m/z, rel intensity (%)] 373 ([M]+, 0.9),
246 ([C12H8NO5]+, 5.2), 127 ([C6H7O3]+, 100). Anal. Calcd for
C18H15NO8: C, 57.91; H, 4.05; N, 3.75. Found: C, 58.07; H,
4.04; N, 3.76.
2
(m, 3H, CH3), 2.73 (dd, J ) 2 Hz, J ) 20 Hz, 1H, CH2), 3.08
(dd, J ) 6 Hz, 2J ) 20 Hz, 1H, CH2), 5.11 (m, 1H, CHBr), 7.32
(m, 1H, dCH).
Coupling of Chloro- and Bromofuranones 8-15 and 17 with
Sheehan Aldehyde 6 (General Procedure). To a solution of
Sheehan aldehyde 6 (10 mmol) in dimethylformamide (DMF;
50 mL) was added potassium tert-butoxide (11 mmol) in a
nitrogen atmosphere. The mixture was cooled to -60 °C, and
a solution of the chloro- or bromofuranone 8-15 or 17 (11
mmol) in DMF (10 mL) was added with stirring. Stirring was
continued for 18 h at room temperature. Then, DMF was
removed in vacuo and the residue was dissolved in a mixture
of water and ethyl acetate. The aqueous layer was extracted
with ethyl acetate (three times), and the combined organic
extracts were washed with water (two times), dried (MgSO4),
and concentrated in vacuo. The crude coupling products 19-
26 and 28 were further purified by flash chromatography and/
or crystallization.
Methyl 2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(3-oxo-1,3-
dihydroisobenzofuran-1-yloxy)acrylate (19). Coupling of 3-bro-
mophthalide (8) with Sheehan aldehyde 6 (2.5 g, 10 mmol)
was carried out as described in the general procedure. The
crude product was purified by crystallization from 2-propanol
to give 19 (2.1 g, 55%) as white crystals: mp 156-160 °C; 1H
NMR (CDCl3, 100 MHz) δ 3.78 (s, 3H, OCH3), 6.72 (br s, 1H,
OCHO), 7.70-7.90 (m, 8H, 8 arom H), 7.97 (s, 1H, dCHO).
Anal. Calcd for C20H13NO7: C, 63.33; H, 3.45; N, 3.69.
Found: C, 62.92; H, 3.43; N, 3.64.
Methyl 2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(5-oxo-2,5-
dihydrofuran-2-yloxy)acrylate (20). Coupling of 5-bromo-2(5H)-
furanone (9) with Sheehan aldehyde 6 (2.5 g, 10 mmol) was
carried out as described in the general procedure. The crude
product was purified by flash chromatography (SiO2, hexane/
ethyl acetate 1:1) to give 20 (1.2 g, 37%) as a white solid. An
analytical sample was obtained by crystallization from
2-propanol: mp 146-148 °C; 1H NMR (CDCl3, 100 MHz) δ 3.78
(s, 3H, OCH3), 6.33 (br s, 1H, OCHO), 6.37 (dm, J ) 5 Hz, 1H,
dCHR), 7.34 (dm, J ) 5 Hz, dCHâ), 7.72-7.96 (m, 5H, 4 arom
H + dCHO); MS [EI, m/z, rel intensity (%)] 329 ([M]+, 1.5),
246 ([C12H8NO5]+, 100), 83 ([C4H3O2]+, 37.5). Analysis Calcd
for C16H11NO7: C, 58.36; H, 3.36; N, 4.25. Found: C, 58.77;
H, 3.34; N, 4.30.
Methyl 2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(4-ethyl-5-
oxo-2,5-dihydrofuran-2-yloxy)acrylate (24) and Methyl 2-(1,3-
Dioxo-1,3-dihydroisoindol-2-yl)-3-[1-(2-oxo-2,5-dihydrofuran-
3-yl)ethoxy]acrylate (33). Sheehan aldehyde 6 (1.1 g, 4.5 mmol)
was treated with the crude mixture, obtained from bromina-
tion of 3-ethyl-2(5H)-furanone (13a ) (8.9 mmol), according to
the general procedure (see Scheme 3). Purification was
accomplished by flash chromatography (SiO2, hexane/ethyl
acetate 1:1) to give coupling products 24 (250 mg, 16%) and
33 (370 mg, 23%) as white solids. Analytical samples of 24
and 33 were obtained by crystallization from ethanol and
n-butyl acetate, respectively.
Compound 24: mp 164 °C; 1H NMR (CDCl3, 100 MHz) δ
1.17 (t, J ) 7.4 Hz, 3H, CH2CH3), 2.35 (br q, J ) 7.4 Hz, 2H,
CH2CH3), 3.79 (s, 3H, OCH3), 6.21 (m, 1H, OCHO), 6.86 (m,
1H, dCH), 7.78 (s, 1H, dCHO), 7.72-7.95 (m, 4H, 4 arom H);
MS [EI, m/z, rel intensity (%)] 357 ([M]+, 2.1), 246 ([C12H8-
NO5]+, 100), 111 ([C6H7O2]+, 29). Anal. Calcd for C18H15NO7:
C, 60.51; H, 4.23; N, 3.92. Found: C, 60.26; H, 4.22; N, 3.91.
Compound 33: mp 162-164 °C; 1H NMR (CDCl3, 100 MHz)
δ 1.54 (d, J ) 6.4 Hz, 3H, CH3), 3.76 (s, 3H, OCH3), 4.90 (m,
2H, OCH2), 5.00 (m, 1H, CHCH3), 7.67-7.97 (m, 6H, 4 arom
H, dCH, dCHO). Anal. Calcd for C18H15NO7: C, 60.51; H,
4.23; N, 3.92. Found: C, 60.26; H, 4.20; N, 4.17.
Methyl 2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(4-phenyl-5-
oxo-2,5-dihydrofuran-2-yloxy)acrylate (25). Coupling of 5-bromo-
3-phenyl-2(5H)-furanone (14) with Sheehan aldehyde 6 (358
mg, 1.45 mmol) was carried out as described in the general
procedure. The crude product was purified by flash chroma-
tography (SiO2, hexane/ethyl acetate 1:1) to give 25 (122 mg,
21%) as a white solid. An analytical sample was obtained by
crystallization from 2-propanol: mp 171-172 °C; 1H NMR
(CDCl3, 100 MHz) δ 3.79 (s, 3H, OCH3), 6.33 (d, J ) 1.6 Hz,
1H, OCHO), 7.35-7.46 (m, 4H, 3 arom H + dCH), 7.70-7.95
(m, 6H, 6 arom H), 7.98 (s, 1H, dCHO); MS [EI, m/z, rel
intensity (%)] 405 ([M]+, 1.7), 246 ([C12H8NO5]+, 81.7), 159
([C10H7O2]+, 100). Anal. Calcd for C22H15NO7: C, 65.19; H,
3.73; N, 3.46. Found: C, 64.84; H, 3.79; N, 3.46.
Methyl 2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(3-phenyl-5-
oxo-2,5-dihydrofuran-2-yloxy)acrylate (26). Coupling of 5-bromo-
4-phenyl-2(5H)-furanone (15) (Steyn et al., 1965) with Sheehan
aldehyde 6 (598 mg, 2.42 mmol) was carried out as described
in the general procedure. The crude product was purified by
flash chromatography (SiO2, hexane/ethyl acetate 2:1) to give
26 (262 mg, 27%) as a white solid. Analytically pure 26 was
obtained by crystallization from 2-propanol: mp 142-144 °C;
1H NMR (CDCl3, 100 MHz) δ 3.77 (s, 3H, OCH3), 6.51 (s, 1H,
Methyl 2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(3-methyl-5-
oxo-2,5-dihydrpfuran-2-yloxy)acrylate (21). Coupling of 5-bromo-
4-methyl-2(5H)-furanone (10) with Sheehan aldehyde 6 (1.23
g, 5.00 mmol) was carried out as described in the general
procedure. The crude product was purified by flash chroma-
tography (SiO2, hexane/ethyl acetate 1:1), followed by crystal-
lization from 2-propanol to give 21 (200 mg, 12%) as white
1
crystals: mp 170-173 °C; H NMR (CDCl3, 100 MHz) δ 2.11
(d, 3H, 4J ) 1.4 Hz, CH3), 3.79 (s, 3H, OCH3), 5.99 (m, 1H,
dCH), 6.08 (br s, 1H, OCHO), 7.72-7.96 (m, 5H, 4 arom H +

N-Phthaloylglycine-Derived Strigol Analogue
J. Agric. Food Chem., Vol. 45, No. 6, 1997 2287
OCHO)*, 6.61 (s, 1H, dCH)*, 7.50 (m, 5H, 5 arom H), 7.78 (m,
4H, 4 arom H), 8.04 (s, 1H, dCHO) (* indicates signals may
be interchanged); MS [EI, m/z, rel intensity (%)] 405 ([M]+,
1.0), 246 ([C12H8NO5]+, 38.6), 159 ([C10H7O2]+, 100). Anal.
Calcd for C22H15NO7: C, 65.19; H, 3.73; N, 3.46. Found: C,
64.9; H, 3.62; N, 3.51.
Sch em e 2. Cou p lin g of D-Rin g P r ecu r sor s 7-18 w ith
Ald eh yd e 6
Methyl 2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(5-oxotet-
rahydrofuran-2-yloxy)acrylate (28). Coupling of 5-chloro-γ-
butyrolactone (17) with Sheehan aldehyde 6 (1.62 g, 6.56
mmol) was carried out as described in the general procedure.
The crude product was purified by recrystallization from
2-propanol to give 28 (1.07 g, 49%) as colorless crystals.
Analytically pure 28 was obtained by repeated crystallization
from 2-propanol: mp 162-164 °C; 1H NMR (CDCl3, 100 MHz)
δ 2.28-2.73 (m, 4H, 2 CH2), 3.78 (s, 3H, OCH3), 5.97 (m, 1H,
OCHO), 7.72-7.97 (m, 5H, 4 arom H + dCHO); MS [CI, m/z,
rel intensity (%)] 332 ([M + 1]+, 2.2), 247 ([C12H9NO5]+, 61),
85 ([C4H5O2]+, 100). Anal. Calcd for C16H13NO7: C, 58.01; H,
3.96; N, 4.23. Found: C, 57.88; H, 3.85; N, 4.23.
Methyl 2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(3-methyl-4-
oxocyclopent-2-enyloxy)acrylate (29). This compound was pre-
pared in a similar way as described for the synthesis of
furanones 19-26, starting from Sheehan aldehyde 6 (1.62 g,
6.56 mmol) and 4-bromo-2-methylcyclopent-2-enone (18) (1.15
g, 6.56 mmol). 1H-NMR analysis of the crude product (2.1 g)
revealed the presence of an equimolar ratio of 29 and cyclo-
pentadienone dimers. Trituration (diisopropyl ether) provided
a solid (1.4 g), consisting of unreacted 6 and coupling product
29. Crystallization from diisopropyl ether/ethyl acetate af-
forded analytically pure 29 (325 mg, 15%) as colorless crys-
stored in the dark for 14 days at 20 °C for Orobanche seeds
and at 30 °C for Striga seeds. Then the conditioning water
was removed and replaced by 100 µL of test solution per disk.
After incubation for 24 h (Striga) and 5 days (Orobanche) in
the dark at indicated temperatures, the germination percent-
age was determined under a microscope. Seeds were consid-
ered to be germinated if the radical protruded through the seed
coat.
In each test series aqueous solutions with 0.1 and 0.001%
(v/v) acetone were used as negative control. Test solutions of
the stimulant GR24 (concentrations of 1 and 0.01 mg/L) were
used as positive controls. All tests were performed in dupli-
cate, and in each test the germination percentages were
determined on 12 disks per treatment.
1
tals: mp 183-184 °C; H NMR (CDCl3, 100 MHz) δ 1.83 (m,
2
3H, CH3), 2.45 (dd, J ) 2.1 Hz, J ) 18.7 Hz, 1H, CH2), 2.89
2
(dd, J ) 6.1 Hz, J ) 18.7 Hz, 1H, CH2), 3.76 (s, 3H, OCH3),
5.28 (m, 1H, OCHCH2), 7.18 (m, 1H, dCH), 7.70-7.95 (m, 5H,
4 arom H + dCHO); MS [EI, m/z, rel intensity (%)] 341 ([M]+,
3.2), 247 ([C12H9NO5]+, 41.9), 95 ([C6H7O]+, 100). Anal. Calcd
for C18H15NO6: C, 63.34; H, 4.43; N, 4.10. Found: C, 63.21;
H, 4.28; N, 4.13.
Methyl 2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-[1-(2-oxo-2,5-
dihydrofuran-3-yl)ethoxy]acrylate (27). To a cooled (-5 °C)
solution of Sheehan aldehyde 6 (2.5 g, 10 mmol) and muco-
chloric acid 16 (1.7 g, 10 mmol) in THF (10 mL) in the presence
of a catalytic amount of dimethylaminopyridine (DMAP) was
added dicyclohexylcarbodiimide (DCC; 2.2 g, 10 mmol).
A
For full details of the bioassay, see Mangnus et al. (1992b).
precipitate of dicyclohexylurea (DCU) gradually formed. After
18 h of stirring at room temperature, the precipitate was
removed by filtration. The residue was concentrated in vacuo.
Purification by flash chromatography (SiO2, hexane/ethyl
acetate 1:1) afforded 27 (1.4 g, 35%) as a white solid. An
analytical sample was obtained by crystallization from acetic
RESULTS AND DISCUSSION
Syn th esis. The final step in the synthesis of D-ring
analogues 5 and 19-29 involves coupling (O-alkylation)
of Sheehan aldehyde 6 with D-rings 7-18 (Scheme 2).
These coupling reactions involve nucleophilic substi-
tution of the corresponding γ-bromo or γ-chloro deriva-
tives 7-15 and 17-18, according to the general proce-
dure for the preparation of strigol and its analogues
(J ohnson et al., 1981), using DMF as the solvent. This
procedure provided the desired products in low to high
yields (Table 1).
The D-ring precursors 7-15 and 17-18 were freshly
prepared before use, because they are generally rather
unstable. The poor stability of these compounds may
account for some of the low yields of the desired products
(Table 1), e.g. during several attempts to prepare carba
D-ring analogue 29. [Dimerization takes place by a
Diels-Alder reaction of a cyclopentadienone intermedi-
ate which results upon dehydrobromination of 18 [cf.
Baraldi et al. (1984, 198) and DePuy et al. (1964).]]
Bischloro-substituted analogue 27 was prepared in an
alternative manner, employing DCC-mediated coupling
conditions in THF with commercially available muco-
chloric acid 16. It was essential to carry out the reaction
in the presence of a catalytic amount of DMAP, which
enhanced the solubility of 16 considerably.
1
acid: mp 157 °C; H NMR (CDCl3, 100 MHz) δ 3.80 (s, 3H,
OCH3), 6.18 (s, 1H, OCHO), 7.73-7.97 (m, 5H, 4 arom H +
dCHO); MS [EI, m/z, rel intensity (%)] 399 ([C16H935Cl37ClNO7]+,
0.7), 397 ([C16H935Cl2NO7]+, 1.1), 368 ([C15H635Cl37ClNO6]+, 1.0),
366 ([C15H635Cl2NO6]+, 1.6), 246 ([C12H8NO5]+, 100), 153
([C4H35Cl37ClO2]+, 9.2), 151 ([C4H35Cl2O2]+, 14.4). Anal. Calcd
for C16H9Cl2NO6: C, 48.27; H, 2.28; N, 3.52. Found: C, 48.13;
H, 2.26; N, 3.44.
Biologica l Activity. Seeds. Seeds of Striga hermonthica
[from Sorghum bicolor (L.) Moench] and Orobanche crenata
(from Vicia faba L.) were harvested in Sudan in 1987 and in
Egypt in 1991, respectively, and were stored in the dark at
room temperature until use in germination tests.
Preparation of Test Solutions. A compound to be tested was
weighed out very accurately to the amount of 10 mg, dissolved
in 10 mL of acetone p.a., and diluted with demineralized water
to 100 mL. Aliquots of this stock solution were further diluted
with water to obtain test solutions containing 1 and 0.01 mg/L
test compound and 0.1 and 0.001% (v/v) acetone, respectively.
Bioassays. For surface sterilization seeds of S. hermonthica
and O. crenata were exposed to an aqueous solution of sodium
hypochlorite (2% active chlorine) for 5 min with agitation. The
seeds were then thoroughly rinsed with water and dried
overnight.
For conditioning the sterilized seeds were spread on glass
fiber filter paper disks (8-mm diameter; approximately 30-
70 seeds per disk) in Petri dishes, wetted with water, and
P r ep a r a tion of D-Rin g P r ecu r sor s 7-18. All
5-bromo-2(5H)-furanones were prepared by radical initi-

2288 J. Agric. Food Chem., Vol. 45, No. 6, 1997
Thuring et al.
Ta ble 1. Yield s of Cou p lin g Rea ction s of 6 a n d D-Rin g
P r ecu r sor s 7-18
Sch em e 4. Red u ction of P h en ylm a leic An h yd r id e 34a
entry
D-ring precursor
product
yield (%)
1
2
3
4
5
6
7
8
9
7
8
9
5
19
20
21
22
23
24
25
26
27
28
29
75
55a
37
12a
95
85
b
21
27
35
49a
15
10
11
12
13
14
15
16
17
18
10
11
12
a
b
Yield after purification by recrystallization. Not determined,
see text.
Regioisomers 13 and 32 could not be separated.
Therefore, coupling with Sheehan aldehyde 6 was
achieved using the crude mixture of 13 and 32 to
provide 24 and 33 in 16% and 23% isolated yields,
respectively.
Sch em e 3. Syn th esis of D-Rin g An a logu es 24 a n d 33
The syntheses of 3- and 4-phenyl-substituted 2(5H)-
furanones 14a and 15a were accomplished via reduction
of maleic anhydride derivative 34a (Scheme 4). Direct
reduction of 34a using LiAlH4 afforded 15a as the main
regioisomer (Kayser and Morand, 1980). For the regi-
oselective formation of 14a a different procedure via
DCA-salt 35a (Scheme 4) had to be followed, the essence
of which has been described (Nefkens et al., 1997b) for
the preparation of 7a (Scheme 4, R ) Me). The
moderate overall yield of 14a is most likely due to
concomitant 1,4-reduction of 36a , a problem that was
also encountered during the reduction of 34a using
selectride reagents (Kayser et al., 1986).
Biologica l Eva lu a tion . The germination stimula-
tory activity of phthalimidoglycine-derived D-ring ana-
logues 5, 19-29, and 33 was assayed using seeds of S.
hermonthica and O. crenata. In each bioassay, GR24
(4) at an optimal concentration [0.01 mg/L [see Zwanen-
burg et al. (1994)] for S. hermonthica and 1 mg/L for O.
crenata] was included as a positive control. The last-
mentioned compound enables a comparison between
results obtained in different test series. This is impor-
tant, since the response of seeds of parasitic weeds, in
particular of S. hermonthica, varies considerably from
test to test. The germination percentages thus obtained
are collected in Table 2.
The data in Table 2 reveal that most D-ring analogues
exert little or no stimulatory effect. In particular, seeds
of O. crenata are extremely sensitive toward structural
modifications in the D-ring (Table 2B). Dimethyl-
substituted 2(5H)-furanone analogue 22, however, shows
a considerable degree of biological activity and is at least
as active as the parent compound 5 in the germination
of seeds of S. hermonthica. However, its activity in the
stimulation of O. crenata seed germination is only
limited. Also R-ethyl 2(5H)-furanone derivative 24 gave
significant stimulation of germination, particularly of
seeds of S. hermonthica. Its isomeric counterpart 33
was completely inactive, as expected because the D-ring
is not a suitable leaving group (see molecular mecha-
nism, Scheme 1). For the same reason carba D-ring
analogue 29 does not exert germination-inducing activ-
ity. A remarkable difference in activity was observed
for â-methoxy-substituted 2(5H)-furanone analogue 23
and its â-methyl counterpart 22 (cf. entries 5 and 6,
Table 2A), which, most likely, must be attributed to
electronic factors. As a consequence, the inherent
reactivity of the R,â-unsaturated carbonyl function
present in the D-ring should be taken into consideration
as a potential recognition site of a receptor protein.
ated allylic bromination of the parent 2(5H)-furanones
(MacAlpine et al., 1976). 5-Chloro-3,4-dimethyl-2(5H)-
furanone (11) was prepared in three steps starting from
propionaldehyde and ethyl pyruvate (Schreiber and
Wermuth, 1965; Cane´vet and Graff, 1978). γ-Chloro-
γ-butyrolactone (17) was obtained in one step by reac-
tion of succinyl dichloride and tri-n-butyltin hydride
(Kuivila, 1960). 4-Bromo-2-methyl-2-cyclopenten-1-one
(18) was obtained upon bromination of 2-methyl-2-
cyclopenten-1-one (Gassman and Pascone, 1973) with
NBS (DePuy et al., 1964). The preparation of 4-meth-
oxy-3-methyl-2(5H)-furanone (12a ) was accomplished by
methylation with dimethyl sulfate of the parent 2-meth-
yltetronic acid (Knight and Pattenden, 1975). The last-
mentioned compound was prepared in a one-pot syn-
thesis by bromination of ethyl 2-methylacetoacetate to
give the 2-bromo derivative (Conrad, 1896), which
rearranged in the presence of hydrobromic acid to the
4-bromo isomer, which on heating gave 2-methyltetronic
acid (Reid et al., 1950). The synthesis of 3-ethyl-2(5H)-
furanone (13a ) was carried out, using the concept
outlined in Scheme 3.
The sequence of R-alkylation using methyl iodide
(Iwai et al., 1977) or R-condensation with simple alde-
hydes (Calde´ron et al., 1987) of phenylthio-γ-butyrolac-
tone (30), followed by oxidation and thermal dehydro-
sulfenylation, is a simple route to 3-substituted 2(5H)-
furanones. The scope, however, is rather limited. In
our hands, quenching the lithio enolate of 30 with ethyl
iodide gave 31 in 60% isolated yield, which upon
oxidation with mCPBA and thermal elimination af-
forded 13a in 40% yield after distillation. Compound
13a has previously been prepared according to other
methods, although no analytical data were reported
(Martin and Moore, 1976; Khan and Paterson, 1982).
Subsequent bromination with NBS in the presence of
R,R′-azodiisobutyronitrile (AIBN) gave a mixture of
mainly two monobrominated furanones 13 and 32 in an
equimolar ratio (Scheme 3).

N-Phthaloylglycine-Derived Strigol Analogue
J. Agric. Food Chem., Vol. 45, No. 6, 1997 2289
Ta ble 2. Ger m in a tion P er cen ta ges for Seed s of S. h er m on th ica a n d O. cr en a ta a fter Exp osu r e to Aqu eou s Solu tion s of
Str igol An a logu es 5, 19-29, a n d 33 a t Con cen tr a tion s of 1 a n d 0.01 m g/La
% germination ( SE
entry
compound
1 mg/L
0.01 mg/L
4b
A. S. hermonthica
40.3 ( 1.7
1.5 ( 0.4c
13.1 ( 1.9
25.8 ( 5.1
63.8 ( 6.8
12.0 ( 4.9
48.5 ( 2.7
15.5 ( 2.8d
8.0 ( 0.7c
18.2 ( 5.3d
6.7 ( 2.1c
5.7 ( 1.2c
7.3 ( 0.7c
1
2
3
4
5
6
7
8
9
10
11
12
13
5, R1 ) Me, R2 ) H
19, R1, R2 ) -(CH)4-
20, R1 ) H, R2 ) H
21, R1 ) H, R2 ) Me
22, R1 ) Me, R2 ) Me
23, R1 ) Me, R2 ) OMe
24, R1 ) Et, R2 ) H
25, R1 ) Ph, R2 ) H
26, R1 ) H, R2 ) Ph
27, R1 ) Cl, R2 ) Cl
28
4.1 ( 0.9c
1.0 ( 0.0c
2.0 ( 0.0c
9.6 ( 5.2c
5.8 ( 1.3c
5.1 ( 0.8c
9.3 ( 1.6c
7.6 ( 0.5c
8.3 ( 1.0c
11.3 ( 1.9d
7.3 ( 1.5c
5.5 ( 1.0c
10.8 ( 4.7c
52.5 ( 12.5
52.5 ( 12.5
52.5 ( 12.5
52.5 ( 12.5
62.5 ( 10.8
62.5 ( 10.8
59.5 ( 2.1
38.6 ( 10.3
45.3 ( 8.7
43.4 ( 1.9
42.0 ( 8.4
73.3 ( 1.5
59.5 ( 2.1
29
33
B. O. crenata
34.2 ( 9.8
15.1 ( 1.3
14.0 ( 0.9
0-4.9e
1
2
3
4
5f
1.1 ( 0.6e
0.0 ( 0.0e
0.0 ( 0.0e
0-0.8e
68.1 ( 8.3
66.1 ( 1.8
63.8 ( 5.8
51.7-74.9
22g
24
19-21, 23, 25-29, 33
a
Germination percentages given are the mean ( SE of two replicate tests. b Values are the mean germination percentages ( SE obtained
by treatment of the seeds with GR24 4 (S. hermonthica, 0.01 mg/L; O. crenata, 1 mg/mL) in the same bioassay. c Values are not significantly
d
different from germination percentages obtained in the aqueous control. Relatively high germination percentage in aqueous control;
values are not significantly different. e Values are not significantly different from germination percentages obtained in the control (without
stimulant). f Germination percentage 58.3 ( 1.3% at a concentration of 2 mg/L. Germination percentage 14.5 ( 2.8% at a concentration
g
of 2 mg/L.
ACKNOWLEDGMENT
Reduction of this highly reactive double bond (compound
28) results in complete loss of activity. Strigol ana-
logues containing 3-phenyl-, 4-phenyl-, and 3,4-dichloro-
2(5H)-furanone moieties as D-ring have previously been
assayed as germination stimulants (Hassanali, 1984).
It was concluded that these compounds exhibit no
stimulatory activity, although no data were provided.
These results are confirmed here, using the related
analogues 25-27.
We thank Dr. A. G. T. Babiker and Dr. F. M. F.
Zaitoun for supplying Striga and Orobanche seeds. We
thank H. Amatdjais, P. van Galen, and A. Swolfs for
conducting elemental analysis, mass, and 400 MHz H-
NMR measurements.
1
LITERATURE CITED
Con clu d in g Rem a r k s. Several D-ring analogues of
strigol have been synthesized and assayed for germina-
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furanone D-ring, which is present in all known strigo-
lactones 1-3, is very critical for the bioactivity. This
finding suggests an essential role of the D-ring in the
receptor interaction. From a practical point of view,
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another D-ring is of considerable interest, as its prepa-
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steps from simple, cheap starting materials. Second,
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Received for review J une 28, 1996. Revised manuscript
received February 24, 1997. Accepted April 1, 1997.X These
investigations were supported by the Netherlands Foundation
of Chemical Research (SON) with financial aid from the
Netherlands Organization for the Advancement of Research
(NWO).
J F9604652
X Abstract published in Advance ACS Abstracts, May
15, 1997.
Mangnus E. M.; Dommerholt, F. J .; de J ong, R. L. P.;
Zwanenburg, B. Improved synthesis of strigol analogue