Synthesis based on cyclohexadienes. Part 23. Total synthesis of 5-epi-pupukean-2-one

Article abstract of DOI:10.1039/a704312k

A new strategy for the construction of the isotwistane skeleton is reported from easily available cyclohexadienes which involves stereoselective alkylation of a bicyclooctenone derivative and a decarboxylative 5-exo-trig radical cyclisation as the key ste

Full text of DOI:10.1039/a704312k

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1
Synthesis based on cyclohexadienes. Part 23. Total synthesis of
-epi-pupukean-2-one
5
Krishna Kaliappan and G. S. R. Subba Rao*
Department of Organic Chemistry, Indian Institute of Science, Bangalore-560 012, India
A new strategy for the construction of the isotwistane skeleton is reported from easily available
cyclohexadienes which involves stereoselective alkylation of a bicyclooctenone derivative and a
decarboxylative 5-exo-trig radical cyclisation as the key steps in the total synthesis of 5-epi-
pupukean-2-one.
A few naturally occurring sesquiterpenes have the unique tri-
cyclo[4.3.1.0 ]decane carbon framework (isotwistane) 1, the
the total synthesis of 5-epi-pupukean-2-one, an epimer of the
degradation product of 2-isocyanopupukeanane.
3,7
first example of which, 9-isocyanopupukeanane 2, was reported
by Scheuer et al., who isolated it from the nudibranch Phyllidia
A closer examination of pupukean-2-one 6 reveals that it
contains a bicyclo[2.2.2]octane subunit 10 with a bridgehead
methyl group. Although, this structural subunit can be readily
2
varicosa and also from its prey, a sponge Hymeniacidon sp.
An isomeric substance, 2-isocyanopupukeanane 3 was sub-
9
made from 1-methylcyclohexa-1,3-diene 11 by a Diels–Alder
3
sequently isolated from the same source by this group. The
pupukeananes are named after the place where the mollusk
and sponge were collected.
Me
O
Structures of 2 and 3 were established by chemical degrad-
ation through the corresponding ketones 5 and 6 and confirmed
O
NC
6
10
11
9
NC
8
1
reaction with a ketene equivalent, this method suffers from two
disadvantages: (i) the cycloaddition will not be regiospecific and
1
0
5
2
6
7
3
(
ii) preparation of the 1-methylcyclohexa-1,3-diene involves
4
9
cumbersome procedures and often results in isomeric diene
mixtures. This has been overcome in our laboratory by utilis-
ing dihydrotoluic acids as the equivalent of 1-methylcyclohexa-
10
1
2
3
O
CN
1
,3-dienes which resulted in the regiospecific construction of
the functionalised bicyclo[2.2.2]octene carboxylates having a
O
bridgehead methyl group.
This new methodology has been both utilised in the total
11
12
synthesis of (±)-seychellene 12 and extended to the prep-
aration of the keto ester 13 as a synthon for the total synthesis
of eremolactone 14.
9
-epi-isocyano-
5
6
pupukeanane
4
NC
MeO2C
SCN
O
O
O
1
2
13
14
NCS
4
-Thiocyanato-
2-Thiocyanato-
neopupukeanane 8
9-Isocyano-
neopupukeanane 9
With this background, we initiated a new strategy for the
neopupukeanane 7
total synthesis of pupukean-2-one 6. The retrosynthesis of 6
(
see Scheme 1) suggests that 15 would be the ideal choice for an
by a single crystal X-ray analysis; the absolute configuration of
the two compounds was also established in the latter study.
Since then, several other pupukeananes have been isolated.
intramolecular cyclisation to afford the tricyclic skeleton. The
keto ester 15 can be prepared from the bicyclic keto ester 16
which, in turn, can be made by cycloaddition of the diene 17
with a ketene equivalent. The conjugated diene ester 17 can be
obtained from 3-methylbenzoic acid 18 employing the method-
4,5
A total synthesis of these sesquiterpenes is challenging since
they possess (i) a new rearranged isoprenoid skeleton with a
3,7
unique tricyclo[4.3.1.0 ]undecane framework having a bicyclo-
2.2.2]octane subunit with a methyl group at the bridgehead
10
ology developed earlier.
[
position and (ii) an isopropyl group in a thermodynamically
unfavourable position. Owing to their unique molecular archi-
tecture, several syntheses of these tricyclic sesquiterpenes have
been reported. In continuation of our interest in the total
synthesis of sesquiterpenes having a bicyclo[2.2.2]octane struc-
tural subunit with a bridgehead methyl group, herein we report
Results and discussion
6,7
8
Synthesis of the bicyclic intermediate 16
Reduction of 3-methylbenzoic acid 18 with sodium in liquid
ammonia and quenching of the reaction with ammonium
J. Chem. Soc., Perkin Trans. 1, 1997
3387

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unit α to the carbonyl group could be achieved through succes-
sive alkylations, the question remained as to the stereo-
chemistry of the alkylating groups. The order in which the
alkylation is carried out depends on whether the alkyl group is
endo or exo.
O
O
O
MeO2C
MeO2C
6
15
16
The alkylation of lithium enolates generated from bicyclic
ketones at low temperature has been reported to yield
13
exclusively the endo alkylated products. Thus, further efforts
were directed towards the synthesis of pupukean-2-one 6, from
the bicyclic keto ester 16 with the order of alkylation: first,
methylation followed by alkylation with the five-carbon unit.
Since the five-carbon unit forms the latent functionality of
the five-membered ring and an isopropyl group, the prenyl
group was chosen as the five-carbon unit. Thus, alkylation of
the lithium enolate, generated from the bicyclic keto ester 16
with MeI afforded the monomethylated product 22 having an
endo methyl group (Scheme 3) as evidenced from its spectral
CO2H
CO2Me
1
8
17
Scheme 1
CO2H
CO2H
CO2Me
CO2Me
a
b
c
O
O
1
8
19
20
17
a
d
MeO2C
MeO C
2
1
6
22
Cl
b
O
e, f
CN
MeO2C
MeO2C
O
1
6
21
Scheme 2ϩ Reagents and conditions: a, Na/liq. NH , THF, reflux; b,
3
MeO2C
MeOH/H (or) CH N ; c, DBU (cat), benzene, heat; d, CH ᎐C(Cl)CN,
2
2
2
᎐
benzene, heat; e, aq. KOH/DMSO; f, CH N
2
2
1
5
chloride afforded quantitatively 3-methylcyclohexa-2,5-diene-
carboxylic acid 19 (Scheme 2), the structure of which was con-
firmed from its analytical and spectral data. 3-Methylcyclo-
hexa-2,5-dienecarboxylic acid 19 was esterified by treatment
with either MeOH/conc. H SO or diazomethane to afford the
Scheme 3 Reagents and conditions: a, LDA, MeI, THF, Ϫ78 ЊC; b,
LDA, Me C᎐CHCH Br, THF, HMPA, Ϫ78 ЊC
2
᎐
2
1
data. The H NMR spectrum of 22 showed signals at δ 1.05 (d,
2
4
endo Me), 1.33 (s, bridgehead Me), 3.82 (s, CO Me) and 6.86 (d,
2
Ϫ1
methyl ester 20 which showed IR absorption at 1730 cm
saturated ester). This on treatment with a catalytic amount of
DBU in refluxing benzene afforded the conjugated diene ester
7, whose structure was deduced from spectral evidence; IR
olefinic H). The mass spectrum showed a base peak at 152,
corresponding to loss of methyl ketene in a retro Diels–Alder
fragmentation. Further, alkylation of the keto ester 22 with
LDA and quenching with 3,3-dimethylallyl bromide gave the
(
1
Ϫ1
absorption at 1720 and 1600 cm (α,β-unsaturated carbonyl
and olefinic stretching frequencies, respectively) and H NMR
product 15 as a single isomer with an endo prenyl group as
1
1
evidenced by its spectral data: H NMR signals at δ 1.05, 1.25,
H
signals at δ 6.76 and 6.12 (both t, olefinic H) and 1.85 (s, Me);
disappearance of the methine proton multiplet adjacent to the
ester group was also discovered.
1
.5 and 1.68 (Me), 3.26 (m, bridgehead H) and 5.05 and 6.8
(
both s, olefinic H).
The bicyclic keto ester 15 with all the functional groups
Diels–Alder reaction of the diene ester 17 with α-chloro-
having been prepared, the next task was its cyclisation to the
tricyclic system. Initially, a base-catalysed cyclisation was
attempted, which is briefly discussed below. Selective epoxid-
ation of the keto ester 15 with m-chloroperoxybenzoic acid
acrylonitrile afforded the bicyclic adduct 21 which showed IR
Ϫ1
absorption at 2240 and 1723 cm (nitrile and unsaturated
1
ester) and H NMR signals at δ 6.88 (d, lone olefinic H), 3.7
(
s, CO Me), 3.3 (br, bridgehead H) and 1.5 (s, Me); the mass
1
2
(MCPBA) afforded the epoxy keto ester 23 (Scheme 4) in the H
spectrum showed its base peak at 152 due to the diene obtained
by the loss of a ketene formed by the retro-Diels–Alder frag-
mentation. This spectral evidence supported the assignment of
structure 21 to the cycloaddition product. This structure was
further confirmed by converting the compound into the keto
ester 16 by a hydrolysis with 20% aqueous potassium hydroxide
in dimethyl sulfoxide followed by esterification with diazometh-
ane. The IR spectrum of the keto ester 16 showed no CN
O
O
a
MeO2C
MeO2C
O
1
5
23
Ϫ1
absorption at 2240 cm although there was absorption at 1722
Ϫ1
b
cm (unsaturated ester and the keto group).
Synthesis of 5-epi-pupukean-2-one 33
O
The bicyclic keto ester 16 having been prepared in good yield, its
conversion into pupukean-2-one 6 required (i) introduction of
a methyl group α to the carbonyl group; (ii) introduction of a
five-carbon unit α to the carbonyl group in the endo position;
MeO2C
O
2
4
(
(
iii) intramolecular cyclisation to form the tricyclic system; and
iv) removal of the methoxycarbonyl group.
Scheme 4 Reagents and conditions: a, MCPBA, CH Cl ; b, H , Pd–C,
2
2
2
Although introduction of a methyl group and a five-carbon
EtOAc
3
388
J. Chem. Soc., Perkin Trans. 1, 1997

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NMR spectrum of which there was no signal at δ 5.1 (t) but
instead one at δ 2.92 (t, epoxide-bearing CH). Hydrogenation
of the epoxy keto ester 23 afforded the saturated keto ester 24
whose IR spectrum showed strong absorption at 1737 and 1720
O
OH
OH
a
b
MeO2C
MeO C
2
MeO C
2
Ϫ1
cm (ester and the keto). Attempted intramolecular cyclisation
t
of the epoxy keto ester 24 with various bases (LDA and KOBu )
15
28
29
gave only recovery of starting material.
c
Since the base-catalysed intramolecular cyclisation of the
epoxy keto ester 24 failed to produce the tricyclic skeleton pres-
ent in pupukean-2-one 6, intramolecular radical mediated
cyclisation was then attempted. The thiohydroxamate ester
O
O
d
14
2
5 was considered as ideal for generation of the radical
HO2C
MeO2C
2
7
30
O
O
e, f
N
O
O
O
S
O
O
2
5
+
g
PyS
N
O
which will undergo an intramolecular 5-exo-trig cyclisation to
pupukean-2-one 6.
S
With this in mind, we hydrolysed the α,β-unsaturated
keto ester 15 with LiOH in MeOH to afford the keto acid 26
2
5
32
33
Scheme 6 Reagents and conditions: a, NaBH , EtOH; b, Mg, MeOH;
4
(
Scheme 5), whose IR spectrum showed broad absorption at
c, PCC, CH Cl ; d, LiOH, MeOH; e, (COCl) ; f, 1-hydroxypyridine-2-
2
2
2
thione sodium salt 31; g, TBTH, AIBN, heat
O
O
thiohydroxamate ester 25 via its acid chloride followed by
treatment of this with the sodium salt of 1-hydroxypyridine-
a
MeO2C
HO2C
2
-thione 31. The resultant crude thiohydroxamate ester 25
14
underwent smooth Barton’s decarboxylation followed by an
intramolecular 5-exo-trig radical cyclisation to afford the 5-epi-
pupukean-2-one 33 along with a little of the uncyclised thio-
pyridyl compound 32. The spectral data of 33 were identical
1
5
26
b
7
1
with those reported. The H NMR spectrum of 33 showed
signals at δ 0.83 and 0.9 (both d), 0.92 and 1.13 (both s, bridge-
head Me) and 2.16 (m, 10-exo H). It is interesting to note that,
as expected, the carboxy group of m-toluic acid played three
significant roles: (i) helped in the formation of the required
diene during the base-catalysed isomerisation; (ii) controlled
the cycloaddition to give a regiospecific adduct; and (iii) finally
turned into a latent functionality for the generation of a radical
for the formation of the isotwistane skeleton.
O
HO2C
2
7
Scheme 5 Reagents and conditions: a, LiOH, MeOH; b, Li/liq. NH3
Ϫ1
1
3
200–2800 and 1690 cm and in the H NMR spectrum of
In conclusion, an efficient method for the construction of the
isotwistane skeleton is reported from easily available cyclo-
hexadienes involving, as the key steps, stereoselective alkyl-
ations of a bicyclo[2.2.2]octenone and a decarboxylative radical
cyclisation which culminated in the total synthesis of 5-
epi-pupukean-2-one. Some of the salient features of this
strategy are: preparation of the required diene from the readily
available m-toluic acid; the construction of the bicyclo[2.2.2]-
octane moiety with a bridgehead methyl group; successive
highly stereoselective alkylation of the bicyclo[2.2.2]octenone
with electrophiles: and a decarboxylative 5-exo-trig radical
cyclisation route to the isotwistane skeleton.
which there was no signal at δ 3.8 (s, CO Me). Since metal–
2
ammonia reduction of the keto acid 26 under a variety of condi-
tions followed by oxidation of the resulting product afforded
the keto acid 27 in only poor yield (<10%), an alternative strat-
egy was adopted to obtain the thiohydroxamate ester 25 (see
Scheme 6).
Reduction of the keto ester 15 with sodium borohydride
afforded the hydroxy ester 28, whose IR spectrum showed
Ϫ1
strong absorption at 3300 and 1720 cm (OH and ester,
respectively). Selective reduction of the hydroxy ester 28 with
15
Mg in MeOH gave the bicyclic hydroxy ester 29, whose IR
Ϫ1
spectrum showed strong absorption at 3320 and 1735 cm (OH
1
and ester, respectively) and in the H NMR spectrum of which
there was no signal at δ 6.9 (olefinic H). PCC oxidation of the
hydroxy ester 29 afforded the keto ester 30 whose structure was
deduced from the spectral data: IR spectrum of 30 showed
Experimental
General
Ϫ1
strong absorption at 1735 and 1720 cm (ester and keto) but
Unless otherwise stated, all materials were obtained from
commercial suppliers and were used without further purifi-
cation. THF and ether were distilled from sodium benzophe-
Ϫ1
none at 3320 cm . Whilst hydrolysis of 30 with KOH in MeOH
failed to give the keto acid 27, LiOH in THF gave a mixture of
the keto ester 30 and the keto acid 27. Finally, 30 was success-
none ketyl under a N atmosphere whenever necessary. Benzene
2
fully hydrolysed with LiOH/MeOH to the keto acid 27, whose
and toluene were distilled over CaH prior to use. CH Cl was
2
2
2
Ϫ1
IR spectrum showed absorption at 3300–2800 and 1700 cm
.
distilled over CaH and stored over 4 Å molecular sieves. Abso-
2
1
The H NMR spectrum of 27 showed signals at δ 0.96 and 1.14
both s, bridgehead Me), 1.67 and 1.72 (both s, allylic Me) and
.12 (s, olefinic H). The keto acid 27 was converted into the
lute ethanol was obtained by distillation over magnesium
ethoxide and stored over 4 Å molecular sieves. Liquid ammonia
was distilled over sodamide prior to use. BF ؒEt O was distilled
(
5
3
2
J. Chem. Soc., Perkin Trans. 1, 1997
3389

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over LAH just before use. Wherever NaH is mentioned, it is a
0% dispersion in mineral oil and was used after being twice
(3H, s, CO Me), 6.12 (1H, t, J 1.2, olefinic), 6.78 (1H, t, J 4.2,
2
olefinic).
6
washed with dry light petroleum. MeLi was prepared from MeI
and lithium and standardised before use. BuLi was prepared
Methyl 6-chloro-6-cyano-1-methylbicyclo[2.2.2]oct-2-ene-3-
carboxylate 21
from BuCl and lithium and standardised before use. BH in
3
THF was prepared from BF ؒEt O and NaBH in THF and
standardised prior to use.
All reactions involving air- and moisture-sensitive reagents
were performed under a blanket of argon. Glassware used for
these reactions were dried in an oven at 150 ЊC and cooled
under an atmosphere of nitrogen. Wherever it is mentioned,
A mixture of the diene 17 (7 g, 46 mmol), α-chloroacrylonitrile
(10 ml) and hydroquinone (20 mg) in benzene (10 ml) was
refluxed for 36 h and then evaporated. The residue was loaded
on a column of silica gel. Elution with ethyl acetate–hexane
(1:19) gave an epimeric mixture of the adducts 21 as a viscous
3
2
4
Ϫ1
liquid (9.2 g, 86%); νmax/cm 3030, 2920, 2240 and 1723; δH
‘
work-up’ means that the reaction mixture was poured into
1.3–2.3 (5H, m), 1.57 (3H, s, Me), 2.67 (1H, d, ¹AB , J 14.4 and
q
¯
²
water and extracted with ether; the combined ether extracts
were then washed with water and brine, dried (Na SO ) and
1.8), 3.31 (1H, m, bridgehead H), 3.77 (3H, s, CO Me) and 6.88
2
and 7.02 (1H, s, olefinic) (Found: C, 60.53; H, 5.99; N, 5.44.
C H ClNO requires C, 60.13; H, 5.88; N, 5.84%).
2
4
concentrated on a rotary evaporator at aspirator pressure to
give the product mixture. Column chromatography was per-
formed on silica gel (60–120 mesh). TLC was performed with
Acme’s silica gel. Hexane refers to light petroleum boiling in the
range 60–80 ЊC.
Mp and bp are uncorrected and were recorded on a Mettler
FP1 instrument. IR spectra were recorded as either neat
samples or solution in CHCl3 on either Hitachi 270-50 or
12
14
2
Methyl 1-methyl-6-oxobicyclo[2.2.2]oct-2-ene-3-carboxylate 16
A solution of the adduct 21 (4.5 g, 18.8 mmol) in DMSO (35
ml) and 20% aqueous KOH (25 ml) was stirred at 55 ЊC for 48 h,
after which the reaction mixture was acidified with dilute HCl
and extracted with ether. The ether extract was washed with
water and brine, dried (Na SO ) and evaporated. The resulting
2
4
1
13
Perkin-Elmer 781 spectrophotometer. H NMR (90) and
NMR (22.5, 100 MHz) spectra were recorded on JEOL FX-
0Q, Bruker ACF-200 and Bruker AMX-400 spectrophoto-
C
crude acid was esterified with ethereal diazomethane and puri-
fied by chromatography over silica gel (ethyl acetate–hexane,
Ϫ1
9
1:9, as eluent) to yield the keto ester 16 (2.8 g, 75%); νmax/cm
meters. All the NMR spectra were recorded on solutions in
3010, 2930 and 1722; δ 1.27 (3H, s, Me), 1.4–1.9 (4H, m), 2.07
H
1
CDCl with TMS as internal standard for H NMR and the
(2H, d, J 2, COCH ), 3.53 (1H, m, bridgehead H), 3.75 (3H, s,
3
2
13
central line of CDCl (77.1 ppm) for C NMR spectra. Chem-
CO Me) and 6.88 (1H, d, J 2, olefinic); δ 17.0 (q), 25.5 (t), 30.1
3
2
C
ical shifts are reported in δ units and J values are given in Hz.
High resolution mass measurements were carried out with a
JEOL JMS-DX 303 GC-MS instrument using a direct inlet
mode. Elemental analyses were carried out using a Carlo Erba
(t), 31.5 (d), 39.2 (t), 50.4 (s), 51.4 (q), 139.1 (s), 143.3 (d), 164.1
ϩ
(s) and 210.7 (s); m/z 194 (M , 60%), 152 (100), 93 (50) and 31
ϩ
(20) (Found: M , 194.0939 C H O requires M, 194.0943).
11
14
1
106 analyser.
Methyl 1,5-dimethyl-6-oxobicyclo[2.2.2]oct-2-ene-3-carboxylate
2
2
3
-Methylcyclohexa-2,5-dienecarboxylic acid 19
A 1  solution of BuLi in hexane (14.7 ml, 14.7 mmol) was
added to diisopropylamine (2.1 ml, 16.1 mmol) in THF (30 ml)
at Ϫ78 ЊC under argon. The resultant solution of lithium
diisopropylamide was stirred for 1 h at Ϫ78 ЊC for 45 min after
which a solution of the ketone 16 (2.6 g, 13.4 mmol) in dry
THF (40 ml) was added dropwise to it. The resultant lithium
enolate was stirred at Ϫ78 ЊC for 1 h after which a solution of
MeI (2.5 ml, 40 mmol) in THF was added at once. After being
stirred for 1 h, the reaction mixture was poured onto saturated
Sodium metal (348 mmol) was added to the mixture of the m-
toluic acid 18 (13.6 g, 100 mmol) in dry THF (150 cm ) and
3
anhydrous liquid ammonia (700 ml) until the blue colour per-
sisted. After the mixture had been stirred for 30 min, excess of
sodium was destroyed by addition of solid ammonium chloride
until it became colourless. After the ammonia had been allowed
to evaporate, the residue was dissolved in water and the solution
washed with ether to remove impurities. It was then acidified
with 5% aq. HCl and extracted with ether. The ether extract was
washed with brine, dried (Na SO ) and evaporated to yield the
aqueous NH Cl and extracted with ether (3 × 50 ml). The
4
combined ether extracts were washed successively with water,
aqueous sodium thiosulfate, water and brine and then dried
(Na SO ) and evaporated. Purification of the product by col-
2
4
19
acid 19 (11 g, 80%), mp 79 ЊC (hexane) (lit., 78.5–82.5 ЊC);
νmax/cm 3300–2300 and 1695; δ 1.74 (3H, s, Me), 2.62 (2H, d,
Ϫ1
H
2
4
J 9), 3.72 (1H, m, CHCO H), 5.5 (1H, m, olefinic) and 5.9 (2H,
m, olefinic); δC 23.1 (q), 30.6 (t), 42.7 (d), 115.9 (d), 121.3 (d),
umn chromatography (ethyl acetate–light petroleum, 1:9)
afforded the product 22 (2.5 g, 90%); νmax/cm 3010, 2930 and
2
Ϫ1
1
26.7 (d), 134.2 (s) and 179.6 (s) (Found: C, 69.38; H, 7.2.
1722; δH 1.04 (3H, d, J 7.1, CH CH), 1.3 (3H, s, Me), 1.4–1.8
3
C H O requires C, 69.54; H, 7.29%).
(4H, m), 2.1 (1H, m, CHCH ), 3.36 (1H, m, bridgehead H),
8
10
2
3
3
.79 (3H, s, CO Me) and 6.9 (1H, d, J 1.9, olefinic); δ 16.1 (q),
2
C
Methyl 3-methylcyclohexa-2,5-dienecarboxylate 20
A mixture of the acid 19 (10 g, 72 mmol) and conc. H SO (0.5
16.9 (q), 25.4 (t), 29.1 (t), 37.8 (d), 42.5 (d), 49.6 (s), 50.9 (q),
ϩ
137.8 (s), 141.7 (d), 164.1 (s) and 211 (s); m/z 208 (M , 20%),
2
4
ϩ
ml) in MeOH (100 ml) was refluxed for 12 h. The excess meth-
anol was removed under reduced pressure and the residue was
taken up in ether and the solution washed with aq. NaHCO3
water and brine, dried (Na SO ) and evaporated. Distillation of
152 (100) and 93 (50) (Found: M , 208.1101. C H O requires
12
16
3
M, 208.1099).
Methyl 1,5-dimethyl-5-endo-(3-methylbut-2-enyl)-6-oxobicyclo-
[2.2.2]oct-2-ene-3-carboxylate 15
2
4
the residue gave the ester 20 (9.1 g, 90%) (bp 52 ЊC/2 mm); νmax/
Ϫ1
cm 3010, 2920 and 1735; δH 1.72 (3H, s, Me), 2.58 (2H, d, J
To a freshly prepared LDA solution [prepared from a 1  solu-
tion of BuLi (10.5 ml, 10.5 mmol) and diisopropylamine (1.5
ml, 11.53 mmol) in THF (20 ml)] at Ϫ78 ЊC under argon, was
added dropwise a solution of the ketone 22 (2 g, 9.61 mmol) in
THF (30 ml). The resultant enolate was stirred for 1 h at the
same temperature and then quenched with a solution of prenyl
bromide (2.5 ml, 20 mmol) in THF; HMPA (3.8 ml, 20 mmol)
was then added to the mixture. After being stirred overnight the
reaction mixture was poured onto 2  aqueous HCl (100 ml).
Work-up followed by column chromatography (ethyl acetate–
light petroleum, 1:9) then afforded compound 15 as a colour-
9
.1), 3.68 (1H, m, CHCO Me), 3.75 (3H, s, CO Me), 5.5 (1H, br
2
2
s, olefinic) and 5.81 (2H, br s, olefinic).
Methyl 5-methylcyclohexa-1,5-dienecarboxylate 17
The above ester 20 (8 g, 52 mmol) was refluxed with DBU (0.5
ml) in benzene (60 ml) for 5 h, after which the mixture was
washed successively with 2% aq. HCl, water and brine, dried
(
Na SO ) and evaporated. Distillation of the residue (60 ЊC, 3
2 4
Ϫ1
mmHg) gave a 17 as a colourless liquid (7.2 g, 90%); νmax/cm
3
010, 2930 and 1722; δ 1.82 (3H, s, Me), 1.6–2.4 (4H, m), 3.75
H
3
390
J. Chem. Soc., Perkin Trans. 1, 1997

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Ϫ1
less oil (2.1 g, 80%); νmax/cm 3010, 2920 and 1725; δ 1.06 (3H,
ml) and extracted with ether (3 × 25 ml). The combined extracts
were washed with water and brine, dried (Na SO ) and evapor-
H
s, Me), 1.26 (3H, s, Me), 1.4–2.1 (6H, m), 1.49 (3H, s, Me), 1.67
2
4
(
3H, s, Me), 3.26 (1H, m, bridgehead H), 3.74 (3H, s, CO Me),
ated. Purification by column chromatography using ethyl
2
5
.06 (1H, t, J 6.8, olefinic) and 6.78 (1H, s, olefinic); δC 17.2
acetate–hexane (1:9) as eluent afforded 29 as a colourless oil
(650 mg, 90%); νmax/cm 3300, 2930 and 1735; δH 0.89 (3H, s,
Me), 0.93 (3H, s, Me), 1.1–2.6 (10H, m), 1.54 (3H, s, Me), 1.69
Ϫ1
(
(
2 × q), 21.0 (q), 21.9 (t), 25.4 (q), 30.0 (t), 36.5 (t), 40.0 (d), 45.9
s), 50.1 (s), 51.0 (q), 119.1 (d), 133.5 (s), 139.9 (s), 140.8 (d),
ϩ
1
63.9 (s) and 213.9 (s); m/z 276 (M , 85%), 152 (100), 124 (25)
(3H, s, Me), 3.13 (1H, m, CHOH), 3.67 (3H, s, CO Me) and
2
ϩ
and 96 (45) (Found: M , 276.1718. C H O requires M,
5.16 (1H, t, J 8.4).
17
24
3
2
76.1725).
A slurry of the hydroxy ester 29 (500 mg, 1.78 mmol), PCC
(
600 mg, 2.67 mmol) and NaOAc (2 g) in dry CH Cl (10 ml)
2 2
Methyl 1,5-dimethyl-5-endo-(3-methyl-2,3-epoxybutyl)-6-oxo-
bicyclo[2.2.2]oct-2-ene-3-carboxylate 23
was stirred for 3 h, after which it was evaporated, diluted with
ether filtered through a pad of Celite and evaporated. The resi-
due was chromatographed over silica gel (ethyl acetate–hexane,
1:9) to afford the keto ester 30 (380 mg, 80%); νmax/cm 2920,
1
(3H, s, Me), 1.68 (3H, s, Me), 3.67 (3H, s, CO Me) and 5.05
(1H, m, olefinic); m/z 278 (M , 18%), 210 (24), 124 (50), 93 (25),
69 (33) and 41 (3) (Found: M , 278.1884. C H O requires M,
278.1882).
To an ice-cold solution of MCPBA (600 mg), in CH Cl (5 ml)
2
2
was added the keto ester 15 (280 mg, 1 mmol) in CH Cl (5 ml).
Ϫ1
2
2
The resultant mixture was stirred for 1.5 h at the same temper-
ature after which it was diluted with CH Cl (25 ml) and washed
735 and 1715; δH 0.98 (6H, s, 2 × Me), 1.1–2.4 (10H, m), 1.53
2
2
2
with 10% aq. Na SO , saturated aq. NaHCO , water and brine
ϩ
2
3
3
and then dried (Na SO ) and evaporated to afford the epoxy
ϩ
2
4
17
26
3
Ϫ1
ester 23 (260 mg, 90%); νmax/cm 2920 and 1720; δH 0.9–2.0
(
6H, m), 1.16 (3H, s, Me), 1.17 (3H, s, Me), 1.21 (6H, s,
2
3
× Me), 2.9 (1H, t, J 6.8, OCH), 3.38 (3H, m, bridgehead H),
1,3-Dimethyl-3-endo-(3-methylbut-2-enyl)-2-oxobicyclo[2.2.2]-
octane-5-carboxylic acid 27
.73 (3H, s, CO Me) and 6.84 (1H, br s, olefinic).
2
A solution of the keto ester 30 (250 mg, 0.9 mmol), LiOH (30
mg, 1.75 mmol) and MeOH (5 ml) was stirred for 15 h, after
which it was concentrated in vacuo, acidified with dil. aq. HCl
and extracted with ether (3 × 15 ml). The combined extracts
were washed with water and brine, dried (Na SO ) and evapor-
Methyl 1,3-dimethyl-3-endo-(3-methyl-2,3-epoxybutyl)-2-oxo-
bicyclo[2.2.2]octane-5-carboxylate 24
A suspension of the epoxy keto ester 23 (200 mg, 0.62 mmol)
and 10% Pd–C (20 mg) in dry EtOAc (10 ml) was magnetically
2
4
stirred under an H atmosphere for 12 h. After this, the reaction
Ϫ1
2
ated to give a colourless oil 27 (180 mg, 80%); νmax/cm 3200–
800 and 1700; δH 0.92 (3H, s, Me), 1.1 (3H, s, Me), 1.2–2.4
9H, m), 1.64 (3H, s, Me), 1.73 (3H, s, Me), 2.98 (1H, m) and
.16 (1H, t, J 8.1, olefinic).
mixture was filtered through a Celite pad and evaporated under
2
(
5
reduced pressure to furnish the saturated epoxy keto ester 24
Ϫ1
(
190 mg, 95%); νmax/cm 1735; δH 1.1 (3H, s, Me), 1.12 (3H, s,
Me), 1.17 (3H, s, Me), 1.18 (3H, s, Me), 1.2–2.1 (10H, m), 2.92
1H, t, J 6.7, OCH) and 3.74 (3H, s, CO Me).
(
2
1,3-Dimethyl-3-endo-(2-methylbut-2-enyl)-5-(2-pyridylthio)-
bicyclo[2.2.2]octan-2-one 32 and 5-epi-pupukean-2-one 33
1
,5-Dimethyl-5-endo-(3-methylbut-2-enyl)-6-oxobicyclo[2.2.2]-
To a solution of the acid 27 (50 mg, 0.15 mmol), in benzene (1
ml) at 25 ЊC was added oxalyl chloride (0.5 ml) and DMF (1
drop). After 5 h, solvent and excess of oxalyl chloride were
removed on a rotary evaporator to give the crude acid chloride.
The crude acid chloride in benzene (5 ml) was added to a sus-
pension of 1-hydroxypyridine-2-thione sodium salt (30 mg, 0.2
mmol) and of DMAP (10 mg) in benzene (35 ml) at reflux.
After 15 min, tributyltin hydride (0.2 ml) and AIBN (5 mg) in
benzene (5 ml) were added dropwise over 30 min to the mixture.
After 3 h, the mixture was evaporated under reduced pressure
and the residue was vigorously stirred for 10 h in a two-phase
system comprising a saturated solution of iodine in dichloro-
methane (10 ml) and saturated aqueous KF (10 ml). The result-
ant residue was filtered through a pad of Celite and washed
with dichloromethane. The combined dichloromethane extracts
were washed with aqueous sodium thiosulfate solution, water
and brine, dried (Na SO ) and evaporated. Column chrom-
oct-2-ene-3-carboxylic acid 26
A mixture of the keto ester 15 (1 g, 3.62 mmol), LiOH (116 mg,
7
.25 mmol) and MeOH (5 ml) was stirred for 15 h and then
concentrated in vacuo, acidified with dil. aq. HCl and extracted
with ether (3 × 25 ml). The combined extracts were washed
with water and brine, dried (Na SO ) and evaporated to give a
colourless oil 26 (800 mg, 90%); νmax/cm 3300–2800 and 1690;
δH 1.12 (3H, s, Me), 1.31 (3H, s, Me), 1.2–2.4 (6H, m), 1.53 (3H,
s, Me), 1.66 (3H, s, Me), 3.28 (1H, m, bridgehead H), 5.07 (1H,
t, J 8.7, olefinic) and 6.98 (1H, d, J 1.9, olefinic) (Found: C,
2
4
Ϫ1
7
3.65; H, 8.76. C H O requires C, 73.25; H, 8.45%).
16 22 3
Methyl 1,5-dimethyl-6-hydroxy-5-endo-(3-methylbut-2-enyl)-
bicyclo[2.2.2]oct-2-ene-3-carboxylate 28
To a solution of the keto ester 15 (800 mg, 2.9 mmol) in MeOH
(
10 ml) was added sodium borohydride (200 mg) at 0 ЊC. The
2
4
mixture was stirred at room temperature for 1 h, after which it
was evaporated under reduced pressure, treated with saturated
aqueous ammonium chloride and extracted with ether. The
ether extract was washed with water and brine, dried (Na SO )
and evaporated. Chromatography of the crude product over
silica gel using ethyl acetate–hexane (1:9) as eluent provided the
atography of the residue (ethyl acetate–hexane as eluent)
afforded initially 5-epi-pupukean-2-one 33 (15 mg, 35%).
Further elution with the same solvent afforded the ketone 32
2
4
Ϫ1
(
3 mg, 5%). For 33: νmax/cm 1710; δ 0.82 and 0.89 (6H, d, J 7,
H
2
× Me), 0.92 (3H, s, Me), 1.12 (3H, s, Me), 1.01–2.01 (11H, m)
ϩ
Ϫ1
and 2.14 (1H, m); m/z 220 (M , 30%), 149 (40) and 93 (100)
alcohol 28 (750 mg, 96%) as a colourless oil; νmax/cm 3300,
ϩ
(
Found: M , 220.1831. C H O requires M, 220.1828). For 32;
15 24
Ϫ1
2
930 and 1722; δH 0.94 (3H, s, Me), 1.16 (3H, s, Me), 1.2–1.9
νmax/cm 1715; δH 1.01 (3H, s, Me), 1–2.5 (9H, m), 1.17 (3H, s,
Me), 1.65 (3H, s, Me), 1.74 (3H, s, Me), 2.9 (1H, m), 5.15 (1H,
m, olefinic), 7.3 (1H, m), 7.6 (2H, m) and 8.4 (1H, t, J 7).
(
6H, m), 1.49 (3H, s, Me), 1.66 (3H, s, Me), 2.78 (1H, m,
bridgehead H), 3.0 and 3.07 (1H, m, CHOH), 3.73 (3H, s,
CO Me), 5.17 (1H, t, J 8.2, olefinic) and 6.86 (1H, d, J 1.9,
2
ϩ
olefinic); m/z 278 (M , 20%), 152 (100), 126 (80) and 93 (100)
Found: M , 278.1872 C H O requires M, 278.1882).
ϩ
(
Acknowledgements
17
26
3
We thank the CSIR, New Delhi for the award of a fellowship.
Methyl 1,3-dimethyl-3-endo-(3-methylbut-2-enyl)-2-oxobicyclo-
2.2.2]octane-5-carboxylate 30
[
A mixture of the hydroxy ester 28 (650 mg, 2.33 mmol), Mg
turnings (600 mg, 250 mmol) and MeOH (10 ml) was stirred at
room temperature for 12 h after which it was evaporated under
reduced pressure. The residue was acidified with dil. aq. HCl (20
References
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(
(
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Paper 7/04312K
Received 19th June 1997
Accepted 31st July 1997
2
1
3
392
J. Chem. Soc., Perkin Trans. 1, 1997