Synthesis based on cyclohexadienes. Part 21. Total synthesis of (±)-hinesol and (±)-10-epi-hinesol

Article abstract of DOI:10.1039/a606197d

An efficient strategy for the construction of the spiro[4.5]decane and eremane systems is described which involves an acid-catalysed rearrangement of an endo alcohol, followed by an oxidative cleavage resulting in the generation of a spiro-system, as the key step. This methodology is extended to the total synthesis of (±)-hinesol and (±)-10-epi-hinesol 2.

Full text of DOI:10.1039/a606197d

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Synthesis based on cyclohexadienes. Part 21.1 Total synthesis of
(±)-hinesol and (±)-10-epi-hinesol
Seenivasaga N. Janaki and G. S. R. Subba Rao*
Department of Organic Chemistry, Indian Institute of Science, Bangalore - 560 012, India
An efficient strategy for the construction of the spiro[4.5]decane and eremane systems is described which
involves an acid-catalysed rearrangement of an endo alcohol, followed by an oxidative cleavage resulting in
the generation of a spiro-system, as the key step. This methodology is extended to the total synthesis of
(±)-hinesol and (±)-10-epi-hinesol 2.
Introduction
OMe
Me
OH
Spirovetivanes are a group of sesquiterpenes having a spiro-
[4.5]decane carbon framework with a 10-methyl group and a 2-
Me
O
isopropyl group. A number of sesquiterpenes belonging to the
spirovetivane family are known 2 in nature and they include β-
5
6
vetivone 1,3 hinesol 24 and agaspirol 3.5 Owing to their novel
structure and interesting biogenesis, several syntheses6 of these
O
sesquiterpenes have been reported. A convenient synthesis of
these sesquiterpenes must address the construction of a stereo-
genic spirocentre. In continuation of our interest in the total
synthesis of spirosystems7 of the β-vetivone family, we describe
herein an efficient total synthesis of (±)-hinesol and its 10-
epimer. A preliminary account of this work has been reported 8
earlier.
OMe
OH
O
Me
Me
7
8
Scheme 1
OH
Before attempting the synthesis of hinesol from 7, model
experiments were carried out using the known tricyclic ketone
10.10 Thus the ketone 10 was rearranged 11 smoothly to the
hydroxy enone 11 with 98% formic acid in good yield. The
enone 11 was oxidatively cleaved 12 with RuCl3/NaIO4 to afford
the dione 12. The IR spectrum of the dione 12 exhibited two
absorption bands at 1740 and 1715 cmϪ1 for the cyclohexanone
and cyclopentanonecarbonylmoietiesrespectively. Thestructure
was further confirmed from its 13C NMR spectrum and ana-
lytical data.
OH
H
H
2
1
*
3
6
*
5
4
7
H
H
H
10
8
O
9
1
2
3
*
*
OMe
O
R
O
O
b
a
4
OH
O
R
R
Results and discussion
7 R = Me
10 R =H
8 R = Me
11 R =H
9 R = Me
12 R =H
Careful examination of the structure of hinesol 2 showed that
the isopropyl side chain and the vinylic carbon of the cyclo-
hexene ring are cis orientated. This cis relationship of these
groups indicated the possibility of obtaining hinesol from the
cyclic structure of the type 4. Scission of the bonds shown in
the structure 4 would generate the spirodecane framework
having the substituents at appropriate positions which can be
further elaborated into hinesol 2.
Scheme 2 Reagents and conditions: a, 98% HCOOH, RT, 1 h; b, RuCl3,
NaIO4, CCl4, CH3CN, H2O; RT, 4 h
Having succeeded in the stereoselective synthesis of the
spiro[4.5]decane moeity on a model system, we turned our
attention towards the synthesis of the tricyclic ketone 7 from 1-
methyl-6-methoxytetralin 13. Birch reduction of 13 with
sodium-tert-butyl alcohol in liquid ammonia gave the diene 14
which was isomerised 13 to the conjugated diene 15 with KNH2
in ammonia in high yield. Cycloaddition of the diene 15 with α-
chloroacrylonitrile at 90 ЊC for 48 h in a sealed tube furnished
an inseparable mixture of adducts 16. Hydrolysis of the
adducts 16 with aq. KOH in dimethyl sulfoxide (DMSO)
Analysis of the structure 4 indicated that it possessed a bi-
cyclo[3.2.1] carbon framework fused to a cyclohexane ring.
Earlier, we reported 9 the formation of 2-methyltricyclo-
[6.2.1.01,5]undec-5-en-7-one
6
from 7-methoxy-2-methyl-
tricyclo[5.2.2.01,5]undec-5-en-8-ol 5, by an acid-catalysed
rearrangement and visualised that the analogous compound 7
should rearrange to the unsaturated ketone 8, which is struc-
turally similar to the carbocyclic framework 4.
1
afforded the tricyclic ketone 7 (60%). The H NMR spectrum
exhibited two doublets at δ 0.87 and 0.94 for the methyl group
J. Chem. Soc., Perkin Trans. 1, 1997
195

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indicating that it is an epimeric mixture. Rearrangement of the
tricyclic ketone 7 with 90% formic acid gave the enone 8 which
upon oxidation with RuCl3/NaIO4 afforded the spiro-dione 9.
NMR spectrum showed a singlet at δ 1.67 integrating for three
protons and indicating the presence of the methyl group on a
double bond.
Me
Me
Me
b
a
23
S
MeO
MeO
MeO
S
13
14
15
25
26
c
OMe
OMe
O
O
Cl
O
d
CN
O
O
Me
Me
O
7
16
Scheme 3 Reagents and conditions: a, Na, liq. NH3, ButOH; b, KNH2,
NH3; c, CH2C(Cl)CN, 90 ЊC, 48 h; d, aq. KOH, DMSO, 55 ЊC, 48 h
29
28
27
Scheme 5
The compounds 12 and 9 possessed the spiro[4.5]decane car-
bon skeleton present in the spirovetivanes. Although a carbonyl
group at C-2 in 12 could be transformed into an isopropyl
group, we envisioned that the tricyclic system of type 21, which
lacked the bridgehead hydroxy group, would produce the
spiro system on oxidation, having a carboxyl group at C᎐2
which could be later elaborated into the isopropyl functionality.
Thus, oxidation of the enone 21, obtained 14 through the analo-
gous skeletal rearrangement of the endo alcohol 17, prepared
from the ketone 10, with RuCl3/NaIO4 afforded the acid, which
was characterised as its methyl ester 24. The stereochemistry of
the C᎐2 substituent in the ester 24 with respect to the spiro
carbon is the same as that present in β-vetivanes as it is derived
from the tricyclic system 21 wherein the stereochemistry of the
ethano bridge has been well defined. In order to accomplish the
total synthesis of (±)-hinesol, a 10-methyl group had to be
introduced which has been successfully accomplished as
detailed in Scheme 4.
To confirm the structure of the isomeric ketone 23 un-
ambiguously, a series of chemical transformations were carried
out. The ketone 23 was converted through its dithioketal 25
into the olefin 26. The 13C NMR spectrum of the olefin 26 was
informative as it had only 11 lines as against the expected 13
carbons, since the molecule has a plane of symmetry. The olefin
26 was oxidised with RuCl3/NaIO4 to afford the diketone 27,
which upon aldol condensation with mild alkali yielded the
enone 28. The formation of the enone 28 conclusively estab-
lished the structure of the ketone as 23. Compound 28 pos-
sessed the structural features of the eremane skeleton and
hence compound 23 can be elaborated into isoeremolactone
29.15
Although the enone 22 upon treatment with BF3ؒOEt2 is
unchanged even after a prolonged period of time, the attempted
ketalisation with ethylene glycol resulted in compound 23. The
mechanism of this novel rearrangement of the endo alcohol 19
into the enone 22 and the ketone 23 appeared to be as depicted
in Scheme 6. The isomerisation of the enone 22 to the ketone 23
OMe
OMe
OH
OMe
OH
O
O+ Me
OMe
OH
OMe
H +
R
R
R
+
10 R = H
7 R = Me
17 R = H
19 R = Me
18 R = H
20 R = Me
R
O
19
30
31
CO2Me
O
O
Me
OMe
21 R = H
23
24
22 R = Me
+
H
Scheme 4
O
O
23
32
22
Reduction of the ketone 7 with NaBH4 afforded a mixture of
Scheme 6
endo and exo alcohols 19 and 20, respectively, in a ratio of 3:1.
The endo alcohol 19 when heated with a catalytic amount of
BF3ؒOEt2 in refluxing benzene for 38 h furnished a mixture of
the enone 22 and the ketone 23 in 3:2 ratio. The IR spectrum
of the enone 22 had absorptions at 1680 and 1600 cmϪ1. The 1H
NMR spectrum exhibited signals at δ 0.92 and 1.00 for the
methyl group indicating the presence of epimers. The bridge-
head proton appeared at δ 2.75 and the olefinic proton at 5.7.
On the other hand, the ketone 23 had IR absorption at 1720
cmϪ1 for the six-membered carbonyl functionality. The 1H
during ketalisation involved a rearrangement of the bicyclo-
[3.2.1] system 31 through the bicyclo[2.2.2] moiety, 32. In con-
clusion, the transformation of the endo alcohol 19 to the ketone
23 featured a novel rearrangement of a bicyclo[2.2.2] carbon
framework to a new bicyclo[2.2.2] system through the inter-
mediacy of a bicyclo[3.2.1] system.
The enone 22, obtained from the endo alcohol 19, was con-
verted into (±)-hinesol as follows. Oxidation of the enone 22
196
J. Chem. Soc., Perkin Trans. 1, 1997

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1
either neat samples or solutions in CHCl3. H and 13C NMR
spectra were recorded as solutions in CDCl3 (unless otherwise
stated) with SiMe4 as internal standard using JEOL FX-90Q,
Bruker WH-270 and Brucker AMX 400 spectrometers. Chem-
ical shifts are reported in δ units, and J values are given in Hz.
Work-up involved dilution of the reaction mixture with water,
extraction with diethyl ether, washing of the organic extract
with water and brine, followed by drying over Na2SO4 and
evaporation at aspirator pressure. Column chromatography was
performed on silica gel (60-120 mesh). Liquid ammonia was
distilled over sodium amide prior to its use.
CO2R
CO2Me
O
HO
22
33 R = H
34 R = Me
35
CO2Me
CO2Me
9-Hydroxytricyclo[7.2.1.01,6]dodec-6-en-8-one 11
+
A solution of the ketone 10 (412 mg, 2 mmol) in 98% formic
acid (2 cm3) was stirred at room temperature for 1 h. The reac-
tion mixture, after work-up, afforded the keto alcohol 11 as a
solid which crystallised from diethyl ether–light petroleum (300
mg, 78%), mp 94-95 ЊC; νmax/cmϪ1 3440, 1680 and 1600 cmϪ1; δH
1.4-2.0 (m, 12 H), 2.2 (br m, 2 H, allylic H), 3.95 (s, 1 H, OH,
exchangeable with D2O) and 5.8 (s, 1 H, olefinic); δC 201.9 (s),
173.2 (s), 120.2 (d), 82 (s), 51.2 (t), 46.9 (s), 34.8 (t), 34.1 (t), 33.8
(t), 30.5 (t), 24 (t) and 21 (t) (Found: C, 75.21; H, 8.47. C12H16O2
requires C, 75.0; H, 8.4%).
37
36
OH
H
Spiro[4.5]decane-2,6-dione 12
The ketone 11 (192 mg, 1 mmol) was dissolved in a mixture of
carbon tetrachloride (2 cm3), acetonitrile (2 cm3) and water (3
cm3). To this mixture was added sodium periodate (877 mg, 4.1
equiv.) and RuCl3ؒ3H2O (2.2%, 5 mg) in water (3 cm3) and
stirred vigorously for 4 h. The reaction mixture was worked up
and the residue in diethyl ether was purified by chromatography
on silica gel. Elution with light petroleum–ethyl acetate (1:1)
furnished the dione 12 (150 mg, 90%), bp 141–42 ЊC (1 mmHg);
νmax/cmϪ1 1740 and 1715; δH 1.6-2.8 (m, 14 H); δC 215.7 (s),
211.8 (s), 53.0 (s), 46.5 (t), 37.8 (2t), 35.6 (t), 30.7 (t), 26.3 (t) and
21.1 (t) (Found: C, 72.31; H, 8.4. C10H14O2 requires C, 72.26; H,
8.49%).
2
Scheme 7
with RuCl3/NaIO4 furnished the keto acid 33, characterised as
its methyl ester 34. The spiro acid 33 possessed the functional
groups at appropriate places with defined stereochemistry,
having the vinylic carbon and the ester group in a cis rela-
tionship, for its conversion into hinesol 2. Reaction of the
spiro acid 33 with methylmagnesium iodide afforded the
tertiary alcohol which gave the ester 35 with ethereal diazo-
methane. Dehydration of the hydroxy ester 35 was accom-
plished with POCl3 in pyridine to give a mixture of endo and
exo cyclic olefins 36 and 37, respectively, in 1:1 ratio. These
were separated on a AgNO3-impregnated silica gel column.
6-Methoxy-1-methyl-1,2,3,4,5,8-hexahydronaphthalene 14
6-Methoxy-1-methyltetralin 13 (5 g, 0.028 mol) in a mixture of
dry THF (10 cm3) and tert-butyl alcohol (20 cm3) was added
with stirring to distilled liquid ammonia (500 cm3). Sodium
(3.1 g) was added as small pieces to the mixture and the result-
ing deep blue solution was stirred for 3 h. The reaction mixture
was quenched with solid NH4Cl. Ammonia was allowed to
evaporate and the residue was diluted with water and extracted
with light petroleum (3 × 100 cm3). Evaporation of the com-
bined extracts under reduced pressure gave the dihydro com-
pound 14 (4.8 g, 95%); νmax/cmϪ1 1690 and 1660; δH 1.0 (d, J 7, 3
H, Me), 1.4-1.9 (m, 7 H), 2.5 (m, 4 H, doubly allylic), 3.45 (s, H,
OMe) and 4.5 (br m, 1 H, olefinic). Since the dihydro aromatic
compounds are known to aromatise with time, the compound
was used immediately for the next reaction.
1
The exocyclic olefin 36 had resonances in its H NMR spec-
trum at δ 4.6 for the olefinic proton in addition to the meth-
oxycarbonyl protons at δ 3.58. The endocyclic olefin 37 had a
broad singlet at δ 5.27 for the olefinic proton along with a
singlet at δ 1.61 for the methyl group situated on the olefin.
The exocyclic olefin 36 was readily converted into the endo-
cyclic olefin 37 on treatment with toluene-p-sulfonic acid in
benzene. Addition of methylmagnesium iodide to the ester 37
resulted in (±)-hinesol 2 and its 10-epimer in 95% yield. The
spectral data of the synthetic sample 2 was comparable to the
reported 16 data, thus completing the total synthesis of these
spiro sesquiterpenes. The salient features of our synthesis are
(i) the construction of the bicyclo[2.2.2] system from the
readily available cyclohexadienes, (ii) the rearrangement of
the bicyclo[2.2.2] system to a bicyclo[3.2.1] system and (iii) a
high degree of stereocontrol in the preparation of the keto
acid 33, a key intermediate required for the synthesis of
hinesol, from the enone 22 wherein the carbonyl carbon and
the carboxy group are cis orientated in a spiro system.
6-Methoxy-1-methyl-1,2,3,4,7,8-hexahydronaphthalene 15
Anhydrous ferric chloride (15 mg) was added to a stirred mix-
ture of potassium (1.5 g) in freshly distilled ammonia (400 cm3).
A solution of the diene 14 (4.8 g) in dry diethyl ether (10 cm3)
was added dropwise to the above freshly prepared potassium
amide in liquid ammonia and the mixture was stirred for 40
min. It was then quenched with solid ammonium chloride and
the residue was diluted with water and extracted with light
petroleum (4 × 75 cm3). Evaporation of the solvent afforded
the diene 15 as a liquid (90%); νmax/cmϪ1 1660 and 1610; δH 1.0
(d, J 7, 3 H, Me), 1.5-2.5 (m, 11 H), 3.5 (s, 3 H, OMe) and 4.6
(s, 1 H, olefinic).
In conclusion, we have demonstrated an efficient method for
the construction of the spiro[4.5]decanes from easily available
cyclohexadienes which represents an acid-catalysed rearrange-
ment of a bicyclo[2.2.2] carbon skeleton to a bicyclo[3.2.1]car-
bon framework. In addition, the basic carbon skeleton of the
eremane group of natural products was generated, which can be
exploited for the synthesis of isoeremolactone.
Experimental
9-Chloro-9-cyano-8-methoxy-2-methyltricyclo[6.2.2.01,6]dodec-
6-ene 16
A mixture of the diene 15 (4 g, 0.022 mmol), α-chloro-
Mps (measured on Mettler FPI) and bps are uncorrected. IR
Spectra were recorded on a Perkin-Elmer 781 spectrometer as
J. Chem. Soc., Perkin Trans. 1, 1997
197

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acrylonitrile (4 g, 0.045 mol) and hydroquinone (10 mg) was
heated in a sealed tube at 90 ЊC for 48 h. Excess of the chloro-
acrylonitrile was removed under reduced pressure and the
crude product was purified by chromatography on silica gel
column. Elution with ethyl acetate–light petroleum (1:9)
the solvent, was esterified with ethereal diazomethane. The
crude ester was purified by chromatography on silica gel and
eluted with light petroleum–ethyl acetate (7:3) to afford the
spiro ester 24 (150 mg); bp 155 ЊC (2 mmHg); νmax/cmϪ1 1735
and 1710; δH 1.2–2.4 (m, 14 H), 2.9 (quintet, 1 H, CHCO2Me)
and 3.65 (s, 3 H, CO2Me); δC 211.8 (s), 174.5 (s), 55.5 (s), 50.6
(q), 42 (d), 38.7 (t), 38.3 (t), 36.8 (t), 27.7 (t), 26.2 (t) and 21.6 (t)
(Found: C, 68.52; H, 8.63. C12H18O3 requires C, 68.54; H,
8.3%).
afforded a mixture of exo and endo adducts 16 (3 g, 50%) in
1
a ratio of 1:2 (by H NMR); bp 165–166 ЊC (1 mmHg); νmax
/
cmϪ1 3030, 2940 and 2220; δH 0.9 (d, J 7, 3 H, Me), 1.2–2.7
(m, 13 H), 3.5 (s, H, OMe) and 5.85 and 6.01 (2 br s, 1 H,
olefinic) (Found: C, 67.8; H, 7.62. C14H20ONCl requires C,
67.78; H, 7.58%).
8-Methoxy-2-methyltricyclo[6.2.2.01,6]dodec-6-en-9-ol 19 and 20
To a stirred solution of ketone 7 (1.5 g, 6.8 mmol) in dry
methanol (50 cm3) was added sodium borohydride (500 mg,
0.013 mol) at 0 ЊC. After the reaction mixture had been allowed
to attain room temperature it was treated with acetone (10 cm3)
to quench the excess of borohydride. After 10 min, methanol
was removed under reduced pressure and the residue was treat-
ed with saturated aqueous ammonium chloride and diethyl
ether. The aqueous layer was extracted with diethyl ether
(3 × 50 cm3) and the combined ethereal extracts were worked
up to yield a mixture which showed two closely separable spots
on TLC due to the exo and endo alcohols. This mixture was
chromatographed on silica gel. Careful elution with light
petroleum–ethyl acetate (9:1) furnished the exo alcohol 20
(385 mg); νmax/cmϪ1 3440 and 1640; δH 0.85 (d, J 6.2, 3 H, Me),
1.0–2.2 (m, 13 H), 3.36 (s, 3 H, OMe), 3.8 (br m, 1 H, CHOH)
and 5.83 (br s, 1 H). Further elution with the same solvent
mixture gave the endo alcohol 19 (1 g), νmax/cmϪ1 3440 and 1650;
δH 0.85 (d, J 6.2, 3 H, Me), 1.0–2.3 (m, 13 H), 3.38 (s, 3 H,
OMe), 3.84 (br m, 1 H, CHOH) and 5.75 (br s, 1 H, olefinic)
(Found: C, 75.44; H, 9.80. C14H22O2 requires C, 75.63; H,
9.97%).
8-Methoxy-2-methyltricyclo[6.2.2.01,6]dodec-6-en-9-one 7
To a solution of the mixture of adducts 16 (1.5 g, 5.6 mmol) in
dimethyl sulfoxide (7 cm3) was added 50% aq. KOH (5 cm3).
The reaction mixture was then stirred and heated to 55 ЊC for
48 h. After cooling, the reaction mixture was diluted with
water and extracted with diethyl ether (4 × 50 ml). Work-up
afforded the crude product which was chromatographed on
silica gel. Elution with light petroleum–ethyl acetate (9:1) fur-
nished the ketone 7 (740 mg, 60%); bp 139–141 ЊC (1 mmHg);
νmax/cmϪ1 3040, 2950 and 1720; δH 0.87, 0.94 (2 d, J 5.2, 3 H,
Me), 1.2-2.4 (m, 13 H), 3.52 (s, 3 H, OMe) and 5.85 (s, 1 H,
olefinic); δC 209.4 (s), 149.8 (s), 119.4 (d), 84.3 (s), 84.05 (s),
52.7 (q), 44.6 (t), 42 (s), 38.2 (t), 32.9 (t), 29.7 (t), 27.3 (t),
27.1 (t), 26.7 (t), 26.5 (t), 26.3 (t), 26.05 (t), 23.3 (t), 20.2 (q)
and 15.3 (q) (Found: C, 76.3; H, 9.12. C14H20O2 requires C,
76.3; H, 9.15%).
9-Hydroxy-2-methyltricyclo[7.2.1.01,6]dodec-6-en-8-one 8
A solution of the ketone 7 (200 mg, 0.9 mmol) in 98% formic
acid (2 cm3) was stirred at room temperature for 1 h. The reac-
tion mixture was diluted with water and extracted with diethyl
ether (3 × 25 cm3). The crude product obtained after removal
of the solvent was chromatographed on silica gel and eluted
with light petroleum–ethyl acetate (4:1) which furnished the
hydroxy enone 8 (135 mg, 77%); νmax/cmϪ1 3440, 1680 and 1600;
δH 0.94, 1.0 (2 d, J 6.6, 3 H, Me), 1.2–2.4 (m, 13 H), 3.45 (br s,
1 H, OH) and 5.65 (m, 1 H, olefinic) (Found: C, 75.63; H, 9.72.
C13H18O2 requires C, 75.73; H, 8.74%).
2-Methyltricyclo[7.2.1.01,6]dodec-6-en-8-one and 5-methyltri-
cyclo[6.2.2.01,6]dodec-5-en-9-one 22 and 23
A mixture of the endo alcohol 19 (1 g, 4.5 mmol) and BF3ؒOEt2
(0.5 cm3) in dry benzene (50 cm3) was refluxed for 48 h. After
cooling, the reaction mixture was diluted with benzene (20
cm3), washed with aq. NaHCO3 and water and dried. After
work-up the crude material was purified by chromatography
on silica gel. Elution with light petroleum–ethyl acetate (9:1)
gave the ketone 23 (248 mg); νmax/cmϪ1 1720; δH 1.67 (br s, 3
H, Me), 1.2-2.1 (m, 14 H) and 2.3 (br s, 1 H); δC 215.9 (s),
128.8 (s), 125.9 (s), 49.6 (d), 43.5 (s), 35.7 (t), 33.7 (t), 31.2
(t), 30.5 (t), 29.8 (t), 22.9 (t), 18.6 (t) and 17.7 (q) (Found: C,
82.2; H, 9.47. C13H18O requires C, 82.06; H, 9.54%). Further
elution with the same solvent mixture afforded the enone 22
(372 mg), λmax 242 nm (ε 10 000); νmax/cmϪ1 1680 and 1600; δH
0.92, 1.0 (2 d, J 7, 3 H, Me), 1.4–2.4 (13 H), 2.75 (m, 1 H,
bridgehead H) and 5.7 (m, 1 H, olefinic); m/z 190 (M+, 100%),
175 (31), 162 (29), 147 (45), 121 (30) and 91 (60) (Found: C,
81.9; H, 9.4. C13H18O requires C, 82.0; H, 9.5%).
10-Methylspirol[4.5]decane-2,6-dione 9
A mixture of compound 8 (206 mg, 1 mmol), sodium periodate
(877 mg, 4.1 equiv.), carbon tetrachloride (2 cm3), acetonitrile
(2 cm3) and water (3 cm3) was stirred vigorously. To this bi-
phasic solution was added RuCl3ؒ3H2O (5 mg, 2.2%) and the
mixture stirred for 4 h at room temperature. Dichloromethane
(10 cm3) was added to the mixture and the aqueous phase was
extracted with dichloromethane (3 × 50 cm3). The combined
organic extract was worked up to afford a residue which was
diluted with diethyl ether (10 cm3), filtered through a Celite pad
and evaporated to yield the product 9 (150 mg, 83%) which was
distilled (bulb–bulb) at 148 ЊC (1 mmHg); νmax/cmϪ1 1740 and
1710; δH 0.92, 0.98 (2 d, J 4.5, 3 H, Me) and 1.8–3.0 (m, 13 H);
δC 216.7 (s), 216.1 (s), 213.2 (s), 212.5 (s), 58.1 (s), 57.5 (s), 45.6
(t), 43.9 (t), 41.2 (2d), 37.3 (t), 37.1 (t), 36.9 (t), 36.3 (t), 31.9 (t),
29.3 (t), 28.0 (t), 26.4 (t), 23.9 (t), 22.1 (t), 16.1 (q) and 15.4 (q)
(Found: C, 73.25; H, 9.07. C11H16O2 requires C, 73.3; H,
8.95%).
Rearrangement of compound 22
To a solution of the enone 22 (100 mg) in benzene (10 cm3) was
added ethylene glycol (2 cm3) and BF3ؒEt2O (0.2 cm3). The mix-
ture was refluxed for 24 h. After cooling, the mixture was
diluted with benzene, washed successively with aq. NaHCO3,
water and brine and dried. Removal of the solvent afforded the
ketal which was dissolved in dichloromethane (3 cm3) and treat-
ed with aqueous HCl (10%, 7 cm3). After being stirred for 12 h,
the mixture was diluted with dichloromethane (10 cm3), washed
with water and brine and dried and evaporated to afford an oil.
This on purification by chromatography on silica gel and elu-
tion with light petroleum–ethyl acetate (9:1) yielded the pure
ketone 23 (40 mg).
Methyl 6-oxospiro[4.5]decane-2-carboxylate 24
The ketone 21 (176 mg, 1 mmol) was dissolved in a mixture of
carbon tetrachloride (2 cm3), acetonitrile (2 cm3) and water (3
cm3). To this mixture was added a solution of sodium periodate
(8.77 mg, 4.1 mmol) and RuCl3ؒ3H2O (5 mg, 2.2%) in water.
The reaction mixture was stirred for 4 h and then diluted and
extracted with dichloromethane (3 × 25 cm3). The residue,
obtained after removal of the solvent from the combined
extracts, was dissolved in diethyl ether and passed through a
Celite pad. The acid (152 mg, 78%), obtained after removal of
5-Methyltricyclo[6.2.2.01,6]dodec-5-ene 26
BF3ؒOEt2 (0.2 cm3) was added to a mixture of the ketone 23
(200 mg, 1.05 mmol) and ethane-1,2-dithiol (0.1 cm3, 1.26
198
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mmol) in dry dichloromethane (5 cm3) which was then stirred
for 30 min at 0 ЊC and for 3 h at room temperature. The mixture
was then diluted with ice-water and extracted with dichloro-
methane (3 × 50 cm3). Evaporation of the dried extract
afforded the thioketal 25 (220 mg, 79%); νmax/cmϪ1 3020, 2950,
1630 and 1110.
A mixture of the above thioketal 25 (200 mg), absolute
ethanol (10 cm3) and Raney nickel (2.5 mg) was heated under
reflux for 12 h. After cooling, the reaction mixture was fil-
tered, diluted with water and extracted with pentane (3 × 25
cm3). The pentane layer was washed with water and brine,
dried and evaporated to furnish the hydrocarbon 26 (125 mg,
95%); νmax/cmϪ1 3040, 2950 and 1630; δH 1.67 (br s, 1 H,
Me), 1.1–1.5 (m, 15 H) and 2.1 (br s, 2 H, allylic H); δC 134.3
(s), 123.9 (s), 46.6 (s), 35.8 (d), 33.5 (t, 2 C), 31.7 (t), 26.8 (t,
2 C), 20.0 (t) and 18.4 (q).
light petroleum–ethyl acetate (4:1) to furnish the alcohol 35
(115 mg, 87% overall); νmax/cmϪ1 3500 and 1735; δH 0.89, 0.95
(2 d, J 5, 3 H, Me), 1.2 (2 s, 3 H, Me), 3.3 (br s, 1 H, OH,
exchangeable with D2O) and 3.62 (s, 3 H, CO2Me).
Methyl 10-methyl-6-methylenespirol[4.5]decane-2-carboxylate
and methyl 6,10-dimethylspiro[4.5]dec-6-ene-2-carboxylate 36
and 37
To a stirred solution of compound 35 (100 mg, 0.42 mmol) in
dry pyridine (1 cm3) was added dropwise freshly distilled
POCl3 (184 mg, 1.2 mmol) at ЊC. The mixture was stirred at
0 ЊC for 24 h after which it was diluted with diethyl ether (10
cm3) and slowly quenched with ice–water (2 cm3) and extracted
with diethyl ether (3 × 25 cm3). The combined extracts were
washed with dilute hydrochloric acid (20%), water and brine,
dried and evaporated to afford the crude olefin. This was passed
though a column of silver nitrate impregnated silica gel.
Elution with light petroleum–ethyl acetate (15:1) furnished the
endo olefin 37 (40 mg); νmax/cmϪ1 1735, 1640, 1450 and 1370; δH
0.84, 0.86 (2 d, J 4.8, 3 H, Me), 1.61 (s, 3 H, Me), 2.7 (br m, 1 H,
CHCO2Me), 3.6 (s, 3 H, CO2Me) and 5.27 (br s, 1 H, olefinic)
(Found: C, 75.51; H, 9.88. C14H22O2 requires C, 75.63; H,
9.97%). Further elution with same solvent mixture furnished
the exo olefin 36 (38 mg); δH 3.58 (s, 3 H, CO2Me) and 4.6 (m, 2
H, ᎐CH ).
1-(4Ј-Oxopentyl)bicyclo[2.2.2]octan-2-one 27
Oxidation of compound 26 (110 mg, 0.63 mmol) with sodium
periodate (548 mg, 4.1 equiv.), water (1.9 cm3), carbon tetra-
chloride (1.3 cm3), acetonitrile (1.3 cm3) and RuCl3ؒ3H2O (3
mg, 2.2%) afforded the dione 27 (84.5 mg, 65%); νmax/cmϪ1
1710; δH 2.1 (s, 3 H, COMe) and 1.4–2.4 (m, 17 H); δC 217.1,
208.7, 44.7, 44.5, 44.1, 33.0, 29.5, 27.9, 27.5, 25.0 and 18.1
(Found: C, 74.91; H, 9.63. C13H20O2 requires C, 74.96; H,
9.68%).
᎐
2
Isomerisation of 36 to 37
A mixture of the exo olefin 36 (35 mg) in benzene (5 cm3) and
toluene-p-sulfonic acid (5 mg) was refluxed for 5 h. After cool-
ing, the reaction mixture was worked up with benzene to give
the endo olefin 37 (32 mg, 90%).
4-Acetyltricyclo[5.2.2.01,5]undec-4-ene 28
A mixture containing compound 27 (50 mg), KOH (100 mg),
water (1 cm3) and methanol (3 cm3) was refluxed for 4 h. After
removal of the methanol, the residue was diluted with water
and extracted with diethyl ether (3 × 20 cm3). After work-up, the
crude product was purified by chromatography on silica gel.
Elution with light petroleum–ethyl acetate (4:1) furnished the
product 28 (35 mg, 77%); νmax/cmϪ1 1670 and 1625; δH 2.2 (s,
3 H, COMe), 1.4–1.8 (m, 12 H) and 2.62 (m, 3 H) (Found: C,
82.12; H, 9.49. C13H18O requires C, 82.06; H, 9.54%). The 2,4-
dinitrophenylhydrozone had mp 198 ЊC (Found: M+, 370.1654.
C19H22O4N4 requires M, 370.1641).
(±) Hinesol and 10-epi-hinesol 2
The olefin 37 (25 mg) in dry diethyl ether (5 cm3) was added
dropwise to an ice-cold solution of methylmagnesium iodide
(10 equiv.) in dry ether (15 cm3). The mixture was stirred for 30
min at 0 ЊC and then at room temperature for 3 h. The crude
product obtained after work-up, was chromatographed on
silica gel. Elution with light petroleum–ethyl acetate (9:1)
furnished 2 (23 mg, 95%); νmax/cmϪ1 3350, 1640 and 1380; δH
0.9, 0.92 (2 d, J 6.5, 3 H, Me), 1.21 (s, 6 H, Me at C-12 and
C-13), 1.64 (s, 3 H, 6᎐Me) and 5.3 (m, 1 H, olefinic); δH
(reported) 0.9 (d, 3 H, J 6), 1.25 (s, 6 H, 2 × Me), 1.64 (s, 3 H,
Me) and 5.3 (m, 1 H, olefinic) (Found: M+, 222.1992. C15H26O
requires M, 222.1980).
10-Methyl-6-oxospiro[4.5]decane-2-carboxylic acid and its
methyl ester 33 and 34
To a stirred solution of the enone 22 (280 mg, 2 mmol) in
carbon tetrachloride (4 cm3), acetonitrile (4 cm3) and water (6
cm3) was added sodium periodate (1.754 g, 8.2 equiv.) and
RuCl3ؒ3H2O (10 mg, 2.2%). The resulting mixture was stirred
vigorously for 4 h. Work-up furnished the spiro acid 33 (230
mg, 75%). The spiro acid (100 mg) in diethyl ether (5 cm3) was
treated with an ethereal solution of diazomethane at Ϫ10 ЊC
and left for 4 h. Excess of diazomethane was destroyed by add-
ing a drop of glacial acetic acid to the diethyl ether solution
which was then washed with water and brine, and evaporated to
give a viscous liquid. This was chromatographed on silica gel.
Elution with light petroleum–ethyl acetate (7:3) afforded the
spiro ester 34 (80 mg); bp 134 ЊC (1 mmHg); νmax/cmϪ1 1735 and
1700; δH 0.9 and 0.93 (2 d, J 7, 3 H, Me), 1.25–2.6 (m, 13 H),
2.72 (br s, 1 H, CHCO2Me) and 3.65 and 3.67 (2 s, 3 H,
CO2Me); δC 213.3, 175.3, 60.5, 51.4, 43.8, 43.6, 42.2, 41.0, 37.9
(2C), 37.2, 33.4, 33.0, 31.4, 30.2, 29.7, 29.4, 28.9, 23.9, 23.3, 15.8
and 15.5 (Found: C, 69.46; H, 8.85. C13H20O3 requires C, 69.61;
H, 8.98%).
Acknowledgements
We thank the CSIR, New Delhi for the award of a fellowship to
S. N. J.
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Received 9th September 1996
Accepted 26th September 1996
200
J. Chem. Soc., Perkin Trans. 1, 1997