Enantiospecific total synthesis of aciphyllene

Article abstract of DOI:10.1016/j.tet.2010.08.045

Enantiospecific total synthesis of the sesquiterpene aciphyllene and its three epimers have been described starting from the readily available monoterpene (R)-limonene employing an intramolecular type II carbonyl ene reaction as the key step.

Full text of DOI:10.1016/j.tet.2010.08.045

Tetrahedron 66 (2010) 8160e8168
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantiospecific total synthesis of aciphyllene
*
A. Srikrishna , Vijendra H. Pardeshi
Department of Organic Chemistry, Indian Institute of Science, C. V. Raman Avenue, Bangalore, Karnataka 560012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2010
Received in revised form 14 August 2010
Accepted 16 August 2010
Available online 21 August 2010
Enantiospecific total synthesis of the sesquiterpene aciphyllene and its three epimers have been de-
scribed starting from the readily available monoterpene (R)-limonene employing an intramolecular type
II carbonyl ene reaction as the key step.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Sesquiterpenes
Aciphyllenes
Limonene
Intramolecular type II carbonyl ene reaction
Enantiospecific synthesis
1. Introduction
H
H
8
Of the various bicyclo[5.3.0]decane containing sesquiterpenes,
guaianes constitute a large group and are present in plant, liver-
wort as well as marine sources. Guaianes, particularly, guaiano-
loides, are known to exhibit a wide spectrum of biological
activities,1 such as anti-inflammatory, cytotoxic, antinociceptive,
antimalarial, antimicrobial, antiviral, antitumaral, and antioxidant
activities. Aciphyllene 1, a guaiane sesquiterpene, was first isolated
in 1983 by Kubota and co-workers2 from the essential oil of the
roots of Lindera glauca. The structure of aciphyllene 1 was deduced
on the basis of spectroscopic analysis. In 1998, Konig and co-
workers, reported3 the isolation of aciphyllene along with a num-
ber of sesquiterpene hydrocarbons from the liverwort Dumortiera
hirusta (Sw.) Nees collected near Sao Fransisco de Paula Rio Grande
do Sul (Brazil). Same structure 1 as that given by the research
group of Kubota was assigned for aciphyllene isolated from
D. hirusta on the basis of two dimensional GC and spectral analysis.
Subsequently, aciphyllene 1 was also found in several medicinally
valuable sources, such as Shorea robusta,4 Toona sinensis,5 and
Pogostemon cablin.6e8 Aciphyllene 1 was also found to be a com-
ponent of the volatile blends let out by ficus trees to attract specific
pollinating wasps.9
6
3
1
1
Although isolation of aciphyllene 1 was reported as earlyas 1983, it
was only in 2007 the first report appeared in the literature on the
synthesis of aciphyllenes. In 2007, research group10 of Pedro reported
thesemi-synthesisoftheputativestructure1of aciphyllene, Scheme 1.
Enantiospecific synthesis of natural guaidienones 2 and 3, and their
diastereomer 4 has been accomplished starting from dihydrocarvone
via cyperone. Subsequent deoxygenation of guaiadienone 2 generated
1, whose NMR spectral data was found to differ with the aciphyllene
isolated from D. hirusta. Deoxygenation of guaidienone 3 generated 5,
whose NMR data was found to be identical to that of the natural aci-
phyllene isolated from D. hirusta. Similarly, deoxygenation of the
guaiadienone 4 generated 6-epiaciphyllene 6. These studies not only
established the revised stereostructure of aciphyllene as (3R,6S,7S)-3-
isopropenyl-6,10-dimethylbicyclo[5.3.0]dec-1(10)-ene, but also esta-
blished the absolute configuration of aciphyllene. In continuation of
our interest on the enantiospecific synthesis of natural products11
employing the readily available monoterpene (R)-limonene as the
chiral starting material, herein we describe an enantiospecific
* Corresponding author. Fax: þ91 80 23600529; e-mail address: ask@orgchem.
iisc.ernet.in (A. Srikrishna).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.045

A. Srikrishna, V.H. Pardeshi / Tetrahedron 66 (2010) 8160e8168
8161
synthesis of aciphyllene and its three diastereomers, employing a type
II carbonyl ene reaction as the key reaction.
H
H
H
H
CHO
OH
H
H
H
H
R
R
1, 5-7
10
9
AlH3
AlH3
O
O
R = H or isopropenyl equivalent
H
2
3
4
ent-1
H
CO2Et
H
R
H
H
H
H
O
H
H
H
revised structure
of aciphyllene
8
12
11
Scheme 2.
5
H
using dimethyl malonate. Thus, alkylation of dimethyl malonate
with the allyl bromide 14 in refluxing acetone using potassium
carbonate as the base furnished the malonate ester 15 in 87% yield.
Krapcho’s dealkoxycarbonylation reaction14 of the malonate 15
with sodium chloride, dimethyl sulfoxide, and water in a sealed
tube for 12 h at 160 ꢁC furnished the ester 16 in 91% yield. Reaction
of the ester 16 with lithium aluminum hydride (LAH) in anhydrous
ether furnished the alcohol 17 in 98% yield, which on oxidation
with pyridinium dichromate (PDC) in methylene chloride furnished
the aldehyde 18. After exploring various conditions, it was found
that the intramolecular type II carbonyl ene reaction proceeds with
boron trifluoride etherate. Thus, treatment of a 0.005 M methylene
chloride solution of the aldehyde 18 with a catalytic amount of
boron trifluoride diethyl etherate for 10 min at ꢀ20 ꢁC resulted in
the formation of the bicyclic alcohol15 19 in 78% yield, in a stereo-
selective manner, whose structure was established from its spectral
data. The stereochemistry at the newly created chiral center was
tentatively assigned as 4R on the basis of the preferred12 transition
state geometry, cf. 20.
H
AlH3
O
6
Scheme 1.
2. Results and discussion
As depicted in the retrosynthetic Scheme 2, an ene reaction
based approach was conceived for the construction of the seven-
membered ring of aciphyllenes 1, 5e7 starting from the readily
available monoterpene (R)-limonene 8. It was anticipated that type
II carbonyl ene reaction of the aldehyde 9 would generate the bi-
cyclic alcohol 10, which could be further elaborated into aci-
phyllenes. The aldehyde 9 could be obtained from the ester 11,
which in turn could be obtained from the aldehyde 12. A two-step
(controlled ozonolysis followed by intramolecular aldol conden-
sation) conversion of (R)-limonene 8 into the aldehyde 12 has
already been developed by us.11a
Prior to the synthesis of aciphyllenes, to test the feasibility of the
strategy, a model study was investigated for the enantiospecific
synthesis of bicyclo[5.3.0]decanol 10 (R¼H), Scheme 3. Sodium
borohydride reduction of the cyclopentene aldehyde 12 in metha-
nol generated the allylic alcohol 13 in 93% yield, which was treated
with phosphorous tribromide in ether in the presence of a catalytic
amount of pyridine at ꢀ5 ꢁC to furnish the allyl bromide 14.13 Two
carbon chain extension of the bromide 14 was then carried out by
After successfully demonstrating the feasibility of the strategy, it
has been extended to the synthesis of aciphyllenes 1, 5e7 starting
from the allyl bromide 14, Schemes 4e6. Alkylation of ethyl ace-
toacetate with the allyl bromide 14 in refluxing acetone using po-
tassium carbonate as the base furnished a diastereomeric mixture of
the
b-ketoester 21 in 87% yield, whose structure was revealed from
its spectral data. Since the
attempt was made to separate the two diastereomers of the
ketoester 21. In order to avoid chemoselectivity problems in
b
-ketoesters are prone to equilibrium, no
H
H
H
PBr3, py
Et2O, -5 °C
NaBH4
MeOH
OH
71%
Br
93%
CHO
12
14
13
O
O
K2CO3, acetone
reflux, 87%
MeO
OMe
H
H
NaCl, DMSO
H2O, 160 °C
H
LAH
Et2O
98%
CO2Me
CO2Me
91%
CH2OH
CO2Me
17
15
16
79% PDC, CH2Cl2
H
H
BF3.OEt2
H
OH
H
0.005 M CH2Cl2
4
O
1
F3B
-20 °C, 78%
H
H
20
CHO
18
19
Scheme 3.

8162
A. Srikrishna, V.H. Pardeshi / Tetrahedron 66 (2010) 8160e8168
H
H
K2CO3
(CH2OH)2, C6H6
O
O
acetone
CO2Et
H
CO2Et
H
p-TSA, reflux
+
14
reflux
87%
100%
O
EtO
H
CH3
O
O
21
22
LAH
93%
Et2O
H
H
BF3.OEt2
IBX
4
OH
0.005 M CH2Cl2
DMSO
CHO
H
3
OH
H
0 °C, 57%
92%
O
+
O
O
25
O
24
O
(Ph3P)3RhCl
23
EtOAc
H
84%
H
H
H
OH
OH
O
O
( 3 : 4 )
26a
26b
Scheme 4.
H
H
H
Et3N, MsCl
H2, 5% Pd/C
hexane, 94%
OH
0 °C-RT, 87%
( 2 : 3 )
H
O
O
27
26a
O
28
Li, liq. NH3
73%
H
H
H
Ph3PCH3Br,
tAmOK
+
H
91%
( 3 : 2 )
X
28 X = O
PDC,
CH2Cl2
76%
( 3 : 2 )
7
6
29 X = H,OH
Scheme 5.
H
H
H
H
H
H
Et3N, MsCl
H2, 5% Pd/C
OH
H
0 °C - rt
CH2Cl2, 85%
hexane
93%
( 1 : 1 )
O
O
26b
O
30
31 and 33
Li, liq. NH3
H
76%
Ph3PCH3Br
tAmOK
94%
H
H
H
Ph3PCH3Br
tAmOK
92%
H
H
H
H
1
+
H
X
1
PDC
CH2Cl2
79%
31 X = O
5
32 X = H,OH
Scheme 6.

A. Srikrishna, V.H. Pardeshi / Tetrahedron 66 (2010) 8160e8168
8163
subsequent reactions, the keto group in the ketoester 21 was pro-
tected as its ethylene ketal by refluxing with 1,2-ethanediol in the
presence of a catalytic amount of p-toluenesulphonic acid (p-TSA) in
anhydrous benzene using a DeaneStark water separator to furnish
the ketal-ester 22 in quantitative yield. Regioselective reduction of
the ketal-ester 22 with LAH in anhydrous ether at 0 ꢁC furnished an
epimeric mixture of the alcohol 23, in 93% yield, which on oxidation
with IBX in DMSO at rt furnished a diastereomeric mixture of the
aldehyde 24 in 92% yield. Treatment of a 0.005 M solution of the
aldehyde 24 in anhydrous methylene chloride with a catalytic
amount of boron trifluoride diethyl etherate at 0 ꢁC for 10 min fur-
nished the bicyclic alcohol 25 in 57% yield, whose structure was
assigned on the basis of the spectral data. It was found that the ketal
group also got deprotected under the reaction conditions. As in the
model study, the reaction proceeded in a highly stereoselective
manner and generated mainly one isomer, and presumably during
the hydrolysis of the ketal, the C-3 center also isomerised to ther-
modynamically preferred configuration via chelation of one of the
oxygens of the ketal oxygen with boron. Although both the chiral
centres (C-3 and 4) in 25 will become achiral at a later stage, ten-
tative stereochemistry 3R,4S was assigned on the basis of the model
study and it was confirmed in the next step.
Next, conversion of the bicyclic hydroxy ketone 25 into aci-
phyllenes 1, 5e7 was investigated. For which, three transformations
were required, namely, selective reduction of the exo methylene
group, deoxygenation of the hydroxy group, and Wittig methyle-
nation of the acetyl group. They were addressed in the same se-
quence. Since reaction was not selective with palladium over carbon
as the catalyst, Wilkinson’s catalyst was chosen for the hydrogena-
tion. Thus, regioselective hydrogenation of the exo methylene group
in the hydroxy ketone 25 at rt with 1.5 mol % Wilkinson’s catalyst in
dry ethyl acetate at one atmospheric pressure of hydrogen (balloon)
for 15 h furnished a 3:4 mixture of the alcohols 26a and 26b in 84%
yield, which were separated by column chromatography on silica
gel. The structures of the compounds 26a and 26b were deduced
from their spectral data. The stereochemistry at the newly created
chiral center C-6 in the hydroxy ketones 26a and 26b was assigned
tentatively on the basis of the preferred approach of the hydrogen
from the less hindered side. It was further confirmed by the single
crystal X-ray diffraction analysis of the hydroxy ketone 26a (details
are given in the Experimental section), the ORTEP diagram is
depicted in Figure 1, which also confirmed the stereochemistry at
the C-3 and C-4 carbons also of the alcohols 25 and 26b.
For the deoxygenation of the hydroxy group, a dehydration
followed by reduction of the resultant enone was contemplated.
First, the sequence was carried out with the minor hydroxy ketone
26a to generate the diastereomers 6 and 7 of aciphyllene. Reaction
of the
b-hydroxy ketone 26a with an excess of methanesulphonyl
chloride and triethylamine in anhydrous methylene chloride at rt
furnished the enone 27 in 87% yield. For the selective reduction of
the enone double bond of the bicyclic dienone 27, first one elec-
tron transfer reduction was explored. Thus, regioselective re-
duction of the bicyclic enone 27 in THF with lithium in liquid
ammonia furnished a 3:2 mixture of ketone 28 along with the
diastereomeric mixture of the alcohol 29, which was treated with
PDC in methylene chloride to furnish a 3:2 mixture of the ketone
27. A controlled hydrogenation was also explored for selective
reduction of the enone 28. Thus, regioselective hydrogenation of
the dienone 27 in hexane at rt using 5% palladium over carbon as
the catalyst at one atmospheric pressure of hydrogen (balloon)
furnished a 2:3 diastereomeric mixture of the ketone 28 in 94%
yield. Wittig methylenation16 of a 3:2 diastereomeric mixture of
the ketone 28 with methylenetriphenylphosphorane in dry ben-
zene at rt furnished a 2:3 mixture of 6-epiaciphyllene 6 and ent-7-
epiaciphyllene 7 in 91% yield, which were found to be inseparable
by column chromatography on silica gel as well as on silver nitrate
impregnated silica gel. The structures of 6 and 7 were established
from the spectral data of the mixture. The 1H and 13C NMR spectra
of the minor guaiadiene 6 obtained in the Wittig reaction of
28 was found to be identical with that reported by Pedro and
co-workers, confirming the stereostructures of 6- and 7-epi-
aciphyllenes 6 and 7.
Next, for the synthesis of aciphyllene 5 and its C-3 epimer 1, the
sequence was carried out with the C-6 epimeric
b-hydroxy ketone
26b. Reaction of the -hydroxy ketone 26b with an excess of
b
methanesulphonyl chloride and triethylamine in methylene chlo-
ride at rt furnished the enone 30 in 85% yield. Regiospecific re-
duction of the bicyclic enone 30 in THF with lithium in liquid
ammonia furnished the ketone 31 in a highly stereoselective
manner (>95%), along with the over reduced product 32, which on
oxidation with PDC in methylene chloride also furnished the ketone
31. Wittig methylenation of the ketone 31 with methylene-
triphenylphosphorane in dry benzene at rt gave 3-epiaciphyllene 1
in 92% yield. The structure of 1 was confirmed by comparing the 1H
and 13C NMR spectral data with that reported10 by Pedro and co-
workers. The synthetic sample exhibited optical rotation value
27
{[
a]
þ13.5 (c 1.3, CHCl3)} comparable to that reported by Pedro
D
and co-workers. {lit.10
[
a]
24 ꢀ13.2 (c 0.35, CHCl3)}, as expected, with
D
opposite sign (synthesis of 1 by Pedro and co-workers resulted in
the compound with R configuration at C-7 position, which is
enantiotopic to that in natural aciphyllene 5). Regioselective hy-
drogenation of the enone 30 in hexane at rt using 5% palladium
over carbon as the catalyst at one atmospheric pressure of hydro-
gen (balloon) for 30 min furnished a 1:1 mixture of the ketones 31
and 33 in 93% yield. Wittig methylenation of a mixture of the ke-
tones 31 and 33 with methylenetriphenylphosphorane in dry
benzene at rt furnished a 1:1 mixture of 3-epiaciphyllene 1 and
aciphyllene 5 in 94% yield, which were separated by column
chromatography using silver nitrate impregnated silica gel. The
structure and absolute configuration of aciphyllene 5 obtained in
this study was confirmed by comparing the 1H and 13C NMR
26
spectral data and optical rotation {[
a]
þ50.7 (c 1.4, CHCl3), lit.
D
24
[a
]
þ52.2 (c 0.53, CHCl3)} with that of (þ)-aciphyllene 5 repor-
D
ted10 by Pedro and co-workers.
3. Conclusions and summary
Enantiospecific syntheses of aciphyllenes 1, 5e7 have been ac-
Figure 1. ORTEP diagram of the hydroxy ketone 26a.
complished employing a chiron based approach. As a model study,

8164
A. Srikrishna, V.H. Pardeshi / Tetrahedron 66 (2010) 8160e8168
an intramolecular type II carbonyl ene reaction based strategy was
developed for the enantiospecific synthesis of the bicyclo[5.3.0]
decanol 19, starting from the readily available monoterpene
(R)-limonene. The strategy has been further extended to the
enantiospecific syntheses of aciphyllenes 1, 5e7 via the hydroxy
ketones 26a and 26b. A single crystal X-ray diffraction analysis of
the hydroxy ketone 26a established the stereochemistry of all the
compounds. Further extrapolation of the present strategy to other
related guaiane sesquiterpenes is under progress.
(1H, m), 1.75e1.65 (1H, m), 1.77 (3H, s) and 1.60 (3H, s)
d 146.8 (C, C]CH2), 141.6
(C), 132.9 (C), 111.8 (CH2, C]CH2), 54.2 (CH, C-3), 37.9 (CH2), 27.6
[2ꢂolefiniceCH3]; 13C NMR (100 MHz):
(CH2), 27.2 (CH2), 18.7 (CH3), 14.4 (CH3).
4.1.2. Dimethyl 2-[((5S)-5-isopropenyl-2-methylcyclopent-1-en-1-yl)
methyl]malonate (15). To a magnetically stirred solution of the
bromide 14 (125 mg, 0.58 mmol) in acetone (3 mL) were added
K2CO3 (400 mg, 2.9 mmol) and dimethyl malonate (0.07 mL,
0.58 mmol), and refluxed for 15 h. Water (5 mL) was then added to
the reaction mixture and extracted with ether (3ꢂ8 mL). The
combined ether extract was washed with brine (8 mL) and dried
(Na2SO4). Evaporation of the solvent and purification of the residue
on a silica gel column using CH2Cl2/hexane (1:5) as eluent fur-
4. Experimental section
4.1. General
Melting points are recorded using Buchi B-540 and M-560
melting point apparatus in capillary tubes and are uncorrected. IR
spectra were recorded on Jasco FTIR 410 and PerkineElmer FTIR
spectrum BX and GX spectrophotometers. 1H (300 and 400 MHz)
nished the diester 15 (135 mg, 87%) as colorless oil. Rf (10% EtOAc/
27
hexane) 0.5; [
a]
þ43.9 (c 7.3, CHCl3); IR (neat): nmax/cmꢀ1 3073,
D
2954, 2845, 1755, and 1739 (OC]O), 1643, 1436, 1372, 1282, 1241,
1204, 1153, 1051, 1026, 892 (C]CH2); 1H NMR (400 MHz):
d 4.69
and 13C (75 and 100 MHz) NMR spectra were recorded on JNM
l
-
(1H, s) and 4.68 (1H, s) [C]CH2], 3.70 (3H, s) and 3.65 (3H, s)
[2ꢂOCH3], 3.46 (1H, dd, J 10.3 and 5.6 Hz, H-2), 3.28 (1H, br s, H-50),
2.77 (1H, dd, J 13.7 and 10.5 Hz), 2.40e2.15 (3H, m), 2.00e1.90 (1H,
m), 1.65e1.55 (1H, m), 1.64 (3H, s) and 1.55 (3H, s)
300 and Brucker Avance 400 spectrometers, using a 1:1 mixture of
CDCl3 and CCl4 as solvent. The chemical shifts ( ppm) and coupling
d
constants (Hz) are reported in the standard fashion with reference
to either internal tetramethylsilane (for 1H) or the central line
(77.0 ppm) of CDCl3 (for 13C). In the 13C NMR spectra, the nature of
the carbons (C, CH, CH2, or CH3) was determined by recording the
DEPT-135 spectra, and is given in parentheses. High resolution
mass spectra were recorded on a Micromass Q-TOF micro mass
spectrometer using electron spray ionization mode. Optical rota-
tions were measured using a Jasco DIP-370 and Jasco P-1020 po-
[2ꢂolefiniceCH3]; 13C NMR (100 MHz):
d 169.4 (C) and 169.3
(C) [2ꢂOC]O], 147.5 (C, C]CH2), 137.5 (C), 131.4 (C), 111.3 (CH2, C]
CH2), 55.2 (CH3) and 53.3 (CH3) [2ꢂOCH3], 52.1 (CH, C-50), 49.7 (CH,
C-2), 37.5 (CH2), 27.6 (CH2), 26.1 (CH2), 18.3 (CH3), 14.0 (CH3);
HRMS: m/z Calcd for C15H22O4Na (MþNa): 289.1416; found:
289.1415.
larimeters and [
a]
values are given in units of 10ꢀ1 deg cm2 g1.
4.1.3. Methyl 3-[(S)-5-isopropenyl-2-methylcyclopent-1-en-1-yl]prop-
anoate (16). To a solution of the malonate 15 (90 mg, 0.34 mmol) in
DMSO (1 mL) and water (0.2 mL) was added NaCl (59 mg,1.0 mmol)
and heated in a sealed tube for 12 h at 160 ꢁC. Water (5 mL) was
added to the reaction mixture and extracted with ether (3ꢂ5 mL).
The combined ether extract was washed with brine (5 mL) and
dried (Na2SO4). Evaporation of the solvent and purification of the
residue on a silica gel column using CH2Cl2/hexane (1:5) as eluent
furnished the propanoate 16 (64 mg, 91%) as colorless oil. Rf (10%
D
Hydrogenation reactions at one atmospheric pressure were carried
out using a balloon filled with hydrogen. Analytical thin-layer
chromatography (TLC) was performed on glass plates (7.5ꢂ2.5 and
7.5ꢂ5.0 cm) coated with Acme’s silica gel G containing 13% calcium
sulfate as binder and various combinations of ethyl acetate/hexane
and methylene chloride/hexane were used as eluent. Visualization
of spots was accomplished by exposure to iodine vapor. Acme’s
silica gel (100e200 mesh) was used for column chromatography
(approximately 15e20 g per 1 g of the crude product). All small-
scale dry reactions were carried out using standard syringe-septum
technique. Low temperature reactions were carried out using a bath
made of sodium chloride and ice, or alcohol and liquid nitrogen. Dry
THF was obtained by distillation over sodium/benzophenone ketyl.
Dry ether was obtained by distillation over sodium and stored over
sodium wire. Dry dichloromethane was prepared by distillation
over phosphorous pentoxide or calcium hydride. Dry benzene was
obtained by distillation over sodium. Liquid ammonia was obtained
in cylinders from Mysore Ammonia Ltd. and distilled over soda-
mide prior to use.
EtOAc/hexane) 0.7; [
a
]
24 þ113.9 (c 4.3, CHCl3); IR (neat): nmax/cmꢀ1
D
3072, 2952, 2845, 1744 (OC]O), 1643, 1436, 1372, 1261, 1169, 1020,
891 (C]CH2), 805; 1H NMR (400 MHz):
d 4.70 (1H, s) and 4.68 (1H,
s) [C]CH2], 3.64 (3H, s, OCH3), 3.29 (1H, br s, H-50), 2.52e2.15 (5H,
m), 2.10e1.90 (2H, m), 1.65e1.55 (1H, m), 1.67 (3H, s) and 1.57 (3H,
s) [2ꢂolefiniceCH3]; 13C NMR (100 MHz):
d 173.6 (C, C]O), 148.0
(C, C]CH2), 135.1 (C), 134.1 (C), 110.9 (CH2, C]CH2), 55.6 (CH3,
OCH3), 51.3 (CH, C-50), 37.5 (CH2), 32.4 (CH2), 27.7 (CH2), 22.2 (CH2),
18.4 (CH3), 14.0 (CH3); HRMS: m/z Calcd for C13H21O2 (MþH):
209.1541; found: 209.1531.
4.1.4. 3-[(S)-5-Isopropenyl-2-methylcyclopent-1-en-1-yl]propan-1-
ol (17). To a cold (0 ꢁC), magnetically stirred solution of the ester 16
(60 mg, 0.29 mmol) in anhydrous ether (2 mL) was added LAH
(38 mg, 1 mmol) and stirred for 1 h at rt. Ethyl acetate (0.5 mL) was
added to the reaction mixture to consume excess LAH. The reaction
was then quenched with 3 N HCl (6 mL) and extracted with ether
(3ꢂ5 mL). The combined ether extract was washed with brine
(8 mL) and dried (Na2SO4). Evaporation of the solvent and purifi-
cation of the residue on a silica gel column using ethyl acetate/
hexane (1:9) as eluent furnished the alcohol 17 (51 mg, 98%) as
4.1.1. (S)-2-Bromomethyl-3-isopropenyl-1-methylcyclopent-1-ene
(14). To a magnetically stirred solution of the allyl alcohol11a,17 13
(608 mg, 4 mmol) in anhydrous ether (6 mL) was added a catalytic
amount of pyridine (e10 mg) and cooled to ꢀ5 ꢁC. PBr3 (0.19 mL,
2 mmol) was slowly added to the reaction mixture over a period of
15 min and stirred for 1 h at the same temperature in an argon
atmosphere. The reaction mixture was then poured into ice-cold
water (5 mL) and extracted with ether (3ꢂ8 mL). The combined
ether extract was washed with brine (5 mL) and dried (Na2SO4).
Evaporation of the solvent and purification of the residue on a silica
colorless oil. Rf (10% EtOAc/hexane) 0.3; [
a
]
23 þ130.3 (c 3.2, CHCl3);
D
gel column using hexane as eluent furnished the bromide13 14
IR (neat): nmax/cmꢀ1 3350 (OH), 3072, 2942, 2856, 1643, 1452, 1442,
23
(604 mg, 71%) as yellow oil. Rf (hexane) 0.9; [
a
]
þ121.7 (c 4.7,
1372, 1060, 1041, 889 (C]CH2); 1H NMR (400 MHz):
d 4.69 (1H, s)
D
CHCl3); IR (neat): nmax/cmꢀ1 3073, 2963, 2915, 2842, 1664, 1644,
and 4.68 (1H, s) [C]CH2], 3.70e3.50 (2H, m, H-1), 3.31 (1H, br s, H-
50), 2.40e2.10 (3H, m), 2.05e1.90 (1H, m), 1.85e1.75 (1H, m),
1.65e1.50 (4H, m), 1.67 (3H, s) and 1.57 (3H, s) [2ꢂolefiniceCH3];
1449, 1438, 1373, 1200, 893 (C]CH2), 631, 605; 1H NMR (400 MHz):
d
4.77 (1H, s) and 4.75 (1H, s) [C]CH2], 4.12 and 3.76 (2H, 2ꢂd,
J 9.7 Hz, CH2Br), 3.55 (1H, br s, H-3), 2.45e2.25 (2H, m), 2.15e2.00
13C NMR (100 MHz):
d 148.3 (C, C]CH2), 135.6 (C), 134.0 (C), 110.7

A. Srikrishna, V.H. Pardeshi / Tetrahedron 66 (2010) 8160e8168
8165
(CH2, C]CH2), 62.9 (CH2, CH2OH), 55.8 (CH, C-50), 37.5 (CH2), 30.8
(CH2), 27.7 (CH2), 22.8 (CH2), 18.4 (CH3), 14.0 (CH3); HRMS: m/z
Calcd for C12H20ONa (MþNa): 203.1413; found: 203.1414.
18.3 (CH3), 14.2 and 14.1 (CH3), 14.2 and 14.1 (CH3, OCH2CH3);
HRMS: m/z Calcd for C16H24O3Na (MþNa): 287.1623; found:
287.1613.
4.1.5. 3-[(S)-5-Isopropenyl-2-methylcyclopent-1-en-1-yl]propanal
(18). To a magnetically stirred solution of the alcohol 17 (51 mg,
0.18 mmol) in anhydrous CH2Cl2 (1 mL) was added PDC (338 mg,
0.9 mmol) and stirred for 7 h at rt. The reaction mixture was then
filtered through a short silica gel column using CH2Cl2. Evaporation
of the solvent and purification of the residue on a silica gel column
4.1.8. Ethyl 3-[(S)-5-isopropenyl-2-methylcyclopent-1-en-1-yl]-2-(2-
methyl-1,3-dioxolan-2-yl)propanoate (22). To
a solution of the
ketoester 21 (528 mg, 2.0 mmol) in dry benzene (15 mL) were
added ethylene glycol (0.33 mL, 6 mmol) and p-TSA (20 mg), and
refluxed for 7 h using DeaneStark apparatus. Aqueous NaHCO3
(8 mL) was added to the reaction mixture and extracted with ether
(3ꢂ8 mL). The combined ether extract was washed with brine
(10 mL) and dried (Na2SO4). Evaporation of the solvent and puri-
fication of the residue on a silica gel column using ethyl acetate/
using ethyl acetate/hexane (1:19) as eluent furnished the aldehyde
23
18 (40 mg, 79%) as colorless oil. Rf (10% EtOAc/hexane) 0.7; [a]
D
þ133.4 (c 4.3, CHCl3); IR (neat): nmax/cmꢀ1 3072, 2925, 2846, 2717
(HeC]O), 1728 (C]O), 1643, 1442, 1410, 1373, 1057, 891 (C]CH2);
hexane (1:19) as eluent furnished the ketal-ester 22 (616 mg, 100%)
24
1H NMR (400 MHz):
d
9.72 (1H, s, CHO), 4.70 (2H, s, C]CH2), 3.29
as colorless oil. Rf (10% EtOAc/hexane) 0.45; [
a]
þ95.6 (c 1.6,
D
(1H, br s, H-50), 2.55e1.90 (7H, m), 1.70e1.50 (1H, m), 1.68 (3H, s)
CHCl3); IR (neat): nmax/cmꢀ1 3073, 2954, 1734 (OC]O), 1643, 1442,
and 1.50 (3H, s) [2ꢂolefiniceCH3]; 13C NMR (100 MHz):
d 202.1 (CH,
1372, 1346, 1298, 1182, 1131, 1040, 950, 887 (C]CH2); 1H NMR
HC]O), 147.9 (C, C]CH2), 135.2 (C), 133.8 (C), 111.1 (CH2, C]CH2),
55.7 (CH, C-50), 42.0 (CH2, C-2), 37.5 (CH2), 27.6 (CH2), 19.5 (CH2),
18.4 (CH3), 14.1 (CH3); HRMS: m/z Calcd for C12H18ONa (MþNa):
201.1256; found: 201.1249.
(400 MHz, mixture of two isomers): d 4.72 and 4.70 (1H, s) and 4.64
(1H, s) [C]CH2], 4.20e3.80 (6H, m), 3.37 and 3.10 (1H, br s, H-5"),
2.85e2.55 (2H, m), 2.40e2.10 (3H, m), 2.00e1.85 (2H, m), 1.66 and
1.61 (3H, s), and 1.56 and 1.55 (3H, s) [2ꢂolefiniceCH3], 1.39 and
1.38 (3H, s, H-4), 1.24 and 1.19 (3H, t, J 7.1 Hz, OCH2CH3); 13C NMR
4.1.6. (4R,7S)-10-Methyl-6-methylenebicyclo[5.3.0]dec-1(10)-en-4-
ol (19). To a cold (ꢀ20 ꢁC) magnetically stirred solution of the al-
dehyde 18 (40 mg, 0.22 mmol) in anhydrous CH2Cl2 (44 mL,
0.005 M) was added BF3$OEt2 (5 mg) and stirred for 10 min at the
same temperature. Saturated NaHCO3 solution (8 mL) was then
added to the reaction mixture and extracted with CH2Cl2 (3ꢂ8 mL).
The combined organic layer was washed with brine (10 mL) and
dried (Na2SO4). Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetate/hexane (1:9) as
(100 MHz, mixture of two isomers): d 172.6 and 172.1 (C, OC]O),
147.8 and 148.2 (C, C]CH2), 135.9 and 135.7 (C, C-10), 133.8 and
132.6 (C, C-20), 111.0 and 110.7 (CH2, C]CH2), 109.8 and 109.6
(C, OeCeO), 64.7 and 64.6 (CH2), 64.5 (CH2), 60.2 and 60.0 (CH2),
56.9 and 54.8 (CH, C-2), 52.8 and 51.2 (CH, C-50), 37.6 and 37.4 (CH2),
28.0 and 27.4 (CH2), 25.7 and 25.5 (CH2), 21.5 and 21.1 (CH3), 18.1
and 18.7 (CH3), 14.3 and 14.2 (CH3), 14.1 (CH3, OCH2CH3); HRMS:
m/z Calcd for C18H28O4Na (MþNa): 331.1885; found: 331.1884.
eluent furnished the alcohol 19 (31 mg, 78%) as colorless oil. Rf (10%
4.1.9. 3-[(S)-5-Isopropenyl-2-methylcyclopent-1-en-1-yl]-2-(2-
methyl-1,3-dioxolan-2-yl)-propan-1-ol (23). To a cold (0 ꢁC), mag-
netically stirred solution of the ester 22 (616 mg, 2.0 mmol) in
anhydrous ether (4 mL) was added LAH (152 mg, 4 mmol) and
stirred for 2 h at rt. Ethyl acetate (0.5 mL) was added to the reaction
mixture to consume excess LAH. The reaction was then quenched
with 3 N HCl (6 mL) and extracted with ether (3ꢂ8 mL). The
combined ether extract was washed with brine (8 mL) and dried
(Na2SO4). Evaporation of the solvent and purification of the residue
on a silica gel column using ethyl acetate/hexane (1:5) as eluent
26
EtOAc/hexane) 0.4; [
a
]
ꢀ19.2 (c, 1.6 CHCl3); IR (neat): nmax/cmꢀ1
D
3441 (OH), 3073, 2926, 2854, 1638, 1439, 1382, 1079, 1056, 1029,
939, 893 (C]CH2); 1H NMR (400 MHz):
d 5.08 (1H, s) and 4.88 (1H,
s) [C]CH2], 3.96 (1H, br s, H-4), 3.36 (1H, br s, H-7), 2.50e1.70 (8H,
m), 1.65 (3H, s, olefiniceCH3), 1.50e1.20 (3H, m); 13C NMR
(100 MHz): d 148.7 (C, C-6), 138.2 (C, C1), 134.3 (C, C-10), 116.6 (CH2,
C]CH2), 66.9 (CH, C-4), 57.5 (CH, C-7), 39.4 (CH2), 38.4 (CH2), 37.9
(CH2), 31.9 (CH2), 21.2 (CH2), 14.8 (CH3); HRMS: m/z Calcd for
C12H18ONa (MþNa): 201.1255; found: 201.1255.
furnished the alcohol 23 (495 mg, 93%) as colorless oil. Rf (10%
26
4.1.7. Ethyl 2-[((S)-5-isopropenyl-2-methylcyclopent-1-en-1-yl)methyl]-
3-oxobutanoate (21). To a magnetically stirred solution of the bro-
mide 14 (430 mg, 2.0 mmol) in acetone (4 mL) were added K2CO3
(1.38 g, 10 mmol) and ethyl acetoacetate (0.26 mL, 2.0 mmol), and
refluxed for 9 h. Water (5 mL) was then added to the reaction
mixture and extracted with ether (3ꢂ8 mL). The combined ether
extract was washed with brine (5 mL) and dried (Na2SO4). Evapo-
ration of the solvent and purification of the residue on a silica gel
column using ethyl acetate/hexane (1:19) as eluent furnished the
ketoester 21 (460 mg, 87%) as pale yellow oil. Rf (10% EtOAc/hexane)
EtOAc/hexane) 0.35; [
a
]
D
þ115.9 (c 1.6, CHCl3); IR (neat): nmax
/
cmꢀ1 3535 (OH), 3070, 2941, 2892, 1643, 1441, 1377, 1211, 1140,
1090, 1048, 948, 889 (C]CH2), 866; 1H NMR (400 MHz, mixture of
two isomers):
d
4.70 and 4.67 (2H, 2ꢂs, C]CH2), 4.10e3.80 (4H, m,
OCH2CH2O), 3.60e3.10 (4H, m), 2.40e2.15 (2H, m, H-1), 2.05e1.80
(4H, m), 1.68 and 1.64 (3H, s), and 1.56 (3H, s) [2ꢂolefiniceCH3],
1.30 (3H, s, tert-CH3); 13C NMR (100 MHz, mixture of two isomers):
d
148.6 and 148.0 (C, C]CH2), 135.8 and 135.4 (C, C-10), 134.5 and
133.6 (C, C-100), 112.9 (C, OeCeO), 111.0 and 110.9 (CH2, C]CH2),
64.5 and 64.4 (CH2), 64.2 and 64.1 (CH2), 63.2 and 62.4 (CH2), 58.2
and 55.0 (CH, C-50), 47.3 and 45.3 (CH, C-3), 37.7 and 37.5 (CH2), 28.0
and 27.4 (CH2), 24.4 and 24.0 (CH2), 20.8 and 20.5 (CH3), 18.6 and
18.2 (CH3), 14.3 and 14.2 (CH3); HRMS: m/z Calcd for C16H26O3Na
(MþNa): 289.1781; found: 289.1780.
0.5; [
a
]
27 þ46.3 (c 2.1, CHCl3); IR (neat): nmax/cmꢀ1 3187, 2966, 2944,
D
2842, 1734 (OC]O), 1718 (C]O), 1633, 1442, 1365, 1266, 1228, 1179,
1145, 1096, 1036, 891 (C]CH2); 1H NMR (400 MHz, mixture of two
isomers): d 4.72 (1H, s) and 4.70 (1H, s) [C]CH2], 4.20e4.00 (2H, m,
OCH2CH3), 3.53 and 3.51 (1H, dd, J 10.2 and 6.3 Hz, H-2), 3.35 and
3.20 (1H, br s, H-500), 2.80e2.70 (1H, m), 2.40e2.10 (3H, m), 2.18 and
2.14 (3H, s, H-4), 2.05e1.90 (1H, m), 1.68e1.58 (1H, m), 1.66 (3H, s)
and 1.56 (3H, s) [2ꢂolefiniceCH3], 1.26 and 1.24 (3H, t, J 7.1 Hz,
4.1.10. 3-[(S)-5-Isopropenyl-2-methylcyclopent-1-en-1-yl]-2-(2-
methyl-1,3-dioxolan-2-yl)propanal (24). To a magnetically stirred
solution of the alcohol 23 (495 mg, 1.86 mmol) in DMSO (3 mL) was
added IBX (625 mg, 2.23 mmol) and stirred for 3 h at rt. Aqueous
NaHCO3 (10 mL) was added to the reaction mixture and extracted
with ether (3ꢂ8 mL). The combined ether extract was washed with
brine (8 mL) and dried (Na2SO4). Evaporation of the solvent and
purification of the residue on a silica gel column using ethyl acetate/
hexane (1:19) as eluent furnished the aldehyde 24 (452 mg, 92%) as
OCH2CH3); 13C NMR (100 MHz, mixture of two isomers):
d 202.4
and 201.9 (C, C]O), 169.4 and 169.3 (C, OC]O), 147.6 and 147.5
(C, C]CH2), 137.1 (C, C-10), 131.7 and 131.6 (C, C-100), 111.3 and 111.2
(CH2, C]CH2), 61.1 and 60.9 (CH2, OCH2CH3), 57.8 and 57.1 (CH,
C-2), 55.5 and 55.1 (CH, C-5"), 37.6 and 37.5 (CH2), 28.7 and 28.5
(CH3, CH3C]O), 27.7 and 27.6 (CH2), 25.7 and 25.4 (CH2), 18.4 and

8166
A. Srikrishna, V.H. Pardeshi / Tetrahedron 66 (2010) 8160e8168
colorless oil. Rf (10% EtOAc/hexane) 0.7; [
a
]
27 þ71.4 (c 2.0, CHCl3); IR
1373, 1277, 1250, 1202, 1188, 1166, 1139, 1025, 964, 934; 1H NMR
(400 MHz): 4.08 (1H, br s, H-4), 2.88 (1H, br s, H-3), 2.71 (1H, ddd,
D
(neat): nmax/cmꢀ1 3072, 2949, 2888, 2844, 2730 (HeC]O), 1727
(HC]O), 1643, 1442, 1379, 1212, 1153, 1086, 1045, 948, 890 (C]
d
J 9.1, 6.8, and 2.9 Hz, H-7), 2.54 (1H, d, J 15.2 Hz), 2.36 (1H, dd, J 15.2
and 9.2 Hz), 2.30e2.10 (2H, m), 2.17 (3H, s, CH3C]O), 1.99 (1H, dt,
J 12.3 and 7.1 Hz), 1.89 (1H, dd, J 13.8 and 5.6 Hz), 1.80e1.60 (2H, m),
1.64 (3H, s, olefiniceCH3), 1.35e1.20 (2H, m), 0.92 (3H, d, J 6.6 Hz,
CH2); 1H NMR (400 MHz, mixture of two isomers):
d 9.61 and 9.46
(1H, d, J 3.8 Hz, HeC]O), 4.75e4.60 (2H, m, C]CH2), 4.10e3.85
(4H, m, OCH2CH2O), 3.24 and 3.13 (1H, br s, H-50), 2.75e2.55 (1H, m,
H-2), 2.40e2.15 (3H, m), 2.05e1.85 (2H, m), 1.65e1.55 (1H, m), 1.66
(3H, s) and 1.54 (3H, s) [2ꢂolefiniceCH3], 1.28 (3H, s, H-4); 13C NMR
sec-CH3); 13C NMR (100 MHz):
d 211.9 (C, C]O),136.4 (C, C-1),133.0
(C, C-10), 71.5 (CH, C4), 57.3 (CH, C-3), 54.9 (CH, C-7), 43.3 (CH2, C-
2), 36.4 (CH2), 35.2 (CH, C-6), 29.9 (CH2), 29.1 (CH3), 23.1 (CH2), 21.8
(CH3), 14.1 (CH3); HRMS: m/z Calcd for C14H22O2Na (MþNa):
245.1517; found: 245.1516.
(100 MHz, mixture of two isomers): d 202.5 and 202.1 (CH, HC]O),
148.1 and 147.7 (C, C]CH2), 136.1 and 135.9 (C, C-10), 133.4 and
132.0 (C, C-100), 111.2 and 111.1 (CH2, C]CH2), 109.6 and 109.5
(C, C-3), 64.7 and 64.6 (CH2), 64.6 (CH2), 59.6 and 57.7 (CH, C-2),
56.7 and 55.0 (CH, C-50), 37.5 and 37.4 (CH2), 27.9 and 27.4 (CH2),
22.7 and 22.5 (CH3), 22.2 and 22.1 (CH2), 18.6 and 18.3 (CH3), 14.3
and 14.2 (CH3); HRMS: m/z Calcd for C16H24O3Na (MþNa):
287.1624; found: 287.1613.
4.1.13. X-ray data for the compound 26a monohydrate. X-ray data
were collected at 295 K on an SMART CCD-BRUKER diffractometer
with graphite-monochromated Mo K
a
radiation (
l
¼0.71073 Å). The
structure was solved by direct methods (SIR 92). Refinement was by
full-matrix least-squares procedures on F2 using SHELXL-97. The
non-hydrogen atoms were refined anisotropically, whereas hy-
drogen atoms were refined isotropically. Mol. For. C14H24O3;
MW¼240.44; colorless; Crystal system: Monoclinic; Space group
P 2 1; cell parameters, a¼5.1049(3) Å, b¼7.7340(3) Å, c¼18.0134
4.1.11. (3R,4S,7S)-3-Acetyl-10-methyl-6-methylenebicyclo[5.3.0]dec-
1(10)-en-4-ol (25). To a cold (0 ꢁC), magnetically stirred solution of
the aldehyde 24 (264 mg, 1 mmol) in anhydrous CH2Cl2 (200 mL,
0.005 M) was added BF3$Et2O (5 mg) and stirred for 10 min at the
same temperature. Saturated NaHCO3 solution (10 mL) was added
to the reaction mixture and extracted with CH2Cl2 (3ꢂ8 mL). The
organic layer was washed with brine (10 mL) and dried (Na2SO4).
Evaporation of the solvent and purification of the residue on a silica
gel column using ethyl acetate/hexane (1:9) as eluent furnished the
bicyclic hydroxy ketone 25 (150 mg, 57%) as colorless oil. Rf (20%
(9) Å;
a
90,
b
93.23(5),
m
g
90, V¼710.08(6) Å3, Z¼2, Dc¼1.124 g cmꢀ3
,
F(000)¼264,
¼0.094 mmꢀ1. Total number of least square re-
finement parameters¼160, R1¼0.0472 for 1775 F0>2
s(F0) and
0.0930 for all 3041 data. wR2¼0.0958, GOF¼0.890, restrained
GOF¼0.890 for all data. An ORTEP diagram is depicted in Figure 1.
Crystallographic data has been deposited with Cambridge Crystal-
lographic Data Centre (CCDC 783504).
EtOAc/hexane) 0.5; [
a
]
25 þ66.4 (c 1.6, CHCl3); IR (neat): nmax/cmꢀ1
D
3518 (OH), 2924, 2851, 1707 (C]O), 1645, 1444, 1350, 1276, 1159,
1096, 1015, 897 (C]CH2), 779; 1H NMR (400 MHz):
d
5.10 (1H, s)
4.1.14. 1-[(6R,7S)-6,10-Dimethylbicyclo[5.3.0]deca-1(10),3-dien-3-yl]
ethanone (27). To a cold (0 ꢁC), magnetically stirred solution of the
hydroxy ketone 26a (54 mg, 0.24 mmol) in anhydrous CH2Cl2
(2 mL) were added Et3N (0.18 mL, 1.3 mmol) and MsCl (0.10 mL,
1.3 mmol), and stirred for 6 h at rt 3 N HCl (8 mL) was added to the
reaction mixture and extracted with CH2Cl2 (3ꢂ6 mL). The com-
bined organic layer was washed with brine (8 mL) and dried
(Na2SO4). Evaporation of the solvent and purification of the residue
on a silica gel column using ethyl acetate/hexane (1:19) as eluent
and 4.90 (1H, s) [C]CH2], 4.35 (1H, br s, H-4), 3.41 (1H, br s, C-7),
2.55e2.35 (3H, m), 2.35e2.10 (4H, m), 2.24 (3H, s, CH3C]O), 2.02
(1H, dt, J 14.2 and 7.7 Hz, H-3), 1.91 (1H, t, J 13.2 Hz), 1.65 (3H, s,
olefiniceCH3), 1.55e1.35 (1H, m); 13C NMR (100 MHz):
d 209.4 (C,
C]O), 146.5 (C, C-6), 135.1 (C), 134.9 (C), 116.5 (CH2, C]CH2), 66.7
(CH, C-4), 60.0 (CH, C-3), 56.6 (CH, C-7), 37.9 (CH2), 37.0 (CH2), 31.0
(CH2), 28.3 (CH3, CH3C]O), 21.5 (CH2), 14.1 (CH3, C10eCH3); HRMS:
m/z Calcd for C14H20O2Na (MþNa): 243.1361; found: 243.1358.
furnished the enone 27 (43 mg, 87%) as colorless oil. Rf (10% EtOAc/
27
4.1.12. (3R,4S,6R,7S)-3-Acetyl-6,10-dimethylbicyclo[5.3.0]dec-1(10)-
en-4-ol (26a) and (3R,4S,6S,7S)-3-acetyl-6,10-dimethylbicyclo[5.3.0]
dec-1(10)-en-4-ol (26b). Wilkinson’s catalyst (9 mg, 1.5 mol %) was
added to a magnetically stirred solution of the hydroxy ketone 25
(150 mg, 0.68 mmol) in dry ethyl acetate (1 mL) and stirred for 15 h
at rt in an atmosphere of hydrogen, created by evacuative re-
placement of air (balloon). The catalyst was then filtered off
through a short silica gel column using ethyl acetate/hexane (1:4).
Evaporation of the solvent and purification of the residue on a silica
gel column using ethyl acetate/hexane (1:9) as eluent first fur-
hexane) 0.7; [
a]
þ17.5 (c 2.3, CHCl3); IR (neat): nmax/cmꢀ1 3048,
D
2952, 2928, 2871, 2841, 1667 (C]O), 1638, 1456, 1376, 1342, 1299,
1260, 1234, 1165, 956, 896; 1H NMR (400 MHz):
d 6.95 (1H, t,
J 7.3 Hz, H-40), 3.82 and 2.49 (2H, 2ꢂd, J 14.6 Hz, H-20), 2.45e2.30
(2H, m), 2.28 (3H, s, CH3C]O), 2.28e2.00 (5H, m), 1.65 (3H, s,
olefiniceCH3), 1.45e1.20 (2H, m), 1.00 (3H, d, J 6.6 Hz, sec-CH3); 13
C
NMR (100 MHz): d
197.3 (C, C]O), 143.6 (C), 143.0 (CH, C-40), 132.4
(C), 132.0 (C), 58.7 (CH, C-70), 38.4 (CH, C-60), 36.0 (CH2), 35.5 (CH2),
29.1 (CH2), 24.9 (CH3, CH3C]O), 23.6 (CH2), 22.4 (CH3), 14.0 (CH3);
HRMS: m/z Calcd for C14H20ONa (MþNa): 227.1412; found:
227.1405.
nished the (6S,7S)-isomer 26b (72 mg, 48%) as colorless oil. Rf (20%
26
EtOAc/hexane) 0.52; [
a]
þ173.7 (c 1.6, CHCl3); IR (neat): nmax
/
D
cmꢀ1 3468 (OH), 2953, 2918, 2873, 1700 (C]O), 1455, 1440, 1380,
4.1.15. 1-[(6R,7S)-6,10-Dimethylbicyclo[5.3.0]dec-1(10)-en-3-yl]
ethanones (28). Lithium metal (14 mg, 2 mmol) was added to
freshly distilled liquid ammonia (20 mL). To the resultant blue
colored solution was added a solution of the enone 27 (43 mg,
0.19 mmol) in dry THF (1 mL) over a period of 5 min and the re-
action mixture was slowly allowed to attain rt over a period of 1 h.
Aqueous NH4Cl (5 mL) was then added to the reaction mixture and
extracted with ether (3ꢂ5 mL). The combined ether extract was
washed with brine (7 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue on a silica gel column using
CH2Cl2/hexane (1:9) as eluent first furnished a 3:2 diastereomeric
mixture of the ketone 28 (17 mg, 39%) as colorless oil. Rf (10%
1357, 1307, 1265, 1165, 1050, 962, 865; 1H NMR (400 MHz):
d
4.17
(1H, s), 3.32 (1H, s), 2.95e2.70 (2H, m), 2.60e1.90 (5H, m), 2.21 (3H,
s, CH3C]O), 1.90e1.20 (4H, m), 1.65 (3H, s, olefiniceCH3), 0.85 (3H,
d, J 7.2 Hz, sec-CH3); 13C NMR (100 MHz):
d 212.5 (C, C]O), 138.2
(C, C-1), 133.1 (C, C-10), 67.9 (CH, C-4), 59.2 (CH, C-3), 52.4 (CH, C-7),
36.4 (CH2), 36.1 (CH2), 28.9 (CH, C-6), 25.5 (CH2), 25.4 (CH3, CH3C]
O), 22.0 (CH2), 19.5 (CH3), 14.0 (CH3); HRMS: m/z Calcd for
C14H22O2Na (MþNa): 245.1517; found: 245.1505.
Further elution of the column using ethyl acetate/hexane (1:5)
as eluent furnished the (6R,7S)-isomer 26a (54 mg, 36%) as a solid,
which was recrystallised along with one molecule of water from
a mixture of ethyl acetate and hexane. Mp 74.5e76.5 ꢁC; Rf (20%
EtOAc/hexane) 0.7; [
a
]
27 þ66.5 (c 1.2, CHCl3); IR (neat): nmax/cmꢀ1
D
EtOAc/hexane) 0.48; [
3422 (OH), 2954, 2924, 2858, 2835, 2803, 1694 (C]O), 1463, 1438,
a
]
26 þ129.1 (c 4.3, CHCl3); IR (KBr): nmax/cmꢀ1
2950, 2924, 2858, 1711 (C]O), 1459, 1439, 1376, 1352, 1263, 1163,
D
1019, 954; 1H NMR (400 MHz, mixture of two isomers):
d 2.60e2.50

A. Srikrishna, V.H. Pardeshi / Tetrahedron 66 (2010) 8160e8168
8167
(2H, m), 2.40e1.75 (6H, m), 2.16 (3H, s, CH3C]O),1.70e1.10 (5H, m),
1.62 and 1.60 (3H, s, olefiniceCH3), 0.94 and 0.91 (3H, d, J 6.7 Hz,
1.6 mmol), and stirred for 7 h at rt. 3 N HCl (8 mL) was then added to
the reaction mixture and extracted with CH2Cl2 (3ꢂ6 mL). The
combined organic layer was washed with brine (10 mL) and dried
(Na2SO4). Evaporation of the solvent and purification of the residue
on a silica gel column using ethyl acetate/hexane (1:19) as eluent
sec-CH3); 13C NMR (100 MHz, mixture of two isomers):
d 211.0 and
211.3 (C, C]O), 136.6 and 135.9 (C, C-10), 132.8 and 133.6 (C, C-100),
57.3 and 55.9 (CH), 50.4 and 51.1 (CH), 39.6 and 39.1 (CH, C-60), 38.3
(CH2), 36.5 and 36.3 (CH2), 31.7 and 31.3 (CH2), 29.9 and 29.8 (CH2),
28.1 and 27.9 (CH3, CH3C]O), 27.7 and 26.9 (CH2), 22.1 and 21.7
(CH3), 13.9 and 14.4 (CH3); HRMS: m/z Calcd for C14H22ONa
(MþNa): 229.1568; found: 229.1570.
furnished the bicyclic enone 30 (56 mg, 85%) as colorless oil. Rf (10%
26
EtOAc/hexane) 0.7; [
a
]
D
þ297 (c 3.0, CHCl3); IR (neat): nmax/cmꢀ1
2955, 2928, 2877, 2841, 1666 (C]O), 1635, 1440, 1379, 1349, 1258,
1232, 1174, 1019; 1H NMR (400 MHz):
d
6.77 (1H, br s, H-40), 3.75
Further elution of the column with CH2Cl2/hexane (1:5) fur-
nished a mixture of the alcohol 29 (15 mg, 34%). To a magnetically
stirred solution of the alcohol 29 in anhydrous CH2Cl2 (0.5 mL) was
added PDC (150 mg, 0.4 mmol) and stirred for 8 h at rt. The reaction
mixture was then filtered through a short silica gel column using
CH2Cl2. Evaporation of the solvent and purification of the residue
on a silica gel column using CH2Cl2/hexane (1:5) as eluent fur-
nished a 3:2 diastereomeric mixture of the ketone 28 (12 mg, 76%)
as colorless oil.
and 2.45 (2H, 2ꢂd, J 16.0 Hz, H-20), 2.86 (1H, br s, H-70), 2.40e2.10
(6H, m), 2.28 (3H, s, CH3C]O), 1.90e1.80 (1H, m), 1.59 (3H, s, ole-
finiceCH3), 1.60e1.40 (2H, m), 0.82 (3H, d, J 6.9 Hz, sec-CH3); 13C
NMR (100 MHz): d
198.2 (C, C]O), 142.7 (CH, C-40), 142.2 (C), 133.4
(C), 132.8 (C), 54.5 (CH, C-70), 36.9 (CH2), 33.7 (CH, C60), 32.8 (CH2),
25.3 (CH3, CH3C]O), 24.9 (CH2), 24.3 (CH2), 16.5 (CH3), 13.8 (CH3);
HRMS: m/z Calcd for C14H20ONa (MþNa): 227.1412; found:
227.1422.
4.1.19. 1-[(3S,6S,7S)-6,10-Dimethylbicyclo[5.3.0]dec-1(10)-en-3-yl]
ethanone (31). Lithium metal (14 mg, 2 mmol) was added to
magnetically stirred freshly distilled (over sodamide) liquid am-
monia (20 mL). To the resultant blue colored solution was added
a solution of the enone 30 (56 mg, 0.27 mmol) in dry THF (1 mL)
over a period of 5 min, and the reaction mixture was slowly allowed
to attain rt over a period of 1 h. Aqueous NH4Cl (5 mL) was then
added to the reaction mixture and extracted with ether (3ꢂ5 mL).
The combined ether extract was washed with brine (8 mL) and
dried (Na2SO4). Evaporation of the solvent and purification of the
residue on a silica gel column using CH2Cl2/hexane (1:9) as eluent
4.1.16. Hydrogenation of the enone 27. To a magnetically stirred
solution of the enone 27 (40 mg, 0.20 mmol) in hexane (1 mL) was
added 5% Pd/C (12 mg) and stirred for 30 min at rt in an atmosphere
of hydrogen, created by evacuative replacement of air (balloon).
The catalyst was then filtered through a short silica gel column
using CH2Cl2. Evaporation of the solvent and purification of the
residue on a silica gel column using CH2Cl2/hexane (1:5) as eluent
furnished a 2:3 mixture of the bicyclic ketone 28 (38 mg, 94%) as
colorless oil.
4.1.17. (3S,6R,7S)-3-Isopropenyl-6,10-dimethylbicyclo[5.3.0]dec-1
(10)-ene (ent-7-epiaciphyllene 7) and (3R,6R,7S)-3-isopropenyl-6,10-
dimethylbicyclo[5.3.0]dec-1(10)-ene (6-epiaciphyllene 6). To a mag-
first furnished the ketone 31 (15 mg, 25%) as colorless oil. Rf (10%
28
EtOAc/hexane) 0.7; [
a
]
D
þ97.0 (c 1.6, CHCl3); IR (neat): nmax/cmꢀ1
2954, 2924, 2871, 2856, 1711 (C]O), 1455, 1376, 1353, 1266, 1158,
netically stirred freshly prepared solution of AmOꢀKþ [prepared
1100, 1019; 1H NMR (400 MHz):
d 2.76 (1H, br s), 2.56 (1H, d,
t
from potassium (58 mg, 1.50 mmol) and tert-amyl alcohol (3 mL),
followed by evaporation of the excess tert-amyl alcohol under re-
duced pressure] in dry benzene (3 mL) was added methyl-
triphenylphosphonium bromide (640 mg, 1.80 mmol). The reaction
mixture was stirred for 30 min at rt and the resultant yellow
colored solution was allowed to settle. The dark yellow colored
supernatant solution of methylenetriphenylphosphorane was
taken in a syringe and added to a magnetically stirred solution of
a 3:2 diastereomeric mixture of the ketone 28 (30 mg, 0.15 mmol)
in dry benzene (0.5 mL) and stirred for 1 h at rt. Water (5 mL) was
then added to the reaction mixture and extracted with ether
(3ꢂ5 mL). The combined ether extract was washed with brine
(8 mL) and dried (Na2SO4). Evaporation of the solvent and purifi-
cation of the residue on a silica gel column using hexane as eluent
J 13.4 Hz), 2.35e1.20 (11H, m), 2.17 (3H, s, CH3C]O), 1.65 (3H, s,
olefiniceCH3), 0.90 (3H, d, J 7.2 Hz, sec-CH3); 13C NMR (100 MHz):
d
211.6 (C, C]O),137.5 (C, C-10),135.5 (C, C100)‑, 55.4 (CH), 52.7 (CH),
36.2 (CH2), 35.8 (CH), 32.7 (CH2), 29.6 (CH2), 28.1 (CH3, CH3C]O),
27.9 (CH2), 25.3 (CH2), 19.7 (CH3), 13.8 (CH3); HRMS: m/z Calcd for
C14H22ONa (MþNa): 229.1568; found: 229.1560.
Further elution of the column with CH2Cl2/hexane (1:5) gave
a diastereomeric mixture of the alcohol 32 (29 mg, 51%) as colorless
oil. To a magnetically stirred solution of a mixture of the secondary
alcohol 32 (29 mg, 0.14 mmol) in anhydrous CH2Cl2 (0.5 mL) was
added PDC (263 mg, 0.7 mmol) and stirred for 8 h at rt. The reaction
mixture was then filtered through a short silica gel column using
CH2Cl2. Evaporation of the solvent and purification of the residue
on a silica gel column using CH2Cl2/hexane (1:5) as eluent fur-
nished the ketone 31 (23 mg, 79%) as colorless oil.
furnished a 3:2 mixture of ent-7-epiaciphyllene 7 and 6-epi-
27
aciphyllene 6 (27 mg, 91%) as colorless oil. Rf (hexane) 0.9; [a]
D
þ58.7 (c 1.2, CHCl3); IR (neat): nmax/cmꢀ1 3074, 2950, 2923, 2858,
4.1.20. (3S,6S,7S)-3-Isopropenyl-6,10-dimethylbicyclo[5.3.0]dec-1
1644, 1457, 1441, 1376, 1020, 887 (C]CH2); 1H NMR (400 MHz,
(10)-ene (3-epiaciphyllene 1). To a magnetically stirred freshly
t
CDCl3, 3:2 mixture of 7 and 6):
d
4.71 and 4.68 (1H, s) and 4.68 and
prepared solution of AmOꢀKþ [prepared from potassium (23 mg,
4.62 (1H, s) [C]CH2], 2.55e1.80 (6H, m),1.75e1.20 (7H, m),1.75 and
1.74 (3H, s) and 1.63 and 1.61 (3H, s) [2ꢂolefiniceCH3], 0.96
(d, J 6.8 Hz) and 0.91 (d, J 6.5 Hz), [3H, sec-CH3]; 13C NMR (100 MHz,
0.6 mmol) and tert-amyl alcohol (1 mL) followed by evaporation of
the excess tert-amyl alcohol under reduced pressure] in dry ben-
zene (2 mL) was added methyltriphenylphosphonium bromide
(285 mg, 0.8 mmol). The reaction mixture was stirred magnetically
for 30 min at rt. The resultant yellow colored solution was allowed
to settle. The dark yellow colored supernatant solution of methyl-
enetriphenylphosphorane was taken in a syringe and added to
a magnetically stirred solution of the ketone 31 (11 mg, 0.13 mmol)
in dry benzene (0.5 mL) and stirred for 1 h at rt. Water (5 mL) was
then added to the reaction mixture and extracted with ether
(3ꢂ5 mL). The combined ether extract was washed with brine
(5 mL) and dried (Na2SO4). Evaporation of the solvent and purifi-
cation of the residue on a silica gel column using hexane as eluent
furnished 3-epiaciphyllene 1 (10 mg, 92%) as colorless oil. Rf
CDCl3, peaks due to 6 and 7):
d 152.5 and 151.3 (C, C]CH2), 138.0
and 138.2 (C, C-1), 132.1 and 131.9 (C, C-10), 107.6 and 108.1 (CH2,
C]CH2), 55.7 and 57.2 (CH, C-7), 45.2 and 45.1 (CH, C-3), 39.8 and
36.5 (CH2), 39.2 (CH, C-6), 36.3 and 32.0 (CH2), 36.1 and 31.1 (CH2),
34.5 and 30.5 (CH2), 30.1 and 30.2 (CH2), 21.6 and 22.2 (CH3), 20.3
and 20.6 (CH3), 14.5 and 13.9 (CH3).
4.1.18. 1-[(6S,7S)-6,10-Dimethylbicyclo[5.3.0]deca-1(10),3-dien-3-yl]
ethanone (30). To a cold (0 ꢁC), magnetically stirred solution of the
hydroxy ketone 26b (72 mg, 0.32 mmol) in anhydrous CH2Cl2
(2 mL) were added Et3N (0.22 mL, 1.6 mmol) and MsCl (0.12 mL,

8168
A. Srikrishna, V.H. Pardeshi / Tetrahedron 66 (2010) 8160e8168
27
24
(hexane) 0.9; [
a
]
D
þ13.5 (c 1.3, CHCl3); {lit.10
[a
]
ꢀ13.2 (c 0.35,
exhibited all the spectral data identical to that of the sample
D
CHCl3)}; IR (neat): nmax/cmꢀ1 3080, 2954, 2919, 2871, 2855, 1643,
obtained earlier. Further elution of the column with hexane gave
26
1454, 1375, 1019, 886 (C]CH2); 1H NMR (400 MHz):
d
4.69 (1H, s)
aciphyllene 5 (12 mg, 46%) as colorless oil. Rf (hexane) 0.9; [a]
D
24
and 4.65 (1H, s) [C]CH2], 2.77 (1H, br s), 2.44 (1H, d, J 11.2 Hz),
2.26e2.14 (1H, m), 2.10 (1H, dd, J 11.2 and 8.8 Hz), 2.00e1.66 (5H,
m),1.74 (3H, s) and 1.63 (3H, s) [2ꢂolefiniceCH3],1.45e1.20 (3H, m),
þ50.7 (c 1.4, CHCl3); {lit.10
[a
]
þ52.2 (c 0.53, CHCl3)}; IR (neat):
D
nmax/cmꢀ1 3072, 2920, 1644, 1448, 1378, 1019, 886; 1H NMR
(400 MHz): d 4.64 (1H, s) and 4.60 (1H, s) [C]CH2], 2.99e2.92 (1H,
0.89 (3H, d, J 7.2 Hz, sec-CH3); 13C NMR (100 MHz):
d
151.7 (C, C]
m), 2.42 (1H, br d, J 14.1 Hz), 2.30e1.40 (11H, m), 1.73 (3H, s) and
1.58 (3H, s) [2ꢂolefiniceCH3], 0.76 (3H, d, J 7.1 Hz, sec-CH3);
CH2), 139.2 (C, C-1), 132.6 (C, C10), 108.0 (CH2, C]CH2), 52.9 (CH),
50.2 (CH), 36.7 (CH2), 36.2 (CH2), 36.1 (CH, C-6), 31.7 (CH2), 30.0
(CH2), 25.2 (CH2), 20.6 (CH3), 20.1 (CH3), 13.8 (CH3).
13C NMR (100 MHz):
d 152.8 (C, C]CH2), 135.1 (C, C-1), 132.5
(C, C-10), 107.5 (CH2, C]CH2), 53.2 (CH, C-7), 45.7 (CH, C-3), 37.4
(CH2), 37.0 (CH2), 36.9 (CH, C-6), 35.1 (CH2), 31.9 (CH2), 28.5 (CH2),
20.2 (CH3), 14.1 (CH3), 12.9 (CH3).
4.1.21. 1-[(3S,6S,7S)-6,10-Dimethylbicyclo[5.3.0]dec-1(10)-en-3-yl]
ethanone (31) and 1-[(3R,6S,7S)-6,10-dimethylbicyclo[5.3.0]dec-1
(10)-en-3-yl]ethanone (33). To a magnetically stirred solution of
the enone 31 (30 mg, 0.15 mmol) in hexane (1 mL) was added 5%
Pd/C (7 mg) and stirred for 30 min at rt in an atmosphere of hy-
drogen, created by evacuative replacement of air (balloon). The
catalyst was then filtered through a short silica gel column using
CH2Cl2. Evaporation of the solvent and purification of the residue
using CH2Cl2/hexane (1:5) as eluent furnished a 1:1 mixture of the
bicyclic ketones 31 and 33 (28 mg, 93%) as colorless oil. Rf (10%
Acknowledgements
We thank Council of Scientific and Industrial Research, New
Delhi for the award of a research fellowship to VHP, and CCD Fa-
cility, Indian Institute of Science for the X-ray diffraction analsysis.
Supplementary data
EtOAc/hexane) 0.7; [
a
]
25 þ103.7 (c 1.6, CHCl3); IR (neat): nmax/cmꢀ1
D
2951, 2924, 2871, 1710 (C]O), 1442, 1378, 1353, 1161, 1019; 1H NMR
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.08.045.
(400 MHz, mixture of 31 and 33):
d 2.87 and 2.75 (1H, br s),
2.60e2.30 (1H, m), 2.30e2.05 (4H, m), 2.14 (3H, s, CH3C]O),
2.00e1.80 (3H, m), 1.80e1.70 (2H, m), 1.63 and 1.58 (3H, s, olefi-
niceCH3), 1.55e1.20 (4H, m), 0.89 and 0.76 (3H, d, J 7.1 Hz, sec-CH3);
References and notes
13C NMR (100 MHz, mixture 31 and 33):
d 211.4 and 211.2 (C, C]O),
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t
stirred freshly prepared solution of AmOꢀKþ [prepared from po-
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and added to a magnetically stirred solution of a 1:1 mixture of the
ketones 31 and 33 (27 mg, 0.13 mmol) in dry benzene (0.5 mL) at rt
and stirred for 1 h. Water (5 mL) was then added to the reaction
mixture and extracted with ether (3ꢂ5 mL). The combined ether
extract was washed with brine (8 mL) and dried (Na2SO4). Evapo-
ration of the solvent and purification of the residue on a silver ni-
trate impregnated silica gel column using hexane as eluent first
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