Stereoselective construction of vicinal stereogenic quaternary carbon atoms. Enantiospecific approaches to (+)-valeranef

Article abstract of DOI:10.1039/b006757l

Two enantiospecific routes to (+)-valerane starting from (R)-carvone, using a combination of Claisen rearrangement and intramolecular diazo ketone cyclopropanation reactions for the stereoselective generation of the vicinal stereogenic quaternary carbon atoms, are described. Thus, orthoester Claisen rearrangement of 3-methylcarveol 6 furnishes the ester 9 containing the first quaternary carbon atom. Intramolecular cyclopropanation of the diazo ketone 10 derived from the ester 9, followed by regioselective reductive cyclopropane cleavage, generates the hydrindanone 11 containing all stereocentres of valerane. Ring expansion of the hydrindanone to tetralone and further reductions transform 11 into (+)-valerane 2. In another direction, homologation of the acid 5 followed by intramolecular cyclopropanation of the diazo ketone 24 and regioselective cyclopropane ring cleavage lead to valerenone 25, which is transformed into (H-)-valerane. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b006757l

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Stereoselective construction of vicinal stereogenic quaternary
carbon atoms. Enantiospecific approaches to (؉)-valerane†
Adusumilli Srikrishna,* Ranganathan Viswajanani and Chikkana Dinesh
1
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received (in Cambridge, UK) 17th August 2000, Accepted 6th October 2000
First published as an Advance Article on the web 22nd November 2000
Two enantiospecific routes to (ϩ)-valerane starting from (R)-carvone, using a combination of Claisen
rearrangement and intramolecular diazo ketone cyclopropanation reactions for the stereoselective generation
of the vicinal stereogenic quaternary carbon atoms, are described. Thus, orthoester Claisen rearrangement of
3-methylcarveol 6 furnishes the ester 9 containing the first quaternary carbon atom. Intramolecular cyclopropanation
of the diazo ketone 10 derived from the ester 9, followed by regioselective reductive cyclopropane cleavage, generates
the hydrindanone 11 containing all stereocentres of valerane. Ring expansion of the hydrindanone to tetralone and
further reductions transform 11 into (ϩ)-valerane 2. In another direction, homologation of the acid 5 followed by
intramolecular cyclopropanation of the diazo ketone 24 and regioselective cyclopropane ring cleavage lead to
valerenone 25, which is transformed into (ϩ)-valerane.
The phenomenal structural diversity present in sesquiterpenes1
holds special appeal to synthetic chemists, and provides a fertile
ground for developing and testing new synthetic strategies, par-
ticularly those directed towards construction of the carbocyclic
ring.2 The sesquiterpene valeranone 1 was the first member of
a small group of natural products, valeranes, containing a
rearranged eudesmane carbon framework with methyl sub-
stituents at both the ring junctions of the cis-decalin system
(valerane 2). Valeranone 1 was first isolated by Stoll et al.3a in
1957 from a European valerian, Valeriana officinalis L. and
found to be widely distributed in the members of the valerian-
aceous family.3 The elucidation of the structure of valeranone 1
has been the subject of protracted controversy3 and has pre-
sented a problem in sesquiterpene chemistry. Ultimately,
Hikino et al.3k,4i established the correct stereostructure as well as
the absolute configuration of valeranone 1, which was con-
firmed later by enantiospecific synthesis of both (ϩ)- and
(Ϫ)-valeranone starting from (Ϫ)- and (ϩ)-carvomenthone,
respectively. In addition to valeranone, subsequently a few
other members of the valerane family of natural products were
isolated4 from Japanese valerians (Fig. 1). The presence of an
unusual structure incorporating two vicinal ring junction
quaternary carbon atoms with methyl substituents in a cis-
decalin framework, and three chiral centres, made the valerane
group of sesquiterpenes interesting and challenging synthetic
targets. As a consequence, several approaches to valeranone 1
and to the parent hydrocarbon, valerane 2, both in racemic as
well as chiral form, have been reported in the literature.5
Terpenes, among the ‘chiral pool,’ continue to attract
attention6 in the enantioselective synthesis of complex natural
products. We have initiated a project on the enantiospecific total
synthesis of valeranes starting from (R)-carvone.7 To begin with
a hydrindane-to-decalin-based methodology was contemplated,
Scheme 1. It was conceived that the hydrindanone 3 could serve
Scheme 1
as the precursor for valerane, and could itself be obtained by an
intramolecular cyclopropanation of the diazo ketone derived
from the acid 5 followed by regioselective cyclopropane cleav-
age and hydrogenation of the resulting tricyclic ketone 4. A
stereospecific Claisen rearrangement of the allyl alcohol 6 gen-
erates the first quaternary carbon atom, and hydride reduction
of β-methylcarvone 8 provides the requisite syn allyl alcohol 6.
Results and discussion
The requisite starting material, (S)-(ϩ)-β-methylcarvone 8 was
prepared from (R)-(Ϫ)-carvone 7 by employing a regioselective
1,2-addition of methylmagnesium iodide followed by oxidation
of the resultant allylic tertiary alcohol with pyridinium chloro-
chromate (PCC)8 (Scheme 2). Lithium aluminium hydride
(LAH) reduction of (S)-β-methylcarvone 8 in diethyl ether at
Ϫ70 ЊC furnished the syn allyl alcohol 6, the precursor for the
projected Claisen rearrangement, in 95% yield, with a high
degree of regio- and stereoselectivity. The syn stereochemistry
of hydroxy and isopropenyl groups in the allyl alcohol 6 was
assigned based on the preferential axial approach of the
hydride,9 analogous to the conversion of carvone into carveol.10
An orthoester variant11 of the Claisen rearrangement was
chosen for the stereospecific creation of the first quaternary
Fig. 1
† Chiral synthons from carvone, part 46. For parts 44 and 45, see ref. 15.
DOI: 10.1039/b006757l
J. Chem. Soc., Perkin Trans. 1, 2000, 4321–4327
4321
This journal is © The Royal Society of Chemistry 2000

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Scheme 3 Reagents and yields: a) MeMgI, 85%; b) PTSA, 98%;
c) O3/O2; PPh3; 83%; d) 1 M NaOH–MeOH, 60%; e) BF3ؒEt2O,
NaBH3CN, 89%; f) H2, 10% Pd-C, 84%.
Scheme 2 Reagents and yields: a) ref. 8; b) LAH, 95%; c) CH3C(OEt)3,
EtCO2H; KOH; 63%; d) (COCl)2; CH2N2; 75%; e) CuSO4, 76%; f) Li,
liq. NH3, 76%; g) H2, Pd–C, 98%.
mixture of olefins 13 in methanol–methylene dichloride (1:5)
at Ϫ70 ЊC, followed by reductive work-up of the ozonide with
triphenylphosphine furnished a mixture of keto aldehydes 14
and 15. Intramolecular aldol condensation of the mixture of
keto aldehydes 14 and 15 in tetrahydrofuran (THF) using 1 M
potassium hydroxide in methanol furnished a ≈2:1 mixture
of the regioisomeric enones 16 and 17. For the deoxygenation
of the enones 16 and 17 an ionic hydrogenation, employing
a combination of sodium cyanoborohydride and boron tri-
fluoride–diethyl ether,14 was chosen. Thus, refluxing a solution
of a mixture of the enones 16 and 17 in dry THF with sodium
cyanoborohydride and boron trifluoride–diethyl ether, as anti-
cipated, furnished a regioisomeric mixture of the olefins 18 in
89% yield. Finally, hydrogenation of the mixture of olefins 18
in methanol using 10% Pd/C as the catalyst at one atmosphere
pressure of hydrogen furnished (ϩ)-valerane 2, [α]D26 ϩ88 (c 0.5,
CHCl3) [lit.,4i ϩ76 (c 5, CHCl3)]. The 1H and 13C NMR spectral
data of (ϩ)-valerane 2 obtained in this study were found to be
identical with those reported5j in the literature.
To overcome the regiochemical problems, an alternative
strategy was explored, Scheme 4. It was anticipated that intra-
molecular cyclopropanation of the diazo ketone derived from
the acid 19 would generate the tricyclic ketone 20, which could
be transformed into valerane 2 via reductive cyclopropane ring
cleavage, catalytic hydrogenation, and reductive deoxygenation
of the resulting valeran-3-one. The acid 19 could be generated
by homologation of the γ,δ-unsaturated aldehyde 21, which
could be obtained from the ester 9.
centre. Thus, thermal activation of a solution of the allyl alco-
hol 6, triethyl orthoacetate and a catalytic amount of propionic
acid in a sealed tube for 5 days, furnished the ester 9, which on
alkaline hydrolysis generated the acid 5. The stereochemistry
at the newly created quaternary centre rests secured from the
well established stereospecificity of the Claisen rearrangement.
Reaction of the acid 5 with oxalyl dichloride in benzene fol-
lowed by treatment of the resulting acid chloride with an excess
of ethereal diazomethane furnished the diazo ketone 10 in 75%
yield. Anhydrous copper() sulfate-catalysed decomposition of
the diazo ketone 10 in refluxing cyclohexane, using a tungsten
lamp, led to the intramolecular insertion of the resultant keto-
carbenoid into the ring olefinic moiety in a regio- and stereo-
specific manner,12 resulting in the formation of the cyclopropyl
ketone 4 in 76% yield, whose structure was established from its
spectral data. The cis stereochemistry of the ring junction was
a consequence of the insertion of the ketocarbenoid from
the preferred syn face of the olefin. Treatment of the cyclo-
propyl ketone 4 with lithium in liquid ammonia furnished the
ketone 11 in 76% yield, in a highly regioselective manner. The
regioselectivity in the cyclopropane cleavage can be readily
explained, as it is well established that in cyclopropyl ketones
the cyclopropane bond which possesses maximum overlap with
the p-orbital of the carbonyl system will be cleaved preferen-
tially.13 Hydrogenation of the isopropenyl double bond in the
enone 11 using 10% Pd/C as the catalyst in methanol at one
atmosphere of hydrogen furnished the saturated ketone 3 in
98% yield.
The synthetic sequence is depicted in Scheme 5. Reduction of
the ester 9 with LAH furnished the primary alcohol 22, which
on oxidation with PCC and silica gel furnished the aldehyde 21.
Reaction of the aldehyde 21 with methoxymethylene(triphenyl)-
phosphorane followed by treatment of the resulting Wittig
product 23 with Jones reagent in acetone generated the acid 19
in 60% overall yield. The structure of the acid 19 was estab-
lished from the spectral data of the corresponding methyl ester
19a,‡ obtained via diazomethane esterification. Reaction of the
For the hydrindanone-to-decalin ring expansion, an oxidative
cleavage and aldol condensation sequence was contemplated,
Scheme 3. Treatment of the ketone 3 with methylmagnesium
iodide in diethyl ether provided the tert-alcohol 12 as a mixture
of diastereomers, which on treatment with a catalytic amount
of toluene-p-sulfonic acid (PTSA) in benzene generated the
expected mixture of the olefins 13 in a 3:2 regioisomeric ratio.
No attempt was made to separate the isomers of the olefin 13 as
both the isomers will lead to (ϩ)-valerane 2. Ozonolysis of the
‡ Subsequently, the ester 19a was also obtained by photolysis (Hanovia
450 W medium pressure mercury vapour lamp, pyrex filter) of the diazo
ketone 10 in methanol for 15 min, in 75% yield.
4322
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acid 19 with oxalyl dichloride generated the corresponding
acid chloride, which on treatment with an excess of ethereal
diazomethane furnished the diazo ketone 24. Reaction of the
diazo ketone 24 with anhydrous copper() sulfate and copper
in refluxing cyclohexane, as anticipated, furnished the tricyclic
ketone 20, in 51% overall yield from the acid 19, via stereo-
and regiospecific insertion of the resulting keto carbenoid in
the cyclohexene double bond. Lithium in liquid ammonia-
mediated regioselective reductive cyclopropane ring cleavage
transformed the tricyclic ketone 20 into (ϩ)-valer-11-en-3-one
25, which on hydrogenation employing 10% Pt on carbon as the
catalyst furnished (ϩ)-valeran-3-one 26. Reaction of the ketone
26 with ethane-1,2-dithiol and BF3ؒEt2O in benzene generated
the dithioketal 27 in 95% yield. Desulfurisation of the
dithioketal 27 with Raney nickel in refluxing ethanol furnished
(ϩ)-valerane 2, [α]D26 ϩ72 (c 1, CHCl3) [lit.4i ϩ76 (c 5, CHCl3)],
and 400 MHz) and 13C NMR (22.5, 50, 67.5, 77.5 and 100
MHz) spectra were recorded on Varian T-60, Hitachi R-1500,
JEOL FX-90Q and JNM λ-300, Bruker ACF-200, WH-270
and AMX-400 spectrometers. The chemical shifts (δ/ppm) and
the coupling constants (J/Hz) are reported in the standard
fashion with reference to either internal tetramethylsilane (for
1H) or the central line (δC 77.1) of CDCl3 (for 13C). Low- and
high-resolution mass measurements were carried out with a
JEOL JMS-DX 303 GC-MS instrument using a direct-inlet
mode. Relative intensities of the ions are given in parentheses.
Elemental analyses were carried out using a Carlo Erba 1106
CHN analyser. Optical rotations were measured using a JASCO
DIP-370 digital polarimeter; [α]D values are given in units of
10Ϫ1 deg cm2 gϪ1. Ozonolysis was carried out using a Penwalt
Wallace and Tierman ozonator. Hydrogenation reactions were
carried out using a balloon. All solvent evaporations were
carried out using a Buchi rotary evaporator. Analytical TLC
was performed on glass plates (7.5 × 2.5 and 7.5 × 5.0 cm)
coated with Acme’s silica gel G containing 13% calcium sul-
fate as binder, and various combinations of ethyl acetate and
hexane were used as the developer. Acme’s silica gel (100–200
mesh) was used for column chromatography. All small-scale
dry reactions were carried out using standard syringe-septum
techniques. Low-temperature reactions were conducted in a
bath made of ethanol and liquid nitrogen.
1
which exhibited H and 13C NMR spectra identical with those
of the authentic sample.
In conclusion, two routes for the enantiospecific total syn-
thesis of (ϩ)-valerane 2 starting from (R)-carvone have been
achieved. The two quaternary carbon atoms were created in a
highly regio- and stereoselective manner employing an ortho-
ester Claisen rearrangement and intramolecular diazo ketone
cyclopropanation reaction, respectively.
Experimental
Mps were recorded using a Tempo melting point apparatus and
are uncorrected. IR spectra were recorded on Perkin-Elmer 781
(1S,5S)-5-Isopropenyl-2,3-dimethyl-cyclohex-2-en-1-ol
(3-methylcaveol) 6
1
and Hitachi 270-50 spectrophotometers. H (90, 200, 270, 300
To a magnetically stirred, cold (Ϫ70 ЊC) solution of β-methyl-
carvone8 8 (500 mg, 3.05 mmol) in dry diethyl ether (15 ml) was
added LiAlH4 (60 mg, 1.6 mmol). The reaction mixture was
stirred at the same temperature for 2 h and allowed to attain RT
over a period of 30 min. The reaction was quenched first with
wet diethyl ether and then with dil. aq. HCl. It was then
extracted with diethyl ether (3 × 10 ml) and the combined ether-
eal extract was washed successively with saturated aq. NaHCO3
and brine, and dried (Na2SO4). Evaporation of the solvent and
purification of the product on a silica gel column, using CH2Cl2
as eluent, furnished the alcohol 6 (480 mg, 95%) as a low melt-
ing hygroscopic solid, which was recrystallised from hexanes,
mp 56 ЊC; [α]D29 ϩ45.0 (c 2, CHCl3); νmax (neat) 3340, 1640, 890
cmϪ1; δ (90 MHz; CDCl ) 4.72 (2 H, s, C᎐CH ), 4.15 (1 H, m,
᎐
H
3
2
OCH), 1.82–2.40 (6 H, m), 1.74 (6 H, s) and 1.66 (3 H, s)
(3 × olefinic CH3); δC (22.5 MHz; CDCl3) 149.1 (s), 128.8 (s),
128.6 (s), 108.9 (t), 71.7 (d), 39.8 (d), 38.1 (t), 37.5 (t), 20.6 (q),
19.3 (q), 14.2 (q); m/z 166 (Mϩ, 6%), 151 (18), 148 (25), 133 (25),
Scheme 4
Scheme 5 Reagents and yields: a) LiAlH4, 90%; b) PCC, 95%; c) MeOCH=PPh3; d) Jones reagent, 60% from 21; e) i (COCl)2; ii CH2N2;
f) Cu–CuSO4, 51% from acid 19; g) Li-liq. NH3, 55%; h) H2, 10% Pt-C, 98%; i) (CH2SH)2, BF3ؒEt2O, 95%; j) Raney Ni, 82%.
J. Chem. Soc., Perkin Trans. 1, 2000, 4321–4327
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121 (80), 122 (100), 107 (70), 98 (55); HRMS m/z Calc. for
C11H18O: M, 166.1358. Found: Mϩ, 166.1352.
m), 1.70 (3 H, s, olefinic CH3), 1.23 (6 H, s, 2 × tert-CH3);
δC (22.5 MHz; CDCl3) 212.1 (s), 148.5 (s), 108.7 (t), 54.9 (t),
41.2 (d), 40.2 (d), 36.8 (t), 35.6 (s), 33.4 (s), 28.6 (q), 28.1 (d),
22.6 (t), 20.0 (q), 16.9 (q); m/z 204 (Mϩ, 13%), 123 (40), 122 (40),
121 (85), 120 (40), 119 (40) 107 (85), 105 (45), 95 (55), 94 (56),
93 (100); HRMS m/z Calc. for C14H20O: M, 204.1514. Found:
Mϩ, 204.1535.
(1S,5R)-5-Isopropenyl-1,2-dimethylcyclohex-2-enylacetic acid 5
A solution of the allyl alcohol 6 (700 mg, 4.22 mmol), triethyl
orthoacetate (3.8 ml, 21 mmol) and a catalytic amount (≈5 µl)
of propionic acid was placed in a sealed tube and heated to
160 ЊC for 5 days in an oil-bath. The reaction mixture was
cooled, diluted with diethyl ether (25 ml), washed with 0.5 M aq.
HCl followed by saturated aq. NaHCO3 and brine, and dried
(Na2SO4). Evaporation of the solvent and purification of the
product on a silica gel column, using ethyl acetate–hexane
(1:40) as eluent, furnished the ester 9 (800 mg, 80%) as an
oil, [α]D25 Ϫ20.0 (c 2, CHCl3). νmax (neat) 1735, 1650, 885 cmϪ1;
(1S,3R,6R)-3-Isopropenyl-1,6-dimethylbicyclo[4.3.0]nonan-8-
one 11
To magnetically stirred, freshly distilled (over sodium)
ammonia (50 ml) in a three-necked flask equipped with a
Dewar condenser (cooled with ethanol and liquid nitrogen),
was added a solution of the cyclopropyl ketone 4 (300 mg, 1.47
mmol) in dry THF (1.5 ml) followed by freshly cut lithium (41
mg, 5.88 mmol) in small pieces. The resulting blue coloured
solution was stirred for 30 min and the reaction was quenched
with solid NH4Cl. After evaporation of ammonia, the residue
was taken up in water (15 ml) and extracted with diethyl ether
(3 × 25 ml). The combined extract was washed with brine and
dried (Na2SO4). Evaporation of the solvent and purification of
the product on a silica gel column, using ethyl acetate–hexane
(1:40) as eluent, furnished the ketone 11 (230 mg, 76%) as a
colourless oil, [α]D24 Ϫ31.5 (c 2, CHCl3); νmax (neat) 1735, 1640,
880 cmϪ1; δH (200 MHz; CDCl3) 4.70 (1 H, s) and 4.67 (1 H, s)
δH (90 MHz; CDCl ) 5.41 (1 H, br s, C᎐CH), 4.72 (2 H, s,
᎐
3
C᎐CH ), 4.12 (2 H, q, J 7.2, OCH CH ), 2.45 and 2.38 (2 H, AB
᎐
2
2
3
q, J 14, CH C᎐O), 1.30–2.50 (5 H, m), 1.73 (3 H, s) and 1.66
᎐
2
(3 H, s) (2 × olefinic CH3), 1.26 (3 H, t, J 7.2, OCH2CH3), 1.18
(3 H, s, tert-CH3).
To a magnetically stirred solution of the ester 9 (500 mg, 2.1
mmol) in methanol (4 ml) was added 10% aq. NaOH (4 ml) and
the reaction mixture was refluxed for 6 h. The solvent was evap-
orated under reduced pressure, and the residue was taken in
water (10 ml) and washed with CH2Cl2 (2 × 5 ml). The aqueous
phase was acidified with 3 M aq. HCl and extracted with
CH2Cl2 (3 × 10 ml). The organic extract was then washed with
water (10 ml) followed by brine and dried (Na2SO4). Evapor-
ation of the solvent furnished the acid 5 (350 mg, 79%), which
was recrystallised from a mixture of CH2Cl2–hexane, mp 58 ЊC;
[α]D26 Ϫ30.0 (c 2, CHCl3); νmax (neat) 3000, 1705, 1650, 890 cmϪ1;
(C᎐CH ), 2.65 and 1.80 (2 H, AB q, J 18.6, CH C᎐O), 2.35 and
᎐
᎐
2
2
2.00 (2 H, AB q, J 18.5, CH C᎐O), 1.20–2.25 (7 H, m), 1.71
᎐
2
(3 H, s, olefinic CH3), 1.13 (3 H, s) and 1.00 (3 H, s) (2 × tert-
CH3); δC (22.5 MHz; CDCl3) 218.3, 149.3, 108.4, 52.9, 50.5,
47.8, 41.7, 40.2, 39.6, 32.2, 26.6, 25.5, 20.8, 20.0; m/z 206 (Mϩ,
55%), 191 (50), 163 (20), 149 (30), 123 (40), 110 (100), 107 (57),
95 (40), 93 (40); HRMS m/z Calc. for C14H22O: M, 206.1671.
Found: Mϩ, 206.1685.
δH (90 MHz; CDCl ) 5.42 (1 H, m, C᎐CH), 4.68 (2 H, s,
᎐
3
C᎐CH ), 2.42 (2 H, s, CH C᎐O), 1.30–2.50 (6 H, m), 1.72 (3 H,
᎐
᎐
2
2
s) and 1.67 (3 H, s) (2 × olefinic CH3), 1.17 (3 H, s, tert-CH3).
δC (22.5 MHz; CDCl3) 178.4, 149.6, 137.9, 123.1, 108.7, 45.1,
40.4, 38.1, 37.7, 31.1, 26.0, 20.8, 18.5; m/z 208 (Mϩ, 25%), 148
(96), 133 (92), 119 (30), 107 (100); HRMS m/z Calc. for
C13H20O2: M, 208.1463. Found: Mϩ, 208.1454.
(1S,3R,6R)-3-Isopropyl-1,6-dimethylbicyclo[4.3.0]nonan-8-one 3
To a magnetically stirred solution of the ketone 11 (390 mg,
1.89 mmol) in dry methanol (3 ml) was added 10% Pd/C (15
mg). The reaction mixture was stirred in an atmosphere of
hydrogen, created by evacuative replacement of air using a
balloon filled with hydrogen, for 6 h and the catalyst was filtered
off. Evaporation of the solvent and purification of the product
on a silica gel column, using ethyl acetate–hexane (1:40) as
eluent, furnished the saturated ketone 3 (385 mg, 98%) as a
colourless oil, [α]D23 Ϫ29.5 (c 2, CHCl3); νmax (neat) 1740, 1460,
1405, 1385 cmϪ1; δH (200 MHz; CDCl3) 2.61 and 1.77 (2 H, 2 d,
(1R,2R,4R,6S,9S)-4-Isopropenyl-1,6-dimethyltricyclo[4.3.0.02,9]-
nonan-8-one 4
A solution of the acid 5 (1.8 g, 8.65 mmol) and oxalyl dichlo-
ride (2 ml, 23 mmol) in dry benzene (2 ml) was magnetically
stirred for 1 h at RT. Evaporation of benzene and excess of
oxalyl dichloride under reduced pressure afforded the acid
chloride, which was taken up in dry diethyl ether (10 ml) and
added dropwise to a cold magnetically stirred ethereal solution
of diazomethane (excess, prepared from 15 g of N-methyl-N-
nitrosourea and 100 ml of 60% aq. KOH). The reaction mixture
was stirred for 2 h at RT and the excess of diazomethane and
diethyl ether were carefully evaporated on a water bath. Rapid
purification by filtration of the product through a neutral
alumina column, using CH2Cl2 as eluent, furnished the diazo
ketone 10 (1.5 g, 75%) as yellow oil, νmax (neat) 2100, 1635, 885
J 18.7, CH C᎐O), 2.35 and 1.97 (2 H, 2 d, J 18.4, CH C᎐O),
᎐
᎐
2
2
1.00–1.60 (8 H, m), 1.08 (3 H, s) and 0.97 (3 H, s) (2 × tert-
CH3), 0.85 (6 H, d, J 6.6, CH3CHCH3); δC (22.5 MHz; CDCl3)
219.0 (s), 53.3 (t), 48.2 (s), 48.0 (t), 40.4 (2 C, t and s), 39.3 (d),
32.5 (2 C, t and d), 25.7 (q), 24.8 (t), 20.3 (q), 19.7 (q), 19.5 (q);
m/z 208 (Mϩ, 53%), 193 (30), 165 (40), 151 (65), 137 (40), 123
(65), 110 (50), 109 (65), 107 (50), 95 (90), 81 (100); HRMS m/z
Calc. for C14H24O: M, 208.1827. Found: Mϩ, 208.1834.
cmϪ1; δ (90 MHz; CDCl ) 5.41 (1 H, br s, C᎐CH), 5.22 (1 H, s,
᎐
H
3
CHN ), 4.70 (2 H, s, C᎐CH ), 2.36 (2 H, s, CH C᎐O), 1.50–2.30
(5 H, m), 1.72 (3 H, s) and 1.69 (3 H, s) (2 × olefinic CH3), 1.14
(3 H, s, tert-CH3).
᎐
᎐
2
2
2
(1S,3R,6R)-3-Isopropyl-1,6,8-trimethylbicyclo[4.3.0]nonan-8-ol
12
To a magnetically stirred, refluxing (using two 100 W tung-
sten lamps) suspension of anhydrous copper() sulfate (6 g) in
dry cyclohexane (125 ml) was added, dropwise, a solution of
the diazo ketone 10 (1.5 g, 6.47 mmol) in cyclohexane (25 ml)
over a period of 30 min. The reaction mixture was refluxed for
4 h, then cooled and the copper sulfate was filtered off using a
sintered funnel. Evaporation of the solvent and purification of
the product on a silica gel column, using ethyl acetate–hexane
(1:40) as eluent, furnished the cyclopropyl ketone 4 (998 mg,
76%) as oil, [α]D24 ϩ27.5 (c 2, CHCl3); νmax (neat) 1710, 1640, 885
To a freshly prepared, magnetically stirred, ice-cold suspension
of methylmagnesium iodide [prepared from magnesium (86 mg,
3.58 mmol) and methyl iodide (0.25 ml, 3.96 mmol)] in dry
diethyl ether (5 ml) was added a solution of the ketone 3 (180
mg, 0.87 mmol) in dry diethyl ether (5 ml) over a period of 30
min. The reaction mixture was stirred at RT for 10 h and
poured into an ice-cold solution of saturated aq. NH4Cl. The
ether layer was separated and the aqueous phase was extracted
with diethyl ether (3 × 5 ml). The combined ether phases were
washed with brine and dried (Na2SO4). Evaporation of the
solvent, and purification of the residue on a silica gel column,
using CH2Cl2 as eluent, furnished an ≈2:1 epimeric mixture of
cmϪ1; δH (200 MHz; CDCl ) 4.68 (2 H, s, C᎐CH ), 2.38 (1 H,
᎐
3
2
m), 2.19 and 1.97 (2 H, AB q, J 19.8, CH C᎐O), 1.50–2.25 (6 H,
᎐
2
4324
J. Chem. Soc., Perkin Trans. 1, 2000, 4321–4327

View Article Online
the tert-alcohol 12 (165 mg, 85%) as a colourless oil, νmax (neat)
3350 cmϪ1; δH (200 MHz; CDCl3, peaks due to major isomer)
1.00–2.50 (12 H, m), 1.41 (3 H, s, CH3COH), 0.87 (3 H, s) and
0.85 (3 H, s) (2 × tert-CH3), 0.86 (6 H, d, J 6.6, CH3CHCH3);
δC (50.0 MHz; CHCl3 ϩ CDCl3, mixture of 2:1 diastereomers)
57.9, 56.9, 52.3, 51.4, 50.4, 43.8, 40.4, 39.8, 39.7, 39.5, 33.6,
33.4, 32.5, 26.1, 25.1, 24.1, 21.2, 20.9, 19.8, 19.4, 19.6; m/z 224
(Mϩ, 2%), 206 (12), 191 (100), 181 (27), 163 (55), 151 (65), 123
(55), 121 (40), 109 (58), 107 (60), 95 (68); HRMS m/z Calc. for
C15H28O: M, 224.2140. Found: Mϩ, 224.2136.
39.9, 39.4, 38.8, 38.5, 38.1, 36.3, 35.8, 34.9, 32.6, 26.8, 25.0,
24.0, 23.3, 22.9, 22.1, 21.2, 19.8, 19.6; m/z 220 (Mϩ, 3%), 191
(100), 135 (25), 122 (35), 121 (55), 109 (40), 108 (55), 107 (50),
93 (30); HRMS m/z Calc. for C15H24O: M, 220.1827. Found:
Mϩ, 220.1836.
(1R,3R,6S)-3-Isopropyl-1,6-dimethylbicyclo[4.4.0]decane [(؉)-
valerane] 2
To a magnetically stirred solution of a mixture of the enones 16
and 17 (50 mg, 0.23 mmol) and boron trifluoride–diethyl ether
(0.1 ml, 0.68 mmol) in 0.5 ml of dry THF was added sodium
cyanoborohydride (43 mg, 0.68 mmol) and the mixture was
refluxed for 10 min. The reaction mixture was cooled, quenched
with saturated aq. NaHCO3, and extracted with diethyl
ether (3 × 5 ml). The solvent was carefully evaporated and the
product was purified on a silica gel column with hexane as
eluent to furnish a mixture of the alkenes 18 (42 mg, 89%) as an
oil, νmax (neat) 1460, 1365, 1020 cmϪ1; δH (400 MHz; CDCl3)
5.48–5.60 (1 H, m), 5.20–5.32 (1 H, m), 0.85–2.20 (12 H, m),
0.80–0.90 (12 H, m, 4 × CH3).
Hydrogenation of a mixture of the alkenes 18 (20 mg, 0.09
mmol) in dry methanol (0.3 ml), using 10% Pd/C (5 mg) as
catalyst for 10 h, as described for compound 3, and careful
purification of the product on a silica gel column, using hexane
as eluent, furnished valerane 2 (17 mg, 84%) as a colourless
oil,4i,5j [α]D26 ϩ88.0 (c 0.5, CHCl3), ϩ60.0 (c 0.3, CH3OH) [lit.,4i
ϩ76.0 (c 5, CHCl3)]; νmax (neat) 1470, 1450, 1390, 1370 cmϪ1;
δH (400 MHz; CDCl3) 0.98–2.00 (16 H, m), 0.86 (3 H, s, tert-
CH3), 0.86 (6 H, d, J 6.54, CH3CHCH3), 0.84 (3 H, s, tert-CH3);
δC (100 MHz; CDCl3) 39.5 (CH), 37.31 (CH2), 37.28 (CH2),
37.0 (CH2), 35.5 (C), 34.9 (C), 33.16 (CH), 33.12 (CH2), 25.1
(CH2), 24.8 (CH3), 23.7 (CH3), 22.5 (CH2), 21.9 (CH2), 20.1
(CH3), 19.8 (CH3).
(1S,3R,6R)-3-Isopropyl-1,6,8-trimethylbicyclo[4.3.0]non-7-ene
and (1R,4R,6S)-4-isopropyl-1,6,8-trimethylbicyclo[4.3.0]non-7-
ene 13
To a magnetically stirred solution of the epimeric mixture of
the tert-alcohol 12 (200 mg, 0.89 mmol) in benzene (2 ml) was
added PTSA (10 mg) and the reaction mixture was refluxed for
5 h, cooled, diluted with diethyl ether (15 ml) and washed suc-
cessively with saturated aq. NaHCO3 and brine, and dried
(Na2SO4). Evaporation of the solvent and purification of the
product on a silica gel column, using hexane as eluent, fur-
nished a 3:2 mixture of the alkenes 13 (180 mg, 98%) as a
colourless oil, νmax (neat) 1450, 1380, 1365, 815 cmϪ1; δH (270
MHz; CDCl3) 5.05 and 5.11 (1 H, s, olefinic H), 2.28 and 2.48
(1 H, AB q, J 15), 1.65 (3 H, s, olefinic CH3), 1.00–1.80 (9 H, m),
0.98 and 0.91 (3 H, s) and 0.77 and 0.85 (3 H, s) (2 × tert-CH3),
0.82 (3 H, d, J 6.5) and 0.81 (3 H, d, J 6.5) (CH3CHCH3);
δC (50.0 MHz; CHCl3 ϩ CDCl3, a 3:2 mixture of olefin
isomers) 135.8, 135.3, 51.7, 47.9, 47.3, 43.8, 42.2, 41.7, 39.7,
38.3, 34.4, 33.8, 32.5, 32.2, 29.5, 26.6, 25.9, 24.6, 20.2, 19.7,
19.5, 19.4, 19.3, 17.1, 16.9; m/z 206 (Mϩ, 10%), 191 (18), 163
(10), 151 (10), 135 (12), 121 (20), 107 (20), 95 (20), 40 (100).
(1S,6R,9R)-9-Isopropyl-1,6-dimethylbicyclo[4.4.0]dec-4-en-3-
one 16 and (1R,6S,8R)-8-Isopropyl-1,6-dimethylbicyclo[4.4.0]-
dec-4-en-3-one 17
(؊)-2-[(1S,5R)-5-Isopropenyl-1,2-dimethylcyclohex-2-enyl]-
ethanol 22
Dry ozone in oxygen gas was passed through a cold (Ϫ70 ЊC)
suspension of the alkene 13 (262 mg, 1.27 mmol) and NaHCO3
(10 mg) in 1:5 methanol–CH2Cl2 (5 ml) until the reaction mix-
ture turned blue in colour. Excess of ozone was flushed off with
oxygen. Triphenylphosphine (400 mg, 1.52 mmol) was added,
and the reaction mixture was allowed to attain RT and was
magnetically stirred for 4 h. Evaporation of the solvent and
rapid purification of the product on a silica gel column, using
ethyl acetate–hexane (1:20) as eluent, furnished a 2:1 mixture
of the keto aldehydes 14 and 15 (249 mg, 83%) as an oil, νmax
(neat) 1710 cmϪ1; δH (90 MHz; CDCl3, 2:1 mixture of 14 and
To a cold (Ϫ70 ЊC), magnetically stirred solution of the ester 9
(3.8 g, 16.1 mmol) in dry diethyl ether (60 ml) was added LiAlH4
(1.1 g, 28.9 mmol). The reaction mixture was slowly warmed to
RT, stirred for 2 h and worked up as described for 6. Purifi-
cation of the product over a silica gel column, using ethyl
acetate–hexane (1:5 to 1:2.5) as eluent, furnished the alcohol
22 (2.8 g, 90%), [α]D25 Ϫ19.1 (c 4.5, CHCl3); νmax (neat) 3420,
1635, 880 cmϪ1; δH (90 MHz; CDCl3) 5.30–5.50 (1 H, m,
C᎐CH), 4.72 (2 H, s, C᎐CH ), 3.50–3.80 (2 H, m, CH OH),
᎐
᎐
2
2
1.45–2.40 (7 H, m), 1.75 (3 H, s) and 1.68 (3 H, s) (2 × olefinic
CH3), 1.47 (1 H, s, OH), 1.09 (3 H, s, tert-CH3); δC (22.5 MHz;
CDCl3) 149.2 (s), 138.4 (s), 122.5 (d), 108.2 (t), 58.5 (t), 42.7 (t),
40.3 (t), 37.4 (d), 37.1 (s), 31.0 (t), 26.4 (q), 20.5 (q), 18.1 (q); m/z
194 (Mϩ, 14%), 149 (50), 133 (26), 121 (64), 107 (100), 93 (82);
HRMS m/z for C13H22O: M, 194.1671. Found: Mϩ, 194.1672.
15) 9.72 and 9.79 (1 H, s, CHO), 2.20–3.60 (2 H, m, CH C᎐O),
᎐
2
2.12 and 2.15 (3 H, s, CH C᎐O), 1.00–2.00 (8 H, m), 1.18 and
᎐
3
1.14 (3 H, s) and 1.15 and 0.98 (3 H, s) (2 × tert-CH3), 0.90
(3 H, d, J 6.7) and 0.88 (3 H, d, J 6.7) (CH3CH-CH3).
To a solution of a mixture of the keto aldehydes 14 and 15
(250 mg, 1.05 mmol) in dry THF (2 ml) was added 1 M KOH in
methanol (1.05 ml, 1.05 mmol) and the reaction mixture was
stirred at RT for 12 h. The solvent was evaporated under
reduced pressure, and the residue was taken up in water (3 ml)
and extracted with diethyl ether (3 × 5 ml). The combined
extract was washed with brine and dried (Na2SO4). Evaporation
of the solvent and purification of the product on a silica gel
column, using ethyl acetate–hexane (1:20) as eluent, furnished
a 2:1 mixture of the enones 16 and 17 (115 mg, 50% from
alkene 13) as an oil, νmax (neat) 1670 cmϪ1; δH (200 MHz;
CDCl3, a 2:1 mixture of 16 and 17) 6.53 and 6.48 (1 H, d,
(1S,5R)-(5-Isopropenyl-1,2-dimethylcyclohex-2-enyl)acetalde-
hyde 21
To a magnetically stirred suspension of PCC (750 mg, 3.5
mmol) and silica gel (750 mg) in CH2Cl2 (2 ml) was added a
solution of the alcohol 22 (370 mg, 1.90 mmol) in CH2Cl2 in
one portion. The reaction mixture was stirred at RT for 2 h,
filtered through a silica gel column, and the column was eluted
with more CH2Cl2. The solvent was evaporated to furnish the
aldehyde 21 (350 mg, 95%) as oil, [α]D21 Ϫ31.8 (c 0.88, CHCl3);
νmax (neat) 2740, 1715, 1645, 885 cmϪ1; δH (300 MHz; CDCl3)
J 10.0, CH᎐CHC᎐O), 5.91 and 5.86 (1 H, d, J 10.0, CH᎐
9.67 (1 H, dd, J 3.7 and 2.4, CH᎐O), 5.50 (1H, br s), 4.73 (1 H,
᎐
᎐
᎐
᎐
CHC᎐O), 2.58 and 2.02 (AB q, J 16.9) and 2.88 and 1.81 (AB q,
s) and 4.70 (1 H, s) (C᎐CH ), 2.52 (1 H, dd, J 15.6 and 4.2) and
᎐
2
᎐
J 16.3) (2 H, CH C᎐O), 0.95–1.70 (8 H, m), 1.10 and 0.89 (3 H,
2.26 (1 H, dd, J 15.3 and 3.7) (CH C᎐O), 2.10–1.50 (5 H, m),
᎐
᎐
2
2
s) and 1.05 (3 H, s) (2 × tert-CH3), 0.87 (3 H, d, J 6.4) and 0.80
(3 H, d, J 6.4) (2 × CH3CHCH3); δC (67.5 MHz; CDCl3) 200.9,
200.0, 160.3, 158.9, 127.6, 125.7, 49.3, 48.8, 47.3, 46.5, 41.0,
1.73 (3 H, s) and 1.70 (3H, s) (2 × olefinic CH3), 1.08 (3 H, tert-
CH3); δC (75 MHz; CDCl3, DEPT) 203.8 (CH), 149.3 (C), 137.0
(C), 124.3 (CH), 108.9 (CH2), 53.0 (CH2), 41.7 (CH2), 37.7 (C),
J. Chem. Soc., Perkin Trans. 1, 2000, 4321–4327
4325

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37.4 (CH), 31.2 (CH2), 26.6 (CH3), 20.8 (CH3), 18.6 (CH3);
m/z: 192 (Mϩ, 4%), 149 (20), 148 (18), 133 (30), 121 (30),
107 (100), 93 (30).
MHz; CDCl3 ϩ CCl4) 210.7 (C), 148.7 (C), 109.4 (CH2), 39.9
(CH2), 39.7 (CH), 38.4 (CH2), 37.3 (CH2), 33.4 (CH), 31.1 (C),
29.9 (CH), 29.6 (CH3), 26.3 (CH2), 24.6 (C), 24.2 (CH3), 21.0
(CH3); m/z 219 (M ϩ 1, 12%), 203 (11), 161 (20), 147 (25), 133
(30), 121 (50), 119 (40), 109 (55), 106 (50), 107 (80), 105 (50),
93 (100); HRMS m/z Calc. for C15H22O: M, 218.1670. Found:
Mϩ, 218.1649.
3-[(1R,5R)-5-Isopropenyl-1,2-dimethylcyclohex-2-enyl]propionic
acid 19
To a magnetically stirred solution of methoxymethyl(triphenyl)-
phosphonium chloride (2.8 g, 8.18 mmol) in dry THF (2 ml) at
RT was added potassium tert-amylate (1 g, 8.18 mmol) in THF
(2 ml) and the resulting red-coloured solution was stirred at RT
for 5 min. To the methoxymethylene(triphenyl)phosphorane
thus formed was added a solution of the aldehyde 21 (350 mg,
1.82 mmol) in THF (1 ml) and the mixture was stirred for 30
min. The reaction mixture was then diluted with diethyl ether
(10 ml), washed with brine and dried (Na2SO4). Evaporation of
the solvent furnished the enol ether 23, which was taken up in
acetone (3 ml) and treated with freshly prepared Jones reagent
(1.6 M; 3 ml, 4.8 mmol). The reaction mixture was stirred at RT
for 1 h. Excess of reagent was consumed by adding a few drops
of propan-2-ol and the mixture was then extracted with diethyl
ether. The extract was washed with brine and dried (Na2SO4).
Evaporation of the solvent furnished the acid 19 (243 mg, 60%
from aldehyde 21).
A solution of the acid 19 (50 mg, 0.22 mmol) in diethyl ether
was added to a cold, magnetically stirred, ethereal solution of
diazomethane (excess, prepared from 0.5 g of N-methyl-N-
nitrosourea and 5 ml of 60% aq. KOH). The reaction mixture
was stirred for 2 h at RT and the excess of diazomethane and
diethyl ether were carefully evaporated on a water-bath. Filtra-
tion on a silica gel column furnished the ester 19a (42 mg, 88%)
as a colorless oil, [α]D22 Ϫ20.1 (c 1.0, CHCl3); νmax (neat) 1735,
1635, 1170, 885 cmϪ1; δH (300 MHz; CDCl3 ϩ CCl4) 5.43 (1 H,
(1R,6R,8R)-8-Isopropenyl-1,6-dimethylbicyclo[4.4.0]decan-
3-one 25
To magnetically stirred, freshly distilled (over sodium) ammo-
nia (30 ml) in a three-necked flask equipped with a Dewar con-
denser, was added a solution of the cyclopropyl ketone 20 (140
mg, 0.64 mmol) in dry THF (1 ml) followed by freshly cut
lithium (30 mg, 4.3 mmol), in small pieces. The resulting blue-
coloured solution was stirred for 15 min and the reaction was
quenched with solid NH4Cl. After evaporation of the ammo-
nia, the residue was taken up in water (5 ml) and extracted with
diethyl ether (3 × 5 ml). The combined extract was washed with
brine and dried (Na2SO4). Evaporation of the solvent and puri-
fication of the product on a silica gel column, using ethyl
acetate–hexane (1:40) as eluent, furnished the ketone 25 (77
mg, 55%) as a colourless oil, [α]D23 ϩ47.5 (c 1.6, CHCl3); νmax
(neat) 1705, 1635, 885 cmϪ1; δH (300 MHz; CDCl3 ϩ CCl4) 4.71
(2 H, s, C᎐CH ), 2.87 (1 H, d, J 14.1), 2.49 (1 H, d t, J 14.6 and
᎐
2
6.9), 2.35–2.10 (2 H, m), 2.05–1.85 (2 H, m), 1.75–1.10 (7 H, m),
1.75 (3 H, s, olefinic CH3), 1.02 (3 H, s) and 0.86 (3 H, s)
(2 × tert-CH3); δC (75 MHz; CDCl3 ϩ CCl4) 212.1 (C), 149.7
(C), 108.9 (CH2), 49.1 (CH2), 40.7 (C), 40.1 (CH), 38.4 (CH2),
37.9 (CH2), 37.7 (CH2), 36.2 (CH2), 35.7 (C), 27.0 (CH2), 24.0
(CH3), 23.5 (CH3), 21.3 (CH3); m/z 220 (Mϩ, 10%), 149 (15),
123 (20), 109 (20), 107 (35), 95 (45), 41 (100); HRMS m/z
Calc. for C15H24O: M, 220.1827. Found: Mϩ, 220.1823.
d, J 5.4), 4.69 (1 H, s) and 4.67 (1 H, s) (C᎐CH ), 3.65 (3 H, s,
᎐
2
OCH3), 2.40–1.30 (9 H, series of m), 1.72 (3 H, s, olefinic CH3),
1.60 (3 H, d, J 1.2, olefinic CH3), 1.08 (3 H, s, tert-CH3); δC (75
MHz; CDCl3 ϩ CCl4) 174.4 (C), 149.6 (C), 138.2 (C), 124.0
(CH), 108.9 (CH2), 51.5 (CH3), 39.9 (CH2), 38.3 (C), 37.8 (CH),
35.2 (CH2), 31.5 (CH2), 29.4 (CH2), 26.7 (CH3), 21.0 (CH3),
18.4 (CH3); m/z 237 (M ϩ 1, 4%), 205 (10), 149 (20), 121 (20),
121 (20), 107 (60), 49 (100).
(1R,6R,8R)-8-Isopropyl-1,6-dimethylbicyclo[4.4.0]decan-
3-one 26
To a magentically stirred solution of the ketone 25 (50 mg, 0.22
mmol) in dry ethanol (1 ml) was added 10% Pt/C (10 mg). The
reaction mixture was stirred in an atmosphere of hydrogen,
created by evacuative replacement of air using a balloon filled
with hydrogen, for 12 h and the catalyst was filtered off. Evap-
oration of the solvent and purification of the product on a silica
gel column, using ethyl acetate–hexane (1:40) as eluent, fur-
nished valeran-3-one 26 (49 mg, 98%) as a colourless oil, [α]D23
ϩ28.1 (c 1.6, CHCl3); νmax (neat) 1700 cmϪ1; δH (300 MHz;
CDCl3 ϩ CCl4) 2.83 (1 H, d, J 14), 2.46 (1 H, d t, J 14.3 and
6.9), 2.18 (1 H, m d, J 14.7), 1.92 (1 H, d t, J 14 and 5.1), 1.72
(1 H, t, J 12.4), 1.64 (1 H, dd, J 14 and 2.5), 1.70–1.30 (8 H, m),
0.97 (3 H, s) and 0.84 (3 H, s) (2 × tert-CH3), 0.90 (6 H, d, J 6.2,
2 × sec-CH3); δC (75 MHz; CDCl3 ϩ CCl4) 212.5 (C), 49.1 (CH2),
40.7 (C), 39.1 (CH), 38.0 (CH2), 37.9 (CH2), 36.9 (CH2), 36.3
(CH2), 35.5 (C), 33.2 (CH), 25.4 (CH2), 24.0 (CH3), 23.6 (CH3),
20.2 (CH3), 19.9 (CH3); m/z 222 (Mϩ, 8%), 151 (40), 149 (30),
123 (40), 121 (35), 111 (40), 109 (60), 107 (40), 97 (50), 95 (90).
(1R,2S,6R,8R,10R)-8-Isopropenyl-1,6-tricyclo[4.4.0.02,10]decan-
3-one 20
A solution of the acid 19 (300 mg, 1.35 mmol) and oxalyl
dichloride (0.5 ml, 5.75 mmol) in dry benzene (1 ml) was mag-
netically stirred for 2 h at RT. Evaporation of both benzene and
oxalyl dichloride under reduced pressure afforded the acid
chloride, which was taken up in dry diethyl ether (1 ml) and
added dropwise to a cold, magnetically stirred, ethereal solu-
tion of diazomethane (excess, prepared from 1.5 g of N-methyl-
N-nitrosourea and 15 ml of 60% aq. KOH). The reaction
mixture was stirred for 2 h at RT and the excess of diazo-
methane and diethyl ether were carefully evaporated on a water-
bath. Rapid purification by filtration of the product through a
neutral alumina column, using CH2Cl2 as eluent, furnished the
diazo ketone 24 as yellow oil.
To a magnetically stirred suspension of copper powder (450
mg, 7.1 mmol) and anhydrous copper() sulfate (75 mg, 0.33
mmol) in dry cyclohexane (25 ml) was added, dropwise, a solu-
tion of the diazo ketone 24 (300 mg) in cyclohexane (2 ml) and
the reaction mixture was refluxed for 2 h. It was then cooled,
and filtered through a sintered funnel. Evaporation of the
solvent and purification of the product on a silica gel column,
using ethyl acetate–hexane (1:40) as eluent, furnished the
cyclopropyl ketone 20 (150 mg, 51% from acid 19) as oil, [α]D23
ϩ105 (c 1.8, CHCl3); νmax (neat) 1690, 1635, 885 cmϪ1; δH (300
(1R,6R,8R)-3,3-Ethylenedithio-8-isopropyl-1,6-dimethyl-
bicyclo[4.4.0]decane 27
To an ice-cold, magnetically stirred solution of the ketone 26
(30 mg, 0.13 mmol) and ethane-1,2-dithiol (0.7 ml, 8.3 mmol)
in benzene (1 ml) was added a catalytic amount of boron
trifluoride–diethyl ether. The reaction mixture was stirred at RT
for 1 h, diluted with diethylether (5 ml), washed successively
with 5% aq. NaOH and brine, and dried (Na2SO4). Evaporation
of the solvent and purification of the product on a silica gel
column, using ethyl acetate–hexane (1:40) as eluent, furnished
the thioketal 27 (38 mg, 95%) as colourless oil, [α]D24 50.0 (c 1.0,
CHCl3); νmax (neat) 1450, 1430, 1380, 1365, 1270 cmϪ1; δH (300
MHz; CDCl3 ϩ CCl4) 3.40–3.20 (4 H, m, SCH2CH2S), 2.60
(1 H, d, J 14.3), 2.12 (1H, d t, J 14.4 and 3.5), 1.95–1.80 (2 H,
MHz; CDCl ϩ CCl ) 4.67 (1 H, s) and 4.61 (1 H, s) (C᎐CH ),
᎐
3
4
2
2.35–1.80 (4 H, m), 1.67 (3 H, s, olefinic CH3), 1.60–0.90 (7 H,
series of m), 1.24 (3 H, s) and 1.11 (3 H, s) (2 × tert-CH3); δC (75
4326
J. Chem. Soc., Perkin Trans. 1, 2000, 4321–4327

View Article Online
4 (a) D. K. Banerjee, J. Indian Chem. Soc., 1972, 49, 1; (b) T. R.
m), 1.60–1.00 (10 H, m), 1.03 (3 H, s) and 0.87 (3H, s) (2 × tert-
CH3), 0.86 [6 H, d, J 5.7, CH(CH3)2]; δC (75 MHz; CDCl3 ϩ
CCl4) 68.1 (C), 46.4 (CH2), 39.8 (CH2), 39.7 (CH2), 39.3 (CH),
37.5 (CH2), 37.1 (CH2), 36.9 (2 C, C and CH2), 36.3 (CH2), 34.8
(C), 33.0 (CH), 25.7 (CH3), 25.4 (CH2), 24.3 (CH3), 20.2 (CH3),
19.9 (CH3); m/z 298 (Mϩ, 25%), 283 (24), 152 (25), 131 (25), 109
(50), 47 (100); HRMS m/z Calc. for M, C17H30S2: 298.1788.
Found: Mϩ, 298.1788.
Govindachari, B. R. Pai, K. K. Purushothaman and S. Rajadurai,
Tetrahedron Lett., 1959, issue 15, 5; (c) J. Krepinsky, M. Romanuk,
V. Herout and F. Sorm, Tetrahedron Lett., 1960, issue 7, 9; (d) T. R.
Govindachari, B. R. Pai, K. K. Purushothaman and S. Rajadurai,
Chem Ind. (London), 1960, 1059; T. R. Govindachari, B. R. Pai,
K. K. Purushothaman and S. Rajadurai, Tetrahedron, 1961, 12, 105;
(e) C. Djerassi, T. R. Govindachari, B. R. Pai and K. K.
Purushothaman, Tetrahedron Lett., 1961, 226; ( f ) J. Krepinsky, M.
Romanuk, V. Herout and F. Sorm, Tetrahedron Lett., 1962, 169; J.
Krepinsky, M. Romanuk, V. Herout and F. Sorm, Collect. Czech.
Chem. Commun., 1962, 27, 2638; (g) W. Klyne, Tetrahedron, 1961,
13, 29; (h) H. Hikino, Y. Hikino, Y. Takeshita, K. Meguro and T.
Takemoto, Chem. Pharm. Bull., 1963, 11, 1207; (i) H. Hikino, Y.
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(1R,3R,6S)-3-Isopropyl-1,6-dimethylbicyclo[4.4.0]decane
[(؉)-valerane] 2
A magnetically stirred solution of the thioketal 27 (40 mg, 0.13
mmol) and Raney nickel (30 mg) in dry ethanol (3 ml) was
refluxed for 8 h. The reaction mixture was cooled and filtered
through a silica gel column. Evaporation of the solvent fur-
nished valerane 2 (23 mg, 82%) as colourless oil, [α]D26 ϩ72 (c 1,
CHCl3) [lit.,4i ϩ76 (c 5, CHCl3)], which was identified by com-
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1
parison of the H and 13C NMR spectra with those of the
sample prepared above.
Acknowledgements
We thank the Council of Scientific and Industrial Research,
New Delhi for financial support and for the award of a research
fellowship to C. D., and the University Grants Commission for
the award of a research fellowship to R. V. We are grateful to
Dr M. Vairamani, I.I.C.T., Hyderabad for providing HRMS
for some of the compounds.
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