A new efficient synthesis of GR24 and dimethyl A-ring analogues, germinating agents for seeds of the parasitic weeds Striga and Orobanche spp.

Article abstract of DOI:10.1016/j.tet.2010.06.072

An efficient and high yielding preparation for the synthetic germination stimulant GR24 (5) and its A-ring dimethyl-substituted analogues 30-32 has been described. The first step involves a Stobbe condensation of benzaldehydes 9-11 with dimethyl succinate. Subsequent transposition of the ester and reduction of the double bond provides the building blocks 15-17 for an intramolecular Friedel-Crafts acylation. ABC-lactones 22-25 are prepared from γ-keto esters 18-21 by saponification, subsequent reduction with sodium borohydride followed by acid-catalyzed lactonization. Coupling of the lactones with the D-ring is accomplished by formylation and subsequent treatment with bromobutenolide 8 to give GR24 and its dimethyl analogues. Bioassays with Striga hermonthica seeds reveal that the dimethyl analogues are slightly less active than GR24 itself.

Full text of DOI:10.1016/j.tet.2010.06.072

Tetrahedron 66 (2010) 7198e7203
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new efficient synthesis of GR24 and dimethyl A-ring analogues, germinating
agents for seeds of the parasitic weeds Striga and Orobanche spp.
*
*
Heetika Malik, Floris P.J.T. Rutjes , Binne Zwanenburg
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and high yielding preparation for the synthetic germination stimulant GR24 (5) and its A-
ring dimethyl-substituted analogues 30e32 has been described. The first step involves a Stobbe con-
densation of benzaldehydes 9e11 with dimethyl succinate. Subsequent transposition of the ester and
reduction of the double bond provides the building blocks 15e17 for an intramolecular FriedeleCrafts
Received 6 March 2010
Received in revised form
7 June 2010
Accepted 24 June 2010
Available online 3 July 2010
acylation. ABC-lactones 22e25 are prepared from
g-keto esters 18e21 by saponification, subsequent
reduction with sodium borohydride followed by acid-catalyzed lactonization. Coupling of the lactones
with the D-ring is accomplished by formylation and subsequent treatment with bromobutenolide 8 to
give GR24 and its dimethyl analogues. Bioassays with Striga hermonthica seeds reveal that the dimethyl
analogues are slightly less active than GR24 itself.
Keywords:
Germination stimulants
Strigolactones
GR24 synthesis
Atom efficient synthesis
Bioassays
Ó 2010 Elsevier Ltd. All rights reserved.
Parasitic weeds
1. Introduction
The known syntheses of GR24 all use indan-1-one (6) as the
startingmaterial(Scheme 1). Thefirstroute7b involves
a-bromination,
Parasitic weeds of the genera Striga and Orobanche cause im-
mense damage to food crops, such as maize, sorghum, millet and
rice, especially in third world countries.1 Germination of the seeds
of these parasites is induced by stimulant molecules present in the
root exudates of the host plants that are attacked. The first stimu-
lant was isolated from cotton roots as early as 1966.2 At present
several stimulants, collectively called strigolactones, have been
reported.3 Representative examples, are strigol (1), sorgolactone
(2), orobanchol (3) and 5-deoxystrigol (4), which are pictured in
Figure 1.
Isolation and identification of germination stimulants is ex-
tremely difficult due to the minute amounts present in the root
exudates (estimated production of stimulant per plant is 15 pg per
day).4 As the natural stimulants are difficult to obtain and their total
synthesis is very elaborate,5,6 synthetic analogues with simpler
structures have been prepared.7,8 The aromatic A-ring analogue
GR24 (5) is a successful example as it has a very high germinating
activity (10ꢀ10e10ꢀ12 mol/L). GR24 is currently widely used as the
standard germination agent as a positive control in bioassays of
seeds of parasitic weeds.8e10
followed by reaction with sodium malonic ester, subsequent hydro-
lysis and decarboxylation to give the key intermediate 7. This route
suffers from
improved method11 an ethoxycarbonyl is introduced to enhance the
-CH activity. This is followed by direct alkylation with bromoacetate,
hydrolysis and decarboxylation, again leading to the intermediate 7.
a-dibromination especially on large scale. In the second
a
O
O
O
O
O
O
C
A
B
O
O
D
O
O
OH
1
2
: (+)-strigol
O
: sorgolactone
O
O
O
O
O
C
A
B
O
O
D
O
O
X
3
5a
GR24 (
: X = OH: orobanchol
)
4: X = H: deoxystrigol
* Corresponding authors. Tel.: þ31 24 365 3159; fax: þ31 24 365 3393; e-mail
address: b.zwanenburg@science.ru.nl (B. Zwanenburg).
Figure 1. Naturally occurring strigolactones and synthetic analogue GR24.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.072

H. Malik et al. / Tetrahedron 66 (2010) 7198e7203
7199
So far, a third method involving condensation of indan-1-one (6) with
glyoxylic acid and subsequent removal of the double bond to give
intermediate 7 via a two-step process is the easiest one.9
ester, contains all the carbon atoms required for the construction
of the key intermediate. Transposition of the ester was readily
achieved by saponification to the corresponding diacid, which on
treatment with Amberlyst-15Hþ catalyst in methanol resulted in
a selective esterification to the alternative monoester 12. Catalytic
hydrogenation gave the precursor 15 for the FriedeleCrafts ring
closure to the key intermediate 7. It should be noted that the
FriedeleCrafts cyclization was not as straightforward as was
expected. After careful experimentation, the optimum conditions,
namely 6 equiv AlCl3 in CS2 at low temperature, gave the desired
five-membered ring product 18 in good overall yield. Compound
18 is the methyl ester of key intermediate 7. Surprisingly, with
a smaller amount of AlCl3 (2 equiv) in dichloromethane as the
solvent the six-membered ring lactone 33 was exclusively
obtained in good yield. Unexpectedly, under these conditions,
prior to the FriedeleCrafts ring closure, a remarkable transposition
of functionalities took place leading to the exclusive formation the
six-membered ring product 33 (Scheme 3). Most likely, this
transposition occurs through methoxide transfer to an acylium ion
as is pictured in Scheme 3.
O
O
O
(EtO)2CO
Br2
Br
CO2Et
NaH, DMF
Et2O
6
1) NaCH(CO2Et)2
PhH, heat
1) HO2CCHO
PhH, heat
anisole
1) BrCH2CO2Et
DMF
2) HCl (aq)
AcOH, heat
2) KOH, EtOH
heat
2. H2, Pd/C
3) H+, heat
O
CO2H
7
O
O
C
1) NaBH4
1) HCO2Et
0.2 N NaOH
t-BuOK
7
5a, 5b
A
B
O
2) p-TsOH
PhH, heat
2) Br
O
O
8
1) oxalyl chloride,
CH2Cl2, 0 °C
Scheme 1.
2) AlCl3 (2 equiv)
CH2Cl2, 0 °C to rt
CO2Me
HO2C
Reduction of the carbonyl group with NaBH4 and acid-catalyzed
lactonization leads to the ABC-skeleton of GR24.11,12 Coupling of
this skeleton is accomplished by formylation with ethyl formate
and subsequent treatment with bromobutenolide 8 as shown in
Scheme 1.11 The indanone route was also followed for the prepa-
ration of 6- and 8-methyl GR24. The required substituted inda-
nones were obtained from an appropriate methyl-substituted
benzyl chloride using the malonic ester synthesis.13 8-Methyl-5-
hydroxy GR24 was also reported by first making the appropriately
substituted indanone from 6-methyl dihydrocoumarin.14
CO2Me
33
methoxide transfer
O
O
OMe
MeO
O
O
Scheme 3.
This paper deals with a new practical and atom efficient syn-
thesis of the important germination stimulant GR24 and some of its
A-ring dimethyl-substituted analogues.
Conversion of the
g-ketoester 18 into the ABC-lactone 22 of
GR24 was accomplished by first saponification into the keto acid,
then reduction with sodium borohydride, followed by acid-cata-
lyzed lactonization of the crude reduction product.11,12 Coupling of
building block 22 and the D-ring was accomplished in a one-pot
two-step process, i.e., first formylation of 22 with t-BuOK as the
base and then without isolating the potassium enolate 26, treat-
ment with bromobutenolide 8. The resulting mixture of di-
astereomers 5a and 5b was separated by column chromatography
2. Results and discussion
The new approach to the preparation of the key intermediate 7
makes use of the Stobbe condensation15e17 of benzaldehyde 9 with
dimethyl succinate (Scheme 2). The Stobbe product, which is a half
R2
R2
1) t-BuOK, t-BuOH
R1
R1
R3
R4
R2
R1
R3
R4
O
reflux
R2
R3
R1
H
R3
R4
2) 2 M NaOH, EtOH
reflux
1) oxalyl chloride
CH2Cl2, 0 °C
CO2Me
CO2Me
Pd/C, H2
MeOH
+
O
CO2Me
3) Amberlyst-15H+
MeOH, reflux
CO2Me
2) AlCl3 (6 equiv)
CS2, 0 °C to rt
CO2Me
R4
HO2C
15
HO2C
: R = R2 = R3 = R4 = H
: R1 = R2 = R3 = R4 = H
: R1 = R2 = R3 = R4 = H
: R1 = R2 = R3 = R4 = H
1
9
12
18
19
20
21
10: R2 = R3 = Me, R1 = R4 = H
11: R1 = R4 = Me, R2 = R3 =H
13: R2 = R3 = Me, R1 = R4 = H
14: R1 = R4 = Me, R2 = R3 =H
16: R2 = R3 = Me, R1 = R4 = H
17: R1 = R4 = Me, R2 = R3 =H
: R1 = R2 = Me, R3 = R4 = H
: R2 = R3 = Me, R1 = R4 = H
: R1 = R4 = Me, R2 = R3 = H
R1
A
O
R1
R4
O
R1
O
1) LiOH
THF/H2O
2) NaBH4
Br
O
O
R1
A
O
O
C
O
O
O
C
R2
R3
R2
R2
R3
R2
R3
t-BuOK
8
HCO2Me
B
B
+
R3
O
O
D
O
D
O
DME
THF
O-K+
O
O
R4
0.2 N NaOH (aq)
3) p-TsOH, PhH
R4
R4
reflux
: R1 = R2 = R3 = R4 = H
: R1 = R2 = R3 = R4 = H
: R1 = R2 = R3 = R4 = H
: R1 = R2 = R3 = R4 = H
22
26
27
28
29
5a
30a
31a
32a
5b
: R1 = R2 = Me, R3 = R4 = H
: R2 = R3 = Me, R1 = R4 = H
: R1 = R4 = Me, R2 = R3 = H
: R1 = R2 = Me, R3 = R4 = H
: R2 = R3 = Me, R1 = R4 = H
: R1 = R4 = Me, R2 = R3 = H
: R1 = R2 = Me, R3 = R4 = H
: R2 = R3 = Me, R1 = R4 = H
: R1 = R4 = Me, R2 = R3 = H
: R1 = R2 = Me, R3 = R4 = H
: R2 = R3 = Me, R1 = R4 = H
: R1 = R4 = Me, R2 = R3 = H
23
24
25
30b
31b
32b
Scheme 2.

7200
H. Malik et al. / Tetrahedron 66 (2010) 7198e7203
into the faster moving diastereomer 5a and slower moving di-
astereomer 5b (Scheme 2).11
substituted A-ring analogues of GR24 by starting from appropriately
substituted dimethyl benzaldehydes. Hence, 7,8-dimethyl, 5,8-
dimethyl and 6,7-dimethyl compounds 30e32 were prepared start-
ing from 3,4-dimethylbenzaldehyde and 2,5-dimethylbenzaldehyde,
respectively. The bioassays reveal that dimethyl substitution lowers
the germination activity. Earlier we demonstrated that A-ring sub-
stitution has some but not a dramatic influence on the bioactivity.8
Methyl substitution can in principle be used for fine-tuning the ac-
tivityofGR24 analogues. Thebioassays revealthatGR24 hasa potency
of about ten times higher than the dimethyl analogues. However,
a word of caution is in place, because the response to seeds of other
Striga species may show a different relative behaviour. The dimethyl
GR24 analogues are of particular interest because of the occurrence of
the natural stimulant solanocol,18 which is proposed to have a 5,8-
dimethyl substituted aromatic ring. Recently it is shown that this
structural assignment is not correct. Solanocol has methyl sub-
stituents at the 7- and 8-position.19
It is also of importance to note that strigolactones are currently
in the focus of interest due to the newly discovered bioactivities of
these compounds. It was found that some natural strigolactones, as
well as GR24, are the branching factor of arbuscular mycorrhizal
(AM) fungi.20,21 Moreover, these compounds are active as inhibitor
of shoot branching and bud outgrowth.22,23 It is generally believed
that strigolactones constitute a new type of plant hormones.24 The
synthetic strigolactone GR24 plays an important role in advancing
the knowledge in this exciting field.
Originally, we performed the hydrogenation of the olefinic bond
in 12 in an asymmetric manner with the rhodium complex Rh
(COD)2BF4 in combination with a (S)-BINOL isopropoxy-substituted
phosphite ligand. This catalytic hydrogenation gave the reduced
product 15 in excellent chemical and optical yield (ee 97%). After
FriedeleCrafts ring closure, reduction and lactonization the ABC-
lactone 22 would then have been obtained in optically active form.
Disappointingly, during the FriedeleCrafts ring closure the chiral
integrity was almost entirely lost (ee 16%). Apparently, under the
FriedeleCrafts conditions, the acid chloride undergoes racemization
priortothecyclization, mostprobablyviaaketenetypeintermediate.
After having established the optimal conditions for the synthesis
of GR24, 3,4- and 2,5-dimethylbenzaldehydes were subjected to
this sequence of events. 3,4-Dimethylbenzaldehyde produced
a mixture of the FriedeleCrafts ring-closed products 19 and 20.
They were separated by column chromatography and converted
into ABC-lactones 23 and 24. In contrast, 2,5-dimethylbenzalde-
hyde can proceed only in one way in the FriedeleCrafts cyclization
to give the ABC-lactone 25. ABC-lactones 23e25 were then coupled
with the D-ring as described before. The resulting mixtures of di-
astereomers were separated by column chromatography to give the
faster moving diastereomers 30a, 31a, 32a and the slower moving
diastereomers 30b, 31b, 32b, respectively.
The six dimethyl-substituted GR24 analogues were tested for
germination activity on seeds of the parasitic weed Striga her-
monthica. The results of these bioassays, which are shown in
Figure 2, reveal that dimethyl substitution lowers the activity. The
diastereomers having the relative configuration of the C- and D-
4. Experimental section
4.1. General remarks
ring as in the natural strigolactones [3a(R
expected, a higher activity than the diastereomers with the epi-20-
configuration [3a(R ),8a(R )]. The highest activity for all six
),20(S
*
),8a(R
*
),20(R
*
)], exhibit as
All glass apparatus were oven dried prior to use. Solvents were
distilled from appropriate drying agents prior to use and stored
under nitrogen. Standard syringe techniques were applied for the
transfer of dry solvents and air or moisture-sensitive reagents. All
chemicals were obtained from commercial sources and used
without further purification. 1H NMR and 13C NMR spectra were
recorded on a Bruker DRX-300 (operating at 300 MHz for 1H and at
75 MHz for 13C) spectrometer using CDCl3 as solvent. Tetrame-
thylsilane (0.00 ppm) served as an internal standard in 1H NMR and
CDCl3 (77.0 ppm) in 13C NMR. Coupling constants are reported as J-
values in hertz. Multiplicities are reported as: s (singlet), d (dou-
blet), t (triplet), dd (doublet of doublets), m (multiplet) in 1H NMR.
Reactions were monitored using thin layer chromatography (TLC)
on silica gel-coated plates (Merck 60 F254) with the indicated sol-
vent mixture. Detection was performed with UV-light, and/or by
charring at w150 ꢁC after dipping in to a solution of either 2%
anisaldehyde in ethanol/H2SO4 or (NH4)6Mo7O24$4H2O (25 g/L) or
KMnO4. Melting points were determined with a Buchi melting
point B-545. High resolution mass spectra were recorded on a JEOL
AccuTOF (ESI), or a MAT900 (EI, CI, and ESI). Column chromatog-
raphy was performed over silica gel (0.035e0.070 mm) using
freshly distilled solvents. Air and moisture sensitive reactions were
carried out under an inert atmosphere of dry nitrogen or argon.
*
*
*
analogues is at a concentration 10 times higher than the general
standard germinating agent GR24, which has the natural relative
CD relationship [3a(R
*
),8a(R
*
),20(R
)]. The dose-response of stimu-
*
lant GR24 shows a lower activity at the highest concentration. This
in agreement with the general observation, that the dose response
curves of stimulants have a bell shape with a maximum.9 In the
case of GR24 this maximum is clearly visible. For the dimethyl-
substituted analogues the maximum is at a higher concentration
than for GR24, but due to solubility problems higher concentration
than 33 mM could not be biassayed.
4.1.1. Methyl (E)-2-benzylidenesuccinate (12)15. To a refluxing sus-
pension of t-BuOK (12.4 g, 111 mmol) in t-BuOH (80 mL) was care-
fully added a solution of dimethyl succinate (18.0 g, 120 mmol) and
benzaldehyde 1 (10.0 g, 92.4 mmol) in t-BuOH (80 mL). The reaction
mixture was stirred at reflux temperature for 18 h, after which the
solvent was removed under vacuum. The residue was dissolved in
1 M HCl (80 mL) and this solution was extracted with EtOAc
(3ꢂ80 mL). The organic layers were dried (Na2SO4) and concen-
trated. The resulting monoacid was dissolved and EtOH (40 mL) and
aqueous NaOH (2 M, 80 mL) were added. The resultant mixture was
stirred at reflux temperature for 1 h, followed by evaporation of
Figure 2. Bioassay: germination activity towards seeds of S. hermonthica.
3. Concluding remarks
The sequence of events depicted in Scheme 2, which is based on
theStobbecondensationissuitableforthemultigramsynthesesof the
ABC-lactones 22e25. The route is particularly convenient for GR24,
which is the general standard in bioassays of the germination of seeds
of parasitic weeds. The method also allows the synthesis of dimethyl

H. Malik et al. / Tetrahedron 66 (2010) 7198e7203
7201
most of the EtOH under reduced pressure. Extra H2O (80 mL) was
added and the mixturewas washed with EtOAc(3ꢂ80 mL). Next, the
aqueous layer was acidified (pHw1) with 2 M HCl, extracted with
EtOAc (2ꢂ80 mL) and the organic layers were dried (Na2SO4) and
concentrated. The resulting diacid was dissolved in MeOH (100 mL),
Amberlyst-15Hþ (4.20 g) was added and the reaction mixture was
heated under reflux for 16 h. The mixturewas filteredover Celite and
concentrated under vacuum, resulting in crude ester 12. The product
was recrystallized from toluene/n-heptane, yielding ester 12 as
a white solid. The overall yield was 9.15 g (45%). Analytical data were
in agreement with those reported in the literature.15,25 FTIR (solid)
NMR (75 MHz, CDCl3):
d
180.0 (s), 171.9 (s), 135.5 (s), 134.9 (s), 132.7
(s), 130.1 (2ꢂd), 127.2 (d), 51.3 (q), 41.3 (d), 34.4 (t), 34.0 (t), 20.4 (q),
18.3 (q). HRMS (ESI) m/z calcd for C14H18O4 (MþNa)þ: 273.11028,
found: 273.10814.
4.1.7. Methyl 2-(1-oxo-2,3-dihydro-1H-inden-2-yl)acetate (18). To
a solution of acid 15 (2.0 g, 9.01 mmol) in dry CH2Cl2 (30 mL) was
added oxalyl chloride (1.37 g, 10.8 mmol). Two drops of dry DMF
were added to initiate the reaction. The reaction mixture was
stirred at room temperature for 1 h, after which the solvent was
removed in vacuo. The resulting product was dissolved in carbon
disulfide (20 mL) and then gradually added to a slurry of AlCl3
(7.20 g, 54.1 mmol) in carbon disulfide (30 mL) at ꢀ30 ꢁC. The re-
action mixture was stirred at 0 ꢁC for 4 h and then overnight at
room temperature. Carbon disulfide was removed in vacuo and the
resulting mixture was dissolved in CH2Cl2 (50 mL). Then, water
(30 mL) was added dropwise to quench AlCl3 followed by 1 M HCl
(5 mL) leading to a clear solution. The product was extracted with
CH2Cl2 (2ꢂ50 mL). The organic layer was dried (Na2SO4) and con-
centrated. The residue was chromatographed over silica gel using
EtOAc/n-heptane (2:8) to yield ketone 18 (1.40 g, 78%) as a white
solid. Mp 144.3e144.8 ꢁC, FTIR (solid) cmꢀ1: 1735, 1666. 1H NMR
cmꢀ1: 2941, 1735, 1670, 1631. 1H NMR (300 MHz, CDCl3):
1H), 8.03 (s, 1H), 7.38 (br s, 5H), 3.74 (s, 3H), 3.57 (s, 2H). 13C NMR
(75 MHz, CDCl3):
d 12.34 (s,
d
172.6 (s),171.0 (s),143.8 (d),134.1 (s),128.7 (2ꢂd),
128.2 (3ꢂd), 124.7 (s), 51.8 (q), 32.7 (t).
Compounds 13 and 14 were prepared by following the same
procedure.
4.1.2. (E)-2-(3,4-Dimethylbenzylidene)-4-methoxy-4-oxobutanoic
acid (13). Yield 44%, mp 107e107.5 ꢁC, FTIR (solid) cmꢀ1: 2962,
1739, 1661, 1627. 1H NMR (300 MHz, CDCl3):
d
11.92 (s, 1H), 7.98 (s,
1H), 7.12e7.18 (m, 3H), 3.75 (s, 3H), 3.60 (s, 2H), 2.28 (s, 6H). 13C
NMR (75 MHz, CDCl3): 172.8 (s), 171.1 (s), 144.0 (d), 137.9 (s), 136.5
d
(300 MHz, CDCl3):
d
7.66 (d, 1H, J¼7.5 Hz), 7.53e7.47 (m, 1H), 7.37
(s), 131.7 (s), 130.2 (d), 129.5 (d), 126.3 (d), 123.6 (s), 51.7 (q), 32.7 (t),
19.3 (q), 19.2 (q). HRMS (ESI) m/z calcd for C14H16O4 (MþNa)þ:
271.09463, found: 271.09243.
(d, 1H, J¼7.5 Hz), 7.30e7.26 (m, 1H), 3.59 (s, 3H), 3.40e3.32 (m, 1H),
2.96e2.77 (m, 3H), 2.57e2.51 (m, 1H). 13C NMR (75 MHz, CDCl3):
d
206.0 (s),171.8 (s), 152.7 (s),135.7 (s),134.3 (d),126.9 (d),126.0 (d),
123.3 (d), 51.2 (q), 43.0 (d), 34.3 (t), 32.4 (t). HRMS (ESI) m/z calcd
4.1.3. (E)-2-(2,5-Dimethylbenzylidene)-4-methoxy-4-oxobutanoic
for C12H12O3 (MþNa)þ: 227.06841, found: 227.06719.
acid (14). Yield 43%, mp 107.5e108 ꢁC, FTIR (solid) cmꢀ1: 2958,
Carboxylic acids 16 and 17 were subjected to the same pro-
cedure. Compound 16 gave a mixture of FriedeleCrafts ring-closed
products 19 and 20 in a ratio of 2:3 in 76% yield, which were sep-
arated by column chromatography into the faster moving product
19 and the slower moving product 20. Compound 17 gave the
FriedeleCrafts ring-closed ketone 21 as a single product.
1726, 1679, 1627. 1H NMR (300 MHz, CDCl3):
d
11.78 (s, 1H), 7.06 (s,
1H), 7.12e7.05 (m, 2H), 6.99 (s, 1H), 3.72 (s, 3H), 3.42 (s, 2H), 2.30 (s,
3H), 2.25 (s, 3H). 13C NMR (75 MHz, CDCl3):
171.9 (s), 171.0 (s),
d
143.6 (d), 134.9 (s), 133.3 (s), 133.0 (s), 129.6 (d), 129.3 (d), 128.2 (d),
125.3 (s), 51.6 (q), 32.6 (t), 20.5 (q),18.8 (q). HRMS (ESI) m/z calcd for
C14H16O4 (MþNa)þ: 271.09463, found: 271.09258.
4.1.8. Methyl
acetate (19). Yield 31%, colourless viscous oil, FTIR (liquid film)
cmꢀ1: 1739, 1700. 1H NMR (300 MHz, CDCl3):
7.29 (d, 1H,
2-(6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-2-yl)
4.1.4. 2-Benzyl-4-methoxy-4-oxobutanoic acid (15). To a solution of
acid 12 (5.00 g, 22.5 mmol) in methanol (80 mL) Pd/C (0.45 g) was
added under nitrogen. It was stirred under the same atmosphere
for 10 min, followed by stirring for 18 h at room temperature under
hydrogen, then it was filtrated over Celite. Removal of solvent un-
der vacuum gave acid 15 (4.90 g, 98%) as a viscous oil. Analytical
data were in agreement with those reported in literature.15,26 FTIR
(liquid film) cmꢀ1: 2958, 1735, 1709. 1H NMR (300 MHz, CDCl3):
d
J¼7.5 Hz), 7.12 (d, 1H, J¼7.5 Hz), 3.66 (s, 3H), 3.34e3.26 (m, 1H),
2.89e3.00 (m, 2H), 2.72 (dd, 1H, J¼16.8, 4.8 Hz), 2.60e2.47 (m, 1H),
2.55 (s, 3H), 2.26 (s, 3H). 13C NMR (75 MHz, CDCl3):
d 207.3 (s), 172.2
(s), 151.0 (s), 136.9 (s), 135.8 (s), 135.4 (d), 133.0 (s), 122.7 (d), 51.2
(q), 43.8 (d), 34.6 (t), 31.4 (t), 18.4 (q), 13.1 (q). HRMS (ESI) m/z calcd
for C14H16O3 (M)þ: 233.11777, found: 233.11553.
d
11.17 (s, 1H), 7.32e7.17 (m, 5H), 3.64 (s, 3H), 3.23e3.11 (m, 2H),
2.83e2.75 (m, 1H), 2.70e2.62 (m, 1H), 2.42 (dd, 1H, J¼17.1, 4.5 Hz).
13C NMR (75 MHz, CDCl3):
179.6 (s), 171.8 (s), 137.3 (s), 128.5
(2ꢂd), 128.1 (2ꢂd), 126.3 (d), 51.4 (q), 42.3 (d), 36.8 (t), 33.9 (t).
Similarly, acids 16 and 17 were prepared from 13 and 14,
respectively.
4.1.9. Methyl
acetate (20). Yield 45%, mp 72e72.5 ꢁC, FTIR (solid) cmꢀ1: 1735,
1709.1HNMR(300 MHz,CDCl3):
7.26(s,1H), 7.00(s,1H),3.50(s, 3H),
2-(5,6-dimethyl-1-oxo-2,3-dihydro-1H-inden-2-yl)
d
d
3.17e3.08 (m, 1H), 2.78e2.69 (m, 2H), 2.55 (dd, 1H, J¼16.8, 3.9 Hz),
2.38e2.29 (m,1H), 2.13 (s, 3H), 2.08 (s, 3H).13C NMR (75 MHz, CDCl3):
d
205.3 (s), 171.8 (s), 150.7 (s), 144.3 (s), 135.6 (s), 133.7 (s), 126.5 (d),
4.1.5. 2-(3,4-Dimethylbenzyl)-4-methoxy-4-oxobutanoic acid (16).
Yield 98%, colourless viscous oil, FTIR (liquid film) cmꢀ1: 2945,
123.4 (d), 51.0 (q), 43.1 (d), 34.3 (t), 31.9 (t), 20.0 (q), 19.0 (q). HRMS
(ESI) m/z calcd for C14H16O3 (MþNa)þ: 255.09971, found: 255.09720.
1735, 1705. 1H NMR (300 MHz, CDCl3):
d 11.30 (s, 1H), 7.06e7.03 (d,
1H, J¼7.5 Hz), 6.94e6.89 (m, 2H), 3.64 (s, 3H), 3.18e3.05 (m, 2H),
4.1.10. Methyl
acetate (21). Yield 74%, mp 87.3e87.8 ꢁC, FTIR (solid) cmꢀ1: 1731,
1705. 1H NMR (300 MHz, CDCl3):
2-(4,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-2-yl)
2.72e2.59 (m, 2H), 2.40 (dd, 1H, J¼16.8, 4.5 Hz), 2.22 (d, 6H,
J¼2.1 Hz). 13C NMR (75 MHz, CDCl3):
d
179.2 (s), 171.9 (s), 136.2 (s),
d
7.22 (d,1H, J¼7.5 Hz), 6.99 (d,1H,
134.7 (s), 134.5 (s), 129.8 (d), 129.3 (d), 125.9 (d), 51.3 (q), 42.4 (d),
36.5 (t), 33.9 (t), 19.2 (q), 18.8 (q). HRMS (ESI) m/z calcd for C14H18O4
(MþNa)þ: 273.11028, found: 273.10814.
J¼7.5 Hz), 3.68 (s, 3H), 3.32e3.24 (m, 1H), 3.00e2.91 (m, 2H), 2.56
(s, 3H), 2.64 (dd, 1H, J¼17.1, 4.5 Hz), 2.52e2.46 (m, 1H), 2.26 (s, 3H).
13C NMR (75 MHz, CDCl3):
d 207.2 (s), 172.2 (s), 152.2 (s), 135.6 (s),
134.2 (d), 132.8 (s), 132.1 (s), 128.9 (d), 51.3 (q), 43.2 (d), 34.2 (t), 31.0
(t), 17.4 (q), 16.9 (q). HRMS (ESI) m/z calcd for C14H16O3 (MþNa)þ:
255.09971, found: 255.09960.
4.1.6. 2-(2,5-Dimethylbenzyl)-4-methoxy-4-oxobutanoic acid (17).
Yield 98%, colourless viscous oil, FTIR (liquid film) cmꢀ1: 2958,
1739, 1705. 1H NMR (300 MHz, CDCl3):
d 11.24 (s, 1H), 7.05e7.02 (m,
1H), 6.96e6.88 (m, 2H), 3.63 (s, 3H), 3.02e3.18 (m, 2H), 2.76e2.63
4.1.11. (ꢃ)-3,3a,4,8b-Tetrahydro-2H-indeno[1,2b]furan-2-one (22). A
mixture of ketone 18 (1.40 g, 6.86 mmol) in THF/water (50:50)
(m, 2H), 2.42 (dd, 1H, J¼17.1, 4.5 Hz), 2.29 and 2.28 (2ꢂs, 2ꢂ3H). 13C

7202
H. Malik et al. / Tetrahedron 66 (2010) 7198e7203
(50 mL) and LiOH$H2O (0.56 g, 13.7 mmol) was stirred for 16 h.
Then, THF was evaporated and 1 M HCl (50 mL) was added. The
product was extracted with EtOAc (2ꢂ100 mL). The organic layer
was dried (Na2SO4) and concentrated to obtain the free keto acid
derived from 18 as a white solid in 96% yield. Lactone 22 was
separated diastereomeric products (5a and 5b, 0.54 g, 80%). The
faster moving diastereomer was crystallized from CH2Cl2/n-hexane
to give GR24 (5a) as colourless crystals. The slower moving di-
astereomer was also crystallized from CH2Cl2/n-hexane to give
GR24 isomer 5b as colourless crystals. Analytical data were in
agreement with those reported in the literature.11
GR24 analogues 30a, 30b, 31a, 31b, 32a and 32b were prepared
by the same procedure.
prepared from the g-keto acid obtained above by reduction with
sodium borohydride followed by acid-catalyzed lactonization as
described by House et al. in 90% yield.12 Analytical data were in
agreement with those reported in the literature.12
Diastereomeric products 30a and 30b were obtained in 74%
overall yield.
Lactones 23e25 were prepared following the same procedure.
4.1.12. (ꢃ)-7,8-Dimethyl-3,3a,4,8b-tetrahydro-2H-indeno[1,2b]
4.1.17. (3aR
*
,8bS ,E)-7,8-Dimethyl-3-(((R)-4-methyl-5-oxo-2,5-dihy-
*
furan-2-one (23). Yield 87%, mp 74e74.5 ꢁC, FTIR (solid) cmꢀ1
:
drofuran-2-yl)oxymethylene)-3,3a,4,8b-tetrahydro-2H-indeno[1,2b]
1761, 1726. 1H NMR (300 MHz, CDCl3):
d
7.13 (d, 1H, J¼7.6 Hz), 6.98
furan-2-one (30a). Mp 180.8e181.2 ꢁC, FTIR (solid) cmꢀ1: 1778,
(d, 1H, J¼7.6 Hz), 5.94 (d, 1H, J¼6.9 Hz), 3.39e3.22 (m, 2H),
2.95e2.80 (m, 2H), 2.41 (dd, 1H, J¼17.7, 4.5 Hz), 2.33 (s, 3H), 2.27 (s,
1735, 1683. 1H NMR (300 MHz, CDCl3):
d
7.44 (d, 1H, J¼2.4 Hz), 7.12
(d, 1H, J¼7.8 Hz), 6.97e6.93 (m, 2H), 6.15e6.13 (m, 1H), 5.99 (d, 1H,
J¼8.1 Hz), 3.95e3.87 (m, 1H), 3.38 (dd, 1H, J¼16.5, 9.5 Hz), 3.03 (dd,
1H, J¼16.5, 3.6 Hz), 2.32 (s, 3H), 2.25 (s, 3H), 2.01 (t, 3H, J¼1.5 Hz).
3H). 13C NMR (75 MHz, CDCl3):
d 176.6 (s), 139.8 (s), 137.2 (s), 135.3
(s), 134.6 (s), 131.3 (d), 121.7 (d), 87.0 (d), 37.6 (t), 36.6 (t), 35.5 (d),
18.9 (q), 15.1 (q). HRMS (ESI) m/z calcd for C13H14O2 (MþNa)þ:
225.08915, found: 225.08829.
13C NMR (75 MHz, CDCl3):
d 171.0 (s), 169.8 (s), 150.3 (d), 140.6 (d),
139.7 (s), 137.3 (s), 135.3 (s), 135.2 (s), 134.7 (s), 131.4 (d), 121.5 (d),
113.2 (s), 100.1 (d), 85.4 (d), 38.2 (t), 37.0 (d), 19.1 (q), 15.2 (q), 10.2
(q). HRMS (ESI) m/z calcd for C19H18O5 (MþNa)þ: 349.10519, found:
349.10476.
4.1.13. (ꢃ)-6,7-Dimethyl-3,3a,4,8b-tetrahydro-2H-indeno[1,2b]
furan-2-one (24). Yield 88%, mp 98e98.5 ꢁC, FTIR (solid) cmꢀ1
:
1718, 1696. 1H NMR (300 MHz, CDCl3):
d 7.24 (s, 1H), 7.04 (s, 1H),
5.83 (d, 1H, J¼6.9 Hz), 3.39e3.19 (m, 2H), 2.92e2.77 (m, 2H), 2.36
4.1.18. (3aR
hydrofuran-2-yl)oxymethylene)-3,3a,4,8b-tetrahydro-2H-indeno
[1,2b]furan-2-one (30b). Mp 190.9e191.4 ꢁC, FTIR (solid) cmꢀ1
1778,1739,1679. 1H NMR (300 MHz, CDCl3):
*
,8bS
*
,E)-7,8-Dimethyl-3-(((S
*
)-4-methyl-5-oxo-2,5-di-
(dd, 1H, J¼15.6, 5.4 Hz), 2.26 (s, 6H). 13C NMR (75 MHz, CDCl3):
d
176.5 (s), 139.5 (s), 138.3 (s), 135.9 (s), 135.6 (s), 126.5 (d), 125.7 (d),
:
87.3 (d), 37.1 (2ꢂt), 35.3 (d), 19.5 (q), 19.2 (q). HRMS (ESI) m/z calcd
d
7.46 (d,1H, J¼2.7 Hz),
for C13H14O2 (MþNa)þ: 225.08915, found: 225.08965.
7.11 (d, 1H, J¼7.5 Hz), 6.97e6.93 (m, 2H), 6.18e6.16 (m, 1H), 6.00 (d,
1H, J¼7.8 Hz), 3.95e3.87 (m, 1H), 3.38 (dd, 1H, J¼16.8, 9.6 Hz), 3.02
(dd, 1H, J¼16.8, 3.6 Hz), 2.33 (s, 3H), 2.25 (s, 3H), 2.02 (t, 3H,
4.1.14. (ꢃ)-5,8-Dimethyl-3,3a,4,8b-tetrahydro-2H-indeno[1,2b]
furan-2-one (25). Yield 84%, mp 87.2e87.7 ꢁC, FTIR (solid) cmꢀ1
:
J¼1.5 Hz). 13C NMR (75 MHz, CDCl3):
d 171.0 (s), 169.8 (s), 150.2 (d),
1752, 1692. 1H NMR (300 MHz, CDCl3):
d
7.06 (d, 1H, J¼7.5 Hz), 6.99
140.6 (d), 139.8 (s), 137.2 (s), 135.3 (s), 135.1 (s), 134.6 (s), 131.4 (d),
121.6 (d), 113.3 (s), 100.1 (d), 85.4 (d), 38.2 (t), 37.1 (d), 18.8 (q), 15.2
(q), 10.2 (q). HRMS (ESI) m/z calcd for C19H18O5 (MþNa)þ:
349.10519, found: 349.10543.
(d, 1H, J¼7.5 Hz), 5.95 (d, 1H, J¼7.2 Hz), 3.41e3.31 (m, 1H),
3.29e3.18 (m, 1H), 2.98e2.89 (m, 1H), 2.77 (dd, 1H, J¼16.5, 4.5 Hz),
2.44 (dd, 1H, J¼16.5, 4.5 Hz), 2.38 (s, 3H), 2.21 (s, 3H). 13C NMR
(75 MHz, CDCl3):
d
179.4 (s), 141.1 (s), 136.6 (s), 133.4 (s), 131.2 (s),
Diastereomeric products 31a and 31b were obtained in 76%
overall yield.
130.3 (d), 128.3 (d), 87.2 (d), 36.9 (t), 36.0 (t), 35.6 (d), 18.3 (q), 17.6
(q). HRMS (ESI) m/z calcd for C13H14O2 (MþNa)þ: 225.08915, found:
225.08896.
4.1.19. (3aR
hydrofuran-2-yl)oxymethylene)-3,3a,4,8b-tetrahydro-2H-indeno
[1,2b]furan-2-one (31a). Mp 233.8e234.3 ꢁC, FTIR (solid) cmꢀ1
1787, 1726, 1679. 1H NMR (300 MHz, CDCl3):
*
,8bS
*
,E)-6,7-Dimethyl-3-(((R
*
)-4-methyl-5-oxo-2,5-di-
4.1.15. 5-Bromo-3-methylfuran-2(5H)-one (8). To 3-methylfuran-2
(5H)-one (0.20 g, 2.06 mmol) in dry CCl4 (20 mL) was added NBS
(0.40 g, 2.26 mmol) and AIBN (5 mg) and the resulting reaction
mixture was heated at reflux for 2 h while irradiating with a 250 W
lamp. The mixture was cooled to 0 ꢁC and the solid succinimide was
filtered off. The solvent was removed in vacuo to give bromobute-
nolide 8, which was used as such in the coupling step.
:
d
7.43 (d, 1H, J¼2.7 Hz),
7.24 (s, 1H), 6.99 (s, 1H), 6.95 (t, 1H, J¼1.5 Hz), 6.12 (t, 1H, J¼1.5 Hz),
5.87 (d, 1H, J¼7.5 Hz), 3.93e3.85 (m, 1H), 3.34 (dd, 1H, J¼16.8,
9.3 Hz), 3.01 (dd, 1H, J¼16.8, 3.1 Hz), 2.24 (s, 6H), 2.01 (t, 3H,
J¼1.5 Hz). 13C NMR (75 MHz, CDCl3):
d 170.9 (s), 169.8 (s), 150.4 (d),
140.6 (d), 139.6 (s), 138.4 (s), 136.05 (s), 135.60 (s), 135.36 (s), 126.58
(d), 125.49 (d), 113.04 (s), 100.1 (d), 85.5 (d), 38.7 (t), 36.5 (d), 19.5
(q), 19.2 (q), 10.2 (q). HRMS (ESI) m/z calcd for C19H18O5 (MþNa)þ:
349.10519, found: 349.10503.
4.1.16. (3aR
yl)oxymethylene)-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]furan-2-one
5a and its 20S
diastereomer 5b. Potassium tert-butoxide (0.31 g,
*
,8bS
*
,E)-3-(((R
*
)-4-Methyl-5-oxo-2,5-dihydrofuran-2-
*
2.75 mmol) was added in small portions to a solution of lactone 22
(0.40 g, 2.29 mmol) and methyl formate (0.30 mL, 3.44 mmol) in
anhydrous THF (10 mL, freshly distilled) with stirring at 0 ꢁC under
nitrogen. Stirring was continued at room temperature until all
lactone had reacted (monitored by TLC, EtOAc/n-heptane 3:7). THF
was removed in vacuo. The resulting salt was used as such in the
coupling with bromobutenolide 8.
To a solution of formylated product 26 in DME (10 mL) under
nitrogen was added a solution of bromobutenolide 8 in DME (5 mL).
The reaction mixture was stirred overnight, DME was evaporated,
diluted with water (15 mL) and extracted with EtOAc (3ꢂ20 mL).
The organic layer was dried (Na2SO4) and concentrated. The
resulting diastereomeric mixture was purified by flash chroma-
tography (SiO2, EtOAc/n-heptane 1:1) to afford two partly
4.1.20. (3aR
hydrofuran-2-yl)oxymethylene)-3,3a,4,8b-tetrahydro-2H-indeno
[1,2b]furan-2-one (31b). Mp 195.4e195.9 ꢁC, FTIR (solid) cmꢀ1
1769, 1748, 1674. 1H NMR (300 MHz, CDCl3):
*
,8bS
*
,E)-6,7-Dimethyl-3-(((S )-4-methyl-5-oxo-2,5-di-
*
:
d
7.45 (d, 1H, J¼2.4 Hz),
7.24 (s, 1H), 6.99 (s, 1H), 6.96e6.94 (m, 1H), 6.18e6.16 (m, 1H), 5.88
(d, 1H, J¼7.8 Hz), 3.93e3.85 (m, 1H), 3.33 (dd, 1H, J¼16.8, 9.3 Hz),
3.00 (dd, 1H, J¼16.8, 3.3 Hz), 2.24 (s, 6H), 2.02 (t, 3H, J¼1.5 Hz). 13C
NMR (75 MHz, CDCl3): d 170.9 (s), 169.8 (s), 150.4 (d), 140.6 (d),
139.7 (s), 138.4 (s), 135.9 (s), 135.5 (s), 135.3 (s), 126.5 (d), 125.5 (d),
113.1 (s), 100.2 (d), 85.5 (d), 38.6 (t), 36.5 (d), 19.5 (q), 19.2 (q), 10.2
(q). HRMS (ESI) m/z calcd for C19H18O5 (MþNa)þ: 349.10519, found:
349.10511.
Diastereomeric products 32a and 32b were obtained in 73%
overall yield.

H. Malik et al. / Tetrahedron 66 (2010) 7198e7203
7203
4.1.21. (3aR
hydrofuran-2-yl)oxymethylene)-3,3a,4,8b-tetrahydro-2H-indeno
[1,2b]furan-2-one (32a). Mp 179.3e179.8 ꢁC, FTIR (solid) cmꢀ1
1787, 1744, 1670. 1H NMR (300 MHz, CDCl3):
*
,8bS
*
,E)-5,8-Dimethyl-3-(((R
*
)-4-methyl-5-oxo-2,5-di-
The number of germinated seeds was counted under a microscope.
All tests were carried out in triplicate. The bar diagram in Figure 2
shows the average values with the standard deviation.
:
d
7.47 (d, 1H, J¼2.4 Hz),
7.07e7.04 (m, 1H), 7.00 (s, 1H), 6.98 (t, 1H, J¼1.5 Hz), 6.18 (t, 1H,
J¼1.5 Hz), 5.99 (d, 1H, J¼7.8 Hz), 3.97e3.89 (m, 1H), 3.34 (dd, 1H,
J¼16.8, 9.6 Hz), 2.93 (dd, 1H, J¼16.8, 3.9 Hz), 2.40 (s, 3H), 2.19 (s,
Acknowledgements
We thank Dr. Tatsiana Charnikhova (Plant Research In-
ternational, Wageningen University, The Netherlands) for per-
forming the bioassays.
3H), 2.04 (t, 3H, J¼1.5 Hz). 13C NMR (75 MHz, CDCl3):
d 170.9 (s),
169.6 (s), 150.0 (d), 141.0 (s), 140.4 (d), 136.0 (s), 135.6 (s), 133.5 (s),
131.0 (s), 130.4 (d), 128.2 (d), 113.4 (s), 100.0 (d), 85.2 (d), 37.7 (t),
36.6 (d),17.8 (q),17.5 (q),10.3 (q). HRMS (ESI) m/z calcd for C19H18O5
(MþNa)þ: 349.10519, found: 349.10352.
References and notes
1. Parker, C. Pest Manag. Sci. 2009, 65, 453e459 and refs cited therein.
2. (a) Cook, C. E.; Whichard, L. P.; Turner, B.; Wall, M. E.; Egley, G. H. Science 1966,
154, 1189e1190; (b) Cook, C. E.; Whichard, L. P.; Wall, M. E.; Egley, G. H.; Coggon,
P.; Luhan, P. A.; Mcphail, A. T. J. Am. Chem. Soc. 1972, 94, 6189e6199.
3. Yoneyama, K.; Xie, X.; Yoneyama, K.; Takeuchi, Y. Pest Manag. Sci. 2009, 65,
467e470 and refs cited therein.
4. Humphrey, A. J.; Beale, M. H. Phytochemistry 2006, 67, 636e640.
5. Sugimoto, Y.; Wigchert, S. C. M.; Thuring, J. W. J. F.; Zwanenburg, B. J. Org. Chem.
1998, 63, 1259e1267.
6. (a) Reizelman, A.; Scheren, M.; Nefkens, G. H. L.; Zwanenburg, B. Synthesis 2000,
1944e1955; (b) Matsui, J.; Yokota, T.; Bando, M.; Takeuchi, Y.; Mori, K. Eur. J. Org.
Chem. 1999, 2201e2210.
7. (a) Johnson, A. W.; Roseberry, G.; Parker, C. Weed Res. 1976, 16, 23e227; (b)
Johnson, A. W.; Gowda, G.; Hassanali, A.; Knox, J.; Monaco, S.; Razawi, Z.;
Roseberry, G. J. Chem. Soc., Perkin Trans. 1 1981, 1734e1743.
8. Zwanenburg, B.; Mwakaboko, A. S.; Reizelman, A.; Anilkumar, G.; Sethu-
madhavan, D. Pest Manag. Sci. 2009, 65, 478e491.
4.1.22. (3aR
hydrofuran-2-yl)oxymethylene)-3,3a,4,8b-tetrahydro-2H-indeno
[1,2b]furan-2-one (32b). Mp 230.8e231.3 ꢁC, FTIR (solid) cmꢀ1
1778, 1731, 1674. 1H NMR (300 MHz, CDCl3):
*
,8bS
*
,E)-5,8-Dimethyl-3-(((S
*
)-4-methyl-5-oxo-2,5-di-
:
d
7.48 (d, 1H, J¼2.7 Hz),
7.05 (d, 1H, J¼7.5 Hz), 6.99 (s, 1H), 6.97 (t, 1H, J¼1.5 Hz), 6.19e6.18
(m, 1H), 5.99 (d, 1H, J¼8.1 Hz), 3.96e3.88 (m, 1H), 3.32 (dd, 1H,
J¼17.1, 9.6 Hz), 2.92 (dd, 1H, J¼17.1, 3.6 Hz), 2.39 (s, 3H), 2.18 (s, 3H),
2.03 (t, 3H, J¼1.5 Hz). 13C NMR (75 MHz, CDCl3):
d 171.0 (s),169.8 (s),
150.2 (d), 141.2 (s), 140.5 (d), 136.5 (s), 135.4 (s), 133.4 (s), 131.2 (s),
130.4 (d),128.2 (d),113.4 (s),100.2 (d), 85.5 (d), 37.6 (t), 36.6 (d),18.1
(q), 17.7 (q), 10.3 (q). HRMS (ESI) m/z calcd for C19H18O5 (MþNa)þ:
349.10519, found: 349.10392.
9. Wigchert, S. C. M.; Kuiper, E.; Boelhouwer, G. J.; Nefkens, G. H. L.; Verkleij, J. A.
C.; Zwanenburg, B. J. Agric. Food Chem. 1999, 47, 1705e1710.
10. Mangnus, E. M.; Stommen, P. L. A.; Zwanenburg, B. J. Plant Growth Regul. 1992,
11, 91e98.
11. Mangnus, E. M.; Dommerholt, F. J.; de Jong, R. L. P.; Zwanenburg, B. J. Agric. Food
Chem. 1992, 40, 1230e1235.
4.1.23. Methyl 4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate
(33). To a solution of 15 (2.01 g, 9.01 mmol) in dry CH2Cl2 (40 mL)
was added oxalyl chloride (1.37 g, 10.8 mmol). Two drops of dry
DMF were added to initiate the reaction. The reaction mixture was
stirred at room temperature for 1 h, after which the solvent was
removed in vacuo. The resulting product was dissolved in CH2Cl2
(20 mL) and then gradually added to a slurry of AlCl3 (2.40 g,
18.0 mmol) in CH2Cl2 (20 mL) at ꢀ30 ꢁC. The reaction mixture was
stirred at 0 ꢁC for 4 h and then overnight at room temperature. The
water (30 mL) was added dropwise to quench AlCl3 followed by
1 M HCl (2 mL) to make the solution clear. The product was
extracted with CH2Cl2 (2ꢂ50 mL). The organic layer was dried
(Na2SO4) and concentrated. The product was chromatographed
over silica gel using EtOAc/n-heptane (2:8) to yield 33 (1.25 g, 74%)
as a white solid. Mp 88.8e89.3 ꢁC, FTIR (solid) cmꢀ1: 1726, 1679. 1H
12. House, H. O.; Babad, H.; Toothill, R. B.; Noltes, A. W. J. Org. Chem. 1962, 27,
4141e4146.
13. Wigchert, S. C. M.; Zwanenburg, B. J. Chem. Soc., Perkin Trans.
2617e2624.
1 1999,
14. Kendall, P. M.; Johnson, J. V.; Cook, C. E. J. Org. Chem. 1979, 44, 1421e1424.
15. Hekking, K. F. W.; Lefort, L.; de Vries, A. H. M.; van Delft, F. L.; Schoemaker, H. E.;
de Vries, J. G.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2008, 350, 85e94.
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NMR (300 MHz, CDCl3):
J¼7.4 Hz), 7.28e7.20 (m, 2H), 3.65 (s, 3H), 3.15e3.08 (m, 3H),
2.91e2.70 (m, 2H). 13C NMR (75 MHz, CDCl3):
195.0 (s), 172.8 (s),
d
7.95 (d, 1H, J¼7.4 Hz), 7.43 (t, 1H,
d
141.3 (s), 133.3 (d), 131.2 (s), 128.3 (d), 126.5 (d), 126.4 (d), 51.5 (q),
40.0 (d), 39.4 (t), 31.3 (t). HRMS (ESI) m/z calcd for C12H12O3
(MþNa)þ: 227.06841, found: 227.06642.
4.2. Bioassay
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