Synthesis of C-seco limonoid model insect antifeedants related to ohchinolide and nimbolidin

Article abstract of DOI:10.1055/s-2002-33708

A concise and stereoselective synthesis of a CDE-seco limonoid related to ohchinolide and nimbolidin was accomplished in eleven and twelve steps, respectively, from α-cyclocitral. Opening of the C ring was first attempted by a retro-Claisen reaction, whereby a very unusual rearrangement occurred. However, the ring-opening was successfully accomplished by a selective Baeyer-Villiger reaction.

Full text of DOI:10.1055/s-2002-33708

1728
PAPER
Synthesis of C-seco Limonoid Model Insect Antifeedants Related to
Ohchinolide and Nimbolidin
S
ynthesis of C-sec
.
o
L
imonoidM
F
ode
l
Insect
A
e
ntifeedant
r
s
nández-Mateos,* E. M. Martín de la Nava, R. Rubio González
Departamento de Química Orgánica, Facultad de C. Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008-Salamanca,
Spain
Fax +34(923)294574; E-mail: afmateos@gugu.usal.es
Received 3 May 2002
tion of the -acyl divinylketone 1, obtained in five steps
Abstract: A concise and stereoselective synthesis of a CDE-seco li-
from -cyclocitral followed by the retro-Claisen reaction
monoid related to ohchinolide and nimbolidin was accomplished in
eleven and twelve steps, respectively, from -cyclocitral. Opening
of the keto acetate 2.4
of the C ring was first attempted by a retro-Claisen reaction, where-
O
AcO
by a very unusual rearrangement occurred. However, the ring-open-
ing was successfully accomplished by a selective Baeyer–Villiger
reaction.
Ph
O
Ph
a
Key words: stereoselective synthesis, allylic rearrangement, C-
seco limonoids, ohchinolide, nimbolidin
CHO
α-cyclocitral
H
O
1
2
O
O
Ph
O
Naturally occurring insect antifeedants are the plant
chemical defence against insect predators that have point-
ed the way to environmentally safe methods for avoiding
the agricultural damage. Ohchinolide and nimbolidin
(Figure 1) are degraded triterpenes of the limonoid family
(C-seco group) isolated from the well-known plant Melia
azederach Linn. (Neem tree), which exhibits a very potent
antifeedant activity.1 Only a few synthetic approaches to
the group of the C-seco limonoids have been made with
the exception of the work carried out by Ley et al.2 to ob-
tain model compounds based on the AB and CD rings of
azadirachtin. Part of our own contribution to the synthesis
of model compounds related to C-seco limonoids, which
aims at solving some of the problems arising in this field,
has been reported in two preliminary works.3
b
MeO
Ph
O
CDE fragment of ohchinolide
3
Scheme 1 (a) HClO4, Ac2O, EtOAc; (b) i. KOH, EtOH, H2O, ii. aq
2 M HCl, iii. CH2N2, Et2O
Although all the steps related to the formation of the keto
ester 2 were correct, from that point onward a rectification
was due.3a The structure of the product 3 resulting from
the retro-Claisen reaction of 2 (step b) was in principle
based on the literature background depicted in
Scheme 2.5,6
OH
O
O
AcO
O
KOH
MeOOC
AcO
products (ref.5)
O
O-
AcO
O
O
OH
H
O
KH
AcO
OR
AcO
OR
Nimbolidin
products (ref. 6)
O
O
O
O-
Ohchinolide
Scheme 2
Figure 1 The structures of ohchinolide and nimbolidin.
However, an in-depth study of the H-C correlations of
compound 3, together with certain other evidence (ex-
plained later), changed our original idea about its struc-
ture, and we opted for 6 (Scheme 3).
Our approach to CDE C-seco limonoid models is based on
the construction of the D ring by an electrocyclic reaction
and the opening of the C ring, first attempted by a retro-
Claisen reaction and later successfully accomplished by a
selective Baeyer–Villiger reaction. The key steps of the
first approach depicted in Scheme 1 are the Nazarov reac-
The main proof of the structure assigned to the product
from the retro-Claisen reaction was an X-ray diffraction
study of its methyl ester 6 (Figure 2).7
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1728,1734,ftx,en;P02002SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Synthesis of C-seco Limonoid Model Insect Antifeedants
1729
Ph
O
AcO
O
O
CO2Me
O
O
Ph
Ph
O
O
O
Ph
L-selectride®
THF, -78 °C
a
+
3
Ph
Ph
(30%)
CO2R
O
2
4
5 R = H
7
9a
(58%)
9b
b
6
R = Me
Scheme 4
Scheme 3 (a) i. NaOH, MeOH, H2O, ii. aq 2 M HCl; (b) CH2N2,
Et2O
Figure 3 X ray structure of 9a.
Figure 2 X-ray structure of 6.
To explain the unusual rearrangement that transforms
compound 2 into the keto acid 5 in basic aqueous media,
we propose the tentative complex mechanism shown in
When heated in toluene at reflux, the keto ester 6 was
isomerised to the two new compounds 7 and 8, as shown Scheme 5.
in Table 1.
-O
AcO
O
Ph
O
Ph
Table 1 Thermal Isomerisation of the Keto Ester 6
Ph
KOH, MeOH
H2O
O
Ph
CO2Me
O
CO2Me
+
O
Ph
toluene
reflux
O-
O
2
Ph
CO2Me
6
7
8
Ph
Ph
O
Ph
O-
O
O
Time
Ratio
6 (%)
7 (%)
8 (%)
-OH
O-
O
1 h 30 min
4 h
65
52
33
35
42
45
-
OH
6
H+
O
59 h
22
Ph
COOH
The structures of keto esters 7 and 8 were assigned on the
basis of spectroscopic data, and NOE and H-C correla-
tions. Moreover, the reduction of keto ester 7 with L-selec-
tride® afforded a 2:1 mixture of the isomer lactones 9a and
9b, respectively (Scheme 4), which were separated by
column chromatography. The structure of the major lac-
tone 9a was established after X-ray diffraction analysis7
(Figure 3).
5
Scheme 5
After this frustrated approach, we turned to a biomimetic
Baeyer–Villiger reaction. This type of reaction has been
invoked to explain the hypothetical biogenesis of the li-
monoids with the A, B or D ring opened.1a,8 So why not
explain also the biogenesis of limonoid with the ring C
opened with the same hypothesis? (Scheme 6).9
Synthesis 2002, No. 12, 1728–1734 ISSN 0039-7881 © Thieme Stuttgart · New York

1730
A. Fernández-Mateos et al.
PAPER
O
model compound 15a in good yield (72%), together with
the unsaturated isomer lactone 15c (10%). The transfor-
mation of 13 by an absolutely stereoselective allylic rear-
rangement to give 15a could be explained by the
proximity of the orbital through the space of the lactone
oxygen and the carbocation formed after dissociation of
the chlorosulfite intermediate (Scheme 8).11
O
O
12
O
O
O
O
O
14
15
Ohchinolide
I
II
H
H
Scheme 6
H
O
H
H
O
O
H
Ph
Ph
Ph
O
O
O
O
This idea inspired our new contribution to the synthesis of
model compounds related to C-seco limonoids, which
promises to be a general and useful procedure.
O
O
+
O
Ph
O
O
Now starting from the keto acetate 2, obtained as above,
and taking advantage of the one keto group protected as an
enol acetate and the differences between the C–C double
bonds in 2, a catalytic hydrogenation was undertaken to
obtain the keto acetate 10 in a chemo- and stereoselective
manner.10 The reduction of compound 10 carried out with
NaBH4 gave only the hydroxy acetate 11 in a totally ster-
ereoselective way. Further hydrolysis of the acetate af-
forded the expected hydroxy ketone 12a and the isomeric
hemiacetal 12b in equal amounts, as an inseparable mix-
ture. However, treatment of the mixture with m-chlorop-
eroxybenzoic acid gave only one compound, the hydroxy
lactone 13, in excellent yield (Scheme 7). The relative
stereochemistry of 13 (and indeed of 11 and 12a) was es-
tablished by X-ray diffraction analysis of its hydrolysis
product, the diol acid 14.3b
a
Ph
II
Ph
H
OH
15a (82%)
15c(10%)
13
b
100%
MeOOC
MeOOC
Ph
Ph
c
96%
OH
OAc
16a
17a
Scheme 8 (a) SOCl2, py, CH2Cl2; (b) MeONa, MeOH; (c) Ac2O,
py, DMAP
AcO
AcO
AcO
Our next target, the CDE nimbolidin model compound
17a was obtained from ohchinolide model 15a in two sim-
ple steps: transesterification and acetylation. Another less
biomimetic way to obtain the ohchinolide and nimbolidin
model compounds was carried out from the hydroxy lac-
tone 13 through the sequence described in Scheme 9,
which consists of the oxidation of 13 to give the keto lac-
tone 18, followed by elimination with 1,8-diazabicy-
Ph
Ph
Ph
a
b
97%
95%
H
H
H
O
O
O
OH
2
10
11
c
95%
OH
O
Ph
Ph
Ph
O
clo[5.4.0]undec-7-ene
and
esterification
with
d
+
O
diazomethane to the keto ester 19. The reduction of 19
with diborane gave a diastereomeric 3:1 mixture of hy-
droxy esters 16a and 16b. Acetylation of the major isomer
16a afforded the CDE nimbolidin model compound 17a.
Hydrolysis of the hydroxy ester 16a, followed by the Co-
rey–Nicolaou lactonization of the hydroxy acid interme-
diate, gave the CDE ohchinolide model compound 15a.12
Following the methods described above, the minor hy-
droxy ester 16b was transformed into the diastereomers of
the CDE nimbolidin and ohchinolide model compounds
17b and 15b. The latter two compounds exhibit very po-
tent insect antifeedant activity against Spodoptera littora-
lis larvae.13
100%
H
OH
H
H
OH
13
12a
12b
e
98%
Ph
HO
HO2C
H
OH
14
Scheme 7 (a) H2 (1 atm), Pd/C, EtOAc; (b) NaBH4, MeOH, 0 °C;
(c) aq 5 M KOH, EtOH; (d) m-CPBA, CH2Cl2; (e) i. KOH, H2O,
EtOH, ii) aq 1 M HCl
The relative stereochemistry of compounds 15a and 17a
was established by NOE experiments.3b
The reaction of 13 with thionyl chloride and pyridine,
which must lead to the unsaturated lactone II, the subject
of the allylic rearrangement that we consider to be the cor-
ner-stone of the synthesis, was completely unexpected be-
cause it directly afforded the target CDE ohchinolide
All solvents and reagents were purified, when required, by standard
techniques. Reactions were monitored by TLC on Merck silica 60
F254. Organic extracts were dried over Na2SO4 and concentrated un-
Synthesis 2002, No. 12, 1728–1734 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of C-seco Limonoid Model Insect Antifeedants
1731
Thermal Rearrangement of 6
O
O
O
Ph
Ph
O
MeOOC
b
Ph
O
A solution of 6 (162 mg, 0.54 mmol) in toluene (5 mL) was refluxed
for 59 h. Removal of the solvent under reduced pressure afforded a
residue, which was purified by flash chromatography (hexane–
Et2O, 90:10). The first fraction was identified as 7.
a
90%
92%
H
H
OH
O
13
18
19
(Z)-4-(2,2-Dimethyl-5-oxocyclopentylidene)-3-phenyl-3-yl-pen-
tanoic Acid Methyl Ester (7)
Colourless oil; yield: 73 mg (45%).
IR (film): 2955, 1738, 1699, 702 cm–1.
1H NMR (CDCl3): = 1.23 (3 H, s), 1.29 (3 H, s), 1.68 (3 H, s), 1.70
(2 H, t, J = 8 Hz), 2.40 (2 H, t, J = 8 Hz), 2.74 (1 H, dd, J1 = 9,
J2 = 14 Hz), 2.89 (1 H, dd, J1 = 7, J2 = 14 Hz), 3.60 (3 H, s), 6.30 (1
H, dd, J1 = 7, J2 = 9 Hz), 7.10–7.40 (5 H, m).
13C NMR (CDCl3): = 15.6, 27.5, 28.0, 36.3, 37.2, 37.8, 40.1, 41.3,
51.6, 126.4, 127.6 (2C), 128.3 (2C), 141.3, 141.4, 151.3, 172.2,
207.7.
c
O
O
MeOOC
Ph
d
Ph
OR
15a α-OR 91%
15b β-OR 90%
16a R= β-OH 64%
17a R= β-OAc 96%
e
e
16b R= α-OH 23%
17b R= α-OAc 98%
Scheme 9 (a) PCC, CH2Cl2; (b) i. DBU, toluene, 80 °C, ii. CH2N2,
Et2O; (c) BH3 SMe2, THF, 0 °C; (d) i. aq 5 M KOH, EtOH, ii. aq 1 M
HCl, pH 5, iii. (pyS)2, PPh3, xylene; (e) Ac2O, py, DMAP
MS (EI): m/z (%) =: 300 (M+, 30), 285 (27), 225 (100), 171 (52), 91
(63), 77 (42).
Anal. Calcd for C19H24O3: C, 75.97; H, 8.05. Found: C, 76.00, H,
8.11.
The second fraction was identified as 8.
der reduced pressure with the aid of a rotary evaporator. Column
chromatography was performed on Merck silica gel 60 (0.040–
0.063 mm). 1H and 13C NMR spectra were recorded at 200/400 and
50/75 MHz, respectively.
(E)-4-(2,2-Dimethyl-5-oxocyclopentyl)-3-phenylpent-3-enoic
Acid Methyl Ester (8)
Colourless solid; yield: 36 mg (22%); mp 84–86 °C.
(E)-4-(2,2-Dimethyl-5-oxocyclopentyl)-3-phenylpent-3-enoic
Acid Methyl Ester (6); Treatment of 2 with Aqueous NaOH/
MeOH
IR (film): 2955, 1738, 1161, 706 cm–1.
1H NMR (CDCl3): = 0.79 (3 H, s), 1.00 (3 H, s), 1.50 (1 H, m),
1.70 (1 H, m), 1.76 (3 H, s), 2.24 (2 H, dd, J1 = 6, J2 = 9.5 Hz), 3.08
(1 H, s), 3.28 (1 H, d, J = 16 Hz), 3.53 (1 H, d, J = 16 Hz), 3.65 (3
H, s), 7.1–7.3 (5 H, m) .
13C NMR (CDCl3): = 17.8, 24.3, 29.6, 36.5, 36.6, 40.4, 51.7, 65.5,
126.7, 128.2 (2 C), 128.9 (2 C), 131.2, 135.5, 142.7, 171.6, 219.6.
To a solution of 2 (700 mg, 2.26 mmol) in MeOH (5.9 mL) was add-
ed an aq 6 M solution of NaOH (1 mL). The mixture was stirred at
r.t. for 30 min and then concentrated under reduced pressure. To the
residue were added H2O and Et2O. The organic layer was separated
and the aqueous phase was acidified with aq 2 N HCl and extracted
with Et2O. The combined organic extracts were washed with brine
and concentrated. The residue was dissolved in Et2O and then a so-
lution of CH2N2 in Et2O was added dropwise until the release of N2
had stopped. Removal of the solvent afforded a crude product,
which was purified by flash chromatography (hexane–Et2O, 85:15)
to afford (603 mg, 89%) as a white solid; mp 131–133 °C (t-
BuOMe–hexane).
MS (EI): m/z (%) = 300 (M+, 34), 285 (13), 171 (100), 115 (16), 77
(16), 55 (19).
Anal. Calcd for C19H24O3: C, 75.97; H, 8.05. Found: C, 76.01; H,
8.09.
The third fraction was the starting keto ester 6; recovered yield: 53
mg (33%).
IR (film): 2955, 1738, 733, 704 cm–1.
Reaction of 7 with L-Selectride®
1H NMR (CDCl3): = 1.07 (3 H, s), 1.27 (3 H, s), 1.46 (3 H, s), 1.85
(2 H, m), 2.38 (2 H, m), 3.20 (1 H, s), 3.33 (1 H, d, J = 16 Hz), 3.44
(1 H, d, J = 16 Hz), 3.55 (3 H, s), 7.1–7.4 (5 H, m).
13C NMR (CDCl3): = 19.1, 24.2, 30.0, 36.6, 37.0, 40.5, 42.2, 51.7,
63.7, 126.6, 128.2 (2 C), 128.7 (2 C), 130.9, 134.8, 142.3, 171.4,
219.0.
To a solution of 7 (30 mg, 0.1 mmol) in THF (2 mL) at –78 °C under
argon, was added a 1 M solution of L-selectride® in THF (1.1 mL).
The reaction mixture was stirred at –78 °C for 15 min and then ac-
etone was slowly added and concentrated under reduced pressure.
The residue was dissolved in H2O, extracted with Et2O, and the
combined organic extracts were washed with brine. Removal of the
solvent afforded a crude solid, which was purified and separated by
flash chromatography to give the products 9a and 9b.
MS (EI): m/z (%) = 300 (6, M+), 285 (6), 171 (100), 115 (24), 91
(33), 77 (29), 55 (34).
Anal. Calcd for C19H24O3: C, 75.97; H, 8.05. Found: C, 76.00; H,
8.10.
5,6,6-Trimethyl-4-phenyl-3,4,6,7,8,8a-hexahydrocyclopen-
ta[b]oxepin-2-one (9a)
Eluent: hexane–Et2O, 70:30; colourless solid; yield: 16 mg (58%);
mp 165–167 °C (t-BuOMe–hexane).
IR (film): 2922, 1730, 752, 702 cm–1.
1H NMR (CDCl3): = 1.31 (3 H, s), 1.33 (3 H, s), 1.60 (2 H, m),
1.65 (3 H, d, J = 2 Hz), 2.10 (2 H, m), 2.60 (1 H, m), 3.56 (1 H, m),
3.60 (1 H, m), 5.35 (1 H, t, J = 9 Hz), 7.1–7.4 (5 H, m) .
13C NMR (CDCl3): = 19.6, 27.3, 28.7, 30.1, 39.2, 39.9, 42.8, 48.6,
79.9, 127.2, 127.9 (2 C), 128.8 (2 C), 131.1, 141.6, 143.5, 172.4.
Crystal Data for 6
C19H24O3; Mr = 300.38; orthorhombic; space group P212121; unit
cell dimensions a = 7.555(5) Å, b = 11.348(1) Å; c = 19.843(2) Å,
= 90°, = 90°, = 90°; volume 1701.3 (3) Å3; Z = 4, Dx = 1.173
gcm–3; absorption coefficient 0.620 mm–1; crystal size
0.48 0.16 0.08 mm; range for data collection 4.46 to 64.98°;
limiting indices 0 = h = 8, 0 = k = 13, 0 = l = 23; R = 0.0477;
Rw = 0.0825.
Synthesis 2002, No. 12, 1728–1734 ISSN 0039-7881 © Thieme Stuttgart · New York

1732
A. Fernández-Mateos et al.
PAPER
MS (EI): m/z (%) = 270 (M+, 3), 228 (10), 195 (2), 172 (55), 139
Reaction of 11 with Aqueous KOH/EtOH
(28), 104 (100), 91 (15), 77 (13).
To a solution of 11 (6.30 g, 20.1 mmol) in EtOH (50 mL) was added
an aq 5 M solution of KOH (9 mL). The mixture was stirred at r.t.
for 1 h and then concentrated under reduced pressure. The residue
was partitioned between H2O and Et2O. The organic layer was sep-
arated and the aqueous phase extracted with Et2O. The combined
organic extracts were washed with brine. Removal of the solvent af-
forded a 1:1 inseparable mixture of 12a and 12b (5.19 g, 95%) as a
white solid.
Anal. Calcd for C18H22O2: C, 79.96; H, 8.20. Found: C, 80.01; H,
8.22.
Crystal Data for 9a
C18H22O2; Mr = 270.34; monoclinic; space group P21/c; unit cell di-
mensions a = 5.958(3) Å, b = 22.367(1) Å; c = 11.784(7) Å,
= 90°, = 104.62 (5)°, = 90°; volume 1519.6 (1) Å3; Z = 4,
Dx = 1.173 gcm–3; absorption coefficient 0.589 mm–1; crystal size
0.48 0.40 0.24 mm; range for data collection 3.95 to 65.00°;
limiting indices –7 = h = 7, 0 = k = 26, 0 = l = 13; R = 0.0367;
Rw = 0.0959.
1-Hydroxy-3a,7,7-trimethyl-3-phenyloctahydroinden-4-one
(12a)
IR (CHCl3): 3528, 3451, 2953, 2868, 1699, 1071, 737, 700 cm–1.
MS (EI): m/z (%) = 272 (M+, 28), 257 (15), 157 (98), 139 (49), 105
5,6,6-Trimethyl-4-phenyl-3,4,6,7,8,8a-hexahydrocyclopenta-
[b]oxepin-2-one (9b)
Eluent: hexane–Et2O, 50:50; white solid; yield: 8 mg (30%); mp
98–100 °C.
(53), 91 (62), 55 (100).
1H NMR (CDCl3): = 1.25 (3 H, s), 1.27 (3 H, s), 1.50 (3 H, s), 1.60
(1 H, m), 1.76 (1 H, dd, J1 = 1.5, J2 = 2 Hz), 2.15 (2 H, m), 2.50 (2
H, m), 2.55 (1 H, m), 2.84 (1 H, t, J = 10 Hz), 4.55 (1 H, dt, Jd = 3,
Jt = 6 Hz), 7.15–7.60 (5 H, m).
IR (film): 2924, 1719, 764, 702 cm–1.
1H NMR (CDCl3): = 1.24 (3 H, s), 1.31 (3 H, s), 1.54 (3 H, d, J = 1
Hz), 1.60 (1 H, m), 1,75 (1 H, m), 2.05 (1 H, m), 2.15 (1 H, m), 2.70
(1 H, dd, J1 = 6, J2 = 13 Hz), 3.18 (1 H, t, J = 13 Hz), 3.64 (1 H, dd,
J1 = 6, J2 = 13 Hz), 5.61 (1 H, t, J = 7 Hz), 7.1–7.4 (5 H, m).
13C NMR (CDCl3): = 19.6, 27.0, 28.1, 29.6, 40.2, 41.8, 43.1, 49.6,
80.0, 127.1, 127.3 (2 C), 129.0 (2 C), 132.5, 143.6, 145.1, 173.0.
13C NMR (CDCl3): = 28.0, 29.2, 31.4, 32.8, 37.0, 37.8, 40.7, 55.8,
57.3, 74.5, 127.3, 129.2 (2 C), 130.1 (2 C), 140.4, 216.2.
Hemiketal 12b
1H NMR (CDCl3): = 1.09 (3 H, s), 1.11 (3 H, s), 1.30–1.45 (2 H,
m), 1.33 (3 H, s), 1.60 (1 H, br s), 1.85 (2 H, m), 2.10 (1 H, m), 2.40
(1 H, m), 3.10 (1 H, dd, J1 = 5.5, J2 = 12 Hz), 4.43 (1 H, dd, J1 = 2,
J2 = 3 Hz), 7.15–7.60 (5 H, m).
MS (EI): m/z (%) = 270 (M+, 5), 195 (5), 172 (79), 139 (25), 104
(100), 77 (22).
13C NMR (CDCl3): =15.4, 28.0, 31.9, 32.0 (2 C), 34.1, 36.2, 51.3,
52.2, 63.9, 78.0, 109.2, 126.3, 127.3 (2 C), 129.0 (2 C), 141.5.
Anal. Calcd for C18H22O2: C, 79.96; H, 8.20. Found: C, 79.99; H,
8.23.
6-Hydroxy-5,5,8a-trimethyl-8-phenyloctahydrocyclopenta-
[b]oxepin-2-one (13)
Acetic Acid 3a,7,7-Trimethyl-1-oxo-3-phenyl-2,3,3a,6,7,7a-
hexahydro-1H-inden-4-yl Ester (10)
To a stirred solution of the inseparable mixture of 12a/12b (4.00 g,
14.7 mmol) in CH2Cl2 (93 mL) was added NaHCO3 (126 mg, 1.5
mmol) and m-CPBA (2.79 g, 16.2 mmol). The reaction mixture was
stirred under argon at r.t. for 17 h. Then aq 5% Na2SO3 (20 mL) was
added and the resulting heterogeneous mixture was vigorously
stirred for 1 h. The organic layer was separated and the aqueous
phase was extracted with CH2Cl2. The combined organic extracts
were washed with aq 5% Na2CO3 and brine. Removal of the solvent
afforded 13 (4.23 g, 100%) as a white solid; mp 148–150 °C
(CH2Cl2–hexane).3b
To a solution of 2 (7.0 g, 22.6 mmol) in EtOAc (68 mL) was added
10% Pd/C (1.36 g). The mixture was vigorously stirred at r.t. under
H2 for 10 h. After removal of the catalyst by filtration, the filtrate
was concentrated to yield 10 (6.83 g, 97%) as a colourless solid; mp
82–84 °C (t-BuOMe–hexane).
IR (film): 2962,1748, 1738, 770, 704 cm–1.
1H NMR (CDCl3): = 1.17 (3 H, s), 1.31 (3 H, s), 1.35 (3 H, s), 1.44
(3 H, s), 1.82 (1 H, ddd, J1 = 2, J2 = 7, J3 = 17 Hz), 2.01 (1 H, t, J = 2
Hz), 2.16 (1 H, dd, J1 = 2, J2 = 17 Hz), 2.36 (1 H, m), 2.97 (1 H, m),
3.00 (1 H, s), 5.56 (1 H, dd, J1 = 2, J2 = 7 Hz), 7.20–7.40 (5 H, m).
13C NMR (CDCl3): = 20.2, 23.8, 28.0, 29.1, 33.5, 35.7, 43.4, 49.5,
52.1, 65.6, 117.2, 126.8, 127.7 (2 C), 128.6 (2 C), 138.0, 146.9,
168.9, 216.1.
4-(2,5-Dihydroxy-2-methyl-3-phenylcyclopentyl)-4-methylpen-
tanoic Acid (14)
To a solution of 13 (25 mg, 0.087 mmol) in EtOH (0.2 mL) was add-
ed an aq 6 M solution of KOH (0.036 mL). The mixture was stirred
at r.t. for 15 min and then concentrated under reduced pressure. To
the residue were added H2O and Et2O. The organic layer was sepa-
rated and the aqueous phase was acidified with aq 2 N HCl (pH 5)
and extracted with Et2O. The combined organic extracts were
washed with brine and concentrated. Removal of the solvent afford-
ed 14 (26 mg, 98%) as a colourless solid; mp 179–182 °C (EtOH).3b
MS (EI): m/z (%) = 312 (4, M+), 270 (8), 252 (7), 138 (100), 123
(83), 77 (26), 55 (30).
Acetic Acid 1-Hydroxy-3a,7,7-trimethyl-3-phenyl-2,3,3a,6,7,7a-
hexahydro-1H-inden-4-yl Ester (11)
To a solution of 10 (6.70 g, 21.5 mmol) in MeOH (1 L) at 0 °C was
added NaBH4 (4.10 g, 108 mmol). The reaction mixture was stirred
at 0 °C under argon for 3 h and concentrated after adding acetone.
The residue was treated with brine and Et2O and stirred for 30 min.
The organic layer was separated and the aqueous phase was extract-
ed with Et2O. The combined extracts were washed with brine. Re-
moval of the solvent afforded 11 (6.41 g, 95%) as a colourless oil.
1H NMR (CDCl3): = 1.00–2.20 (4 H, m), 1.17 (3 H, s), 1.29 (3 H,
s), 1.38 (3 H, s), 1.40 (3 H, s), 2.45 (1 H, m), 2.70–2.90 (2 H, m),
4.55 (1 H, m), 5.40 (1 H, m), 7.10–7.40 (5 H, m).
Reaction of 13 with SOCl2/Pyridine
To a solution of 13 (250 mg, 0.87 mmol) in CH2Cl2 (12 mL) at 0 °C
under argon, was added gradually pyridine (0.28 mL, 3.48 mmol)
and a solution of SOCl2 (0.13 mL, 1.74 mmol) in CH2Cl2 (0.87 mL).
The reaction mixture was stirred at 0 °C for 5 min and then poured
into ice water. The organic layer was separated and the aqueous
phase was extracted with CH2Cl2. The combined organic extracts
were washed with aq 5% Na2CO3 and brine. Removal of the solvent
afforded a crude product, which was purified and separated into 15a
(first fraction) and 15c (second fraction) by flash chromatography
(eluent: hexane–Et2O, 70:30).
Synthesis 2002, No. 12, 1728–1734 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of C-seco Limonoid Model Insect Antifeedants
1733
5,5,8a-Trimethyl-7-phenyl-3,4,5,7,8,8a-hexahydrocyclopenta-
[b]oxepin-2-one (15a)
13C NMR (CDCl3): = 23.9, 27.4, 29.0, 32.0, 32.7, 35.3, 42.2, 52.6,
67.5, 87.5, 126.6, 128.1 (2 C), 130.4 (2 C), 135.8, 173.1, 211.7.
Yield: 193 mg (82%); colourless solid; mp 88–90 °C (t-BuOMe–
MS (EI): m/z (%) = 286 (M+, 3), 268 (8), 172 (21), 104 (100), 55
(59).
hexane).3b
5,5,6-trimethyl-7-phenyl-3,4,5,7,8,8a-hexahydro-cyclopenta-
[b]oxepin-2-one 15c
Colourless solid; yield: 23 mg (10%); mp 117–120 °C.
IR (film): 2955, 2874, 1738, 1262, 764, 700 cm–1.
1H NMR (CDCl3): = 0.87 (3 H, s), 1.12 (3 H, s), 1.25 (2 H, m),
1.73 (3 H, s), 2.11 (1 H, d, J = 6 Hz), 2.15 (1 H, m), 2.40 (1 H, m),
2.80 (2 H, br s), 4.41 (1 H, m), 7.10–7.30 (5 H, m).
13C NMR (CDCl3): = 16.7, 22.9, 30.5, 33.8, 35.1, 36.3, 43.0, 61.3,
78.6, 126.8, 128.2 (2 C), 128.5 (2 C), 133.3, 136.5, 137.6, 172.4.
4-Methyl-4-(2-methyl-5-oxo-3-phenylcyclopent-1-enyl)pen-
tanoic Acid Methyl Ester (19)
To a solution of 18 (2.50 g, 8.74 mmol) in toluene (67 mL) was add-
ed DBU (6.5 mL, 43.7 mmol). The reaction mixture was stirred at
80 °C under argon for 10 min. Then, Et2O and aq 2 M HCl were
added, the organic layer was separated and the aqueous phase was
extracted with Et2O. The combined organic extracts were washed
with brine and concentrated to afford a colourless oil, which was
dissolved in Et2O (10 mL). To the solution was added dropwise a
solution of CH2N2 in Et2O until the release of N2 had stopped. Re-
moval of the solvent afforded 19 (2.41 g, 92%) as a colourless oil.
MS (EI): m/z (%) = 270 (M+, 2), 252 (1), 237 (1), 156 (100), 91 (14),
IR (film): 2953, 1738, 1697, 764, 702 cm–1.
77 (6), 55 (8).
1H NMR (CDCl3): = 1.33 (3 H, s), 1.35 (3 H, s), 1.97 (3 H, s), 2.12
(2 H, m), 2.20 (2 H, m), 2.29 (1 H, dd, J1 = 2, J2 = 19 Hz), 2.80 (1
H, dd, J1 = 7, J2 = 19 Hz), 3.65 (3 H,s), 3.70 (1 H, dd, J1 = 2, J2 = 7
Hz), 7.05–7.35 (5 H, m).
13C NMR (CDCl3): = 18.3, 27.7, 28.0, 30.6, 35.5, 36.7, 45.1, 50.3,
51.5, 127.0, 127.3 (2 C), 128.9 (2 C), 142.3, 143.9, 171.2, 174.3,
208.6.
4-(5-Hydroxy-2-methyl-3-phenylcyclopent-1-enyl)-4-methyl-
pentanoic Acid Methyl Ester (16a)
To a solution of 15a (50 mg, 0.19 mmol) in MeOH (5.2 mL) was
added a 5.5 M solution of MeONa in MeOH (0.16 mL). The reac-
tion mixture was stirred at r.t. under argon for 10 min and then
poured into an aq sat. solution of NH4Cl. The organic layer was sep-
arated and the aqueous phase was extracted with Et2O. The com-
bined organic extracts were washed with brine. Removal of the
solvent afforded 16a (56 mg, 100%) as a colourless oil.
MS (EI): m/z (%) = 300 (M+, 6), 281 (4), 269 (15), 227 (100), 213
(66), 91 (79), 69 (47), 55 (47).
IR (film): 3511, 2957, 2876, 1738, 764, 702cm–1.
Reaction of 19 with BH3 SMe2
1H NMR (C6D6): = 1.25 (3 H, s), 1.31 (3 H, s). 1.57 (3 H, s), 1.61
(1 H, m), 1.88 (1 H, m), 1.96 (1 H, m), 2.15 (1 H, m), 2.41 (3 H, m),
3.31 (1 H, dd, J1 = 3, J2 = 9 Hz), 3.42 (3 H, s), 4.60 (1 H, t, J = 6
Hz), 7.12 (1 H, m), 7.25 (2 H, m), 7.37 (2 H, m).
13C NMR (C6D6): = 15.1, 28.0, 28.5, 30.4, 35.8, 37.4, 42.1, 50.8,
56.6, 78.8, 126.2, 128.2 (2 C), 128.5 (2 C), 139.2, 143.1, 145.7,
174.2.
To a solution of 19 (1.80 g, 6.00 mmol) in THF (16 mL) at 0 °C un-
der argon, was added a 2 M solution of BH3 SMe2 in THF (6.0 mL).
The reaction mixture was stirred at 0 °C for 6 h and then MeOH (8
mL) was slowly added and the mixture was stirred for 1 h. Removal
of the solvent afforded a crude product, which was purified by flash
chromatography eluting with hexane–Et2O, 75:25 to furnish 16a
(1.16 g, 64%) and hexane–Et2O, 60:40 to afford 16b (417 mg, 23%)
as colourless oils.
MS (EI): m/z (%) = 284 (M+ – 18, 16), 269 (1), 253 (5), 197 (100),
129 (60), 97 (50), 69 (52).
4-(5-Hydroxy-2-methyl-3-phenylcyclopent-1-enyl)-4-methyl-
pentanoic Acid methyl Ester (16b)
4-(5-Acetoxy-2-methyl-3-phenylcyclopent-1-enyl)-4-methyl-
pentanoic Acid Methyl Ester (17a)
IR (film): 3443, 2955, 2888, 1738, 754, 702 cm–1.
1H NMR (C6D6): = 1.23 (3 H, s), 1.29 (3 H, s), 1.52 (3 H, s), 1.70
(1 H, m), 1.95 (2 H, m), 2.10 (2 H, m), 2.39 (2 H, t, J = 8 Hz), 3.42
(3 H, s), 3.78 (1 H, t, J = 7 Hz), 4.73 (1 H, d, J = 6 Hz), 7.05 (2 H,
m), 7.13 (1 H, m), 7.23 (2 H, m).
13C NMR (C6D6): = 15.1, 28.0, 28.4, 30.4, 35.8, 37.2, 44.6, 50.8,
55.9, 78.5, 126.2, 127.7 (2 C), 128.6 (2 C), 139.7, 144.3, 145.3,
174.3.
To a solution of 16a (200 mg, 0.66 mmol) in pyridine (0.37 mL,
4.62 mmol) was added Ac2O (0.37 mL, 3.96 mmol) and 4-dimeth-
ylaminopyridine (DMAP, 8 mg, 0.07 mmol). The reaction mixture
was stirred at r.t. under argon for 30 min, then diluted with Et2O and
poured into ice water. The organic layer was separated and the aque-
ous phase was extracted with Et2O. The combined organic extracts
were washed with aq 5% NaHCO3 and brine. Removal of the sol-
vent afforded 17a (219 mg, 96%) as a white solid; mp 58–60 °C.3b
MS (EI): m/z (%) = 284 (M+ – 18, 18), 269 (1), 253 (6), 197 (100),
5,5,8a-Trimethyl-8-phenylhexahydrocyclopenta[b]oxepine-2,6-
dione (18)
129 (47), 97 (42), 69 (43).
To a stirred solution of PCC (3.36 g, 15.6 mmol) and silica gel (3.36
g) in CH2Cl2 (87 mL) was added dropwise a solution of the 13 (3.00
g, 10.4 mmol) in CH2Cl2 (22 mL). The reaction mixture was vigor-
ously stirred at r.t. under argon for 7 h. The resulting dark brown
slurry was filtered through a short column of silica gel and eluted
with CH2Cl2. Removal of the solvent afforded 18 (2.68 g, 90%) as
a white solid; mp 123–125 °C (CH2Cl2–hexane).
5,5,8a-Trimethyl-7-phenyl-3,4,5,7,8,8a-hexahydrocyclopenta-
[b]oxepin-2-one (15b)
To a solution of 16b (100 mg, 0.33 mmol) in EtOH (0.87 mL) was
added an aq 5 M solution of KOH (0.45 mL). The mixture was
stirred at r.t. for 15 min and then concentrated under reduced pres-
sure. To the residue were added H2O and Et2O. The organic layer
was separated and to the aqueous phase was added aq 2 M HCl (pH
5) and then extracted with Et2O. The combined organic extracts
were washed with brine. Removal of the solvent afforded the crude
hydroxy acid, which was suitable for using without further purifica-
tion. To a solution of the crude hydroxy acid in deoxygenated xy-
lene (4 mL) were added (pyS)2 (110 mg, 0.50 mmol) and Ph3P (131
mg, 0.50 mmol). The mixture was stirred at r.t. under argon for 20
h and the precipitate formed was filtered. Removal of the solvent af-
IR (Nujol): 2924, 2870, 1728, 1696, 768, 700 cm–1.
1H NMR (CDCl3): = 1.23 (3 H, s), 1.29 (3 H, s). 1.59 (3 H, s), 1.55
(1 H, m), 1.87 (1 H, m), 2.45 (1 H, s), 2.58 (1 H, dd, J1 = 8.5, J2 = 18
Hz), 2.66 (2 H, m), 2.75 (1 H, dd, J1 = 12, J2 = 18 Hz), 3.15 (1 H,
dd, J1 = 8.5, J2 = 12 Hz), 7.20–7.50 (5 H, m).
Synthesis 2002, No. 12, 1728–1734 ISSN 0039-7881 © Thieme Stuttgart · New York

1734
A. Fernández-Mateos et al.
PAPER
forded a crude product, which was purified by flash chromatogra-
phy (eluent: hexane–Et2O, 75:25) to furnish 15b (80 mg, 90%) as a
white solid; mp 74–76 °C (t-BuOMe–hexane).3b
Crystallographic Data Centre as supplementary publication
nos. CCDC 159675 and CCDC 159676, respectively. Copies
of the data can be obtained free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: +44
(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk.
4-(5-Acetoxy-2-methyl-3-phenylcyclopent-1-enyl)-4-methyl-
pentanoic Acid Methyl Ester (17b)
(8) Taylor, D. A. H. Prog. Chem. Org. Nat. Prod. 1984, 45, 1.
(9) Proposals have been made regarding the hypothetical
biogenesis of C-seco limonoids such as ohchinolide, arising
To a solution of 16b (100 mg, 0.33 mmol) in pyridine (0.18 mL,
2.31 mmol) was added Ac2O (0.18 mL, 1.98 mmol) and DMAP (4
mg, 0.03 mmol). The reaction mixture was stirred at r.t. under argon
for 30 min and then diluted with Et2O and poured into ice water. The
organic layer was separated and the aqueous phase was extracted
with Et2O. The combined organic extracts were washed with aq 5%
NaHCO3 and brine. Removal of the solvent afforded 17b (110 mg,
98%) as a colourless oil.3b
from the hydrolytic cleavage of the 12 -hydroxy-14,15 -
13,14
oxide, which can be opened to give the 12-aldehyde-
15 -ol intermediate, followed by attack of the hydrate
-
aldehyde to the allylic carbon C-15 with inversion and later
oxidation to lactone (Scheme 10).
O
O
HO
12
12
OHC
Acknowledgements
13
Financial support for this work from the Ministerio de Educación y
Ciencia of Spain PB 98-0251 and the Junta de Castilla y León SA
24/00B is gratefully acknowledged. We also thank the Ministerio de
Educación y Ciencia for a fellowship to E.M.M.N.
14
15
OH
15
O
O
HO
References
O
O
(1) (a) Champagne, D. E.; Koul, O.; Isman, M. B.; Scudder, G.
G. E.; Towers, G. H. N. Phytochemistry 1992, 31, 377.
(b) Akhila, A.; Rani, K. Prog. Chem. Org. Nat. Prod. 1999,
78, 48.
O
O
(2) Ley, S. V.; Denholm, A. A.; Wood, A. Nat. Prod. Rep. 1993,
109.
Scheme 10
(3) (a) Fernández-Mateos, A.; Martín de la Nava, E. M.; Pascual
Coca, G.; Ramos Silvo, A. I.; Rubio González, R. Synlett
1998, 1372. (b) Fernández-Mateos, A.; Martín de la Nava,
E. M.; Rubio González, R. Synlett 2001, 1399.
(4) Fernández-Mateos, A.; Martín de la Nava, E. M.; Rubio
González, R. Tetrahedron 2001, 57, 1049.
(5) Dauben, W. G.; Hart, D. J. J. Org. Chem. 1977, 42, 3787.
(6) Tice, C. M.; Heathcock, C. H. J. Org. Chem. 1981, 46, 9.
(7) Crystallographic data (excluding structure factors) for the
structures 6 and 9a have been deposited with the Cambridge
(10) All compounds synthesised are racemic although, only one
enantiomer is depicted.
(11) March, J. Advanced Organic Chemistry, 3 rd Ed.; Wiley:
New York, 1985, 286.
(12) (a) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96,
5694. (b) Corey, E. J.; Nicolaou, K. C.; Melvin, L. S. Jr. J.
Am. Chem. Soc. 1975, 97, 654.
(13) Essays of insect antifeedant activity of all compounds
described in this work will be published in due course.
Synthesis 2002, No. 12, 1728–1734 ISSN 0039-7881 © Thieme Stuttgart · New York