Synthesis of active antifeedant CDE fragments of 11- ketoepoxyazadiradione based on an electrocyclization reaction catalyzed by perchloric acid

Article abstract of DOI:10.1021/jo981456q

A synthetic route to mimics of the insect antifeedant epoxyazadiradione containing the CDE molecular fragment with an oxygenated function on ring C has been developed. The key step is based on a 2,6-diene-1,5-dione electrocyclization reaction catalyzed by perchloric acid. The rearrangement of the epoxy alcohol epimers 12 and 19 induced by acids deserves special mention. Several of the compounds obtained show significant antifeedant activity against Spodoptera frugiperda.

Full text of DOI:10.1021/jo981456q

9440
J . Org. Chem. 1998, 63, 9440-9447
Syn th esis of Active An tifeed a n t CDE F r a gm en ts of
11-Ketoep oxya za d ir a d ion e Ba sed on a n Electr ocycliza tion
Rea ction Ca ta lyzed by P er ch lor ic Acid
Alfonso Ferna´ndez-Mateos,*,† Eva M. Mart´ın de la Nava,† Gustavo Pascual Coca,†
Rosa Rubio Gonza´lez,† Ana I. Ramos Silvo,† M. S. J . Simmonds,‡ and W. M. Blaney§
Facultad de C. Qu´ımicas, Departamento de Qu´ımica Orga´nica, Universidad de Salamanca, Plaza de los
Caı´dos 1-5, 37008 Salamanca, Spain, J odrell Laboratory, Royal Botanic Gardens, Kew,
Richmond, Surrey, U.K., and Department of Biology, Birkbeck College, Malet Street, London, U.K.
Received J uly 23, 1998
A synthetic route to mimics of the insect antifeedant epoxyazadiradione containing the CDE
molecular fragment with an oxygenated function on ring C has been developed. The key step is
based on a 2,6-diene-1,5-dione electrocyclization reaction catalyzed by perchloric acid. The
rearrangement of the epoxy alcohol epimers 12 and 19 induced by acids deserves special mention.
Several of the compounds obtained show significant antifeedant activity against Spodoptera
frugiperda.
Sch em e 1
In tr od u ction
The epoxy ketone I, a structural fragment of the
naturally occurring limonoid epoxyazadiradione, has
been shown to be a potent antifeedant at low concentra-
tions and also to have anti-AIDS properties.1 Over the
past few years, studies have been carried out in our
laboratories on the synthesis of azadiradione fragments
and analogues with a view to finding simple compounds
that display biological activity related to that shown by
epoxy ketone I.2 To increase the water solubility and
Resu lts a n d Discu ssion
The strategy we have developed for the synthesis of
model compounds is depicted in Scheme 1. The key step
in the synthesis is cationic electrocyclization, which is
shown idealized in the second general step.
The starting material 1 was obtained from mesityl
oxide and acetylacetone3 by a Robinson-type annelation
catalyzed by boron trifluoride etherate in 50% yield
(Scheme 2). Conversion of the diketone 1 into the key
intermediate 4 was achieved in a three-step sequence.
Thus, selective reduction of the diketone 1 with NaBH4‚
CeCl3 at -40 °C furnished the hydroxy ketone 2, which
on subsequent aldolic condensation with benzaldehyde4
followed by J ones oxidation of the intermediate hydroxy
ketone 3 gave the diketone 4 in 81% overall yield from
1. The first step in this sequence was done to avoid
double condensation with benzaldehyde. It is noteworthy
that the reduction is chemoselective for the conjugated
carbonyl, which shows the high neopentylic character of
the carbonyl side chain.
lower the volatility of compounds related to epoxy ketone
I, it would be of interest to introduce oxygenated func-
tions in the structure of limonoids. A further modifica-
tion, replacement of the furan by a phenyl ring, has been
introduced to simplify chemical manipulation, owing to
the extreme sensitivity of the former to many reagents.
All these changes are directed to SAR studies.
* E-mail: afmateos@gugu.usal.es
† Universidad de Salamanca.
‡ Royal Botanic Gardens.
§ Birkbeck College.
(1) (a) Ferna´ndez-Mateos, A.; de la Fuente, J . A. J . Org. Chem. 1990,
55, 1349. (b) de la Fuente, J . A.; Maruga´n, J . J .; Cross, S. S.; Ferna´ndez-
Mateos, A.; Garc´ıa, S.; Mene´ndez, A. Bioorg. Med. Chem. Lett. 1995,
14, 1471. (c) Champagne, D. E.; Koul, O.; Isman, M. B.; Scudder, G.
G. E.; Towers, G. H. N. Phytochemistry 1992, 31, 377.
(2) (a) Ferna´ndez-Mateos, A.; Lo´pez Barba, A. J . Org. Chem. 1995,
60, 3580. (b) Ferna´ndez-Mateos, A.; Pascual Coca, G.; Rubio Gonza´lez,
R.; Tapia Herna´ndez, C. Tetrahedron 1996, 52, 4817. (c) Ferna´ndez-
Mateos, A.; Lo´pez Barba, A.; Pascual Coca, G.; Rubio Gonza´lez, R.;
Tapia Herna´ndez, C. Synthesis 1997, 1381. (d) Ferna´ndez-Mateos, A.;
Pascual Coca, G.; Pe´rez Alonso, J . J .; Rubio Gonza´lez, R.; Tapia
Herna´ndez, C. Synlett 1997, 1134.
With the diketone 4 in hand, the stage was set for a
study of the cationic electrocyclization key step.5 The
(3) Rubinstein, M. J . Org. Chem. 1962, 27, 3886.
(4) Akiyama, S.; Nakatsuji, S.; Hamamura, T. Tetrahedron Lett.
1979, 20, 2809.
10.1021/jo981456q CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/20/1998

Synthesis of Active Antifeedant CDE Fragments
J . Org. Chem., Vol. 63, No. 25, 1998 9441
Sch em e 2
Sch em e 3
The conditions used for the cyclization of diketone 4
are too drastic for application to the furyl analogue, which
prompted us to look for a more general and milder
procedure. To avoid high temperatures and long reaction
times, we decided to introduce a stronger acid than that
usually employed in Nazarov cyclization, such as per-
chloric acid. This very strong protonic acid has never
been used in this type of reaction. We found that a dilute
solution of perchloric acid in a mixture of acetic anhydride
and ethyl acetate, used to obtain enol acetates from
ketones,7 promotes the Nazarov cyclization of the dike-
tone 4 at room temperature. The reaction of the diketone
4 with a 10-3 M solution of perchloric acid was very
slow: after 24 h, less than 10% of conversion had
occurred. Besides the starting material, we obtained a
mixture of ketoester 9 and diketone 7. After 24 h, the
10-2 M solution of perchloric acid afforded a 65:35
mixture of ketoester 9 and diketone 7 in 85% yield at
room temperature. It is interesting that the enol acetate
10 is not found among the reaction products. This was
interpreted by assuming it to be a transient intermediate,
and this hypothesis later proved to be correct.
The enol acetate 10 was obtained in 87% yield by
treatment of diketone 4 with sodium hydride in THF and
N,N′-dimethylpropyleneurea at room temperature, fol-
lowed by acetic anhydride.8 The reaction of enol acetate
10 with a 10-2 M perchloric acid solution was instanta-
neous, giving the ketoester 9 quantitatively. This cy-
clization procedure is sufficiently mild to be applied to a
large family of enol acetate analogues by changing the
nature of the phenyl substituent.
diketone 4 is not purely a Nazarov substrate, although
its enolic tautomer 5a has the necessary requisites to
afford the electrocyclization. However, the enolization
of 4 would give two enolic forms, 5a and 5b, which could
follow different reactivity pathways. To our knowledge,
this type of compound, a dienedione that is not fully
conjugated, has never been studied as an electrocycliza-
tion substrate. Accordingly, if indeed the reaction occurs,
its behavior and kinetics are not known. We aimed at
finding a general method for the electrocyclization of this
type of compound.
The first treatment was carried out directly on diketone
4 with a mixture of phosphoric and sulfuric acids at ratios
from 1:1 to 9:1. The reaction does not occur below 100
°C and needs 16 h for completion. The reaction afforded
a 3:1 mixture of two bicyclic products, 6 and 7, in 80%
yield.6 As expected, the major product 6 (60%) comes
from electrocyclization of the fully conjugated ketoenol
5a ; formally, this reaction resembles an intramolecular
Michael addition of a benzylvinyl anion to the cyclohex-
enone on 4. On the other hand, the isomeric minor
product 7 (20%) results from a true intramolecular
Michael addition of the not-fully conjugated ketoenol 5b.
To avoid formation of the Michael addition product and
with the aim of accelerating the Nazarov cyclization, we
prepared compound 8. Unfortunately, treatment of
compound 8 with the mixture of phosphoric and sulfuric
acids at room temperature afforded only the dienedione
4. Cleavage of the ketal is faster than the electrocycliza-
tion reaction.
The third step in the synthesis (Scheme 3) was
achieved from ketoester 9 by reduction with sodium
borohydride to give the hydroxy ketone 11, followed by
epoxidation with m-chloroperoxybenzoic acid to afford 12.
Both reactions were absolutely stereoselective, with the
reagent attacking from the exocyclic face. The proposed
structure and stereochemistry of compound 11 were
assigned with the aid of NOE studies.9 The R configu-
(5) (a) Santelli-Rouvier, C.; Santelli, M. Synlett 1983, 429. (b)
Habermas, K. L.; Denmark, S. E.; J ones, T. K. Org. React. 1994, 45,
1.
(6) All compounds synthesized are racemic modifications, although
only one enantiomer is depicted.
(7) Edwards, B. E., Rao, P. N. J . Org. Chem. 1966, 31, 324.
(8) McMurry, J . E.; Musser, J . H.; Ahmad, M. S.; Blaszczak, L. C.
J . Org. Chem. 1975, 40, 1829.

9442 J . Org. Chem., Vol. 63, No. 25, 1998
Ferna´ndez-Mateos et al.
Sch em e 4
F igu r e 1.
ration assigned to the oxyranic oxygen in epoxide 12 is
consistent with the upfield shift in the 13C NMR signal
for the homoallylic carbon bearing an axial proton cis to
the oxygenated function (52.7 ppm for epoxide 12) as
compared with the unsaturated precursor 11 (59.2 ppm).1a
Rearrangement of epoxy alcohol 12 to the enone, the
fourth step of the synthesis (Scheme 1), was carried out
as described in a previous work10 in two ways: directly,
by treatment with TsOH, or in two steps with BF3‚Et2O
and then TsOH. Treatment of epoxy alcohol 12 with
TsOH in toluene under reflux afforded a mixture of
diketone 6 (70%) and an epimeric mixture of the desired
ketones 13a and 13b (14%). This contrasts with our
previous findings for the deoxoanalogue A2c and the
pentacyclic related epoxy alcohol B,10 in which the
orientation of the hydroxyl group is trans with respect
to the angular methyl group and the oxyranic oxygen is
arranged exactly as in 12. The same contrast in reactiv-
ity occurred in the reaction with BF3; whereas 12 afforded
exclusively the hydroxy ketone 14 with the hydroxyl
group in the R position with respect to the phenyl ring,
the two epoxy ketones A and B gave the hydroxy ketones
C and D, respectively, with the hydroxyl group in the â
position with respect to the furyl ring (Figure 1). Another
interesting feature of the rearrangement of 12 was the
need to rigorously exclude oxygen from the reaction.
When the solution was not degassed previously, the only
product obtained was the triketone 15.
deprotection afforded the hydroxy ketone 18, which is an
epimer11 of the unsaturated alcohol 11 (Scheme 4). The
endoselective reduction of 16 must be governed by
coordination of the reagent to the acetal oxygen. Epoxi-
dation of the hydroxy ketone 18 with m-chloroperoxy-
benzoic acid is stereoselective and proceeds exclusively
from the exocyclic face.1a Treatment of the epoxyalcohol
19 with boron trifluoride etherate in methylene dichloride
at room temperature afforded the hydroxy ketone 20 as
a single isomer.12 It is relevant at this stage to comment
on the remarkable stereoselectivity of the rearrangement
of the epoxy alcohol epimers 12 and 19, which could be
atributed to the influence of the carbonyl group on the
cyclohexane ring.
Dehydration of the hydroxy ketone 20 was achieved
by treatment with TsOH in degassed toluene under
reflux. The reaction furnished a 2:1 epimeric mixture
in 80% yield of the unsaturated diketones 13a and 13b,
respectively, which were separated by chromatography.
When the single isomer 13b was treated separately with
TsOH, equilibration took place to afford a 2:1 epimeric
mixture of 13a and 13b, respectively. The major isomer
13a was identified as a CDE structural fragment of 11-
ketoazadiradione. The assignment is based on the
displacement of the methyl angular signal, shielded by
Although no reasons were found to explain the differ-
ent behaviors of 12, A, and B, we decided to explore the
rearrangement of an isomer of 12 with the opposite
configuration of the hydroxylic carbon. To solve this, an
alternative route was envisaged. Fortunately, it was
found that after reduction of the monoketal 16, further
1
the vicinal phenyl group in the H NMR spectrum.13
An alternative and shorter route to 13a was achieved
from the hydroxy ketal 17 in two steps: epoxidation with
(11) The stereochemistry was assigned according to diffential NOE
experiments. Irradiation of H1 resulted in a NOE enhancements of 9%
and 7% at equatorial methyl group at C-7 and H6 axial, respectively.
(12) The 1H and 13C spectra of compounds 11-13a ,b and 18, 19,
22, and 23 were assigned with the aid of 1H-13C correlation experi-
ments and were found to be in complete agreement with the proposed
structures and stereochemistries.
(9) The stereochemistry was assigned according to differential NOE
experiments. Irradiation of H1 resulted in an NOE enhancement of
24% at H7a, indicating a cis orientation of H1 and H7a
.
(10) Ferna´ndez-Mateos, A.; Lo´pez Barba, A.; Mart´ın de la Nava, E.;
Pascual Coca, G.; Pere´z Alonso, J . J .; Ramos Silvo, A. I.; Rubio
Gonza´lez, R. Tetrahedron 1997, 53, 14131.

Synthesis of Active Antifeedant CDE Fragments
J . Org. Chem., Vol. 63, No. 25, 1998 9443
Ta ble 1. Effects of Syn th esized Com p ou n d s 4, 6, 7, 9,
13a , 13b, 15, a n d 22; I ((), I (+), a n d I (-); Un sa tu r a ted
Keton e II, Aza d ir a d ion e, a n d Ep oxya za d ir a d ion e on th e
F eed in g Beh a viou r of La r va e of Spod opter a littor a lis
a n d Spod opter a fr u giper d a
during the past decade. With this aim, we have designed
simple structural mimics of azadiradione and epoxyaza-
diradione to investigate the resulting effects on biological
activity. Larvae of the African leafworm Spodoptera
frugiperda were used to assess the antifeedant activity
of our molecular fragments.14 Unexpectedly, the most
active compound was 7, a bicyclic [3.3.1] system with a
different skeleton of the [4.3.0] system searched (Table
1). This fact makes compound 7 a new prototype in the
search for new insect antifeedants.
antifeedant index at 100 ppma
Spodoptera
littoralis
Spodoptera
frugiperda
compound
compound
azadiradione
epoxyazadiradione
I (()
1
22
28
55b
32
16
4 (()
6 (()
10
16
45b
5
7 (()
I (+)
9 (()
I (-)
II (()
13a (()
13b (()
15 (()
22 (()
4
Exp er im en ta l Section
16
35b
23
Gen er a l Meth od s. Commercial reagents were used as
received. Dichloromethane was distilled under nitrogen from
calcium hydride. Diethyl ether, benzene, and toluene were
distilled from sodium. Hexane, acetone, and ethyl acetate
were distilled before use. Melting points were determined on
a
b
Antifeedant index ) [(C - T)/(C + T)]%. Significant activity
p < 0.05 (Wilcoxon matched pairs test, n ) 10).
m-chloroperoxybenzoic acid to give the epoxide 21 and
subsequent treatment with TsOH in degassed toluene
under reflux. This afforded a 2:1 epimeric mixture of the
unsaturated diketones 13a and 13b in 76% overall yield.
The final step of the synthesis (Scheme 1) consisted of
the epoxidation of the diketone 13a , which was carried
out with basic hydrogen peroxide in methanol in 76%
yield. A â configuration was assigned to the oxyranic
oxygen of 22, with the assumption of the usual endocyclic
attack in this type of compound and on the basis of the
upfield shift of the 13C NMR signal for the homoallylic
carbon bearing an axial hydrogen cis to the oxygenated
function. When the reaction time was prolonged to 30
min at room temperature, a selective Baeyer-Villiger
reaction took place to afford the CDE gedunin fragment
23 as the sole product in 73% yield.
1
a hot-stage apparatus and are not corrected. The H and 13C
NMR spectra were recorded in CDCl3 solution at 200 and 50
MHz, respectively. IR spectra were obtained as thin films.
Mass spectra were obtained on a VG-TS 250 instrument. All
reactions were carried out under an argon atmosphere. Reac-
tions were monitored by TLC. Flash column chromatographies
were carried out using silica gel 60 (0.040-0.063 mm, Merck).
Organic extracts were washed with saturated NaCl solution
dried over Na2SO4 and concentrated under reduced presure
with the aid of a rotary evaporator.
Solu tion of 10-3 M HClO4.6 To 50 mL of absolute ethyl
acetate was added 0.05 mL of 72% perchloric acid (0.575
mmol). Then, 5 mL of this solution was added to 30 mL of
absolute ethyl acetate and 4.8 mL (51 mmol) of acetic anhy-
dride, and the solution was made up to 50 mL with ethyl
acetate to give a reagent 1 M in acetic anhydride and 10-3
in perchloric acid.
M
Solu tion of 10-2 M HClO4. To 40 mL of absolute ethyl
acetate was added 0.05 mL (0.58 mmol) of 72% perchloric acid
and 4.8 mL (51 mmol) of acetic anhydride, and the solution
was made up to 50 mL with absolute ethyl acetate.
Biologica l Resu lts
Efforts to develop safe, selective, and less persistent
pest control agents have attracted increasing attention
4-Acetyl-3,5,5-tr im eth yl-cycloh ex-2-en on e (1). An Er-
Ta ble 2. Assign m en ts Ba sed on Heter on u clea r Mu ltip le Bon d Cor r ela tion
11 12 18
19
13C
1H
4.87
13C
1H
4.59
13C
1H
4.89
13C
1H
4.42
1
2
3
3a
4
5
6
7
76.0
128.3
159.5
36.8
53.5
213.4
52.2
51.7
59.2
26.1
32.0
28.8
73.2
63.4
74.0
47.5
49.2
213.1
52.4
36.7
52.7
21.9
31.9
29.6
76.9
129.3
154.6
51.2
49.3
211.7
50.8
34.9
65.1
30.5
30.5
28.0
73.6
64.5
72.9
48.1
47.8
210.2
50.7
36.2
55.4
22.5
30.9
30.1
5.60
3.50
5.77
3.70
2.71, 2.89
2.00, 3.17
2.95, 1.75
3.08, 1.88
2.5
2.36, 1.84
2.05, 2.42
2.15, 2.39
7a
1.81
1.18
1.13
1.36
1.65
1.17
1.03
1.25
1.94
1.36
1.21
1.16
1.55
1.26
1.09
1.20
Me (C-3)
Me(C-7)R
Me (C-7)â
Ta ble 3. Assign m en ts Ba sed on Heter on u clea r Mu ltip le Bon d Cor r ela tion
13a 13b 22
23
13C
1H
13C
1H
13C
1H
13C
1H
1
2
3
3a
4
5
6
7
7a
126.9
205.5
67.6
50.1
51.6
207.7
52.7
37.9
187.4
26.2
31.9
29.7
6.23
127.8
207.4
66.2
50.3
49.3
208.7
53.0
38.1
189.5
30.2
31.8
29.0
6.27
58.4
207.4
58.3
46.1
49.8
206.9
54.5
37.2
72.9
21.7
27.4
27.3
3.70
1
3
4
4a
5
6
7
8
82.7
166.9
53.2
68.2
38.4
52.8
206.4
47.9
42.9
16.8
27.9
26.0
5.79
3.71
3.57
4.09
3.85
2.67
1.82, 1.99
2.36, 2.48
2.35, 3.01
2.46, 2.73
2.34, 2.67
1.92, 2.69
2.49, 2.55
8a
Me (C-3a)
Me (C-7)R
Me (C-7)â
0.89
1.37
1.35
1.52
1.37
1.37
0.82
1.31
1.04
Me (C-8a)
Me (C-5)R
Me (C-5)â
1.09
1.28
1.02

9444 J . Org. Chem., Vol. 63, No. 25, 1998
Ferna´ndez-Mateos et al.
lenmeyer flask was surrounded by ice, and mesityl oxide (15
g, 0.15 mol), acetylacetone (15 g, 0.15 mol), and boron trifluo-
ride etherate solution (43 g, 0.3 mol) were added and mixed.
The resulting solution was allowed to stand on ice with
intermittent shaking for 1 h and then was transferred to a
refrigerator (0-5 °C) for 5 days. The reaction mixture was
poured over cracked ice and carefully neutralized with sodium
carbonate. The organic layer was separated, and the water
layer was extracted twice with diethyl ether. The combined
organic layers were dried and filtered. The solvent was
removed, and the residue was purified by flash chromatogra-
phy using hexane-diethyl ether (7:3) as eluent to yield the
diketone 1 as a colorless oil (8.1 g, 50%): IR 1713, 1699, 1636
fu r ic Acid s. Diketone 4 (4 g, 15 mmol) was dissolved in a
mixture of 85% phosphoric acid (14 mL) and sulfuric acid (14
mL), and the mixture was heated at 100 °C for 16 h under a
nitrogen atmosphere. After being allowed to cool, the reaction
mixture was treated with water and extracted with diethyl
ether. The organic layer was washed with NaOH (2%) and
brine, dried, and evaporated. The residue was chromato-
graphed using hexane-diethyl ether (8:2) as eluent. The first
fraction (2.46 g, 60%), which was a crystalline product, was
identified as (3aR*,7aS*)-3a,7,7-trimethyl-3-phenyl-3a,6,7,7a-
tetrahydro-4H-indene-1,5-dione (6): mp 120-121 °C; IR 1697,
1
1684 cm-1; H NMR δ 1.01 (s, 3H), 1.40 (s, 3H), 1.44 (s, 3H),
2.28 (s, 2H), 2.30 (s, 1H), 2.68 (d, 1H, J ) 17 Hz), 2.81 (d, 1H,
J ) 17 Hz), 6.25 (s, 1H), 7.42 (s, 5H); 13C NMR δ 209.4, 206.9,
181.1, 134.0, 130.3, 129.9, 128.8 (2), 127.7 (2), 63.4, 52.2, 47.3,
47.0, 34.2, 31.3, 30.3, 24.1; MS m/z (relative intensity) 268 (31,
M+), 225 (33), 184 (68), 171 (32), 152 (17), 141 (29), 128 (22),
91 (22), 77 (26). Anal. Calcd for C18H20O2: C, 80.56; H, 7.51.
Found: C, 80.43; H, 7.63.
1
cm-1; H NMR δ 0.99 (s, 6H), 1.61 (s, 3H), 1.92 (d, 1H, J ) )
17 Hz), 2.25 (s, 3H), 2.55 (d, 1H, J ) ) 17 Hz), 3.18 (s, 1H),
5.88 (s, 1H); 13C NMR δ 206.6, 198.4, 155.1, 127.2, 64.8, 46.5,
36.3, 33.4, 28.8, 27.2, 23.7; MS m/z (relative intensity) 180 (2,
M+), 138 (36), 123 (100), 96 (11), 79 (18), 67 (13).
1-(4-H yd r oxy-2,6,6-t r im et h yl-cycloh ex-2-en yl)-et h a -
n on e (2). To a mixture of diketone 1 (7.5 g, 42 mmol) and
CeCl3‚7H2O (3.1 g, 8.4 mmol, 20%) in methanol (100 mL) at
-40 °C was added NaBH4 (800 mg, 21 mmol) in small
amounts. The mixture was stirred for 20 min. Then, the
solvent was distilled under reduced pressure, and the residue
was treated with water and extracted with diethyl ether. The
extracts were then washed with brine and dried. The solvent
was evaporated under reduced presure to afford a solid
identified as hydroxy ketone 2 as a colorless oil (7.2 g, 95%):
IR 3410, 1699, 1670 cm-1; 1H NMR δ 0.91 (s, 3H), 0.92 (s, 3H),
1.59 (s, 3H), 1.60 (d, 2H, J ) ) 7 Hz), 2.20 (s, 3H), 2.74 (s,
1H), 4.15 (m, 1H), 5.64 (br s, 1H); 13C NMR δ 210.7, 131.9,
127.8, 65.2, 64.0, 40.1, 34.1, 31.7, 28.0, 27.9, 22.5; MS m/z
(relative intensity) 182 (1, M+), 125 (28), 122 (21), 107 (100),
91 (24), 69 (13).
The second fraction (0.8 g, 20%), which was an amorphous
solid, was identified as (1S*,5R*,8R*)-4,9,9-trimethyl-8-phenyl-
bicyclo[3.3.1]non-3-ene-2,6-dione (7): IR 2971, 1717, 1670
1
cm-1; H NMR δ 1.01 (s, 3H), 1.20 (s, 3H), 1.98 (s, 3H), 2.48
(m, 1H), 2.81 (s, 1H), 3.14 (d, 1H, J ) 13 Hz), 3.22 (d, 1H, J )
13 Hz), 3.65 (m, 1H), 6.11 (s, 1H), 7.0-7.5 (m, 5H); 13C NMR
δ 207.8, 198.6, 157.4, 139.6, 129.0, 128.5 (2), 127.6 (2), 127.2,
66.2, 59.5, 41.1, 40.8, 37.5, 26.2, 26.0, 23.4; MS m/z (relative
intensity) 268 (14, M+), 211 (33), 185 (11), 137 (38), 131 (100),
91 (67), 77 (95).
E-1,1-(Eth ylen edioxy)-3,5,5-tr im eth yl-4-(3-ph en yl-acr yl-
oyl)-cycloh ex-2-en on e (8). The diketone 4 (100 mg, 0.37
mmol), ethylene glycol (91 mg, 1.48 mmol), a catalytic amount
of p-TsOH, and anhydrous benzene (1 mL) were heated at
reflux under argon for 12 h with a Dean and Stark apparatus.
Saturated sodium bicarbonate was added, and the mixture was
extracted with diethyl ether. The combined ethereal layers
were washed with aqueous NaHCO3 (10%) and brine, dried,
filtered, and evaporated in vacuo to give a clear oil. Purifica-
tion by flash chromatography (hexane-diethyl ether, 8:2) gave
the ketal 8 as a crystalline product (87 mg, 75%): mp 90-91
E-1-(4-Hydr oxy-2,6,6-tr im eth yl-cycloh ex-2-en yl)-3-ph en -
yl-p r o-2-en -1-on e (3). To a solution of the hydroxy ketone 2
(7 g, 38.5 mmol) and benzaldehyde (4.1 g, 38.5 mmol) in
ethanol (47 mL) at -20 °C was gradually added NaOH (3.1 g,
77 mmol) in H2O (10 mL). The reaction was stirred vigorously
for 2 h at -20 °C. The mixture was concentrated in vacuo to
afford a residue, which was dissolved with water and extracted
with diethyl ether. The organic layers were washed with
brine, dried, and filtered. The solvent was evaporated, and
the residue was purified by flash chromatography using
hexane-diethyl ether (7:3) as the eluting solvent to give a
product identified as the hydroxy ketone 3 as a colorless oil
1
°C; IR 1626, 1096 cm-1; H NMR δ 1.16 (s, 6H), 1.60 (s, 3H),
1.74 (s, 2H), 2.34 (s, 2H), 4.00 (s, 4H), 6.77 (d, 1H, J ) 16 Hz),
7.4-7.6 (m, 5H), 7.47 (d, 1H, J ) 16 Hz).
Cycliza tion of Dik eton e 4 w ith HClO4. Diketone 4 (3 g,
11.2 mmol) was dissolved in 300 mL of the 10-2 M HClO4
reagent, and the solution was allowed to stand under argon
for 18 h at room temperature. The solution was washed with
saturated sodium bicarbonate solution and extracted with
ethyl acetate. The combined organic layers were washed with
sodium carbonate solution and brine, dried, and evaporated.
The remaining residue was flash chromatographed (hexane-
diethyl ether, 75:25) to yield acetic acid (3aR*,7aS*)-3a,7,7-
trimethyl-1-oxo-3-phenyl-3a,6,7,7a-tetrahydro-1H-inden-5-yl es-
ter 9 as a crystalline product (1.9 g, 55%): mp 93 °C; IR 1753,
(9.3 g, 90%): IR 3408, 1667, 1599 cm-1 1H NMR δ 0.93 (s,
;
3H), 1.02 (s, 3H), 1.63 (br s, 3H), 1.68 (d, 2H, J ) 8 Hz), 3.03
(s, 1H), 4.25 (m, 1H), 5.73 (br s, 1H), 6.95 (d, 1H, J ) 16 Hz),
7.3-7.6 (m, 5H), 7.60 (d, 1H, J ) 16 Hz); 13C NMR δ 201.4,
143.1, 134.6, 132.9, 130.6, 128.9 (2), 128.6 (2), 128.3, 126.1,
65.9, 62.3, 41.0, 35.1, 28.7, 28.4, 23.1.
E -3,5,5-Tr im e t h yl-4-(3-p h e n yl-a cr yloyl)-cycloh e x-2-
en on e (4). To a stirred and ice-cooled solution of hydroxy
ketone 3 (9 g, 33.3 mmol) in acetone (125 mL) was added J ones
reagent dropwise until the red color in solution became
permanent after 15 min. Then, isopropyl alcohol was added.
The solvent was evaporated under reduced presure to afford
a residue, which was dissolved in water and extracted with
diethyl ether. The extracts were washed with brine, dried,
and evaporated to afford a solid product identified as diketone
4 (8.5 g, 95%): mp 116-118 °C; IR 1678, 1657, 1601, 1574
1
1694 cm-1; H NMR δ 0.94 (s, 3H), 1.27 (s, 3H), 1.47 (s, 3H),
1.83 (d, 1H, J ) 16 Hz), 2.10 (s, 3H), 2.20 (s, 1H), 2.35 (dd,
1H, J ) 16 and 2 Hz), 5.54 (d, 1H, J ) 2 Hz), 6.04 (s, 1H),
7.42 (s, 5H); 13C NMR δ 208.0, 179.4, 168.8, 147.6, 134.5, 129.4,
129.2, 128.6 (2), 127.8 (2), 114.9, 63.7, 48.6, 41.7, 35.3, 31.4,
28.6, 23.9, 20.9; MS m/z (relative intensity) 310 (9, M+), 268
(28), 253 (100), 184 (56), 131 (14), 123 (11), 77 (15). Anal. Calcd
for C20H22O3: C, 77.39; H, 7.14. Found: C, 77.58; H, 7.23. The
second fraction was identified as diketone 7 (0.9 g, 30%).
Acetic a cid 3,5,5-tr im eth yl-4-(3-p h en yl-a cr yloyl)-cy-
cloh exa -1,3-d ien yl ester (10). A solution of diketone 4 (300
mg, 1.12 mmol) in dry THF (1.7 mL) was added to a degreased
suspension of sodium hydride (67 mg of 60% dispersion in
mineral oil, 1.7 mmol) in dry THF (3.5 mL). N,N′-dimethyl-
propyleneurea (3.5 mL) was added, and the reaction mixture
was stirred for 45 min under argon at room temperature.
Acetic anhydride (230 mg, 2.24 mmol) in THF (1.7 mL) was
added, and the mixture was stirred for an additional 30 min,
diluted with water, and extracted with diethyl ether. The
ether extracts were combined, washed with saturated brine,
dried, filtered, and concentrated to yield a yellow oil identified
1
cm-1; H NMR δ 1.06 (s, 3H), 1.14 (s, 3H), 1.91 (s, 3H), 2.10
(d, 1H, J ) 17 Hz), 2.74 (d, 1H, J ) 17 Hz), 3.48 (s, 1H), 6.06
(s, 1H), 6.88 (d, 1H, J ) 16 Hz), 7.4-7.6 (m, 5H), 7.67 (d, 1H,
J ) 16 Hz); 13C NMR δ 197.9, 197.2, 155.6, 143.5, 133.5, 130.3,
128.3 (2), 128.0 (2), 126.7, 126.1, 61.4, 46.5, 36.1, 28.3, 26.7,
23.2; Ms m/z (relative intensity) 268 (1, M+), 184 (1), 131 (100),
103 (31), 91 (3), 77 (31). Anal. Calcd for C18H20O2: C, 80.56;
H, 7.51. Found: C, 80.66; H, 7.72.
Cycliza tion of Dik eton e 4 w ith P h osp h or ic a n d Su l-
(13) Kraus, W.; Cramer, R. Tetrahedron Lett. 1978, 21, 2395.
(14) Blaney, W. M.; Simmonds, M. S. J .; Ley, S. V.; Anderson, J . C.;
Toogood, P. L. Entomol. Exp. Appl. 1990, 55, 149.

Synthesis of Active Antifeedant CDE Fragments
J . Org. Chem., Vol. 63, No. 25, 1998 9445
as enol acetate 10 (295 mg, 87%): IR 2961, 1755, 1634, 1206
66.2, 53.0, 50.3, 49.3, 38.1, 31.8, 30.2, 29.0; MS m/z (relative
intensity) 268 (8, M+), 253 (20), 184 (100), 115 (47), 105 (22),
91 (72), 89 (31), 77 (53).
1
cm-1; H NMR δ 1.16 (s, 6H), 1.71 (s, 3H), 2.16 (s, 3H), 2.34
(s, 2H), 5.64 (s, 1H), 6.79 (d, 1H, J ) 16 Hz), 7.3-7.6 (m, 5H),
7.49 (d, 1H, J ) 16 Hz); 13C NMR δ 200.2, 168.8, 150.1, 145.5,
137.2, 134.5, 130.6, 128.9 (3), 128.3 (3), 114.0, 42.2, 37.2, 26.5
(2), 21.1, 19.8; MS m/z (relative intensity) 310 (4, M+), 268 (15),
137 (18), 131 (100), 91 (12), 77 (29).
The third compound (18 mg, 9%) was an oily product
identified as (3R*,3aS*)-3a,7,7-trimethyl-3-phenyl-3a,4,6,7-
tetrahydro-3H-indene-2,5-dione 13a : IR 1705, 1607 cm-1; 1H
NMR δ 0.89 (s, 3H), 1.35 (s, 3H), 1.37 (s, 3H), 2.49 (d, 1H, J )
12 Hz), 2.55 (d, 1H, J ) 12 Hz), 2.67 (s, 2H), 3.71 (s, 1H), 6.23
(s, 1H), 7.0-7.5 (m, 5H); 13C NMR δ 207.7, 205.5, 187.4, 134.8,
130.0 (2), 128.5 (2), 127.5, 126.9, 67.6, 52.7, 51.6, 50.1, 37.9,
31.9, 29.7, 26.2; MS m/z (relative intensity) 268 (13, M+), 184
(28), 141 (24), 115 (56), 105 (35), 91 (83), 77 (90), 51 (100).
(2R*,3S*,3aS*,7aS*)-2-Hydr oxy-3a,7,7-tr im eth yl-3-ph en -
yl-p er h yd r oin d en e-1,5-d ion e (14). To a solution of the
epoxide 12 (97 mg, 0.34 mmol) in dry CH2Cl2 (1.6 mL) was
added a solution of 0.5 M boron trifluoride-diethyl ether in
CH2Cl2 (0.05 mL) at room temperature, and the reaction
mixture was stirred for 10 min. Then, it was diluted with
diethyl ether, and water was added. The layers were sepa-
rated, and the organic phase was washed with NaHCO3 (5%)
and brine and then dried. Evaporation of the solvent afforded
the hydroxy ketone 14 as a crystalline solid (92 mg, 95%): mp
159 °C; IR 3488, 1738, 1699 cm-1; 1H NMR δ 0.94 (s, 3H), 1.15
(s, 3H), 1.39 (s, 3H), 2.20 (d, 1H, J ) 18 Hz), 2.28 (d, 1H, J )
18 Hz), 2.34 (d, 1H, J ) 17 Hz), 2.35 (s, 1H), 2.73 (d, 1H, J )
17 Hz), 3.05 (d, 1H, J ) 13 Hz), 4.72 (d, 1H, J ) 13 Hz), 7.2-
7.4 (m, 5H); 13C NMR δ 214.7, 209.7, 135.3, 128.5 (2), 128.4
(2), 127.7, 75.2, 60.2, 58.9, 53.1, 49.9, 39.7, 35.4, 31.7, 28.5,
24.1; MS m/z (relative intensity) 286 (3, M+), 129 (16), 115 (30),
91 (100), 77 (49). Anal. Calcd for C18H22O3: C, 75.49; H, 7.74.
Found: C, 75.35; H, 7.61.
Cycliza tion of En ol Aceta te 10 w ith HClO4. Enol acetate
10 (250 mg, 0.81 mmol) was dissolved in 25 mL of the 10-2
M
HClO4 reagent, and the solution was allowed to stand under
argon for 5 min at room temperature. The solution was
washed with saturated sodium bicarbonate solution and
extracted with ethyl acetate. The combined organic layers
were washed with sodium carbonate solution and brine, dried,
and evaporated. The remaining white solid crystals were
identified as enol acetate 9 (250 mg, 100%).
(1R*,3a R*,7a S*)-1-Hyd r oxy-3a ,7,7-tr im eth yl-3-p h en yl-
1,3a ,4,6,7-h exa h yd r o-in d en -5-on e (11). To a mixture of enol
acetate 9 (1.0 g, 3.20 mmol) and CeCl3‚7H2O (1.2 g, 3.20 mmol)
in methanol (40 mL) at 0 °C was added NaBH4 (486 mg, 12.8
mmol). The mixture was stirred for 1 h. Then, the solvent
was distilled under reduced presure, and the residue was
treated with saturated NaCl (100 mL) and diethyl ether (50
mL) and stirred for 4 h at room temperature. The organic
layer was separated, and the aqueous phase was washed with
brine and dried. The solvent was evaporated under reduced
presure to afford a crystalline solid identified as hydroxy
ketone 11 (700 mg, 83%): mp 110-112 °C; IR 3482, 1699 cm-1
;
1H NMR δ 1.13 (s, 3H), 1.18 (s, 3H), 1.36 (s, 3H), 1.81 (d, 1H,
J ) 5 Hz), 2.00 (d, 1H, J ) 12 Hz), 2.71 (d, 1H, J ) 12 Hz),
2.89 (d, 1H, J ) 12 Hz), 3.17 (d, 1H, J ) 12 Hz), 4.87 (dd, 1H,
J ) 5 and 3 Hz), 5.60 (d, 1H, J ) 3 Hz), 7.2-7.4 (m, 5H); 13C
NMR δ 213.3, 159.5, 136.3, 128.3 (3), 127.7, 127.4 (2), 76.0,
59.2, 53.5, 52.2, 51.7, 36.8, 32.0, 28.8, 26.1; MS m/z (relative
intensity) 270 (5, M+), 185 (31), 172 (93), 115 (42), 91 (61), 77
(80), 55 (100). Anal. Calcd for C18H22O2: C, 79.96; H, 8.20.
Found: C, 79.85; H, 8.08.
Rea r r a n gem et of Hyd r oxy Keton e 14 w ith TsOH. To a
solution of hydroxy diketone 14 (90 mg, 0.31 mmol) in degassed
toluene (1 mL) was added a catalytic amount of TsOH, and
the mixture was heated at reflux under argon for 30 min.
Then, a saturated solution of NaHCO3 was added, and the
mixture extracted with diethyl ether. The extracts were
washed with H2O and brine and dried. The solvent was
evaporated under reduced pressure to afford a crude oil.
Purification by flash chromatography (hexane-diethyl ether,
7:3) gave the diketones 6 (61 mg, 73%), 13b (4 mg, 4%), and
13a (7 mg, 9%).
(1S*,2R*,3S*,3a R*,7a S*)-2,3-E p oxy-1-h yd r oxy-3a ,7,7-
tr im eth yl-3-p h en yl-p er h yd r o-in d en -5-on e (12). A solution
of m-chloroperoxybenzoic acid (638 mg, 3.7 mmol) in dry CH2-
Cl2 (7 mL) was added dropwise under argon at room temper-
ature to a solution of hydroxy ketone 11 (500 mg, 1.85 mmol)
in dry CH2Cl2 (7 mL), and the resulting mixture was stirred
at this temperature for an additional 40 min. A solution of
Na2SO3 (10%) was added, and the resulting heterogeneous
mixture was stirred. The organic layer was separated, and
the aqueous phase was extracted with CH2Cl2. The combined
extracts were washed with NaHCO3 (5%), water and brine,
dried, and filtered. Removal of the solvent afforded the epoxy
compound 12 as a crystalline solid (402 mg, 76%): mp 128-
(3aR*,7aS*)-2-Hydr oxy-3a,7,7-tr im eth yl-3-ph en yl-3a,6,7,-
7a -tetr a h yd r o-4H-in d en e-1,5-d ion e (15). To a solution of
hydroxy diketone 14 (30 mg, 0.1 mmol) in toluene (1 mL) was
added a catalytic amount of TsOH, and the mixture was heated
at reflux for 30 min. Then, a saturated solution of NaHCO3
was added, and the mixture extracted with diethyl ether. The
extracts were washed with H2O and brine and dried. The
solvent was evaporated under reduced pressure to afford a
crude oil. Purification by flash chromatography (hexane-
diethyl ether, 75:25) gave the triketone 15 as a crystaline solid
(28 mg, 93%): mp 88 °C (dec); IR 3310, 2924, 1700, 1682, 1630
1
130 °C; IR 3434, 1699 cm-1; H NMR δ 1.03 (s, 3H), 1.17 (s,
3H), 1.25 (s, 3H), 1.65 (d, 1H, J ) 5 Hz), 1.75 (d, 1H, J ) 12
Hz), 1.88 (d, 1H, J ) 12 Hz), 2.95 (d, 1H, J ) 12 Hz), 3.08 (d,
1H, J ) 12 Hz), 3.50 (s, 1H), 4.59 (d, 1H, J ) 5 Hz), 7.3-7.4
(m, 5H); 13C NMR δ 213.1, 133.6, 129.0 (2), 128.3, 127.8 (2),
74.0, 73.2, 63.4, 52.7, 52.4, 49.2, 47.5, 36.7, 31.9, 29.6, 21.9.
Anal. Calcd for C18H22O2: C, 75.49; H, 7.74. Found: C, 75.68;
H, 7.91.
1
cm-1; H NMR δ 1.01 (s, 3H), 1.41 (s, 3H), 1.43 (s, 1H), 2.31
(s, 2H), 2.35 (s, 1H), 2.77 (s, 2H), 7.3-7.6 (m, 5H); 13C NMR δ
210.0, 201.8, 147.8, 147.1, 132.1, 128.9 (2), 128.6 (2), 127.7,
60.0, 51.8, 47.8, 42.6, 34.2, 31.5, 30.3, 23.8; MS m/z (relative
intensity) 284 (31, M+), 186 (100), 158 (13), 115 (20), 83 (57),
77 (17). Anal. Calcd for C18H20O3: C, 76.03; H, 7.09. Found:
C, 76.21; H, 6.88.
Rea r r a n gem en t of Ep oxid e Alcoh ol 12 w ith TsOH. To
a solution of epoxide alcohol 12 (210 mg, 0.73 mmol) in
degassed toluene (3 mL) was added a catalytic amount of
TsOH, and the mixture was heated at reflux under argon for
30 min. Then, a saturated solution of NaHCO3 was added,
and the mixture was extracted with diethyl ether. The
extracts were washed with H2O and brine and dried. The
solvent was evaporated under reduced pressure to afford a
crude oil. Purification by flash chromatography (hexane-
diethyl ether, 7:3) gave the diketone 6 (137 mg, 70%).
The second fraction (9 mg, 5%), which was a colorless oil,
was identified as (3S*,3aS*)-3a,7,7-trimethyl-3-phenyl-3a,4,6,7-
tetrahydro-3H-indene-2,5-dione 13b: IR 1717, 1699 cm-1; 1H
NMR δ 1.37 (s, 6H), 1.52 (s, 3H), 1.82 (d, 1H, J ) 16 Hz), 1.99
(d, 1H, J ) 16 Hz), 2.36 (d, 1H, J ) 16 Hz), 2.48 (d, 1H, J )
16 Hz), 3.57 (s, 1H), 6.27 (s, 1H), 6.9-7.5 (m, 5H); 13C NMR δ
208.7, 207.4, 189.5, 137.0, 128.9 (2), 128.6 (2), 127.8, 127.6,
(3a R *,7a S *)-5,5-(E t h yle n e d ioxy)-3a ,7,7-t r im e t h yl-3-
ph en yl-3a,6,7,7a-tetr ah ydr o-4H-in den e-1,5-dion e (16). The
diketone 6 (2 g, 7.5 mmol), ethylene glycol (0.93 g, 15 mmol),
and a catalytic amount of TsOH were heated to 80 °C in
anhydrous benzene (25 mL) under argon for 12 h with a Dean
and Stark apparatus. Saturated sodium bicarbonate was
added, and the mixture was extracted with diethyl ether. The
combined ethereal layers were washed with aqueous NaHCO3
(10%) and brine, dried, filtered, and evaporated in vacuo to
give a clear oil. Purification by flash chromatography (hex-
ane-diethyl ether, 8:2) gave the compound 16 (2.1 g, 90%):
IR 1694, 1593 cm-1; 1H NMR δ 0.86 (s, 3H), 1.17 (s, 3H), 1.29
(s, 3H), 1.56 (d, 1H, J ) 16 Hz), 1.65 (d, 1H, J ) 16 Hz), 1.90
(d, 1H, J ) 13 Hz), 1.94 (s, 1H), 2.02 (d, 1H, J ) 13 Hz), 3.6-
3.8 (m, 4H), 5.97 (s, 1H), 7.2-7.4 (m, 5H); 13C NMR δ 208.0,

9446 J . Org. Chem., Vol. 63, No. 25, 1998
Ferna´ndez-Mateos et al.
182.3, 134.9, 130.0, 129.3, 128.4 (2), 127.7 (2), 109.1, 63.7, 63.6,
63.4, 48.4, 46.9, 41.0, 33.7, 32.5, 28.9, 23.9; MS m/z (relative
intensity) 312 (3, M+), 165 (15), 152 (16), 127 (100), 113 (53),
102 (32), 91 (32), 77 (43).
(1S*,3a R*,7a S*)-5,5-(Eth ylen ed ioxy)-1-h yd r oxy-3a ,7,7-
tr im eth yl-3-p h en yl-1,3a ,4,6,7-h exa h yd r oin d en -5-on e (17).
Lithium aluminum hydride (116 mg, 3.05 mmol) was added
portionwise to a solution of the ketal 16 (1.9 g, 6.10 mmol) in
dry diethyl ether (32 mL) cooled to 0 °C. The mixture was
vigorously stirred for 10 min, after which it was quenched with
Na2SO4‚10H2O. The resulting mixture was filtered, and the
filtrate was concentrated in vacuo to give the alcohol 17 as a
3a ,7,7-Tr im et h yl-3-p h en yl-3a ,4,6,7-t et r a h yd r o-3H -in -
d en e-2,5-d ion e (13). To a solution of hydroxy ketone 20 (160
mg, 0.56 mmol) in degassed toluene (3 mL) was added a
catalytic amount of TsOH, and the mixture was heated at
reflux for 30 min. Then, a saturated solution of NaHCO3 was
added, and the mixture was extracted with diethyl ether. The
extracts were washed with H2O and brine and then dried. The
solvent was evaporated under reduced pressure to afford a
crude oil. Purification by flash chromatography (hexane-
diethyl ether,7:3) gave the minor diketone 13b (40 mg, 27%)
and the major diketone 13a (80 mg, 53%).
Ep im er iza tion of Dik eton e 13b. Diketone 13b (20 mg,
0.07 mmol) dissolved in toluene (0.5 mL) was refluxed in the
presence of p-toluenesulfonic acid and under N2 for 30 min.
Then, a saturated solution of NaHCO3 was added, and the
mixture was extracted with diethyl ether. The extracts were
washed with H2O and brine and dried. The solvent was
evaporated under reduced pressure to afford a crude oil.
Purification by flash chromatography (hexane-diethyl ether,
7:3) gave the diketone 13b (6 mg, 30%) and the diketone 13a
(12 mg, 60%).
crystalline product (1.9 g, 100%): mp 70-71 °C; IR 3430 cm-1
;
1H NMR δ 1.16 (s, 3H), 1.25 (s, 3H), 1.35 (s, 3H), 1.6-2.1 (m,
5H), 3.8-4.1 (m, 4H), 4.76 (dd, 1H, J ) 7 and 2 Hz), 5.65 (d,
1H, J ) 2 Hz), 7.2-7.4 (m, 5H); 13C NMR δ 155.2, 136.7, 129.4,
127.7 (2), 127.6 (2), 126.6, 109.2, 76.3, 64.9, 64.2, 62.6, 49.5,
43.9, 43.3, 32.9, 30.8, 30.6, 26.9. Anal. Calcd for C20H26O3:
C, 76.40; H, 8.33. Found: C, 76.57; H, 8.15.
(1S*,3a R*,7a S*)-1-Hyd r oxy-3a ,7,7-tr im eth yl-3-p h en yl-
1,3a ,4,6,7-h exa h yd r o-in d en -5-on e (18). A catalytic amount
of pyridinium p-toluenesulfonate was added to a stirred
solution of ketal 17 (1.5 g, 5.4 mmol) in acetone (21 mL) and
water (0.7 mL). The reaction mixture was stirred at room
temperature for 48 h under an argon atmosphere. The solvent
was evaporated under reduced pressure, and the resulting
residue was dissolved in diethyl ether. The organic layer was
successively washed with 10% aqueous NaHCO3 solution and
water and then dried and evaporated to give a crude colorless
oil, which was flash chromatographed using hexane-diethyl
ether (9:1) as eluent to yield 18 as a colorless oil (1.14 g,
(1S*,2R*,3S*,3a R*,7a S*)-5,5-(Eth ylen ed ioxy)-2,3-ep oxy-
1-h ydr oxy-3a,7,7-tr im eth yl-3-ph en yl-1,3a,4,6,7-h exah ydr o-
in d en -5-on e (21). A solution of m-chloroperoxybenzoic acid
(260 mg, 1.5 mmol) in dry CH2Cl2 (2 mL) was added dropwise
under argon at room temperature to a solution of hydroxy ketal
17 (320 mg, 1 mmol) in dry CH2Cl2 (4 mL), and the resulting
mixture was stirred at this temperature for an additional 30
min. A solution of Na2SO3 (10%) was added, and the resulting
heterogeneous mixture was stirred. The organic layer was
separated, and the aqueous phase was extracted with CH2-
Cl2. The combined extracts were washed with NaHCO3 (5%),
water and brine, dried, and filtered. Removal of the solvent
afforded the epoxide compound 21 as a crystalline solid (320
mg, 95%): mp 97-99 °C; IR 3381, 1074 cm-1; 1H NMR δ 1.10
(s, 3H), 1.19 (s, 3H), 1.35 (s, 3H), 1.1-1.6 (m, 5H), 3.60 (d, 1H,
89%): IR 3430, 1072 cm-1 1H NMR δ 1.16 (s, 3H), 1.21 (s,
;
3H), 1.36 (s, 3H), 1.94 (d, 1H, J ) 5 Hz), 2.15 (d, 1H, J ) 16
Hz), 2.39 (d, 1H, J ) 16 Hz), 2.50 (m, 2H), 4.89 (dd, 1H, J )
2 and 5 Hz), 5.77 (d, 1H, J ) 2 Hz), 7.2-7.4 (m, 5H); 13C NMR
δ 211.7, 154.6, 135.7, 129.3, 128.2 (2), 127.9 (2), 127.7, 76.9,
65.1, 51.2, 50.8, 49.3, 34.9, 30.5 (2), 28.0.
J ) 1 Hz), 3.7-4.0 (m, 4H), 4.18 (m, 1H), 7.3-7.4 (m, 5H); 13
C
(1R*,2R*,3S*,3a R*,7a S*)-2,3-E p oxy-1-h yd r oxy-3a ,7,7-
tr im eth yl-3-ph en yl-1,3a,4,6,7-h exah ydr o-in den -5-on e (19).
A solution of m-chloroperoxybenzoic acid (1.28 g, 7.4 mmol)
in dry CH2Cl2 (6 mL) was added dropwise under N2 at room
temperature to a solution of hydroxy ketone 18 (1 g, 3.71 mmol)
in dry CH2Cl2 (7 mL), and the resulting mixture was stirred
at this temperature for an additional 30 min. A solution of
Na2SO3 (10%) was added, and the resulting heterogeneous
mixture was stirred. The organic layer was separated, and
the aqueous phase was extracted with CH2Cl2. The combined
extracts were washed with NaHCO3 (5%), water, and brine,
dried, and filtered. Removal of the solvent afforded the epoxide
compound 19 as a crystalline solid (1 g, 95%): mp 160 °C; IR
NMR δ 134.2, 129.4 (2), 128.1, 127.8 (2), 109.3, 73.6, 73.5, 64.8,
64.3, 63.0, 54.8, 45.4, 43.6, 40.6, 32.7, 31.5, 30.7, 21.6; MS m/z
(relative intensity) 330 (3, M+), 167 (27), 127 (100), 109 (8),
105 (54), 77 (65). Anal. Calcd for C20H26O4: C, 72.70; H, 7.93.
Found: C, 72.77; H, 7.79.
Rea r r a n gem en t of Ep oxid e Alcoh ol 21 w ith TsOH. To
a solution of epoxide alcohol 21 (300 mg, 0.91 mmol) in
degassed toluene (4 mL) was added a catalytic amount of
TsOH, and the mixture was heated at reflux under argon for
30 min. Then, a saturated solution of NaHCO3 was added,
and the mixture was extracted with diethyl ether. The
extracts were washed with H2O and brine and dried. The
solvent was evaporated under reduced pressure to afford a
crude oil. Purification by flash chromatography (hexane-
diethyl ether, 7:3) gave the diketones 13a (130 mg, 53%) and
13b (65 mg, 27%).
1
3466, 1696, 1045 cm-1; H NMR δ 1.09 (s, 3H), 1.20 (s, 3H),
1.26 (s, 3H), 1.55 (d, 1H, J ) 8 Hz), 1.84 (d, 1H, J ) 13 Hz),
2.05 (d, 1H, J ) 13 Hz), 2.36 (d, 1H, J ) 14 Hz), 2.42 (d, 1H,
J ) 14 Hz), 3.70 (s, 1H), 4.42 (m, 1H), 7.32 (m, 5H); 13C NMR
δ 210.2, 132.8, 128.9 (2), 125.5, 128.0 (2), 73.6, 72.9, 64.5, 55.4,
50.7, 48.1, 47.8, 36.2, 30.9, 30.1, 22.5; MS m/z (relative
intensity) 271 (2, M+ - Me), 202 (12), 171 (16), 123 (28), 115
(22), 105 (100), 91 (28), 77 (71). Anal. Calcd for C18H22O3: C,
75.49; H, 7.74. Found: C, 75.67; H, 7.87.
(1S*,3S*,3aS*,7aS*)-1,7a-Epoxy-3a,7,7-tr im eth yl-3-ph en -
yl-3a,4,6,7-tetr ah ydr o-3H-in den e-2,5-dion e (22). To a stirred
solution of diketone 13a (22 mg, 0.08 mmol) in methanol (0.2
mL) maintained under argon at 0 °C were added H2O2 (0.1
mL, 30%) and NaOH (0.2 mL, 6 N, 1.2 mmol). The resulting
solution was stirred for 40 min at this temperature and then
poured into a solution of NaHCO3 (10%). The aqueous solution
was extracted with diethyl ether, dried, and filtered. Removal
of the solvent afforded the epoxide compound 22 as a crystal-
(1R*,3S*,3aR*,7aS*)-1-Hydr oxy-3a,7,7-tr im eth yl-3-ph en -
yl-h exa h yd r o-in d en e-2,5-d ion e (20). To a solution of the
epoxide 19 (200 mg, 0.70 mmol) in dry CH2Cl2 (8 mL) was
added boron trifluoride-diethyl ether (0.05 mL) at room
temperature, and the reaction mixture was stirred for 5 min.
Then, it was diluted with diethyl ether, and water was added.
The layers were separated, and the organic phase was washed
with NaHCO3 (5%) and brine and then dried. Evaporation of
the solvent afforded the hydroxy ketone 20 as a colorless oil
line solid (18 mg, 76%): mp 113-114 °C; IR 1755, 1713 cm-1
;
1H NMR δ 0.82 (s, 3H), 1.04 (s, 3H), 1.31 (s, 3H), 2.35 (dd, 1H,
J ) 13 and 2 Hz), 2.46 (dd, 1H, J ) 14 and 2 Hz), 2.73 (d, 1H,
J ) 14 Hz), 3.01 (d, 1H, J ) 13 Hz), 3.70 (s, 1H), 4.09 (s, 1H),
7.0-7.4 (m, 5H); 13C NMR δ 207.4, 206.9, 132.1, 130.6 (2),
128.3 (2), 127.9, 72.9, 58.4, 58.3, 54.5, 49.7, 46.1, 37.2, 27.4,
27.3, 21.7; MS m/z (relative intensity) 284 (3, M+), 186 (18),
129 (21), 118 (100), 115 (36), 109 (21), 91 (66), 77 (42), 69 (60).
Anal. Calcd for C18H20O3: C, 76.03; H, 7.09. Found: C, 76.21;
H, 7.20.
1
(184 mg, 92%): IR 3453, 1748, 1709 cm-1; H NMR δ 1.24 (s,
3H), 1.29 (s, 3H), 1.33 (s, 3H), 1.51 (d, 1H, J ) 10 Hz), 1.9-
3.0 (m, 4H), 3.51 (s, 1H), 4.34 (d, 1H, J ) 10 Hz), 6.9-7.4 (m,
5H); 13C NMR δ 213.7, 209.6, 133.2, 130.2 (2), 128.1 (2), 127.4,
74.4, 62.0, 56.5, 50.7, 49.7, 30.6, 28.5, 28.1; MS m/z (relative
intensity) 269 (2, M+ - OH), 253 (8), 169 (34), 153 (28), 115
(39), 105 (84), 91 (45), 77 (100).
(1S*,4S*,4aS*,8aS*)-4,4a-Epoxy-5,5,8a-tr im eth yl-1-ph en -
yl-octa h yd r o-2-ben zop yr a n e-3,7-d ion e (23). To a stirred
solution of diketone 13a (11 mg, 0.04 mmol) in methanol (0.1

Synthesis of Active Antifeedant CDE Fragments
J . Org. Chem., Vol. 63, No. 25, 1998 9447
mL) maintained under argon at 20 °C was added H2O2 (0.05
mL, 30%) and NaOH (0.1 mL, 6 N, 0.6 mmol). The resulting
solution was stirred for 1 h at this temperature and then
poured into a solution of NaHCO3 (10%). The aqueous solution
was extracted with diethyl ether, dried, and filtered. Removal
of the solvent afforded the lactone 23 as a crystalline solid (9
mg, 73%): mp 140 °C; IR 1742, 1713 cm-1; 1H NMR δ 1.02 (s,
3H), 1.09 (s, 3H), 1.28 (s, 3H), 1.92 (dd, 1H, J ) 13 and 2 Hz),
2.34 (dd, 1H, J ) 13 and 2 Hz), 2.67 (d, 1H, J ) 13 Hz), 2.69
(d, 1H, J ) 13 Hz), 3.85 (s, 1H), 5.79 (s, 1H), 7.0-7.4 (m, 5H);
13C NMR δ 206.4, 166.9, 133.4, 128.8, 128.0 (2), 127.9 (2), 82.7,
68.2, 53.2, 52.8, 47.9, 42.9, 38.4, 27.9, 26.0, 16.8; MS m/z
(relative intensity) 300 (2, M+), 165 (12), 123 (22), 115 (18),
105 (83), 91 (48), 77 (100). Anal. Calcd for C18H20O4: C, 71.98;
H, 6.71. Found: C, 71.83; H, 6.55.
gratefully acknowledged. We also thank the J unta de
Castilla y Leo´n for the fellowship to A.I.R.S. and the
Ministerio de Educacio´n y Ciencia for the fellowship to
E.M.N. The experiments with Spodoptera littoralis and
Spodoptera frugiperda were covered by MAFF license
no. PHF 1020/806/113. We would like to thank P. Green
and M. Cullum for technical assistance in culturing the
insects.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra and assignments based on heteronuclear mul-
tiple bond correlation of compounds 7, 11-13a ,b, 18, 19, 22,
and 23 (9 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Ack n ow led gm en t. Financial support for this work
from the Ministerio de Educacio´n y Ciencia of Spain PB
95-0943 and the J unta de Castilla y Leo´n SA 45/97 is
J O981456Q