A diastereoselective synthesis of (1SR,3SR,7RS)-3-methyl-a-himachalene, the sex

pheromone of the sandy, Lutzomyia longipalpis (Diptera: Psychodidae)

Samuel Dufour, Pascalie Castets, John A. Pickett, Antony M. Hooper
*
Biological Chemistry Department, Centre for Sustainable Pest and Disease Management, Rothamsted Research, Harpenden, Hertfordshire AL5 2JQ, UK
a r t i c l e i n f o
Article history:
Received 14 November 2011
Received in revised form 20 March 2012
Accepted 10 April 2012
Available online 19 April 2012
Keywords:
3-Methyl-a-himachalene
a-Himachalene
Lutzomyia longipalpis
Sex pheromone
Diastereoselective synthesis
a b s t r a c t
The sandy, Lutzomyia longipalpis, vectors the causative agent of visceral leishmaniasis in the New World.
The male-produced pheromone, (1S,3S,7R)-3-methyl-a-himachalene provides an opportunity for pest
managing this pest problem by inuencing the behaviour of the biting female. Previous syntheses of the
pheromone have all focused on a late stage DielseAlder cyclisation to generate the bicyclic cis-hi-
machalene skeleton. By adopting a new retrosynthetic analysis that depends on an early stage
DielseAlder cyclisation, the number of steps has been reduced to ten, of which ve are catalytic and so
provides access to quantities suitable for eld-scale experiments.
2012 Elsevier Ltd. All rights reserved.
1. Introduction
The sandy, Lutzomyia longipalpis (Diptera: Psychodidae) is the
vector of the protozoan parasite Leishmania chagasi (Kinetoplas-
tida: Trypanosomatidae), the causative agent of visceral leish-
maniasis in the New World.
1
The parasite is transmitted by biting
females seeking a blood meal, to aid egg development, after
mating in leks formed by males, which attract females through the
release of a pheromone.
2
Amongst the Brazilian population, the
sex pheromone structure is different among biochemical pheno-
types (chemotypes). The pheromone structures elucidated so far
include the Lapinha chemotype, (S)-9-methylgermacrene B,
3
and
the Jacobina chemotype, (1S,3S,7R)-3-methyl-a-himachalene (1).
4
A facile synthesis, suitable for scale-up, would allow production of
the sex pheromone for lures to attract the biting females and
therefore provides the potential to reduce infection rates in
humans. The structure of the Lapinha chemotype pheromone, (S)-
9-methylgermacrene B, has been veried through total synthesis
both racemically
5
and enantiospecically.
6
In this case, the large
number of transformations were unsuitable for large-scale syn-
thesis, however, we subsequently developed a route from ger-
macrone, isolated fromthe essential oil of the renewable resource,
Geranium macrrorhizum, that is suitable for scale-up.
7
The struc-
ture of the Jacobina pheromone was also veried by total
synthesis both racemically
8
and enantioselectively.
9,10
Behav-
ioural and electrophysiological work demonstrated that of the
eight isomers of 3-methyl-a-himachalene, only one was natural
and biologically active while the other isomers would not
interfere with the biological activity, as they themselves were not
active.
11
These and other syntheses of 3-methyl-a-himachalene all
required a late-stage DielseAlder reaction to generate the hima-
chalene ring-system (Fig. 1),
12
and the only enantioselective syn-
thesis of a-himachalene also used an enantioselective late-stage
DielseAlder reaction.
13
In the work reported here, we discon-
nected the himachalene skeleton to generate an early, monocyclic
DielseAlder intermediate (Fig. 1). Although this appears less ele-
gant initially, the stereoselectivity of the DielseAlder reaction was
expected to be higher than the tethered late-stage reaction, while
the predominantly catalytic reactions used for the rest of the
synthesis would make it shorter (ten steps) and more efcient for
scale-up.
The disconnection approach shown (Fig. 1) reveals a synthetic
route with an early stage DielseAlder reaction to construct the six-
membered ring with the seven-membered ring generated later by
a RCMreaction. Ring junction diastereoselectivity is predicted to be
cis through a concerted DielseAlder mechanism. The 3-methyl
group would then be introduced either by a diastereoselective
methylation reaction (R]H) of the reduced norhimachalene ketone
or by methylation of the enol intermediate generated by 1,4 re-
duction of the unsaturated ketone. A third option is diaster-
eselective protonation after 1,4 reduction of the methylated
unsaturated ketone (R]Me).
* Corresponding author. Tel.: 44 1582 763133; fax: 44 1582 762595; e-mail
addresses: tony.hooper@rothamsted.ac.uk, tony.hooper@bbsrc.ac.uk (A.M. Hooper).
Contents lists available at SciVerse ScienceDirect
Tetrahedron
j ournal homepage: www. el sevi er. com/ l ocat e/ t et
0040-4020/$ e see front matter 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.037
Tetrahedron 68 (2012) 5102e5108
2. Results and discussion
Following the disconnection approach proposed in Fig. 1, the
synthesis was undertaken as shown in Scheme 1. Synthesis of the
triene 3 was achieved from a commercially available mixture of
ethyl chrysanthemate ester isomers. LiAlH
4
reduction was followed
by catalytic TPAP oxidation, which could be completed using 2%
catalyst, to yield 2. Acid catalysed rearrangement with p-TsOH
generated an aldehyde with the artemesyl carbon skeleton,
14
which
underwent Wittig chemistry to give triene 3 in 41% yield over 4
steps (Scheme 1).
The DielseAlder cyclisation could be catalysed by a range of
Lewis acids (20% SnCl
4
.5H
2
O, ZnCl
2
or ZnBr
2
), which all gave only
one detectable regioisomer and high diastereoselectivity. The cat-
alyst of choice was ZnCl
2
(Scheme 1). This gave a endo:exo ratio of
16:1, which demonstrated an improvement on the diaster-
eoselectivity compared to late-stage DielseAlder selectivity of
4.6:1.
8
In the rst instance, intermediate 4-endo was transformed
into a-himachalene by reaction with vinylmagnesium bromide,
ring-closing metathesis (RCM) using Grubbs rst generation cat-
alyst, followed by TPAP oxidation of the alcohol to give enone 7a in
75% yield over 4 steps. RCM was performed at the allylic alcohol
H
H
O
H
H
OH
H
H
O
H
H
R
O
OEt
1. Reduce
2. TPAP
3. p-TsOH
4. Wittig
Early-stage
Diels-Alder
1. Grignard
2. RCM
TPAP
1. Reduce
(methylate)
2. Methylenate
(1SR,3SR,7RS)-1 R = H, Me
O
Late-stage
Diels-Alder reaction
O
Fig. 1. Retrosynthetic analysis for the disconnection of 3-methyl-a-himachalene via an early stage DielseAlder reaction.
H
O
H
H
H
O
H
H
H
O
4-endo 4-exo
H
H
H
H
H
H
O
OEt
O
iii) p-TsOH,
benzene,
iv) P(Ph)
3
CH
2
v) Acrolein,
Lewis acid cat., 20%
CH
2
Cl
2
+
SnCl
4.
5H
2
O 95% endo:exo 10:1
ZnBr
2
84% endo:exo 10:1
ZnCl
2
95% endo:exo 16:1
5a, R = H; 95%
5b, R = Me; 95%
viii) TPAP, NMO
R
R R
7a, R = H; 98%
7b, R = Me; 91%
i) LiAlH
4
ii) TPAP, NMO
vi)
OH
vii) Grubbs' first
generation catalyst,
benzene
6a, R = H; 85%
6b, R = Me; 76%
OH
2 3
94% 2 steps 43% 2 steps
MgBr R
Scheme 1. Synthesis of the norhimachalene and normethylhimachalene carbon skeletons.
S. Dufour et al. / Tetrahedron 68 (2012) 5102e5108 5103
stage (5a) rather than after oxidation of the alcohol as the reaction
proceeded more smoothly. The synthesis of a-himachalene could
be completed by reduction of the double bond with L-Selectride
and methylenation with Tebbe reagent,
4
which occurred smoothly
with yields of 76% and 50%, respectively (Scheme 2). The overall
yield of a-himachalene was 12% from ethyl chrysanthemate.
In order to adapt this synthesis to produce the desired phero-
mone with the extra stereogenic centre at the 3-methyl position,
we proposed that the cis-ring fusion would direct methylation of
the intermediate formed by L-Selectride onto the top face of 7a.
This approach, however, was unsuccessful with the intermediate
resistant to methylation even at 0

C and when forced, the only
isolated product was the incorrect diastereoisomer (1SR,3RS,7RS)-
8b. As a result of this we attempted to alkylate a lithium enolate of
8a, analogous to the intermediate generated in the L-Selectride
approach. Again, the substrate was resistant to alkylation at low
temperatures and at 0

C the only isolable product was again the
incorrect diastereoisomer (1SR,3RS,7RS)-8b.
As late-stage methylation proved problematic and only gener-
ated methylation on the back face of the molecule, we synthesised
the unsaturated ketone 7b, in which the methyl group is already
present. Surprisingly, Grignard addition to 4-endo with iso-
propenylmagnesium bromide produced only one detectable di-
astereoisomer, which was acetylated and the product characterised
as (1SR,2SR,7RS)-10 by 1D selective GOESY NMR spectroscopy. The
H-1 proton of 10 could be relaxed by irradiating one of the 6-Me
groups and so is on the same face, while the other 6-Me group
relaxed the acetate moiety (Fig. 2) and so is on the opposite face.
As quenching the L-Selectride intermediate of 7a produced back
face methylation we proposed by analogy back face protonation
would occur with 7b under the same conditions to yield the desired
isomer (1SR,3SR,7RS)-8b. After a normal quench the product was
a 3:1 mixture of 8b isomers but again, the major product was the
incorrect isomer after protonation on the top face. The best results
were obtained by a reverse quench of the reaction after it was held
at 78

C for 4 h. Under such conditions only 1,4-reduction oc-
curred and ketone reduction was prevented. This produced the two
diastereoisomers in a 1.4 (1SR,3RS,7RS)-8b:1 (1SR,3SR,7RS)-8b ratio
(Scheme 3). Although unfavourable, previous diastereoselective
synthetic routes are even less favourable giving the ratio of 8b
isomers as 1.75:1 when generated through DielseAlder chemistry.
8
The desired isomer (1SR,3SR,7RS)-8b was unstable in solution
and in time produced an insoluble white solid unlike its di-
astereoisomer (1SR,3RS,7RS)-8b. After the two diastereoisomers
were separated by ash column chromatography, methylenation
was attempted with Tebbe reagent as described by the literature
procedures and analogous to our synthesis of a-himachalene
(above).
8,9
However, in our hands we were only able to isolate
(1SR,3RS,7RS)-1, the product from methylenation of the undesired
isomer, while the desired product (1SR,3SR,7RS)-1 was obtained
only very slowly and in poor yield. Adding an excess of reagent,
warming the reagent and preparing fresh Tebbe reagent were all
unsuccessful. Freshly prepared Lombardos reagent was successful
on a small scale but could not be applied on larger synthetic scales.
Finally, TiCH
2
MgCl
2
$THF complex was freshly prepared and used to
methylenate (1SR,3SR,7RS)-8b to (1SR,3SR,7RS)-1, which could be
carried out on a gramscale. The stereochemistry of the product was
veried by 1D GOESY NMR spectroscopy. Irradiation of the H-1
proton relaxed H-7, verifying the cis ring junction, and the 6-Me
group on the same face. The other 6-Me group, when irradiated,
relaxed H-3 demonstrating H-3 to be on the opposite face to H-1
and H-7 (Fig. 2). The structure and purity of the product was also
veried by comparison with literature data for the natural product
and by gas chromatographic analysis.
3. Conclusion
This synthesis produces the L. longipalpis pheromone
(1SR,3SR,7RS)-1 in 10 steps. It is amenable to large scale prepa-
rations due to its diastereoselectivity and use of catalysis to reduce
the number of steps, reagents and purications. The sequence
could be adapted to an enantioselective synthesis to double the
active component if the DielseAlder reaction could be performed
enantioselectively. We have previously shown that small amounts
of diasteroisomeric impurities do not interfere with biological
activity induced by the pheromone.
11
Therefore, this work de-
scribes a route, by which quantities suitable for studying eld
monitoring or eld trapping of the disease vector can be obtained.
4. Experimental
4.1. General
Nuclear magnetic resonance was performed using a Bruker
Avance 500 MHz instrument and deuteriochloroform as solvent.
Mass spectra were recorded on a Mat95 XP magnetic sector mass
spectrometer (Thermo Finnigan). Ionisation was by electron impact
at 70eV in positive ion mode with a source temperature of 220

C.
Infra-red spectra were recorded on a PerkineElmer Spectrum 100
FTIR spectrometer. Column chromatography was performed on
H
H
O
H
H
ix) L-Selectride
7a 9
H
H
O
x) Tebbe reagent
8a
76% 69 %
Scheme 2. Synthesis of a-himachalene.
O
H
H
H
O
10
H
H
H
(1SR,3SR,7RS)-1
Fig. 2. Key NOE correlations dening the relative stereochemistry of the acetate (10),
and pheromone (1SR,3SR,7RS)-1.
S. Dufour et al. / Tetrahedron 68 (2012) 5102e5108 5104
silica gel (220e400 mesh, Fluka) and silica gel Merck 60 F
254
plates
were used for TLC. Solvents were dried by distillation over CaH
2
(benzene, dichloromethane) or sodium wire (tetrahydrofuran).
Chiral GC was performed using a b-cyclodextrin column
(30 m0.25 mm id25 mm lm thickness) operated from 40

C to
180

C at 3

C/min and held at 180

C for a further 30 min.
4.1.1. Chrysanthemyl aldehyde (2). To a suspension of LiAlH
4
(3.87 g, 2.0 equiv, 0.10 mol) in THF (170 mL) under nitrogen at 0

C
was added dropwise a solution of ethyl chrysanthemate (mixture of
isomers, 10.0 g, 0.051 mol) in THF (50 mL). The reaction mixture
was stirred at room temperature overnight then quenched by
careful addition of water (4 mL), NaOH (15%, 4 mL) and water
(12 mL). The aluminium salts formed were removed by ltration
through Celite and the solution was dried over MgSO
4
. The solvent
was evaporated to give a quantitative yield of crude chrysanthemyl
alcohol (mixture of isomers, 7.85 g) as a clear, colourless oil, R
f
0.47
(ethyl acetate/hexane 2:3);
IR (neat) n
max
3324, 1448, 1376, 1019, 845 cm
1
; d
H
(500 MHz,
CDCl
3
) major isomer 4.87 (1H, d, J 8.1, ]CH), 3.77 (1H, dd, J 6.6, 11.4,
CHHOH), 3.55 (1H, dd, J 8.5, 11.4, CHHOH), 1.70 (3H, s, CH
3
), 1.67 (3H,
s, CH
3
), 1.15 (3H, s, CH
3
), 1.11 (1H, dd, J 5.3, 8.1, cyclopropaneeCH),
1.06 (3H, s, CH
3
), 0.83 (1H, ddd, J 8.5, 6.6, 5.3, cyclopropaneeCH);
minor isomer 4.96 (1H, d, J 8.2, ]CH), 3.67 (1H, dd, J 7.6, 11.6,
CHHOH), 3.61 (1H, dd, J 8.0, 11.6, CHHOH), 1.73 (3H, s, CH
3
), 1.70 (3H,
s, CH
3
), 1.38 (1H, dd, J 8.2, cyclopropaneeCH), 1.12 (3H, s, CH
3
),
1.07e1.04 (1H, m, cyclopropaneeCH), 1.04 (3H, s, CH
3
); d
C
(125 MHz, CDCl
3
) major isomer 133.0, 123.5, 63.5, 35.1, 28.6, 25.6,
22.7, 21.3, 18.3, 15.5; minor isomer 135.0, 119.1, 60.4, 31.0, 28.8, 26.2,
25.8, 22.3, 20.8, 18.4; EIMS (rel intensity) m/z 154 (M

, 8), 123 (100),

111 (10), 93 (18), 81 (59), 69 (14), 67 (14), 55 (18); EI-HRMS m/z
calcd for C
10
H
18
O [M]

154.1358, found 154.1359.

Without further purication, a solution of the alcohol (7.12 g,
46.2 mmol) in CH
2
Cl
2
(20 mL) was added dropwise to a mixture of
TPAP (324 mg, 0.92 mmol), NMO (10.90 g, 92 mmol) and 4

A mo-
lecular sieves in CH
2
Cl
2
(150 mL). The mixture was stirred over-
night at room temperature and was then ltered through a pad of
silica. The solvent was removed. The crude residue was puried by
column chromatography on silica gel, eluting with petroleEtOAc
(95:5), to give the corresponding aldehyde 2 (6.58 g, 94%) as a clear,
colourless oil; R
f
0.67 (ethyl acetate/hexane 1:4); IR (neat) n
max
1696, 1450, 1378, 1111, 845 cm
1
; d
H
(500 MHz, CDCl
3
) major isomer
9.37 (1H, d, J 5.5, CHO), 4.89 (1H, dm, J 7.9, ]CH), 2.30 (1H, dd, J 5.1,
7.9, cyclopropaneeCH), 1.69 (3H, s, CH
3
), 1.67 (3H, s, CH
3
), 1.59 (1H,
dd, J 5.1, 5.5, CHCHO), 1.30 (3H, s, CH
3
), 1.14 (3H, s, CH
3
); minor
isomer 9.30 (1H, d, J 6.7, CHO), 5.34 (1H, dm, J 7.5, ]CH), 2.06 (1H, t,
J 7.5, cyclopropaneeCH), 1.71 (3H, s, CH
3
), 1.73e1.70 (1H, m,
CHCHO), 1.66 (3H, s, CH
3
), 1.35 (3H, s, CH
3
), 1.18 (3H, s, CH
3
); d
C
(125 MHz, CDCl
3
) major isomer 200.9, 136.0, 120.2, 45.1, 34.6, 31.5,
25.6, 22.1, 21.6, 18.4; minor isomer 202.3, 137.2, 117.1, 40.9, 35.4,
29.6, 28.6, 25.6, 18.4, 15.9; EIMS (rel intensity) m/z 152 (M

, 3), 123
(100), 111 (16), 109 (16), 107 (31), 95 (26), 81 (55), 69 (22), 67 (26),
55 (26); EI-HRMS m/z calcd for C
10
H
16
O [M]

152.1201, found
152.1199.
4.1.2. (5E)-4,4,7-Trimethylocta-1,5,7-triene (3).
14
To a solution of
aldehyde 2 (5.20 g, 34.2 mmol) in dry benzene (200 mL), under
nitrogen, was added dried 4

A molecular sieves (1.00 g) and a cat-
alytic amount of dried p-TsOH(60 mg, 0.32 mmol). The mixture was
heated at 70

C for 3 h. Once the reaction cooled, water (100 mL)
was added and the aqueous layer was extracted with Et
2
O
(2100 mL). The combined organic layers were dried over MgSO
4
and ltered before the solvents were removed under reduced
pressure to give the crude intermediate compound (4.99 g, 96%) as
a light brown oil; R
f
0.65 (ethyl acetate/hexane 1:4); IR (neat) n
max
1721, 1608, 1479, 1366, 970, 676 cm
1
; d
H
(500 MHz, CDCl
3
) 9.69
(1H, t, J 3.1, CHO), 6.12 (1H, d, J 16.1, trans-CH), 5.71 (1H, d, J 16.1,
trans-CH), 4.94 (2H, s, ]CH
2
), 2.37 (2H, d, J 3.1, CH
2
), 1.76 (3H, s,
CH
3
), 1.17 (6H, s, 2CH
3
); d
c
(125 MHz, CDCl
3
) 203.2, 141.5, 137.7,
129.9, 115.9, 55.2, 35.2, 27.8 (2C), 18.6; EIMS (rel intensity) m/z 152
(M

, 6), 135 (15), 123 (73), 109 (81), 96 (77), 95 (81), 81 (80), 67 (92),
55 (56); EI-HRMS m/z calcd for C
10
H
16
O [M]

152.1201, found
152.1197.
To a suspension of methyltriphenylphosphonium bromide
(23.4 g, 65.5 mmol) in THF (100 mL) was added dropwise n-
butyllithium (2.5 M, 27.6 mL, 69.0 mmol) at 10

C. The mixture
was warmed to roomtemperature and after 30 min it was cooled to
10

C. A solution of the rearranged aldehyde (4.99 g, 32.8 mmol)
in THF (50 mL) was then added dropwise via canula and the mix-
ture stirred for 3 h at roomtemperature. Water (100 mL) was added
and the aqueous layer was extracted with Et
2
O (2100 mL). The
combined organic layers were dried over MgSO
4
, ltered and the
solvent removed under reduced pressure. The crude residue was
puried by column chromatography, eluting with petroleum ether,
to give 3 (2.20 g, 45%) as a colourless oil; R
f
0.71 (petroleum ether);
IR (neat) n
max
1682, 1640, 1609, 1467, 1437, 1383, 1363, 969, 912,
882 cm
1
; d
H
(500 MHz, CDCl
3
) 6.11 (1H, d, J 16.1, trans-CH), 5.80
(1H, ddt, J 10.2, 17.2, 7.5, H-2), 5.69 (1H, d, J 16.1, trans-CH),
5.07e5.02 (1H, m, H-1a), 5.05e5.01 (1H, m, H-1b), 4.95 (1H, br s, H-
8a), 4.94 (1H, br s, H-8b), 2.12 (2H, d, J 7.5, H-3), 1.88 (3H, s, 7-Me),
H
H
H
H
O
H
H
O
H
H
O
7b
H
H
ix) L-Selectride
(1SR,3SR,7RS)-8b
(1SR,3RS,7RS)-8b
Tebbe reagent
Ti=CH
2
MgCl
2
.THF,
(1SR,3SR,7RS)-1
(1SR,3RS,7RS)-1
Ratio 1 (1SR,3SR,7RS)-8b: 1.4 (1SR,3RS,7RS)-8b
81%
51%
84%
Scheme 3. Completion of the synthesis of the sex pheromone of Lutzomyia longipalpis (1SR,3SR,7RS)-1 and its diastereoisomer.
S. Dufour et al. / Tetrahedron 68 (2012) 5102e5108 5105
1.08 (6H, s, 2(4-Me)); d
c
(125 MHz, CDCl
3
) 142.2, 140.1, 135.5, 128.8,
116.8, 114.6, 47.5, 35.9, 27.0 (2C), 18.7; EIMS (rel intensity) m/z 150
(M

, 7), 137 (11), 123 (28), 111 (100), 97 (29), 95 (34), 85 (44), 83
(52), 71 (58), 55 (72); EI-HRMS m/z calcd for C
11
H
18
[M]

150.1409,
found 150.1401.
4.1.3. (1SR,2RS)-1-Carboxaldehyde-2-(1
0
,1
0
-dimethylbut-3
0
-enyl)-4-
methylcyclohex-3-ene (4). To a solution of ZnCl
2
(0.2 equiv, 1.00 g,
7.34 mmol) in CH
2
Cl
2
(250 mL) was added acrolein (4.0 equiv,
10.3 mL, 147 mmol), then triene 3 (5.49 g, 36.6 mmol). The reaction
was stirred overnight, then preabsorbed onto silica. Purication by
quick ltration through silica gel, eluting with petroleEtOAc (95:5)
gave 4 (7.17 g, 95%) as a clear, colourless oil. Analysis of the minor
product aldehyde signal d 9.57 (1H, d, J 2.0, CHO) and integration by
NMR showed the ratio of isomers to be 94:6, a diastereomeric ex-
cess of 88%; R
f
0.34 (diethyl ether/petroleum ether 1:19); IR (neat)
n
max
1712, 1638, 1446, 1390, 1368, 912 cm
1
; d
H
(500 MHz, CDCl
3
)
9.90 (1H, d, J 5.8, CHO), 5.78 (1H, ddt, J 10.4, 16.8, 7.5, H-3
0
), 5.50 (1H,
d, J 1.2, H-3), 5.04e5.02 (1H, m, H-4
0
a), 5.03e5,00 (1H, m, H-4
0
b),
2.67 (1H, br qu, J 3.9, H-1), 2.34e2.29 (1H, br m, H-2), 2.11e1.86 (6H,
m, H
2
-5, H
2
-6, H
2
-2
0
), 1.73 (3H, s, 4-Me), 0.87 (3H, s, Me-1
0
a), 0.84
(3H, s, Me-1
0
b); d
c
(125 MHz, CDCl
3
) 208.3, 135.2, 134.9, 121.2, 117.6,
47.5, 46.9, 45.4, 36.0, 27.4, 27.0, 25.6, 25.0, 23.8; EIMS (rel intensity)
m/z 206 (M

, 4), 191 (2), 177 (2), 165 (13), 147 (8), 137 (24), 124 (65),
109 (21), 95 (46), 93 (90), 83 (76), 67 (20), 55 (100); EI-HRMS m/z
calcd for C
14
H
22
O [M]

206.1671, found 206.1667.

4.1.4. (1SR,2RS,1
0
SR)-1-(1
0
-Hydroxyprop-2
0
-enyl)-2-(1
00
,1
00
-dime-
thylbut-3
00
-enyl)-4-methylcyclohex-3-ene (5a). To a solution of al-
dehyde 4 (1.30 g, 6.31 mmol) in THF (100 mL) at 78

C was added
dropwise vinylmagnesium bromide (9.40 mmol, 9.40 mL). The re-
action mixture was warmed to room temperature and stirred for
2 h. Water (70 mL) was added and the aqueous layer was extracted
with Et
2
O (250 mL). The combined organic layers were dried over
MgSO
4
and ltered before the solvents were removed under re-
duced pressure. The crude residue was puried by column chro-
matography on silica gel, eluting with petroleum ethereEtOAc
(9:1), to give compound 5a (1.40 g, 95%) as a clear, colourless oil; R
f
0.37 (diethyl ether/petroleum ether 1:9); IR (neat) n
max
3565, 1638,
1449, 1370, 993, 912 cm
1
; d
H
(500 MHz, CDCl
3
) 5.92e5.81 (2H, m,
H-2
0
, H-3
0
), 5.59 (1H, br s, H-3), 5.34 (1H, dt, J 17.2, 1.7. H-3a
0
), 5.16
(1H, dt, J 10.7, 1.7, H-3b
0
), 5.07 (1H, d, J 10.1, H-4a
0
), 5.06 (1H, d, J 16.9,
H-4b
0
), 4.76 (1H, br s, H-1
0
), 2.77 (1H, br s, OH), 2.35 (1H, br s, H-2),
2.29e2.27 (1H, m, H-5a), 2.18 (2H, d, J 7.5, H-2
0
), 2.10 (1H, ddd, J 2.4,
6.6, 13.7, H-6a), 2.01 (1H, br s, H-1), 1.91 (1H, dd, J 7.1, 17.9, H-5b),
1.71 (3H, s, 4-Me), 1.60 (1H, m, H-6b), 1.06 (3H, s, 2
0
-Me), 1.05 (3H, s,
2
0
-Me); d
c
(125 MHz, CDCl
3
) 139.5, 138.2, 135.3, 122.5, 117.4, 113.5,
74.1, 46.3, 45.6, 37.1, 35.6, 28.8, 25.5, 24.7, 24.5, 23.9; EIMS (rel in-
tensity) m/z 234 (M

, 1), 216 (3), 201 (3), 177 (10), 175 (10), 133 (18),
119 (10), 109 (32), 95 (100), 81 (23); EI-HRMS m/z calcd for C
16
H
26
O
[M]

234.1984, found 234.1987.

4.1.5. (1SR,2SR,7RS)-6,6,9-Trimethylbicyclo[5.4.0]undeca-3,8-dien-2-
ol (6a). To a solution of rst generation Grubbs rst generation
catalyst (28.0 mg, 0.03 mmol) in degassed benzene (80 mL) under
N
2
was added a solution of alcohol 5a (160 mg, 0.68 mmol) in
benzene (10 mL) at room temperature. The reaction mixture was
stirred for 3 h until disappearance of the starting material was
observed by TLC analysis. The solution was passed through a pad of
silica under vacuum and was rinsed with petroleum ether: EtOAc
(85:15) to give compound 6a as a clear, colourless oil (120 mg, 85%);
R
f
0.25 (diethyl ether/petroleum ether 1:4); IR (neat) n
max
3379,
1659, 1447, 1364, 907, 729 cm
1
; d
H
(500 MHz, CDCl
3
) 5.66 (1H, dt, J
11.3, 2.3, H-3), 5.54e5.49 (1H, m, H-4), 5.43 (1H, s, H-8), 4.40 (1H, br
d, J 10.1, H-2), 2.24 (1H, br s, H-7), 2.19e2.16 (1H, m, H-11a),
2.17e2.14 (1H, m, H-1), 2.10 (1H, dd, J 5.7, 15.2, H-5a), 2.07e2.00
(1H, m, H-10a), 1.93 (1H, br s, OH), 1.87 (1H, dd, J 5.9, 17.9, H-10b),
1.77 (1H, dd, J 7.5, 15.2, H-5b), 1.70 (3H, s, 9-Me), 1.58e1.52 (1H, m,
H-11b), 0.99 (3H, s, 6-Me), 0.94 (3H, s, 6-Me); d
c
(125 MHz, CDCl
3
)
137.6, 135.4, 126.8, 121.4, 68.4, 49.5, 38.1, 36.8, 34.5, 29.1, 28.2, 27.0,
26.2, 23.8; EIMS (rel intensity) m/z 206 (M

, 25), 191 (24), 188 (60),

173 (43), 163 (21), 145 (100), 119 (52), 93 (64), 91 (73), 79 (58); EI-
HRMS m/z calcd for C
14
H
22
O [M]

206.1671, found 206.1669.

4.1.6. (1SR,7RS)-6,6,9-Trimethylbicyclo[5.4.0]undeca-3,8-dien-2-one
(7a). To solution of alcohol 6a (800 mg, 3.86 mmol) in CH
2
Cl
2
(100 mL) were added NMO (905 mg, 7.73 mmol), 4

A molecular
sieves (1.00 g) and TPAP (136 mg, 0.38 mmol). The mixture was
stirred for 2 h at room temperature and was then ltered through
a pad of silica eluting with petroleum ether/EtOAc (95:5). The
solvent was removed to give the corresponding ketone 7a (780 mg,
98%) as a white, waxy solid; R
f
0.33 (diethyl ether/petroleum ether
1:9); IR (neat) n
max
1661, 164, 1447, 1366, 7484 cm
1
; d
H
(500 MHz,
CDCl
3
) 6.17 (1H, ddd, J 3.8, 5.9, 12.7, H-4), 5.96 (1H, br d, J 12.7, H-3),
5.45 (1H, s, H-8), 2.83 (1H, q, J 4.3, H-1), 2.45 (1H, dt, J 19.7, 3.8, H-
5a), 2.40e2.35 (1H, m, H-11a), 2.31 (1H, br s, H-7), 2.13 (1H, dd, J 5.9,
19.7, H-5b), 2.04e1.98 (1H, m, H-10a), 1.78 (1H, dd, J 5.9, 18.1, H-
10b), 1.65 (1H, ddd, J 3.9, 5.8, 12.6, H-11b), 1.64 (3H, s, 9-Me), 1.06
(3H, s, 6-Me), 1.05 (3H, s, 6-Me); d
c
(125 MHz, CDCl
3
) 206.1, 142.8,
136.3, 132.4, 120.2, 47.2, 45.8, 42.1, 35.8, 29.9, 27.7, 27.1, 26.2, 23.9;
EIMS (rel intensity) m/z 204 (M

, 73), 189 (43), 161 (25), 148 (20),

133 (20), 121 (52), 97 (100), 79 (47); EI-HRMS m/z calcd for C
14
H
20
O
[M]

204.1514, found 204.1517.

4.1.7. (1SR,7RS)-6,6,9-Trimethylbicyclo[5.4.0]undec-8-en-2-one
(8a). To a solution of ketone 7a (300 mg, 1.47 mmol) in dry THF
(10 mL) at 78

C was added a 1 M solution of L-Selectride in THF
dropwise (1.3 equiv, 1.90 mL, 1.90 mmol). The solution was stirred
for 4 h at 78

C, water (20 mL) was added and the aqueous layer
was extracted with Et
2
O (220 mL). The combined organic layers
were dried over MgSO
4
and ltered before the solvents were re-
moved under reduced pressure. The crude residue was puried by
column chromatography on silica gel, eluting with petroleum
ether/Et
2
O (95:5), to give 8a (230 mg, 76%) as a clear, colourless oil;
R
f
0.32 (diethyl ether/petroleum ether 1:9); IR (neat) n
max
1693,
1646, 1450, 1367, 753 cm
1
; d
H
(500 MHz, CDCl
3
) 5.55 (1H, s, H-8),
2.71 (1H, q, J 4.1, H-1), 2.52 (1H, ddd, J 2.8, 11.3, 13.8, H-3a), 2.35 (1H,
dd, J 6.8, 11.3, H-3b), 2.20 (1H, br s, H-7), 2.11e2.07 (1H, m, H-10a),
1.88e1.80 (3H, m, H-10b, H
2
-11), 1.71 (1H, dd, J 3.9, 13.5, H-5a), 1.71
(3H, s, 9-Me), 1.70e1.62 (1H, m, H-4a), 1.46 (1H, ddq, J 1.6, 2.8, 12.9,
H-4b), 1.30 (1H, dt, J 3.7, 13.5, H-5b), 1.06 (3H, s, 6-Me), 0.88 (3H, s,
6-Me); d
c
(125 MHz, CDCl
3
) 218.3, 134.4, 122.3, 48.0, 45.2, 44.6, 38.0,
36.5, 31.2, 28.9, 27.1, 25.2, 24.0, 21.7; EIMS (rel intensity) m/z 206
(M

, 100), 191 (21), 161 (21), 159 (24), 147 (42), 134 (37), 123 (50),
121 (42), 105 (41), 94 (71), 79 (60); EI-HRMS m/z calcd for C
14
H
22
O
[M]

206.1671, found 206.1677.

4.1.8. a-Himachalene (9). To a solution of ketone 8a (160 mg,
0.78 mmol) in THF (5 mL) at 78

C was added dropwise a solution
of Tebbe reagent in toluene(0.5 M, 3.10 ml, 1.55 mmol). The solution
was stirred overnight, warming to room temperature, after which
15% aqueous NaOH (5 mL) was added very slowly. The crude resi-
due was puried by a ltration through a pad of silica gel, eluting
with petroleum ether/ether (9:1), to give 9 (110 mg, 69%) as a clear,
colourless oil. R
f
0.85 (diethyl ether/petroleum ether 1:19); IR
(neat) n
max
1629, 1447, 1389, 1377, 1363, 884, 867 cm
1
d
H
(500 MHz, CDCl
3
) 5.54 (1H, s, H-8), 4.83 (1H, s, methyleneeH), 4.78
(1H, s, methyleneeH), 2.88 (1H, br s, H-1), 2.52 (1H, br dd, J 4.2, 6.5,
12,1, H-3a), 2.19 (1H, br s, H-7), 2.10 (1H, t, J 12.1, H-3b), 1.96e1.89
(2H, m, H-10a, H-11a), 1.84e1.80 (2H, m, H-10b, H-11b), 1.73 (3H, s,
9-Me), 1.74e1.68 (1H, m, H-4a), 1.65 (1H, dd, J 4.1, 13.5, H-5a),
1.42e1.32 (1H, m, H-4b), 1.23e1.18 (1H, m, H-5b), 1.06 (3H, s, 6-Me),
S. Dufour et al. / Tetrahedron 68 (2012) 5102e5108 5106
1.02 (3H, s, 6-Me); d
c
(125 MHz, CDCl
3
) 159.9, 133.9, 123.7, 111.2,
47.8, 39.9, 38.3, 36.6, 36.6, 34.8, 32.1, 28.3, 26.6, 25.1, 24.2; EIMS (rel
intensity) m/z 204 (M

, 65), 189 (60), 161 (49), 133 (47), 119 (80),

105 (66), 93 (100), 79 (55); EI-HRMS m/z calcd for C
15
H
24
[M]

204.1878, found 204.1869.

4.1.9. (1SR,2RS,1
0
SR)-1-(1
0
-Hydroxy-2
0
-methylprop-2
0
-enyl)-2-(1
00
,1
00
-
dimethylbut-3
00
-enyl)-4-methylcyclohex-3-ene (5b). To a solution of
aldehyde 4 (3.50 g, 17.0 mmol) inTHF (300 mL) at 30

C was added
isopropenylmagnesium bromide (1 M in THF, 25.5 mL 25.5 mmol)
dropwise. The reaction mixture was warmed to room temperature
and stirred for 4 h. The reaction was quenched with aqueous am-
moniumchloride (70 mL) and the aqueous layer was extracted with
Et
2
O (350 mL). The combined organic layers were dried over
MgSO
4
ltered and the solvent removed under reduced pressure.
The crude residue was puried by column chromatography, eluting
with petroleumether/EtOAc (9:1), to give 5b (3.70 g, 88%) as a clear,
colourless oil; R
f
0.74 (diethyl ether/petroleum ether 1:4); IR (neat)
n
max
3560, 1638, 1448, 1371, 994, 900 cm
1
; d
H
(500 MHz, CDCl
3
)
5.88 (1H, ddt, J 10.3, 17.0, 7.4, H-3
00
), 5.62 (1H, s, H-3), 5.22 (1H, s, H-
3
0
a), 5.09e5.06 (1H, m, H-4
00
a), 5.07e5.04 (1H, m, H-4
00
b), 4.96 (1H,
s, H-3
0
b), 4.60 (1H, s, H-1), 2.97 (1H, s, OH), 2.39 (1H, br s, H-2),
2.33e2.21 (1H, m, H-5a), 2.21 (2H, d, J 7.4, H-2
00
), 2.15 (1H, br s, H-1),
1.95 (1H, ddd, J 2.9, 7.0, 13.7, H-5b), 1.89 (1H, dd, J 7.0, 18.3, H-6a),
1.73 (6H, s, 2
0
-Me, 4-Me), 1.55 (1H, m, H-6b), 1.08 (3H, s, 1
00
-Me), 1.07
(3H, s, 1
00
-Me); d
c
(125 MHz, CDCl
3
) 145.0, 138.5, 135.4, 122.6, 117.4,
109.7, 76.4, 45.9, 45.6, 35.6, 33.6, 28.7, 25.6, 24.4, 24.3, 24.0, 20.1;
EIMS (rel intensity) m/z 248 (M

, 1), 230 (3), 215 (5), 189 (8), 177 (9),

147 (18), 137 (21), 121 (15), 109 (45), 95 (100), 81 (28); EI-HRMS m/z
calcd for C
17
H
28
O [M]

248.2140, found 248.2145.

4.1.10. (1SR,2SR,7RS)-3,6,6,9-Tetramethylbicyclo[5.4.0]undeca-3,8-
dien-2-ol (6b). To a solution of Grubbs rst generation catalyst
(300 mg, 0.36 mmol) in degassed benzene (450 mL) under N
2
at
50

C was added a solution of 5b (3.70 g, 14.9 mmol) in benzene
(50 mL). The reaction mixture was stirred overnight. The solution
was ltered through a pad of silica under vacuum, eluting with
petroleum ether/EtOAc (95:5), to give the cyclised alkene 6b
(2.49 g, 76%) as a clear, colourless oil; R
f
0.35 (diethyl ether/petro-
leum ether 1:4); IR (neat) n
max
1668, 1446, 1385, 1377, 1362, 1036,
1011, 759 cm
1
; d
H
(500 MHz, CDCl
3
) 5.49e5.46 (2H, m, H-4, H-8),
4.41 (1H, dd, J 5.8, 8.4, H-2), 2.19 (1H, br s, H-7), 2.10e2.03 (1H, m,
H-10a), 2.02e1.90 (5H, m, H-10b, H-11, H
2
-5, H-1), 1.81 (3H, s, 3-
Me), 1.72 (3H, s, 9-Me), 1.67 (1H, d, J 5.8, OH), 1.65e1.61 (1H, m,
H-11b), 0.95 (3H, s, 6-Me), 0.91 (3H, s, 6-Me); d
c
(125 MHz, CDCl
3
)
140.9, 135.3, 122.4, 122.3, 72.6, 47.3, 39.4, 38.1, 34.9, 29.9, 28.8, 27.8,
25.1, 23.8, 20.2; EIMS (rel intensity) m/z 220 (M

, 33), 218 (47), 203

(30), 177 (14), 161 (40), 135 (100), 125 (36), 119 (69), 107 (37), 93
(45), 79 (33); EI-HRMS m/z calcd for C
15
H
24
O [M]

220.1827, found
220.1821.
4.1.11. (1SR,2SR,7RS)-2-Acetoxy-3,6,6,9-tetramethylbicyclo[5.4.0]un-
deca-3,8-diene (10). Alcohol 6b (20 mg, 0.091 mmol) was added to
a solution of pyridine (0.5 mL) and acetyl chloride (0.25 ml) in Et
2
O
(10 mL) and reuxed overnight. The reaction was diluted with Et
2
O
(30 mL), extracted with water (50 mL), washed with aqueous HCl
(1 M, 20 mL), and brine (20 mL) and the ethereal solution dried
(MgSO4), ltered and the solvent removed in vacuo to yield 10
(20 mg, 84%) as a clear, colourless oil; R
f
0.32 (diethyl ether/pe-
troleum ether 1:9); IR (neat) n
max
1736, 1669, 1436, 1370, 1237,
1029 cm
1
; d
H
(500 MHz, C
6
D
6
) 5.61 (1H, br d, J 7.4, H-2), 5.57 (1H, s,
H-8), 5.52, (1H, t, J 7.2, H-4), 2.27 (1H, br s, H-7), 2.22 (1H, br s, H-1),
2.10 (1H, dd, J 7.2, 14.2, H-5a), 2.00e1.94 (1H, m, H-5b), 1.90 (3H,
obscured m, H
2
-10, H-11a), 1.89 (3H, s, MeCO
2
), 1.76 (3H, s, 3-Me),
1.73 (3H, s, 9-Me), 1.52e1.48 (1H, m, H-11b), 0.99 (3H, s, 6-Me), 0.96
(3H, s, 6-Me); d
c
(125 MHz, CDCl
3
) 170.6, 137.5, 135.3, 124.1, 122.2,
75.4, 47.4, 37.9, 36.5, 35.0, 29.8, 28.5, 27.7, 24.8, 23.7, 20.8, 20.5;
EIMS (rel intensity) m/z 262 (M

, 1), 220 (61), 202 (72), 187 (44), 159

(100), 146 (46), 125 (62), 107 (29), 94 (47), 79 (34); EI-HRMS m/z
calcd for C
17
H
26
O
2
[M]

262.1933, found 262.1932.

4.1.12. (1SR,7RS)-3,6,6,9-Tetramethylbicyclo[5.4.0]undeca-3,8-dien-
2-one (7b). To a mixture of TPAP (200 mg, 0.57 mmol), NMO
(2.55 g, 21.8 mmol) and 4

A molecular sieves (1.50 g) in CH
2
Cl
2
(150 mL), was added dropwise a solution of alcohol 6b (2.40 g,
10.9 mmol) in CH
2
Cl
2
(20 mL). The mixture was stirred for 3 h at
room temperature and was then ltered through a pad of silica,
eluting with petroleum ether/EtOAc (95:5), to yield the corre-
sponding ketone 7b (1.99 g, 84%) as a clear, colourless oil; R
f
0.42
(diethyl ether/petroleum ether 1:19); IR (neat) n
max
1665, 1654,
1448. 1366, 1084, 872, 798 cm
1
; d
H
(500 MHz, CDCl
3
) 6.20 (1H, t, J
5.2, H-4), 5.31 (1H, s, H-8), 2.90 (1H, dt, J 6.6, 3.5, H-1), 2.40e2.35
(2H, m, H-7, H-10), 2.30e2.26 (2H, m, H-5). 2.13e2.09 (1H, m, H-11),
1.80 (3H, s, 9-Me), 1.79e1.76 (1H, m, H-10), 1.65 (3H, s, 3-Me),
1.64e1.56 (1H, m, H-11), 1.04 (3H, s, 6-Me), 0.75 (3H, s, 6-Me); d
c
(125 MHz, CDCl
3
) 206.8, 138.9, 138.2, 135.6, 119.6, 47.4, 47.1, 42.3,
36.7, 28.4, 27.5, 26.5, 25.7, 23.9, 19.9; EIMS (rel intensity) m/z 218
(M

, 100), 203 (30), 175 (22), 162 (15), 147 (22), 135 (17), 121 (60),
109 (41), 93 (24), 79 (24); EI-HRMS m/z calcd for C
15
H
22
O [M]

218.1671, found 218.1663.

4.1.13. (1SR,3SR,7RS)-3,6,6,9-Tetramethylbicyclo[5.4.0]undec-8-en-2-
one (8b).
8
To a solution of ketone 7b (100 mg, 0.46 mmol) in THF
(4 mL) at 78

C was added dropwise a solution of L-Selectride
(1.0 M in THF, 0.60 mL, 0.60 mmol). The solution was stirred while
warming to room temperature over 3 h and then cooled to 78

C.
The reaction was reverse quenched by transferring it cold through
a canula into water (20 mL) and the aqueous layer then extracted
with Et
2
O (220 mL). The combined organic layers were dried over
MgSO
4
and ltered before the solvents were removed under re-
duced pressure. The crude residue was passed through a silica gel
plug, eluting with petrol-Et
2
O (95:5), to give the 8b (93 mg, 92%) as
a 1 (1SR,3SR,7RS)-8b : 1.4 (1SR,3RS,7RS)-8b mixture of di-
astereoisomers as analysed by
1
H NMR spectroscopy and chiral GC.
Separation of the diastereoisomers was performed by ash column
chromatography using 2% diethyl ether in petroleum ether to yield
clear, colourless oils.
(1SR,3RS,7RS)-8b. Chiral GC; 44.88 min; R
f
0.45 (diethyl ether/
petroleum ether 1:19); IR (neat) n
max
1701, 1452, 1389, 1376, 1365,
755 cm
1
; d
H
(500 MHz, CDCl
3
) 5.47 (1H, br s, H-8), 2.90e2.84 (1H,
m, H-3), 2.68 (1H, br s, H-7), 2.42 (1H, ddd, J 3.0, 6.2, 11.9, H-1), 2.18
(1H, ddd, J 2.8, 6.2, 13.9, H-11a), 2.02 (1H, dd, J 5.9, 17.6, H-10a),
1.93e1.86 (1H, m, H-10b), 1.70 (3H, s, 9-Me), 1.67 (1H, dq, J 13.9, 4.8,
H-4a), 1.58e1.44 (3H, m, H-5, H-11b), 1.36e1.28 (1H, m, H-4b), 1.05
(3H, d, J 6.6, 3-Me), 1.00 (3H, s, 6-Me), 0.69 (3H, s, 6-Me); d
C
(125 MHz, CDCl
3
) 216.2, 135.3, 122.0, 51.4, 44.3, 43.8, 42.1, 37.9, 31.7,
31.0, 29.7, 24.0, 23.0, 20.2, 17.0; EIMS (rel intensity) m/z 220 (M

,
79), 205 (12), 163 (6), 151 (19), 123 (100), 107 (13), 94 (53), 79 (32),
69 (12), 56 (26); EI-HRMS m/z calcd for C
15
H
24
O [M]

220.1827,
found 220.1827.
(1SR,3SR,7RS)-8b. Chiral GC; 42.01, 42.25 min; R
f
0.42 (diethyl
ether/petroleum ether 1:19); IR (neat) n
max
1702, 1451, 1389, 1375,
1365, 1187, 865 cm
1
; d
H
(500 MHz, CDCl
3
) 5.59 (1H, br s, H-8),
2.80e2.78 (1H, m, H-1), 2.70 (1H, d sextet, J 2.5, 6.6, H-3), 2.19 (1H,
br s, H-7), 2.09 (1H, ddd, J 1.7, 5.4, 10.0, H-11a), 1.90e1.86 (1H, m, H-
10a), 1.83 (1H, t, J 10.0, H-11b), 1.81e1.77 (1H, m, H-5a), 1.74 (3H, s,
9-Me), 1.75e1.70 (1H, m, H-10b), 1.45 (1H, dq, J 14.5, 3.8, H-4a),
1.36e1.30 (1H, m, H-4b), 1.27 (1H, dt, J 14.5, 3.5, H-5b), 1.10 (3H, s, 6-
Me), 0.98 (3H, d, J 6.6, 3-Me), 0.87 (3H, s, 6-Me); d
C
(125 MHz,
CDCl
3
) 219.4, 134.4, 122.4, 48.1, 46.4, 45.3, 37.3, 36.1, 31.6, 30.9, 29.7,
27.0, 24.8, 24.0, 17.1; EIMS (rel intensity) m/z 220 (M

, 80), 205 (18),

177 (10), 163 (6), 151 (23), 123 (100), 107 (18), 94 (63), 79 (37), 55
S. Dufour et al. / Tetrahedron 68 (2012) 5102e5108 5107
(18); EI-HRMS m/z calcd for C
15
H
24
O [M]

220.1827, found
220.1823.
4.1.14. (1SR,3RS,7RS)-1. 3-Methyl-a-himachalene.
8
To a solution of
ketone (1SR,3RS,7RS)-8b (80 mg, 0.36 mmol) in THF (2 mL) at
78

C was added dropwise a solution of Tebbe reagent (0.5 M in
toluene, 1.45 mL, 0.73 mmol). The solution was stirred overnight,
warming to room temperature, and quenched by adding 15%
aqueous NaOH (2 mL) very slowly. The crude residue was puried
by a ltration through a pad of Celite and then silica, eluting with
5% diethyl ether in petrol, to give (1SR,3RS,7RS)-1 (66 mg, 84%) as
a colourless oil.
Chiral GC; 39.74 min; R
f
0.80 (petroleum ether); IR (neat) n
max
1634, 1386, 1363, 885 cm
1
; d
H
(500 MHz, CDCl
3
) 5.52 (1H, br s, H-
8), 4.89 (1H, s, methyleneeH), 4.85 (1H, s, methyleneeH),
2.48e2.38 (1H, m, H-3), 2.39e2.35 (2H, m, H-1, H-7), 2.09e1.99 (3H,
m, H-10, H-11a), 1.84e1.78 (1H, m, H-4a), 1.73 (3H, s, 9-Me),
1.73e1.65 (1H, m, H-11b), 1.54 (1H, ddd, J 3.4, 8.2, 13.9, H-5a), 1.36
(1H, ddd, J 3.3, 9.7, 13.9, H-5b), 1.28 (1H, dt, J 3.3, 9.7, H-4b), 1.13 (3H,
d, J 6.9, 3-Me), 0.97 (3H, s, 6-Me), 0.83 (3H, s, 6-Me); d
c
(125 MHz,
CDCl
3
) 158.9, 133.9, 123.6, 105.4, 44.1 (2C), 42.5, 38.0, 37.4, 34.1,
32.0, 30.3, 25.1, 24.0, 23.8, 21.8. EIMS (rel intensity) m/z 218 (M

,
19), 203 (30), 175 (19), 162 (18), 148 (26), 133, (17), 121 (48), 107
(34), 94 (100), 79 (49); EI-HRMS m/z calcd for C
16
H
26
[M]

218.2035, found 218.2028.

4.1.15. (1SR,3SR,7RS)-1. 3-Methyl-a-himachalene.
8
Dry CH
2
Cl
2
(2 mL)
was added to Mg turnings (70 mg, 2.88 mmol) in a ame-dried ask.
TiCl
4
(1 Min CH
2
Cl
2
, 0.73 mL, 0.73 mmol) was added, followed by dry
THF (1 mL) dropwise. After 20 min, a solution of ketone
(1SR,3SR,7RS)-8b (80 mg, 0.36 mmol) in CH
2
Cl
2
(1 mL) was added
dropwise and the solution stirred for 48 h. The reaction was
quenched by adding saturated aqueous K
2
CO
3
(1 mL) slowly. The
crude residue was washed through a pad of Celite with diethyl ether
and then puried on ash silica, eluting with 5% diethyl ether in
petrol, to give (1SR,3SR,7RS)-1 (40 mg, 51%) as a clear, colourless oil.
Chiral GC; 36.16, 36.45 min; R
f
0.78 (petroleum ether); IR (neat)
n
max
1627, 1447, 1389, 1377, 1363, 885, 864 cm
1
; d
H
(500 MHz,
CDCl
3
) 5.54 (1H, br s, H-8), 4.84 (1H, s, methyleneeH), 4.79 (1H, s,
methyleneeH), 2.88e2.85 (1H, m, H-1), 2.30 (1H, dq, J 10.6, 6.9, H-
3), 2.16 (1H, br s, H-7), 1.92e1.86 (1H, m, H-11a), 1.83e1.78 (2H, m,
H-10), 1.78e1.74 (1H, m, H-11b), 1.70 (3H, s, 9-Me), 1.65 (1H, dt, J 4.1,
13.2, H-5a), 1.52 (1H, dm, J 13.6, H-4a), 1.25e1.18 (1H, m, H-4b),
1.17e1.11 (1H, m, H-5b), 1.04 (3H, d, J 6.9, 3-Me), 1.02 (3H, s, 6-Me),
0.99 (3H, s, 6-Me); d
c
(125 MHz, CDCl
3
) 162.2, 134.1, 124.0, 107.1,
47.6, 41.5, 37.9, 36.8, 36.5, 36.4, 35.2, 32.0, 26.7, 25.1, 24.2, 21.6; EIMS
(rel intensity) m/z 218 (M

, 29), 203 (44), 175 (60), 161 (23), 147

(26), 133 (31), 121 (56), 107 (51), 94 (100), 79 (40), 69 (32); EI-HRMS
m/z calcd for C
16
H
26
[M]

218.2035, found 218.2037.

Acknowledgements
Rothamsted Research receives grant-aided support from the
Biotechnology and Biological Sciences Research Council of the UK
(BBSRC).
References and notes
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bacchi, R.; Sano, S.; Mori, K. J. Insect Physiol. 2005, 51, 1366e1375.
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