A new diastereoselective entry to the (1S,4R)- and (1S,4S)-isomers of 4-isopropyl-1-methyl-2-cyclohexen-1-ol, aggregation pheromones of the ambrosia beetle Platypus quercivorus

Article abstract of DOI:10.1016/j.tetasy.2009.08.009

A concise diastereoselective and enantiopure route to the (1S,4R)- and (1S, 4S)-isomers of 4-isopropyl-1-methyl-2-cyclohexen-1-ol via a palladium-catalysed deoxygenation of the enol triflate derived from limonene glycol. Crown Copyright

Full text of DOI:10.1016/j.tetasy.2009.08.009

Tetrahedron: Asymmetry 20 (2009) 2149–2153
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A new diastereoselective entry to the (1S,4R)- and (1S,4S)-isomers
of 4-isopropyl-1-methyl-2-cyclohexen-1-ol, aggregation pheromones
of the ambrosia beetle Platypus quercivorus
*
Michael Blair, Kellie L. Tuck
School of Chemistry, Monash University, Clayton, VIC 3800, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2009
Accepted 11 August 2009
Available online 14 September 2009
A concise diastereoselective and enantiopure route to the (1S,4R)- and (1S, 4S)-isomers of 4-isopropyl-1-
methyl-2-cyclohexen-1-ol via a palladium-catalysed deoxygenation of the enol triflate derived from lim-
onene glycol.
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
1. Introduction
many ambrosia beetles (P. quercivorus) versus any other beetle
species, and 3.32 times as many males to females.4
Over the past two decades, the epidemic mortality of the decid-
uous oak Quercus crispula has posed a significant threat to Japan’s
forest ecosystem.1 The dieback is caused by the fungus Raffaela
quercivorus, which is transmitted by the ambrosia beetle Platypus
quercivorus (Murayama). It has recently been revealed that the
invasion of Q. crispula and subsequent boring by the beetles are
mediated by the semiochemicals (1S,4R)-4-isopropyl-1-methyl-2-
cyclohexen-1-ol (cis-2-menthen-1-ol, 1), and (1S,4S)- and (1R,4R)-
4-isopropyl-1-methyl-2-cyclohexen-1-ol (trans-2-menthen-1-ol, 2
and 20) (Fig. 1), first isolated and reported by Nakashima et al.2
The isomer (1S,4R)-1 is the major aggregation pheromone of the
ambrosia beetle. (1S,4S)-2 and (1R,4R)-20 were also identified as
minor components of P. quercivorus, although their precise semio-
chemical role is yet to be determined.
The synthesis of highly enriched single enantiomers of these
molecules 1 and 2 has not been facile.3 Base-promoted isomerisa-
tion of epoxides typically leads to the undesired exo-alkene.5 The
(1S,4R)-1 isomer can be synthesised in one step by methylation
of (R)-cryptone. However, this reaction is unselective, and pro-
duces a diastereomeric mixture of (1S,4R)-1 and (1R,4R)-20 from
which (1S,4R)-1 could be obtained in a 44% yield after chromato-
graphic purification and distillation (Scheme 1).3 The enantiomeric
purity of (1S,4R)-1 was determined as 93.3% ee and it was contam-
inated with small amounts of (1R,4R)-20. Furthermore the synthesis
of (R)-cryptone is accomplished in six steps (28% overall yield), uti-
lising (S)-perillyl alcohol as the chiral pool starting material, via a
modified literature procedure for the preparation of 4-isopro-
penyl-2-cyclohexenone.6
OH
OH
OH
OH
O
MeLi
(1S,4R)-1
LiBr, Et2O, THF
6 steps
28% yield
44%
(1S,4R)-1
(1S,4S)-2
(1R,4R)-2'
(S)-perillyl alcohol
(R)-cryptone
Figure 1. The frass volatiles of P. quercivorus.
Scheme 1. Mori’s methylation of (R)-cryptone to afford the synthetic pheromone 1.3
Mori confirmed the absolute stereochemistry via the total syn-
thesis of all three of these pheromones 1, 2 and 20,3 thus allowing
field bioassays to be conducted on the synthetic pheromone
(1S,4R)-1 and confirming its role as a conspecific beetle aggrega-
tion sex pheromone. The (1S,4R)-1 isomer lured 14.4 times as
The (1S,4S)-2 and (1R,4R)-20 isomers were synthesised by Mori
from the desired enantiomer of limonene oxide (3:2 mixture of
cis- and trans-diastereomers) utilising Sharpless’ organoselenium
chemistry on dihydrolimonene oxide (Scheme 2). A regio- and dia-
stereomeric mixture of phenylselenohydrins was obtained, from
which the desired selenide could be separated by chromatography.
The presence of pyridine was essential for the success of the
* Corresponding author. Tel.: +61 3 99054510; fax: +61 3 99054597.
E-mail address: kellie.tuck@sci.monash.edu.au (K.L. Tuck).
0957-4166/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.009

2150
M. Blair, K. L. Tuck / Tetrahedron: Asymmetry 20 (2009) 2149–2153
thetic route was a Stille type reduction of the enol triflate with an
organostannane/silane (Scheme 4). The deoxygenation of ketones
to the corresponding olefin via a Pd[0]catalysed enol triflate reduc-
tion has been well studied,15 and it was anticipated that we could
utilise similar chemistry in the synthesis of the pheromones 1 and
2. If successful, this would be a novel route for the synthesis of ter-
tiary endocyclic allylic alcohols, which is complementary to the
organoselenium chemistry.
OH
SePh
OH
HO
O
SePh
SePh
2 steps
(-)-limonene oxide
30% H2O2,
THF, C5H5N
61%
(1R,4R)-2'
HO
HO
O
OTf
(1S,4S)-2
3 steps
(+)-limonene oxide
(1S,4R)-1
Scheme 2. Mori’s synthetic strategy for accessing the minor constituents.
Scheme 4. Key synthetic strategy for the synthesis of compounds 1 and 2.
selenoxide elimination, otherwise acid-catalysed allylic rearrange-
ment products of 2 ensued. The enantiomeric purity of (1S,4S)-2
and (1R,4R)-20 was 94.5% and 94.3%, respectively.3
2. Results and discussion
2.1. Total synthesis of the (1S,4R)- and (1S,4S)- isomers of 4-iso-
In light of the problems associated with the current synthesis,
we hoped to gain access to the pheromones (1S,4R)-1 and (1S,
4S)-2 both enantiomerically and diastereomerically pure via the
hydrolytic by-products isolated from the kinetic separation of the
commercial mixture of cis and trans (+)- or (ꢀ)-limonene oxide.
Limonene oxide has only recently begun to enjoy widespread
use as a chiral pool reagent, unlike other monoterpene building
blocks popularised in total synthesis such as carvone,7 peryillyl
alcohol,8 isopulegol9 and limonene.10 We believe that limonene
oxide has not been adopted as an enantiomerically pure building
block in total synthesis because the commercially available (+)-
or (ꢀ)-limonene oxide is a diastereomeric mixture (approximately
a 1:1 mixture of cis and trans epoxides) and there are relatively few
practical and preparative routes to obtain the desired diastereoiso-
mer.11–13 Recently we reported a highly diastereoselective hydro-
lytic kinetic separation of the commercial mixture of cis and
trans limonene oxide to afford either trans-diequatorial-1,2-
dihydrolimonene or trans-diaxial-1,2-dihydrolimonene, depending
on the reaction protocol employed.14 Herein, we report a highly
diastereoselective, novel second total synthesis of the volatile
pheromones (1S,4R)-1 and (1S,4S)-2 of the beetle P. quercivorus uti-
lising either the trans-diaxial diol or the trans-diequatorial diol as
the chiral pool building block (Scheme 3). The key step in the syn-
propyl-1-methyl-2-cyclohexen-1-ol
Our initial attempts to synthesis the required enol triflate were
with the unprotected analogue (Scheme 4). The first step was oxi-
dation of the (1S,2S,4S)-trans-diequatorial diol to the correspond-
ing hydroxy ketone 3a. Standard oxidation conditions for
secondary alcohols, pyridinium chlorochromate (PCC), Swern con-
ditions and TEMPO/TCCA gave poor product purity and yields of
the ketol 3a. The use of IBX (o-iodoxybenzoic acid)16 gave superior
yields and product purity (>95%) while ketol 3a was typically used
without further purification (Scheme 5). Ketol 3b was obtained in
excellent yields using the same conditions.
Our attempts to synthesise the enol triflate directly from either
ketol 3a or 3b using KHMDS (2 equiv) and N-phenylbistrifluoro-
sulfonamide (PhNTf2) were unsuccessful. The corresponding tert-
butyldimethylsilyl derivatives 4a and 4b reacted cleanly under
similar conditions, but with 1 equiv of base, to give either the
tert-butyldimethylsilyloxy enol triflate 5a or 5b. Selective reduc-
tion of the exo-cyclic olefin was achieved with Adam’s catalyst
(PtO2)3 under an atmosphere of hydrogen. Under these conditions,
racemisation of the 4-position of the enol triflates 6a and 6b does
not occur.17
HO
i) Hg2+
pH = 7
HO
O
OH
ii) NaBH4
(-)-limonene
oxide
(1S,2S,4S)-trans-
diequatorial-1,2-
dihydrolimonene
1
(1S,4R)-
HO
HO
O
H3O+
OH
pH = 3
(1S,2S,4R)-trans-
diaxial-1,2-
2
(1S,4S)-
(+)-limonene
oxide
dihydrolimonene
Scheme 3. Complementary routes to compounds 1 and 2 from (+)- or (ꢀ)-limonene oxide.

M. Blair, K. L. Tuck / Tetrahedron: Asymmetry 20 (2009) 2149–2153
2151
to a competing side reaction of TBAF with residual organostann-
anes/silanes.
TBSO
RO
OTf
O
An alternate reagent for the palladium-catalysed reduction of
enol triflates is a trialkylammonium formate—palladium com-
plex.21–23 This reagent can be used for the efficient and straightfor-
ward reduction of enol triflates to alkenes, it is also tolerant of a
wide range of functional groups including tertiary alcohols and es-
ters. Treatment of enol triflate 6a or 6b with HCO2H and PPh3 in the
presence of Pd(OAc)2 and PPh3 gave the desired olefin in good
yields after a simple extraction and elution through a short silica
plug in neat hexane.
3b; R = OH
5b
4b; R = OTBS
TBSO
TBSO
OTf
Finally, the tert-butyldimethylsilyloxy pheromone 7a or 7b was
deprotected; TBAF (1.5 equiv) in refluxing THF gave the synthetic
pheromones (1S,4R)-1 or (1S,4S)-2, respectively, in excellent yields
(>90%). No racemisation, which would produce diastereomers, was
observed throughout the synthesis. The enantiomeric excess of the
pheromones (1S,4R)-1 or (1S,4S)-2 was 98–99% ee, identical to that
of the chiral pool reagent (+)- or (ꢀ)-limonene oxide. Furthermore,
we have established an alternate route for the synthesis of tertiary
allylic alcohols that does not use the conventional organoselenium
chemistry.
6b
7b
The synthesis of the endo-cyclic allylic ether 7a or 7b by Stille
reduction of the enol triflate was successful [Pd(PPh3)4
(20 mol %), LiCl and 5 M equiv of either Bu3SnH or Et3SiH, in DMF
at 75 °C, 2 h,18 as determined via 1H NMR analysis of the crude
reaction sample. However, the excess starting material and by-
products of the reaction (Bu3SnH/Bu3SnCl or Et3SiCl) could not be
removed by chromatography due to the similarity of their polarity
to the TBS-protected pheromone 7a or 7b on silica. Fluorolytic
methods (KF(aq) or 10% KF/silica) to remove the excess Bu3SnCl or
Et3SiCl were investigated; however, neither of these were success-
ful.19,20 In an effort to separate the alkylsilanes or stannanes, an
in situ deprotection of 7a and 7b was attempted, thus allowing
their separation from the pheromone. However, even 7 equiv of
TBAF and prolonged heating were unsuccessful in removing the
tert-butyldimethylsilyl protecting group. This is presumably due
3. Conclusion
The pheromones (1S,4R)-cis-2-menthen-1-ol 1 and (1S,4S)-
trans-2-menthen-1-ol 2 were synthesised in high diastereoselec-
tivity (>98% de), enantiomeric purity (98–99% ee) and good overall
yields (32% 1, 45% 2 from trans-1,2-dihydrolimonene). Utilising
this synthetic sequence, the synthesis of all components of the vol-
atiles of P. quercivorus in high enantiomeric purity is now possible.
This will facilitate further field studies on the roles of the minor
constituents of P. quercivorus, which will aid in evaluating their
activity, with the eventual hope of improved trapping techniques
being developed, thereby addressing the invasion and epidemic
mortality of the deciduous oak Q. crispula by the ambrosia beetle.
HO
RO
TBSO
(i)
OH
O
(iii)
OTf
4. Experimental
4.1. General
(1S,2S,4S)-limonene
3a
; R=OH
5a
(ii)
glycol
4a; R=OTBS
All reagents were purchased from the Aldrich Chemical Co. and
used without further purification. Solvents were dried, when nec-
essary, by standard methods. Organic solutions were dried over
MgSO4. The progress of the reactions was monitored by thin layer
chromatography (TLC) on Merck 60 F240 precoated silica gel poly-
ester plates, and products were visualized with vanillin dip. Flash
(iv)
HO
TBSO
TBSO
OTf
(v)
(vi)
chromatography was performed with Davisil LC60A, 40–63
ica media.
lm sil-
Proton (1H) and carbon (13C) NMR spectra were recorded in CDCl3
on either a Bruker AM300, Bruker AV400 or Varian DRX 500 spec-
trometer operating at 300, 400 and 500 MHz, respectively, for pro-
ton and 75, 100 and125 MHz for carbon nuclei. Chemical shifts (d)
are expressed in parts per million (ppm) and referenced to residual
7a
6a
(1S,4R)-1
HO
HO
(i) - (vi)
solvent signal as the internal standard. Infrared spectra (mmax) were
OH
recorded on a Perkin–Elmer RXI FTIR Spectrometer as thin films on
NaCl plates. Low resolution mass spectrometry (ESI) was performed
on a Micromass Platform QMS spectrometer. High resolution mass
spectra (HRMS) were recorded on either a Bruker BioApex 47e FTMS
fitted with an analytical electrospray source using NaI for accurate
mass calibration or a Waters GC-TOF. Low resolution (EI) mass spec-
tra were recorded on a VG Micromass 70/70F mass spectrometer
with an ion source temperature of 200 °C and electron impact en-
ergy of 70 eV. Optical rotations were obtained using a PolAAR
2001 automatic polarimeter, using a 1 dm cell with chloroform as
a solvent, at a wavelength of 589 nm (sodium D line).
(1S,4S)-2
(1S,2S,4R)-limonene
glycol
Scheme 5. Total synthesis of the synthetic pheromones 1 and 2. Reagents and
conditions: (i) IBX, EtOAc, reflux, 3a 93%, 3b 98%; (ii) TBSOTf, 2,6-lutidine, DCM,
ꢀ78 °C to rt, 4a 61%, 4b 99%; (iii) KHMDS, THF, ꢀ78 °C then PhNTf2, ꢀ78 °C to rt, 5a
91%, 5b 82%; (iv) 1 mol % PtO2, H2, MeOH, 6a 75%, 6b 88%; (v) 5 mol % Pd(OAc)2,
PPh3, DIPEA, formic acid, DMF, 70 °C, 7a 75%, 7b 88%; (vi) TBAF, THF, reflux, 1 81%, 2
91%.

2152
M. Blair, K. L. Tuck / Tetrahedron: Asymmetry 20 (2009) 2149–2153
4.2. (2S,5S)-2-Hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclohexanone
3a
HRMS (ESI) calcd for C16H30NaO2Si (M+Na)+ 305.1913, found:
305.1905.
To a solution of trans-diequatorial-1,2-dihydrolimonene14 (1.47 g,
8.63 mmol) in EtOAc (40 mL) was added iodoxybenzoic acid (IBX)
(6.28 g, 22.4 mmol). After the heterogeneous solution was refluxed
for 12 h, it was cooled to ambient temperature and filtered through
a sintered funnel. The residue was washed with EtOAc (20 mL), the
filtrate dried and concentrated in vacuo to afford the title com-
pound as a colourless oil (1.36 g, 93% yield), which was typically
used without further purification. An analytical sample was ob-
tained by purification of a small portion by flash column chroma-
4.6. (3S,6S)-6-(tert-Butyldimethylsilyloxy)-6-methyl-3-(prop-1-
en-2-yl)cyclohex-1-enyl trifluoromethane-sulfonate 5a
A solution of the TBS-ether 4a (1.10 g, 3.89 mmol) in anhydrous
THF (5 mL) was cooled to ꢀ78 °C, and potassium bistrimethyl-
silylamide (0.5 M solution in toluene, 8.6 mL, 4.22 mmol) was added
dropwise under an atmosphere of nitrogen; stirring was maintained
at this temperature for 30 min, after which N-phenyl-bis(trifluo-
romethanesulfonimide) (1.53 g, 4.28 mmol) in anhydrous THF
(5 mL) was introduced via a syringe to the ꢀ78 °C solution of the
potassium enolate. Stirring was continued whilst warming to
ambient temperatures over 2.5 h, after which the reaction was
deemed to have gone to completion via TLC analysis. The reaction
mixture was quenched with water (10 mL), diluted with ether
(50 mL) and was washed with saturated brine (3 ꢂ 20 mL). The or-
ganic phase was dried, concentrated, and subjected to flash column
chromatography (5% EtOAc: 95% hexanes) to yield the title
compound as colourless oil (1.48 g, 91% yield). Alternatively, dissolu-
tion of the crude residue in MeOH precipitated residual N-phenyltri-
fluorosulfonimide, which then afforded the title compound after
filtration and removal of solvent in vacuo. The material obtained
tography (25% EtOAc: 75% hexanes). ½a D20
ꢁ
¼ þ2:5 (c 1.0 CHCl3). 1H
NMR (500 MHz) d 1.41 (s, 3H), 1.64–1.72 (m, 2H), 1.75 (s, 3H),
1.90 (m, 1H), 2.18 (m, 1H), 2.35–2.40 (m, 2H), 2.52–2.55 (m, 2H),
4.75 (s, 1H), 4.80 (m, 1H). 13C NMR (125 MHz) d 18.7, 26.5, 30.1,
39.0, 41.3, 42.9, 68.0, 113.2, 145.3, 214.0. IR (film): 3486 (m),
2972 (m), 2856 (w), 1715 (s) cmꢀ1. MS (ESI) m/z: 207.10 (M+K)+.
HRMS (ESI) calcd for C10H17O2 (M+H)+ m/z 169.1223, found:
169.1223.
4.3. (2S,5R)-2-Hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclohexanone
3b
The above procedure was repeated with trans-diaxial-1,2-
dihydrolimonene,14 the title compound was obtained as a colourless
was of acceptable purity (>90% by 1H NMR analysis). ½a 2D0
¼
ꢁ
ꢀ66:15 (c 1.1, CHCl3). 1H NMR (400 MHz) d 0.11 (s, 3H), 0.13 (s,
3H), 0.87 (s, 9H), 1.43 (s, 3H), 1.56 (m, 1H), 1.75 (s, 3H), 1.83–1.88
(m, 2H), 1.95 (m, 1H), 2.97 (m, 1H), 4.70 (m, 1H), 4.85 (m, 1H),
5.67 (d, J = 4.0 Hz, 1H). 13C NMR (100 MHz) d ꢀ2.3, ꢀ2.1, 18.4,
21.6, 23.8, 25.8, 25.9, 26.8, 37.7, 42.7, 72.0, 112.7, 120.8, 145.5,
152.8. IR (CDCl3): 2956 (w), 2931 (w), 2858 (w), 1260(m), 1248
(m), 1215 (s), 1143 (s) cmꢀ1. HRMS (EI) calcd for C16H27F3O4SSi
(MꢀCH4)Å 399.1268, found: 399.1241 (6%), 357.0830 (84),
207.0271 (37), for 133.1351 (100).
oil in a 98% yield. ½a D20
ꢁ
¼ ꢀ49:2 (c 1.1 CHCl3,). 1H NMR (500 MHz) d
1.36 (s, 3H), 1.70 (m, Hz, 3H), 1.75–2.05 (complex, 4H), 2.58 (dd,
J = 5.6, 13.6 Hz, 1H), 2.66 (m, 1H), 2.78 (ddd, J = 1.6, 5.4, 13.6 Hz,
1H), 2.96 (br s, 1H), 4.69 (d, J = 0.5 Hz, 1H), 4.86 (d, J = 0.5 Hz,
1H). 13C NMR (125 MHz) d 21.8, 25.3, 25.5, 37.4, 41.7, 44.3, 75.9,
112.2, 146.3, 213.7. IR (film): 3348 (br s), 3157 (m) 3057 (w),
2860 (w), 1711 (s) cmꢀ1. HRMS (ESI) calcd for C10H16NaO2
(M+Na)+ 191.1043, found: 191.1041.
4.4. (2S,5S)-2-(tert-Butyldimethylsilyloxy)-2-methyl-5-(prop-1-
4.7. (3R,6S)-6-(tert-Butyldimethylsilyloxy)-6-methyl-3-(prop-1-
en-2-yl)cyclohexanone 4a
en-2-yl)cyclohex-1-enyl trifluoromethane-sulfonate 5b
To a solution of the hydroxy ketone 3a (1.26 g, 7.49 mmol) 2,6-
lutidine (2.0 mL, 17.3 mmol) in dry DCM (20 mL), at ꢀ78 °C under
an atmosphere of nitrogen, was added tert-butyldimethylsilyl tri-
fluoromethanesulfonate (2.2 mL, 3.9 mmol) dropwise. The solution
was allowed to warm to room temperature over 1.5 h. The reaction
mixture was quenched with cold 1 M HCl(aq) (1 ꢂ 20 mL), washed
with brine (3 ꢂ 20 mL), dried and concentrated in vacuo and sub-
sequently subjected to flash column chromatography (10% EtOAc:
90% hexanes), to afford the title compound as a colourless oil
The above procedure was repeated with the TBS-ether 4b, the
title compound was obtained as a colourless oil in an 82% yield.
½
a 2D0
ꢁ
¼ þ5:8 (c 1.25, CHCl3). 1H NMR (500 MHz) d 0.047 (s, 3H),
0.054 (s, 3H), 0.08 (s, 9H), 1.36 (s, 3H), 1.60–1.68 (m, 2H), 1.67 (s,
3H), 2.03 (m, 1H), 2.94 (m, 1H) 4.84 (s, 1H), 4.87 (m, 1H), 5.63
(d, J = 2.5 Hz, 1H). 13C NMR (125 MHz) d ꢀ2.3, ꢀ2.1, 18.4, 20.8,
24.2, 25.9, 26.6, 38.9, 44.0, 71.6, 112.4, 117.4, 121.7, 146.6, 152.7.
IR (film): 2954 (s), 2932 (s), 2859 (s), 1249 (s), 1211 (s), 1145 (s)
cmꢀ1. MS (EI) m/z 399.1 ((MꢀCH4)+Å 4%)+, 357.1(58), 207.1 (25),
,
(1.29 g, 61%). ½a D20
ꢁ
¼ ꢀ41:3 (c 2.3, CHCl3). 1H NMR (200 MHz) d
133.2 (100). HRMS (ESI) calcd for C17H33F3NO4SSi (M+NH4)+
434.1852, found: 432.1848.
0.08 (s, 3H), 0.11 (s, 3H), 0.86 (s, 9H), 1.36 (s, 3H), 1.66 (m, 1H),
1.72 (s, 3H), 1.76 (m, 1H), 1.90–1.97 (m, 2H), 2.39–2.47 (m, 2H),
2.53–2.57 (m, 1H), 4.72 (s, 1H), 4.78 (m, 1H). 13C NMR (125 MHz)
d ꢀ2.4, ꢀ2.1, 18.6, 21.2, 25.7, 26.2, 27.4, 41.1, 43.6, 45.7, 79.2,
110.7, 147.1, 211.3. IR (film): 2950 (m), 2935 (s), 2856 (m), 1728
4.8. (3R,6S)-6-tert-Butyldimethylsilyloxy)-3-isopropyl-6-meth-
ylcyclohex-1-enyl trifluoromethanesulfonate 6a
(s), 1472 (w), 1462 (m), 1360 (w), 1253 (s), 1207 (m) cmꢀ1
.
A solution of enol triflate 5a (1.38 g, 3.32 mmol) and PtO2
(7.5 mg, 1 mol %) in absolute methanol (15 mL), under an atmo-
sphere of hydrogen, was stirred at room temperature for 3 h, after
which time the reaction had gone to completion (TLC analysis,
100% hexane). Filtration of the crude reaction mixture through a
bed of Celite followed by concentration of the filtrate in vacuo
afforded the title compound as a colourless oil (1.28 g 93% yield),
4.5. (2S,5R)-2-(tert-Butyldimethylsilyloxy)-2-methyl-5-(prop-1-
en-2-yl)cyclohexanone 4b
The above procedure was repeated with the hydroxy ketone 3b,
the title compound was obtained as a colourless oil in a 99% yield.
½
a 2D0
ꢁ
¼ þ59:8 (c 1.25, CHCl3). 1H NMR (400 MHz) d 0.02 (s, 3H),
which was used without further purification. ½a D20
¼ ꢀ21:7 (c
ꢁ
0.12 (s, 3H), 0.91 (s, 9H), 1.30 (s, 3H), 1.42–1.63 (complex, 2H),
1.73 (s, 3H), 1.95–2.07 (m, 2H), 2.20–2.32 (m, 2H), 2.99 (m, 1H),
4.72–4.76 (m, 2H). 13C NMR (100 MHz) d ꢀ2.9, ꢀ1.8, 18.5, 20.6,
23.9, 26.16, 26.23, 41.9, 43.0, 47.6, 110.1, 147.9, 211.7. IR (film):
2.65, CHCl3). 1H NMR (400 MHz) d 0.11 (s, 6H), 0.88, (s, 9H), 0.89
(d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 1.38–1.45 (complex,
4H), 1.66 (m, 1H), 1.75 (m, 1H), 1.85–2.00 (m, 2H), 2.19–2.26 (m,
1H) 5.60 (dd, J = 3.0, 0.6 Hz, 1H). 13C NMR (100 MHz) d ꢀ2.2,
ꢀ2.1, 18.4, 19.8, 19.9, 23.0, 24.9, 26.8, 31.9, 39.6, 41.8, 72.5,
2857 (s), 1723 (s), 1463 (m), 1375 (m), 1254 (s), 1198 (m) cmꢀ1
.

M. Blair, K. L. Tuck / Tetrahedron: Asymmetry 20 (2009) 2149–2153
2153
120.3, 121.3, 152.4. IR (film): 2959 (s), 2933 (s), 2865 (sh), 2859 (s),
1248 (s), 1211, 1146 (s) cmꢀ1. HRMS (EI) calcd for C16H28F3O4SSi
(MꢀCH4)+Å 401.1430, found: 401.1408 (11%), 359.1017 (83),
135.1534 (100).
253.1988, found: 253.1956 (7%), 211.1815 (41), 135.1434 (23),
93.1005 (57), 75.0566 (100).
4.12. (1S,4R)-4-Isopropyl-1-methyl-2-cyclohexen-1-ol 1
4.9. (3S,6S)-6-tert-Butyldimethylsilyloxy)-3-isopropyl-6-meth-
ylcyclohex-1-enyl trifluoromethanesulfonate 6b
Tetrabutylammonium fluoride (1.0 M in THF; 1.5 mL, 1.5 mmol)
was added to a stirred solution of the tert-butyldimethylsilyloxy
pheromone 7a (268 mg, 1 mmol) in anhydrous THF (5 mL) under
an atmosphere of nitrogen; the reaction mixture was brought to
reflux and maintained at this temperature for 18 h. After this time,
the reaction was cooled and carefully concentrated in vacuo
(357 mbar, 40 °C), and the resulting residue was subjected directly
to flash column chromatography (15% EtOAc: 75% hexanes);
affording the synthetic pheromone (140 mg, 91% yield) as a colour-
The above procedure was repeated with the enol triflate 5b, the
title compound was obtained as a colourless oil in an 81% yield.
½
a 2D0
ꢁ
¼ ꢀ35:5 (c 1.55, CHCl3). 1H NMR (500 MHz) d 0.10 (s, 3H),
0.12 (s, 3H), 0.86 (s, 9H), 0.95 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 7.0 Hz,
3H), 1.4 (s, 3H), 1.51 (m, 1H), 1.60–1.64 (m, 2H), 1.75 (m, 1H), 1.97
(m, 1H), 2.16 (m, 1H), 5.59 (d, J = 2 Hz, 1H). 13C NMR (125 MHz) d
ꢀ2.4, ꢀ2.2, 18.3, 19.4, 19.7, 20.6, 25.9, 26.7, 32.0, 39.6, 42.9, 71.7,
119.1, 122.3, 152.6. IR (film): 2959 (s), 2932 (s), 2859 (s), (s), 1210
(s), 1173 (m), 1145 (s), cmꢀ1. MS (EI) m/z 401.1 (C16H28F3O4SSiÅꢀCH4,
6%)+, 359.1 (44), 265 (18), 251 (30), 207 (49), 183 (24), 135 (100).
HRMS (EI) calcd for C16H28F3O4SSi (MꢀCH4)+Å 401.1430, found:
401.1410 (6%), 359.0930 (90), 265.0194 (26), 251.0470 (52),
207.0099 (78), 135.1462 (100).
less oil. ½a 2D0
¼ ꢀ72:4 (c 1.0, CHCl3) lit. ꢀ65.9 (Ref. 3 CHCl3 c 1.17,
ꢁ
96.67% ee). 1H NMR (500 MHz) d 0.86 (d, J = 6.8 Hz, 3H), 0.89 (d,
J = 6.8 Hz, 3H), 1.27 (s, 3H), 1.38 (m, 1H), 1.55–1.66 (m, 2H), 1.67
(br s, 1H), 1.73 (m, 1H), 1.86 (ddd, J = 2.8, 5.9, 12.6 Hz, 1H), 1.94
(m, 1H), 5.58–5.64 (m, 2H). 13C NMR (125 MHz) d 19.6, 20.0,
23.8, 28.7, 32.0, 38.3, 41.9, 69.9, 131.5, 134.8.
4.13. (1S,4S)-4-Isopropyl-1-methyl-2-cyclohexen-1-ol 2
4.10. (1S,4R)-tert-Butyl((1S,4S)-4-isopropyl-1-methylcyclohex-
2-enyloxy)dimethylsilane 7a
The above procedure was repeated with the tert-butyldimethyl-
silyloxy pheromone 7b, the title compound was obtained as a col-
Following a modified procedure of both Cacchi et al.21,22 and Liu
et al.,23 to a stirred solution of the dihydroenoltriflate 6a (1.15 g,
2.76 mmol), DIPEA (2.1 mL, 6.03 mmol), Pd(OAc)2 (31 mg, 148
ourless oil in an 81% yield. ½a D20
¼ ꢀ11:5 (c 1.0, CHCl3) lit. ꢀ12.0
ꢁ
(Ref. 3 CHCl3, c 2.06, 98.66% ee). 1H NMR (500 MHz) d 0.89 (d,
J = 7 Hz, 3H), 0.91 (d, J = 7 Hz, 3H), 1.27 (s, 3H), 1.43 (m, 1H), 1.46
(br s, 1H), 1.52 (dt, J = 3.0, 13.5 Hz, 1H), 1.59–1.67 (m, 2H), 1.81–
1.90 (m, 2H), 5.64–5.70 (complex, 2H). 13C NMR (125 MHz) d
19.5, 19.9, 21.8, 29.8, 31.9, 37.5, 42.3, 67.7, 133.5, 133.8.
l
mol) and triphenylphosphine (72 mg, 275
(20 mL), under an atmosphere of nitrogen, was slowly added
98%formic acid (208 L, 5.50 mmol). The reaction temperature
lmol) in dry DMF
l
was warmed to 70 °C with the aid of an external oil bath, and main-
tained at this temperature for 2 h. After this period, complete con-
version to the title compound was observed via TLC analysis. The
reaction mixture was diluted with water (40 mL), extracted into
hexanes and dried, after which it was subjected directly to a short
silica gel plug in neat hexanes, to afford a clear volatile oil
(556 mg, 75% yield) after concentration of the solvent under reduced
Acknowledgment
The authors acknowledge the support of the School of Chemis-
try, Monash University.
pressure (330 mbar, 40 °C). ½a D20
ꢁ
¼ ꢀ77:3 (c 2.07, CHCl3). 1H NMR
References
(500 MHz) d 0.06 (s, 3H), 0.07 (s, 3H), 0.86 (s, 9H), 0.86 (d,
J = 8.5 Hz, 3H), 0.88 (d, J = 8.5 Hz, 3H), 1.23 (s, 3H), 1.32 (m, 1H),
1.57 (m, 1H), 1.67–1.80 (m, 3H), 1.92 (m, 1H), 5.49 (ddd, J = 1.0,
2.4, 10.3 Hz, 1H), 5.60 (ddd, J = 1.3, 2.6, 10.3 Hz, 1H). 13C NMR
(100 MHz) d ꢀ1.9, ꢀ1.8, 19.6, 20.0, 22.9, 24.0, 26.1, 30.3, 32.1, 38.7,
41.9, 72.3, 129.9, 136.1. IR (film): 3021 (w), 2958 (s), 2930 (s),
2858 (s), 1130 (s) cmꢀ1. ESI (MS) m/z: 301.08 (M+MeOH+H)+ HRMS
(EI) calcd for C15H29OSi (MꢀCH4)+Å 253.1988 (MꢀCH4)+Å, found:
253.1988 (12%), 211.1770 (31), 135.1405 (28), 93.1008 (73),
75.0529 (100).
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The above procedure was repeated with the dihydroenoltriflate
6b, the title compound was obtained as a colourless oil in 88% yield.
½
a 2D0
ꢁ
¼ ꢀ49:75 (c 2.07, CHCl3). 1H NMR (500 MHz) d 0.04 (s, 3H),
0.07 (s, 3H), 0.85 (s, 9H) 0.88 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 7.0 Hz,
3H), 1.25 (s, 3H), 1.38 (dt, J = 3.0, 12.5 Hz, 1H), 1.48–1.66 (m, 3H),
1.78–1.85 (m, 2H) 5.59–5.65 (complex, 2H). 13C NMR (125 MHz) d
ꢀ1.7, 14.4, 19.7, 20.1, 21.9, 22.9, 26.1, 31.2, 31.9, 32.2, 39.1, 42.7,
70.0, 132.2, 134.4. IR (film): 3021 (w), 2957 (s), 2930 (s), 2858 (m),
1131 (m) cmꢀ1. MS (EI) 253.2 ((M-CH4)+ꢃ, 12%), 211.2 (57), 13.2
(43), 93.1 (44), 75.1 (100). HRMS (EI) calcd for C15H29OSi (MꢀCH4)+Å