Enantioselective synthesis of the essential oil and pheromonal component ar-himachalene by a chiral pool and chirality induction approach

Article abstract of DOI:10.1016/j.tetasy.2012.09.008

The enantioselective synthesis of both isomers of ar-himachalene has been achieved starting from enantiomerically pure citronellal and p-methyl α-methyl styrene as an application of a chiral pool and chirality induction approach, respectively. The key reactions involved in the synthesis include the Sharpless asymmetric dihydroxylation for the induction of chirality at benzylic carbon bearing the methyl group and the use of a hypervalent iodine reagent or trimethylsilyldiazomethane (TMSCHN₂) for the six to seven membered ring expansion.

Full text of DOI:10.1016/j.tetasy.2012.09.008

Tetrahedron: Asymmetry 23 (2012) 1410–1415
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of the essential oil and pheromonal component
ar-himachalene by a chiral pool and chirality induction approach
⇑
Subhash P. Chavan , Harshali S. Khatod
Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 August 2012
Accepted 12 September 2012
The enantioselective synthesis of both isomers of ar-himachalene has been achieved starting from enan-
tiomerically pure citronellal and p-methyl a-methyl styrene as an application of a chiral pool and chiral-
ity induction approach, respectively. The key reactions involved in the synthesis include the Sharpless
asymmetric dihydroxylation for the induction of chirality at benzylic carbon bearing the methyl group
and the use of a hypervalent iodine reagent or trimethylsilyldiazomethane (TMSCHN2) for the six to
seven membered ring expansion.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
acylation, and Robinson annulations, starting from citronellal as a
chiral building block have been reported in the literature.7
A large number of naturally occurring sesquiterpenes are
known in the literature, which possess a broad range of applica-
tions in drugs, pharmaceuticals, rubber, paints, perfumery, agricul-
ture, and so on. Many methods have been reported for the
synthesis of this class of natural products. Himachalene is a struc-
turally and biologically important class of the naturally occurring
sesquiterpene hydrocarbons containing the synthetically challeng-
ing benzo[7]annulene ring system.1 They are found as essential oil
components in several cedar woods (Fig. 1), which include Cedrus
deodara Loud, Cedrus atlantica, and Cedrus libani2 found in Himala-
yan and Morroccon forests. The essential oil and different constit-
uents of C. deodara account for the insecticidal and larvicidal action
and therefore their use in pest management.3 Himachalene was
also isolated as a male specific aggregation pheromonal compo-
nent of the flea beetles, Aphthona flava and Phyllotreta cruciferae
(Fig. 1).4 These aggregation pheromones, which are typically pro-
duced by only one sex but attract both sexes, have become impor-
tant scientific tools for monitoring and managing economically
important insects. However, only the (R)-enantiomer of ar-hima-
chalene exhibits the desired pheromonal activity,5 which intrinsi-
cally requires the compound to be used in enantiomerically pure
form. Although (R)-ar-himachalene can be used under field exper-
iments for the control of economically important insects, it consti-
tutes only 0.5% of the total oil of Aphthona flava,4 and this shows
the need for the development of its chemical synthesis. In recent
times, several himachalene type sesquiterpenes have gained atten-
tion because of the revision of absolute stereochemistry by Mori
et al.6 Several syntheses of himachalenes based on Friedel–Crafts
The construction of a seven-membered ring fused to an aro-
matic ring, and the introduction of stereogenic center at the ben-
zylic position and geminal dimethyl groups are the main tasks of
an enantioselective total synthesis. Many chemical transforma-
tions of ar-himachalene are also known to afford other structurally
important synthetic compounds.8 These activities as well as inter-
esting structural features gained our interest in its synthesis.
2. Results and discussion
As part of our ongoing program toward the synthesis of bioac-
tive sesquiterpene natural products9 we envisioned that enantio-
merically pure citronellal 2 can be used as a chiral building block
for the enantioselective synthesis of ar-himachalene. Based on
the chemistry involving Sharpless asymmetric dihydroxylation
and intramolecular ring expansion either by using a hypervalent
iodine reagent or by using TMS diazomethane, we realized that
ar-himachalene could be synthesized in enantiomerically pure
form from p-methyl a-methyl styrene 3. As per our proposed ret-
rosynthetic plan (Scheme 1), (S)-ar-himachalene can be accessed
from (S)-4-(p-tolyl)-pentanoic acid 8 by using a trifluoroacetic acid
and trifluoroacetic anhydride mediated cyclization followed by a
ring expansion reaction. Acid (S)-8 can be obtained by two routes;
(i) from (S)-citronellal 2 by a one-pot Michael addition, Robinson
annulation, and decarboxylation, followed by aromatization and
Jones oxidation reaction and (ii) from the p-methyl a-methyl sty-
rene 3, in which chirality at the benzylic position can be introduced
using the Sharpless asymmetric dihydroxylation reaction as the
key step.
According to the retrosynthetic analysis, our synthesis started
⇑
Corresponding author. Tel.: +91 20 25902289; fax: +91 20 25902629.
E-mail address: sp.chavan@ncl.res.in (S.P. Chavan).
with the chiral building block (S)-citronellal 210 to give acid (S)-8
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.09.008

S. P. Chavan, H. S. Khatod / Tetrahedron: Asymmetry 23 (2012) 1410–1415
1411
essential oil components
of cedarwood
pheromonal components
O
of flea beetle
OH
5 steps, Ref. 11
(82%)
O
H
(S)-2
(S)-8
Scheme 2. Preparation of (S)-4-(p-tolyl)pentanoic acid 8 from (S)-citronellal.
(S)-ar-himachalene 1a
(R)-ar-himachalene 1a'
H
primary alcohol (R)-5. We studied various reagents under different
hydrogenation conditions for removal of the tertiary hydroxyl
group and the introduction of chirality at the benzylic position
(Table 1). As expected, in most cases an inversion of configuration
was observed.13 However, the use of freshly activated Raney Ni in
refluxing ethanol gave (S)-5 that is retention of configuration oc-
curred with 78% yield with 86% ee. (by chiral HPLC) (entry 7).
The use of Et3SiH in the presence of a Lewis acid catalyst gave
the product with very poor ee (entries 1 and 2), whereas, Pd(OH)2
under room temperature as well as under refluxing conditions
gave a moderate yield with good ee (entries 3 and 4).14 Using
Pd(OH)2 in the presence of ammonium formate as a hydrogen
source resulted in the decomposition of starting material (entry
8). The best result for inversion was observed when using 10%
Pd/C under a hydrogen atmosphere of 60 psi to obtain product
(R)-5 with 72% yield and 97.5% ee (by chiral HPLC) (entry 5).15
Alcohol (R)-5 was then converted into its iodo derivative (R)-6 by
using triphenylphosphine, imidazole and iodine in 81% yield. The
iodo compound (R)-6 was further treated with diethyl malonate,
sodium hydride, and tetrabutyl ammonium iodide (TBAI) as a
phase transfer catalyst to obtain diester (S)-7 in 88% yield. Diester
(S)-7 was then hydrolyzed under basic conditions to the corre-
sponding diacid, which was used without further purification for
thermal decarboxylation to furnish the desired chiral acid (S)-8
in 83% yield with 96% ee (by chiral HPLC) (Scheme 3). Acid (S)-8
was then subjected to a trifluoroacetic acid and trifluoroacetic
anhydride mediated intramolecular acylation reaction11 to obtain
the (S)-trinorsesquiterpene 9 in 83% yield and with 96% ee (by chi-
ral HPLC). It is worth mentioning that trinorsesquiterpene is a nat-
ural product which can be isolated from the Japanese species J.
truncate as a 1:1 mixture of enantiomers.16 Although, it is difficult
to construct a seven membered ring fused to an aromatic ring, few
references are known in the literature to make this frame-
work.1,17,18 We chose Koser’s reagent and TMSCHN2 for the six to
seven membered ring expansion. One-carbon Wittig olefination
of p-methyl-tetralone (S)-9 gave compound (S)-10 with an exocy-
clic methylene group in 60% yield and 35% of starting material
was recovered. This compound upon treatment with Koser’s re-
agent, [hydroxy(tosyloxy)iodo]benzene (HTIB), underwent facile
ring expansion to furnish ketone (S)-11 in 82% yield.17 Ketone
(S)-11 was also obtained directly from p-methyl-tetralone (S)-9
by insertion of the methylene group using trimethylsilyl diazo-
methane in 49% yield.18 Dimethylation of compound (S)-11 with
excess methyl iodide using potassium tert-butoxide as a base fur-
nished compound (S)-12 in 87% yield which after WolffꢀKishner
reduction of the carbonyl group furnished the (S)-ar-himachalene
1a in 67% yield (Scheme 3).19 We decided to check the enantio-
meric purity of the final natural product (S)-1a by using a chiral
HPLC method but all of our attempts to resolve a sample of ( )-
ar-himachalene on suitable chiral HPLC columns were unsuccess-
ful. Finally, we carried out chiral GC analysis and determined the
enantiomeric excess as 94% for the final (S)-ar-himachalene 1a.20
Mori et al. reported (R)-ar-himachalene was dextrorotatory in n-
hexane and levorotatory in chloroform.6 We observed that (S)-ar-
himachalene was dextrorotatory in chloroform while levorotatory
in n-hexane.
(6R,7R)-1f
α-himachalene 1b
H
(7R,5aR)-1g
β-himachalene 1c
H
O
(6R,7R)-1h
δ-cadinene 1d
H
OH
(3S,7R)-1i
(3R,7R)-1j
curcumene 1e
Figure 1. Natural sesquiterpenes isolated along with ar-himachalene.
O
(S)-11
(S)-ar-himachalene 1a
OH
OH
O
(R)-5
(S)-8
(S)-2
O
H
3
Scheme 1. Retrosynthetic analysis for (S)-ar-himachalene.
using the procedure reported earlier (Scheme 2).11 Acid (S)-8 could
also be obtained from styrene derivative 3. Sharpless asymmetric
dihydroxylation of p-methyl
a-methyl styrene 3 using AD-mix-b,
furnished diol (R)-4 in 89% yield and 99% ee (by chiral HPLC).12
The diol (R)-4 was then subjected to hydrogenolysis to obtain

1412
S. P. Chavan, H. S. Khatod / Tetrahedron: Asymmetry 23 (2012) 1410–1415
Table 1
Asymmetric hydrogenolysis of (R)-2-(p-tolyl)propane-1,2-diol 4
OH
OH
Hydrogenolysis
OH
(R)-5
(R)-4
a
Entry
Catalyst
Reaction conditions
Yield (%)
ee (%)
½
a 2D5
Rb
ꢁ
1
2
CF3COOH
BF3ꢂOEt2
Pd(OH)2
Pd(OH)2
Pd/C
Et3SiH, 25 °C, 3 h
Et3SiH, 25 °C, 3 h
H2(60 psi), EtOH, 25 °C, 7 h
H2, EtOH, reflux, 4 h
H2(60 psi), EtOH, 25 °C, 10 h
H2, EtOH, reflux, 12 h
EtOH, reflux, 3 h
79
62
74
83
72
88
78
De
—
—
Rb
3
+16.8
+13.9
+17.4
+16.2d
ꢀ15.1
—
93
84
97.5
92
86
—
4c
5
6c
7
Pd/C
Raney Ni
NH4CO2H, Pd(OH)2
8
THFꢀMeOH (1:1), reflux, 5 h
a
b
c
Specific rotations measured at (c 1, CHCl3).
Product formed with racemization.
Reaction was performed under balloon pressure hydrogen atmosphere.
Product formed with retention of configuration.
Decomposition of the starting material was observed.
d
e
H2, Pd/C, EtOH
25 oC, 8 h
PPh3, iodine, Im.
OH
OH
CHCl3, 0−25 oC, 4 h
AD-mix-β
OH
(89%)
(72%)
(81%)
(R)-4 (99% ee)
3
(R)-5 (97.5% ee)
NaH, diethyl malonate
CO2Et
CO2Et
TBAI (10 mol%), DMF
I
OH
120 oC, 10 h
(i) KOH, EtOH−H2O (1:1)
(ii) 140 oC, 4 h (74%)
O
(88%)
(S)-7
(R)-6
(S)-8 (92% ee)
tBuOK, MeI, THF
PPh3MeI
HTIB, MeOH
TFA−TFAA,
0−25 oC, 3 h
0−25 oC, 45 min.
BuLi, THF, 5 h
0−25 oC, 4 h
(60% + 35% SM)
(82%)
(83%)
(87%)
O
O
(S)-11 (93% ee)
(S)-10 (92.5% ee)
(S)-9 (96% ee)
TMSCHN2, BF3OEt2, 0 oC, 45 min
(49%)
N2H4.2H2O, NaOH
Diethylene Glycol
8 h, 180 oC
(67%)
O
(S)-ar-himachalene 1a
(S)-12 (93% ee)
(94% ee)
Scheme 3. Total synthesis of (S)-ar-himachalene 1a.
Thus, we have accomplished the enantioselective total synthe-
sis of (S)-ar-himachalene starting from (S)-citronellal 2 and p-
methyl -methyl styrene 3 in 10 and 11 steps, respectively in 5%
and 6% overall yields, respectively. We have also synthesized the
opposite enantiomer (R)-ar-himachalene 1a0 by following the same
reaction sequence starting from (R)-citronellal by a chiral pool ap-
3. Conclusion
a
In conclusion, we have accomplished the enantioselective syn-
thesis of both isomers of ar-himachalene. The synthetic sequence
involved a Sharpless asymmetric dihydroxylation reaction, hydrog-
enolysis, and the use of TMSCHN2 or a hypervalent iodine reagent
for the ring expansion. We believe this protocol could be of general
interest and also useful for the synthesis of several complex bioac-
tive natural and unnatural products.
proach and also from p-methyl
a-methyl styrene 3 followed by
Sharpless asymmetric dihydroxylation, using AD-mix-
a for the
induction of chirality with equivalent overall yields.

S. P. Chavan, H. S. Khatod / Tetrahedron: Asymmetry 23 (2012) 1410–1415
1413
was added Pd/C (90 mg, 10 wt%). The reaction mixture was stirred
under a hydrogen atmosphere at 25 °C and 60 psi pressure for 6 h.
After completion of the reaction, the catalyst was filtered off and
the residue washed with hot ethanol (3 ꢃ 5 mL). The combined fil-
trate was evaporated under reduced pressure and the residue ob-
tained was purified using 60–120 silica gel column
chromatography (5% ethyl acetate–petroleum ether) to furnish
alcohol 5 as a colorless oil [0.075 g, 72%, 97.5% ee for the (R)-iso-
4. Experimental
4.1. General
Optical rotations were recorded on a JASCO J-20C polarimeter.
The 1H NMR spectra were recorded on 200 MHz NMR spectrome-
ter, 400 MHz NMR spectrometer, and 500 MHz NMR spectrometer
using TMS as the internal standard. The 13C NMR spectra were re-
corded on 200 NMR spectrometer (50 MHz), 400 NMR spectrome-
ter (100 MHz), and 500 NMR spectrometer (125 MHz). Mass
spectra were taken on a MS-TOF mass spectrometer. The IR spectra
were recorded on a FT-IR spectrometer. Column chromatographic
separations were carried out on silica gel (60–120, 200–400 and
mer, 93% for the (S)-isomer]. ½a D25
¼ þ17:4 (c 1, CHCl3) for the
ꢁ
(R)-isomer, ½a 2D5
ꢁ
¼ ꢀ16:7 (c 1, CHCl3) for the (S)-isomer; 1H NMR
(CDCl3, 200 MHz) d 1.28 (d, J = 8 Hz, 3H), 2.36 (s, 3H), 2.92 (sextet,
J = 8 Hz, 1H), 3.67 (d, J = 6 Hz, 2H), 7.00–7.25 (m, 4H); 13C NMR
(CDCl3, 50 MHz) d 17.7, 21.0, 42.0, 68.6, 127.3 (2 Carbons), 129.3
(2 Carbons), 136.0, 140.6; ESIMS (m/z) 151 [M+H]+; IR (CHCl3) mmax
100–200 mesh).
Commercially
available
(DHQ)2PHAL,
3320, 1606, 1515 cmꢀ1
.
(DHQD)2PHAL, OsO4, Pd-C, Pd(OH)2, HTIB, t-BuOK, and TMSCHN2
were used.
4.2.3. 1-Iodo-2-(4-methylphenyl) propane 6
To a stirred solution of alcohol 5 (3.9 g, 26 mmol) together with
triphenyl phosphine (8.86 g, 33.8 mmol) and imidazole (2.30 g,
33.8 mmol) in methylene dichloride (40 mL), iodine (8.59 g,
33.8 mmol) was added in three equal portions at 10 °C and the
solution was allowed to warm at 25 °C and stirred for 4 h. After
completion of the reaction, petroleum ether (40 mL) was added
to the reaction mixture and then filtered through Celite and
washed with petroleum ether–ethyl acetate (10:1 mL). The com-
bined filtrate was evaporated under reduced pressure and the res-
idue obtained was purified using 60–120 silica gel column
chromatography (petroleum ether) to obtain compound 6 as a
4.2. Experimental procedures and tabulated spectroscopic data
4.2.1. 2-(p-Tolyl)propane-1,2-diol 4
To
a stirred solution of potassium ferricyanide (22.3 g,
3.0 mmol) and potassium carbonate (9.4 g, 3.0 mmol) in water
(150 mL) was added methane sulfonamide (2.2 g, 1.1 mmol) fol-
lowed by tert-butanol (150 mL) and then allowed to stir until the
suspension became clear. Next, ligand (DHQD)2PHAL [for the (R)-
isomer] or (DHQ)2PHAL [for the (S)-isomer] (0.055 g, 4.0 mol %) fol-
lowed by 1 M solution of osmium tetraoxide in tert-butanol
(0.010 mL, 1.0 mol %) were added at 0 °C and the resulting suspen-
sion was stirred until an orange color was obtained. To this mix-
thick oil (5.4 g, 82%). ½a D25
¼ þ30:1 (c 1, CHCl3) for the (R)-isomer,
ꢁ
½
a 2D5
ꢁ
¼ ꢀ29:7 (c 1, CHCl3) for the (S)-isomer; 1H NMR (CDCl3,
ture was added p-methyl
a-methyl styrene 3 (3.0 g, 1.0 mmol) in
200 MHz) d 1.43 (d, J = 8 Hz, 3H), 2.36 (s, 3H), 3.03 (sextet,
J = 8 Hz, 1H), 3.23–3.50 (m, 2H), 7.05–7.20 (m, 4H); 13C NMR
(CDCl3, 50 MHz) d 14.9, 21.2, 21.7, 42.1, 126.6 (2 Carbons), 129.3
(2 Carbons), 136.3, 141.3; ESIMS (m/z) 301 [M+K]+; IR (CHCl3) mmax
a dropwise manner. The resultant heterogeneous suspension was
stirred vigorously at 0 °C until the reaction was complete, as mon-
itored by TLC (24 h). Sodium sulfite (5 g) was added slowly to the
reaction mixture and the resulting suspension stirred at room tem-
perature for 1 h. The reaction mixture was transferred into a
100 mL separatory funnel and extracted with ethyl acetate
(4 ꢃ 20 mL). The organic layer was washed with brine then dried
over anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure to furnish a residue. The residue obtained was
purified by using 60–120 silica gel column chromatography, (30%
ethyl acetate–petroleum ether) to furnish diol 4 as a colorless oil
[3.36 g, 89%, 99% ee for the (R)-isomer, 97% ee for the (S)-isomer
3012, 2925, 1514, 668 cmꢀ1
.
4.2.4. Diethyl 2-(2-(p-tolyl)propyl)malonate 7
To a stirred suspension of sodium hydride (60% dispersion in
mineral oil, 1.12 g, 28 mmol) in anhydrous DMF (10 mL) at 0 °C
was added diethyl malonate (4.25 mL, 28 mmol) in a dropwise
manner. After 30 min, iodo compound 6 (5.2 g, 20 mmol) in anhy-
drous DMF (5 mL) was added dropwise over a period of 10 min fol-
lowed by a catalytic amount of tetrabutyl ammonium iodide
(10 mol %) after which the reaction mixture was heated at 120 °C
for 10 h. The reaction mixture was then allowed to cool to room
temperature and diluted with ethyl acetate. The organic layer
was washed with brine then dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure to furnish a res-
idue. The residue obtained was then purified by flash column chro-
matography using 60–120 silica gel (5% ethyl acetate–petroleum
ether) to furnish the diester compound 7 as a viscous oil (5.19 g,
½
a 2D5
ꢁ
¼ ꢀ10:7 (c 1, CHCl3)] for the (R)-isomer, ½a D25
¼ þ10:5 (c 1,
ꢁ
CHCl3 for the (S)-isomer); 1H NMR (CDCl3, 200 MHz) d 1.46 (s,
3H), 2.33 (s, 3H), 2.80 (br s, 2H), 3.54 (d, J = 11 Hz, 1H), 3.71 (d,
J = 11 Hz, 1H), 7.13 (d, J = 8 Hz, 2H), 7.29 (d, J = 8 Hz, 2H); 13C
NMR (CDCl3, 50 MHz) d 21.0, 25.9, 70.8, 74.8, 125.0 (2 Carbons),
129.0 (2 Carbons), 136.5, 142.2; ESIMS (m/z) 189 [M+Na]+; IR
(CHCl3) mmax 3448, 3049, 1216, 1040 cmꢀ1
.
4.2.2. 2-(4-Methylphenyl)propanol 5
88%). ½a 2D5
ꢁ
¼ þ22:4 (c 1, CHCl3) for the (S)-isomer, ½a D25
¼ ꢀ22:2
ꢁ
4.2.2.1. Method A: with Raney Ni.
2-(p-tolyl)propane-1,2-diol
To a stirred solution of (R)-
(0.850 g, 20 mmol) in ethanol
(c 1, CHCl3) for the (R)-isomer; 1H NMR (CDCl3, 200 MHz) d 1.05–
1.43 (m, 9H), 2.00–2.27 (m, 2H), 2.33 (s, 3H), 2.54–2.81 (m, 1H),
3.14 (dd, J = 10 and 6 Hz, 1H), 4.00–4.30 (m, 4H), 6.95–7.20 (m,
4H); 13C NMR (CDCl3, 50 MHz) d 14.2, 21.0, 22.6, 29.7, 37.0, 37.4,
50.3, 61.2, 127.0 (2 Carbons), 129.2 (2 Carbons), 135.8, 142.3,
169.3; ESIMS (m/z) 315 [M+Na]+; IR (CHCl3) mmax 3021, 1744,
1724 cmꢀ1, HRMS (EI) calculated for C17H25O4 [M+H]+ 293.1752,
found 293.1747.
4
(20 mL) was added freshly prepared Raney Ni (2 g, 80 mmol) at
25 °C and the reaction mixture was heated at reflux for 3 h. After
completion of the reaction, it was allowed to cool at room temper-
ature, the catalyst was filtered off through a bed of Celite and the
residue was washed with ethanol (3 ꢃ 5 mL). The combined filtrate
was evaporated under reduced pressure and the residue was puri-
fied using 60–120 silica gel column chromatography (5% ethyl ace-
tate–petroleum ether) to afford alcohol (S)-5 as a colorless oil
4.2.5. 4-(p-Tolyl)pentanoic acid 8
(0.663 g, 78%, 86% ee). ½a D25
¼ ꢀ15:1 (c 1, CHCl3).
ꢁ
To a solution of diester compound 7 (5 g 17.1 mmol) in water
(20 mL) and ethanol (20 mL) was added solution of KOH (3.83 g,
68.4 mmol) in 10 mL of water and the reaction mixture was stirred
for 2–3 h at room temperature until the emulsion became clear.
4.2.2.2. Method B: with H2, Pd/C.
To a stirred solution of 2-
(p-tolyl)propane-1,2-diol 4 (0.110 g, 20 mmol) in ethanol (5 mL)

1414
S. P. Chavan, H. S. Khatod / Tetrahedron: Asymmetry 23 (2012) 1410–1415
The ethanol was removed under reduced pressure and the aqueous
solution was neutralized with 10% HCl, extracted with diethyl
ether (3 ꢃ 10 mL), dried over anhydrous sodium sulfate, and fil-
tered. Removal of the solvent under reduced pressure afforded
the diacid. This crude product was used as such for further decar-
boxylation, and was heated at 140 °C for 4 h. The residue was dis-
solved in DCM (2.5 mL) and passed through silica gel flash column
chromatography (10% ethyl acetate–petroleum ether) to furnish
acid 8 as a viscous oil [2.52 g, 78%, 92% ee for the (S)-isomer, 97%
1H), 7.07 (d, J = 8 Hz, 1H), 7.15 (d, J = 8 Hz, 1H), 7.47 (s, 1H);
13C NMR (CDCl3, 100 MHz) d 21.2, 22.4, 30.3, 31.8, 33.0, 107.6,
124.8, 128.0, 128.8, 134.1, 135.0, 139.2, 143.9; ESIMS (m/z) 227
[M+ Na+MeOH]+; IR (CHCl3) mmax 1629, 1217 cmꢀ1
.
4.2.8. 3,9-Dimethyl-8,9-dihydro-5H-benzo[7]annulen-6(7H)-
one 11
4.2.8.1. Method A.
Compound 9 (1.20 g, 33.6 mmol) was sus-
pended in Et2O (34 mL) and cooled to 0 °C under a nitrogen atmo-
sphere. Next, BF3.OEt2 (4.70 mL, 37.1 mmol) was added followed
by the dropwise addition of TMSCHN2 (18.5 mL, 37.0 mmol). The
mixture was stirred at 0 °C for 45 min after which saturated aq.
NaHCO3 (100 mL) was added carefully. The two layers were sepa-
rated and the aqueous layer was extracted with diethyl ether
(3 ꢃ 20 mL). The combined organic layer was washed with water
and brine, dried over anhydrous sodium sulfate, filtered, and con-
centrated under reduced pressure to furnish a yellow oil, which
was purified by using 60–120 silica gel column chromatography,
(5% ethyl acetate–petroleum ether) to give compound 11 as a light
yellow oil (0.635 g, 49%).
ee for the (R)-isomer]. ½a D25
¼ þ14:2 (c 1, CHCl3) for the (S)-isomer,
ꢁ
½
a 2D5
ꢁ
¼ ꢀ14:5 (c 1, CHCl3) for the (R)-isomer; 1H NMR (CDCl3,
200 MHz) d 1.31 (d, J = 6 Hz, 3H), 1.77–2.13 (m, 2H), 2.26 (t,
J = 8 Hz, 2H), 2.36 (s, 3H), 2.59–2.86 (m, 1H), 6.95–7.30 (m, 4H),
10.4 (s, 1H); 13C NMR (CDCl3, 50 MHz) d 21.0, 22.3, 32.3, 32.9,
38.8, 126.8 (2 Carbons), 129.2 (2 Carbons), 135.7, 143.0, 180.1;
ESIMS (m/z) 263 [M+K+MeOH]+; IR (CHCl3) mmax 1707, 1217 cmꢀ1
.
4.2.6. 4,7-Dimethyl-3,4-dihydronaphthalen-1(2H)-one
(trinorsesquiterpene) 9
Acid 8 (2.4 g, 12.5 mmol) was dissolved in the minimum
amount of freshly distilled trifluoroacetic acid (8 mL) in
a
25 ml round bottom flask under a nitrogen atmosphere. To this
solution, freshly distilled trifluoroacetic anhydride (10.6 g,
15 mmol) was added dropwise at 0 °C with constant stirring.
The reaction mixture was then allowed to warm to room tem-
perature and stirred for 3 h. After completion of the reaction, it
was neutralized with the saturated sodium bicarbonate solution.
The aqueous layer was extracted with ethyl acetate (3 ꢃ 5 mL),
dried over anhydrous sodium sulfate, filtered, and the solvent
was evaporated under reduced pressure to obtain a residue.
The residue obtained was purified by using 60–120 silica gel col-
umn chromatography, (5% ethyl acetate–petroleum ether) to fur-
nish the trinorsesquiterpene 9 as a viscous oil [1.75 g, 83%, 96%
4.2.8.2. Method B.
To a stirred solution of 10 (1.43 g,
11.0 mmol) in methanol (40 mL) was added crystalline HTIB
(3.92 g, 10.0 mmol). The solid dissolved rapidly to give a colorless
solution. The solution was stirred at room temperature for
30 min and the solvent was then removed to obtain an oily mix-
ture. This mixture was then partitioned between CH2Cl2 (50 mL)
and H2O (25 mL) and transferred to a separatory funnel. The organ-
ic layer was separated, washed with water and brine, dried over
anhydrous sodium sulfate, filtered, and concentrated under re-
duced pressure to furnish a bright yellow oil, which was purified
by using 60–120 silica gel column chromatography, (5% ethyl ace-
tate–petroleum ether) to give tetralone 11 as a light yellow oil
[0.720 g, 82%, 93% ee for the (S)-isomer, 93.3% ee for the (R)-iso-
ee for the (S)-isomer, 93% ee for the (R)-isomer]. ½a D25
¼ ꢀ10:0 (c
ꢁ
1, CHCl3) for the (S)-isomer, ½a D25
ꢁ
¼ þ9:4 (c 1, CHCl3) for the (R)-
mer]. ½a 2D5
ꢁ
¼ þ69:2 (c 1, CHCl3) for the (S)-isomer, ½a D25
¼ ꢀ69:4
ꢁ
isomer; 1H NMR (CDCl3, 200 MHz) d 1.39 (d, J = 8 Hz, 3H), 1.77–
1.99 (m, 1H), 2.14–2.34 (m, 1H), 2.36 (s, 3H), 2.45–2.88 (m, 2H),
2.95–3.17 (m, 1H), 7.15–7.37 (m, 2H), 7.83 (s, 1H); 13C NMR
(CDCl3, 50 MHz) d 20.8 (2 Carbons), 30.8, 32.5, 36.4, 127.3,
127.5, 131.7, 134.5, 136.0, 145.9, 198.1; ESIMS (m/z) 197
(c 1, CHCl3) for the (R)-isomer; 1H NMR (CDCl3, 200 MHz) d 1.40
(d, J = 8 Hz, 3H), 1.46–1.74 (m, 1H), 1.98–2.22 (m,1H), 2.22–2.62
(m, 2H), 2.32 (s, 3H), 3.00–3.25 (m, 1H), 3.48 (d, J = 18 Hz, 1H),
3.85 (d, J = 18 Hz, 1H), 6.94 (s, 1H), 7.02–7.22 (m, 2H); 13C NMR
(CDCl3, 50 MHz) d 19.5, 20.8, 34.1, 34.2, 41.3, 49.5, 125.1, 128.2,
130.4, 133.8, 136.1, 140.0, 210.2; ESIMS (m/z) 197 [M+Na]+; IR
[M+Na]+; IR (CHCl3) mmax 1683, 1611 cmꢀ1
.
(CHCl3) mmax 1705, 1216 cmꢀ1
.
4.2.7. 1,6-Dimethyl-4-methylene-1,2,3,4-
tetrahydronaphthalene 10
4.2.9. 3,5,5,9-Tetramethyl-8,9-dihydro-5H- benzo[7]annulen-
6(7H)-one 12
To a magnetically stirred solution of 11 (0.6 g, 3.2 mmol) and
methyl iodide (2.7 g, 19.2 mmol) in anhydrous THF (5 mL) under
To a mechanically stirred mixture of methyltriphenylphos-
phonium iodide (7.67 g, 19 mmol) in dry THF (50 mL) at 0 °C
was slowly added a 1.6 M THF solution of n-BuLi (11. 9 mL,
19 mmol) under an argon atmosphere and the solution was stir-
red vigorously for 20 min. A solution of tetralone 9 (1.32 g,
7.60 mmol) in dry THF (20 mL) was then added dropwise to
the reaction mixture over a period of 5 min. The color of the
mixture gradually changed from yellow to orange. After 5 h,
the reaction was quenched by the addition of a saturated solu-
tion of NH4Cl and the resulting precipitate was filtered off
through a bed of Celite, and washed thoroughly with diethyl
ether (3 ꢃ 30 mL). The combined filtrate was washed with water,
brine, dried over anhydrous sodium sulfate, and filtered. The sol-
vent was concentrated under vacuum to obtain a residue. The
residue obtained was purified by using 60–120 silica gel column
chromatography, eluted with petroleum ether to furnish com-
pound 10 as a colorless oil [0.78 g, 60%, 92.5% ee for the (S)-iso-
a
nitrogen atmosphere, was added potassium tert-butoxide
(1.07 g, 9.6 mmol) in three equal portions over period of
a
30 min. The reaction mixture was stirred at room temperature
for 4 h, poured into an ice-water slurry and extracted with
diethyl ether (3 ꢃ 50 mL). The combined organic layer was
washed with
a
saturated sodium bicarbonate solution
(2 ꢃ 10 mL) followed by brine (2 ꢃ 10 mL), dried over anhydrous
sodium sulfate, and filtered. The solvent was removed under re-
duced pressure. The residue obtained was purified by using 60–
120 silica gel column chromatography, (5% ethyl acetate–petro-
leum ether) to furnish the ketone 12 as a colorless oil [0.602 g,
87%, 93% ee for the (S)-isomer, 93.3% ee for the (R)-isomer].
½
a 2D5
ꢁ
¼ þ32:1(c 1, CHCl3) for the (S)-isomer, ½a D25
¼ ꢀ32:3 (c 1,
ꢁ
CHCl3) for the (R)-isomer; 1H NMR (CDCl3, 200 MHz) d 1.26–
1.43 (m, 6H), 1.50 (s, 3H), 2.03–2.29 (m, 2H), 2.38 (s, 3H),
2.57–2.80 (m,1H), 2.80–3.04 (m,1H), 7.05–7.25 (m, 3H); 13C
NMR (CDCl3, 50 MHz) d 19.3, 21.3, 25.8, 26.5, 32.5, 35.9, 36.9,
52.6, 124.8, 126.0, 127.9, 136.0, 137.8, 143.9, 217.5; ESIMS (m/
mer, 93.4% ee for the (R)-isomer]. ½a D25
¼ þ3:2 (c 1, CHCl3) the
ꢁ
(S)-isomer, ½a 2D5
ꢁ
¼ ꢀ3:6 (c 1, CHCl3) for the (R)-isomer; 1H NMR
(CDCl3, 400 MHz) d 1.35 (d, J = 8 Hz, 3H), 1.60–1.75 (m, 1H),
1.98–2.13 (m, 1H), 2.38 (s, 3H), 2.45–2.56 (m, 1H), 2.62–
2.75(m, 1H), 2.91–3.57 (m, 1H), 4.96 (d, J = 2 Hz, 1H), 5.48 (s,
z) 238 [M+Na]+; IR (CHCl3) mmax 1702, 1216 cmꢀ1
.

S. P. Chavan, H. S. Khatod / Tetrahedron: Asymmetry 23 (2012) 1410–1415
1415
2004, 45, 6867; (c) Challand, B. D.; Hikino, H.; Kornis, G.; Lange, G.; de Mayo, P.
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Ecol. 2001, 27, 2397.
4.2.10. 2,5,9,9-Tetramethyl-6,7,8,9-tetrahydro-5H-
benzo[7]annulene 1a
A mixture of 12 (0.4 g, 1.85 mmol), anhydrous hydrazine hy-
drate (0.360 g, 360 ll, 7.4 mmol), and sodium hydroxide (0.296 g,
7.4 mmol) in a freshly distilled diethylene glycol (5 mL) was heated
at 150 °C. After 1 h, the excess hydrazine hydrate was removed and
the bath temperature was allowed to rise to 180 °C. Refluxing was
then continued for an additional hour. The cooled reaction mixture
was poured into ice and extracted with ether (3 ꢃ 50 mL). The
combined organic layer was washed with a saturated sodium
bicarbonate solution (2 ꢃ 10 mL) followed by brine (2 ꢃ 10 mL)
and dried over anhydrous sodium sulfate, filtered, and concen-
trated under reduced pressure. The crude product obtained was
purified by using 60–120 silica gel column chromatography,
(petroleum ether only) to furnish ar-himachalene 1 [0.242 g, 64%,
94% ee for the (S)-isomer,20 97% ee for the (R)-isomer6].
5. Mori, K. Chem. Rec. 2005, 5, 1.
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Pandey, R. C.; Dev, S. Tetrahedron 1968, 24, 3829.
8. Hossini, I.; Harrad, M. A.; Boualy, B.; Ait Ali, M.; El Firdoussi, L.; Karim, A. Green
Sustainable Chem. 2011, 1, 111.
9. (a) Chavan, S. P.; Thakkar, M.; Kalkote, U. R. Tetrahedron Lett. 2007, 48, 535; (b)
Chavan, S. P.; Thakkar, M.; Jogdand, G. F.; Kalkote, U. R. J. Org. Chem. 2006, 71,
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½
a 2D5
ꢁ
¼ þ2:9 (c 1, CHCl3) for the (S)-isomer ½a D25
¼ ꢀ2:1 (c 1, CHCl3)
ꢁ
for the (R)-isomer; 1H NMR (CDCl3, 200 MHz) d 1.36–1.46 (m, 6H),
1.50 (s, 3H), 1.55–1.95 (m, 4H), 2.38 (s, 3H), 3.22–3.44 (m, 1H), 7.03
(d, J = 8 Hz, 1H), 7.17 (d, J = 8 Hz, 1H), 7.24 (s, 1H); 13C NMR (CDCl3,
50 MHz) d 21.1, 21.3, 24.1, 29.8, 34.1, 34.5, 36.6, 39.5, 41.2, 125.4,
126.6, 127.5, 134.9, 141.1, 147.6; ESIMS (m/z) 203 [M+H]+; IR
(CHCl3) mmax 3008, 2961, 1456, 1216 cmꢀ1
.
10. Lenardão, E. J.; Botteselle, G. V.; de Azambuja, F.; Perin, G.; Jacob, R. G.
Tetrahedron 2007, 63, 6671.
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Tetrahedron: Asymmetry 1997, 8, 2517.
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K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem.
1992, 57, 2771.
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S. B.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 5611.
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and references cited therein.
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Acknowledgements
H.S.K. thanks CSIR, New Delhi, for the award of a research
fellowship and Dr U.R. Kalkate for helpful discussions. S.P.C. thanks
NCL in-house project for financial support. We thank the Takasan-
go International Company, Japan for the generous gift of chiral
citronellal, Dr Kenji Mori for providing us with GC data for (R)-
ar-himachalene and (Mrs.) S. S. Kunte from NCL, Pune, for the HPLC
data.
References
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47.9 min = 97.1%, tR: 48.8 min = 2.8%.
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