Synthesis of (1S,4R)-4-isopropyl-1-methyl-2-cyclohexen-1-ol, the aggregation pheromone of the ambrosia beetle Platypus quercivorus, its racemate, (1R,4R)- and (1S,4S)-isomers

Article abstract of DOI:10.1016/j.tetasy.2006.07.030

(S)-Perillyl alcohol was converted to (R)-cryptone (91.5-93% ee) in six steps, which was then treated with methyllithium to give (1S,4R)-4-isopropyl-1-methyl-2-cyclohexen-1-ol, the aggregation pheromone of the ambrosia beetle Platypus quercivorus. The racemic pheromone was also prepared by methylation of (±)-cryptone. Both (1R,4R)- and (1S,4S)-isomers (98% ee) of the pheromone were synthesized from the enantiomers of dihydrolimonene oxide.

Full text of DOI:10.1016/j.tetasy.2006.07.030

Tetrahedron: Asymmetry 17 (2006) 2133–2142
Synthesis of (1S,4R)-4-isopropyl-1-methyl-2-cyclohexen-1-ol,
the aggregation pheromone of the ambrosia beetle Platypus
quercivorus, its racemate, (1R,4R)- and (1S,4S)-isomersI
Kenji Mori*
Photosensitive Materials Research Center, Toyo Gosei Co., Ltd, Wakahagi 4-2-1, Inba-mura, Inba-gun, Chiba 270-1609, Japan
Insect Pheromone and Traps Division, Fuji Flavor Co., Ltd, Midorigaoka 3-5-8, Hamura-shi, Tokyo 207-8503, Japan
Received 26 June 2006; accepted 20 July 2006
Abstract—(S)-Perillyl alcohol was converted to (R)-cryptone (91.5–93% ee) in six steps, which was then treated with methyllithium to
give (1S,4R)-4-isopropyl-1-methyl-2-cyclohexen-1-ol, the aggregation pheromone of the ambrosia beetle Platypus quercivorus. The race-
mic pheromone was also prepared by methylation of ( )-cryptone. Both (1R,4R)- and (1S,4S)-isomers (98% ee) of the pheromone were
synthesized from the enantiomers of dihydrolimonene oxide.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
OH
Over the last decade, deciduous oak (Quercus crispula) die-
back has been prevalent in northern Japan on the Japan
Sea side, as reported by Kamata et al.2,3 The disease is
quite problematic and is capable of damage Japan’s forest
eco-system. Recent studies on this disease revealed that the
dieback is caused by an ambrosia beetle Platypus quercivo-
rus Murayama (Coleoptera: Platypodidae), which is the
(1S,4R)-1
Pheromone of Platypus quercivorus
vector of Raffaelea quercivora, one of the ambrosia fungi,
which causes oak dieback. In order to monitor the popula-
OH
OH
tion of the beetle P. quercivorus, its chemical communica-
tion system was studied by Nakashima et al., who
isolated and identified (1S,4R)-4-isopropyl-1-methyl-2-
cyclohexen-1-ol (cis-2-menthen-1-ol, 1, Scheme 1) as its
male-produced aggregation pheromone.4,5
(1R,4R)-2
(1S,4S)-2'
The synthesis of (1S,4R)-1 in gram quantities was studied
in order to examine its applicability as the population mon-
itoring agent against P. quercivorus. Since (1R*,4R*)-4-iso-
propyl-1-methyl-2-cyclohexen-1-ol (2 or 20) was detected as
a minor component of the frass volatiles of P. quercivorus,6
2 and 20 were also chosen as synthetic targets so as to deter-
O
major
MeLi
=
O
(R)-cryptone (3)
minor
(1S,4R)-1 + (1R,4R)-2
major
minor
q Pheromone synthesis, Part 232. For Part 231, see Ref. 1.
*
Scheme 1. Structure and synthetic plan of the target molecules.
Fax: +81 3 3813 1516; e-mail: kjk-mori@arion.ocn.ne.jp
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.030

2134
K. Mori / Tetrahedron: Asymmetry 17 (2006) 2133–2142
mine definitely the absolute configuration of the minor
component. Clarification of the biological role of 2 or 20
either as a synergist or as an inhibitor of the pheromone
activity of 1 was important from a practical point of view.
Another practical consideration was to develop an efficient
synthesis of ( )-1 to evaluate its pheromone activity under
field conditions. Herein, we report the synthesis of ( )-1,
(1S,4R)-1, (1R,4R)-2, and (1S,4S)-20 in amounts sufficient
for field bioassay. The simple and key strategy was to pre-
pare (1S,4R)-1 or ( )-1 by methylation of (R)-cryptone (3)
or ( )-3 as shown in Scheme 1. Methylation of 3 would
give 1 as the major product due to the steric hindrance
caused by the axial H-atom at C-6 of 3.
At this stage, it became relevant to know whether ( )-4-
isopropyl-1-methyl-3-cyclohexen-1-ol 7 could attract P.
quercivorus or not. Treatment of 6 with MeMgI yielded
( )-7.8 Kamata’s bioassay of ( )-7 showed it to be totally
inactive.
2.2. Synthesis of ( )-cryptone and its conversion to
(1S*,4R*)-4-isopropyl-1-methyl-2-cyclohexen-1-ol
Among the many methods for the preparation of ( )-cryp-
tone 3,9–11 Stork’s enamine procedure12 was examined due
to its applicability in a large scale preparation (Scheme 3).
Accordingly, the known enamine 8 was treated with methyl
vinyl ketone. After acid treatment of the resulting adduct,
it was obtained as a mixture of ( )-3 and 6 (85:15 as
revealed by the NMR signals of their olefinic protons).
These two isomers were reported to be separable by careful
fractional distillation,9 although no separation was
attempted in the present case.
2. Results and discussion
2.1. Synthesis of ( )-4-isopropyl-1-methyl-3-cyclohexen-1-ol
The first attempt to prepare ( )-cryptone 3 is shown in
Scheme 2. According to Soffer and Jevnik, p-isopropylani-
sole 4 can be subjected to the Birch reduction to give 5.7
Treatment of 5 with dil HCl gave poor results, and ( )-3
could not be obtained. Accordingly, 5 was hydrolyzed with
aqueous oxalic acid to give pure 6, whose isomerization to
( )-3 was attempted under several different conditions with
no useful result. Nukada kindly carried out the semi-empir-
ical MO calculation of the heat of formation of 3 and that
of 6 employing MOPAC (AM1 Hamiltonian). The heat of
formation of 3 was ꢀ49.0 kcal/mol, while that of 6 was
ꢀ52.5 kcal/mol, meaning that the b,c-unsaturated ketone
6 was 3.5 kcal/mol more stable than the a,b-unsaturated
ketone 3, and therefore the former could not be isomerized
to 3.
O
O
N
a, b
+
:
8
( )-3
6
(85
15)
OH
O
e
c, d
9
10
O
O
SePh
OMe
OMe
f
a
b
( )-11
( )-3
4
5
Scheme 3. Synthesis of ( )-cryptone 3. Reagents and conditions: (a)
CH2@CHCOMe, room temp, 1 day; (b) dil HCl, room temp, 3 days, then
reflux, 30 min, 54%; (c) H2, PtO2, AcOH, room temp, 62%; (d) Jones
CrO3, acetone, 0–5 ꢁC, 10 min, 76%; (e) PhSeCl, EtOAc, room temp,
40 min, 40–55%; (f) 30% H2O2, 0–35 ꢁC, 1.5 h, 70%.
O
O
c
The next attempt to obtain pure ( )-3 was to employ the
standard organoselenium chemistry of Sharpless et al.13
for the conversion of 4-isopropylcyclohexanone 10 to
( )-3 (Scheme 3). Commercially available p-isopropylphe-
nol 9 was hydrogenated over PtO2 in AcOH, and the result-
ing alcohol was oxidized with Jones chromic acid to give
10. Treatment of 10 with phenylselenenyl chloride afforded
pure ( )-11 after chromatographic purification. Subse-
quent oxidation of ( )-11 with H2O2 furnished ( )-3 with
no contamination of the b,c-unsaturated ketone 6.
Although the chemical purity of ( )-3 obtained by this
method was satisfactory, it took four steps to convert 9
into ( )-3 with an overall yield of 13–18%. It was therefore
6
( )-3
OH
d
( )-7
Scheme 2. Synthesis of ( )-1-methyl-4-isopropyl-3-cyclohexen-1-ol (7).
Reagents and conditions: (a) Li, t-BuOH, liq. NH3, THF, 90%; (b)
(CO2H)2Æ2H2O, MeOH, H2O, room temp, 40 min, 64%; (c) dil HCl, no
reaction; (d) MeMgl, Et2O, 22% after SiO2 chromatography and
distillation.

K. Mori / Tetrahedron: Asymmetry 17 (2006) 2133–2142
2135
necessary to explore a much more efficient method to
prepare ( )-3.
employed photosensitized oxygenation of (+)-dihydrol-
imonene (carvomenthene) as the preparative method.19
This method, however, furnishes a mixture of six products,
and is inappropriate for the synthesis of enantiomerically
pure 1 and 2 in amounts sufficient enough for biological
evaluation.
Scheme 4 shows the method finally adopted for the prepa-
ration of ( )-1. Wallach was the first to prepare ( )-cryp-
tone 3 by treating (+)-nopinone 12 with acid.14 Since then,
this reaction has only been employed occasionally.15,16
A new method was therefore developed for the preparation
of gram quantities of (1R,4R)- and (1S,4S)-2 as shown in
Scheme 5. The key step was the application of Sharpless’
organoselenium chemistry20 to convert 14b to (1R,4R)-2
via phenylselenide 15c.
O
O
O
a
b
+
(+)-nopinone 12
O
O
( )-3
6
a
OH
OH
OH
(–)-limonene oxide
14
+
+
13
SePh
H
( )-1
( )-2
( )-7
δ = 3.85
b
t-like
OH
Scheme 4. Synthesis of (1S*,4R*)-( )-4-isopropyl-1-methyl-2-cyclohexen-
1-ol 1. Reagents and conditions: (a) AlCl3, CH2Cl2, 0–5 ꢁC, 70 min, 89%;
(b) MeLi, LiBr, Et2O, THF, ꢀ40 ꢁC to room temp, 44% of 1 and 10% of 2.
J = 2 Hz
15a
O
14a
OH
SePh
H
When (+)-12 was treated with AlCl3 in CH2Cl2, ( )-3 was
obtained in about 90% yield with purity of no less than 80–
85%. The contaminant was its more stable isomer 6. In
spite of this unsatisfactory purity of the resulting ( )-3,
the present preparation starting from (+)-nopinone (12)
was chosen as the method of choice owing to its simplicity.
O
δ = 3.22
15b
dd, J = 2, 8 Hz
14b
b
OH
OH
H
Methyllithium in Et2O containing LiBr was then added
to ( )-3 to give a mixture of the desired product ( )-1,
its stereoisomer ( )-2 and alcohol ( )-7 derived from the
contaminating ketone 6. Fortunately, ( )-1 could be
separated from ( )-2 and ( )-7 by SiO2 chromatography,
and gram quantities of ( )-1 could be secured after distil-
lation. Its EI-MS was identical to that of the sex phero-
mone of P. quercivorus. The pheromone activity of ( )-1
against P. quercivorus was confirmed by Professor Kama-
ta’s bioassay. It was also possible to purify ( )-2 by careful
SiO2 chromatography followed by distillation. However,
only a very small amount of ( )-2 was obtained by this
method. Accordingly, even with a supply of optically active
cryptone 3, it proved difficult to synthesize optically active
2 in a sufficient amount for field bioassay. It, therefore,
became necessary to develop a different method for the
preparation of the enantiomers of 2.
c
δ = 3.40
t-like
SePh
J = 2 Hz
15c
(1R,4R)-2
OH
O
(+)-limonene oxide
(1S,4S)-2'
13'
Scheme 5. Synthesis of (1R,4R)- and (1S,4S)-4-isopropyl-1-methyl-2-
cyclohexen-1-ol 2 and 20. Reagents and conditions: (a) H2, PtO2, MeOH,
92%; (b) Ph2Se2, NaBH4, EtOH, reflux, 2 h, 44% of 15c; (c) 30% H2O2,
THF, C5H5N, room temp, 1 h, 61%.
Commercially available (ꢀ)-limonene oxide 13 (cis/trans =
ca. 3:2, 99% ee) was hydrogenated over PtO2 in MeOH to
give (ꢀ)-dihydrolimonene oxide as a mixture of 14a and
14b (2:3). The hydrogen at C-2 of 14a absorbed at
d = 3.02 (0.4H, t, J 1.5 Hz) in its 1H NMR spectrum, while
that of 14b showed its signal at d = 2.97 (0.6H, d, J 5.4 Hz).
This mixture of 14a and 14b was treated with NaSePh gen-
erated from Ph2Se2 and NaBH4 in EtOH. Epoxide 14a gen-
erated selenides 15a and 15b, while epoxide 14b furnished
selenide 15c. These three products could be characterized
2.3. Synthesis of (1R,4R)-and (1S,4S)-4-isopropyl-1-
methyl-2-cyclohexen-1-ol
The synthesis of 1-oxygenated menthane compounds has
been studied for many years.17 Klein and Ohloff prepared
both (1R,4R)- and (1S,4S)-4-isopropyl-1-methyl-2-cyclo-
hexen-1-ols 2 and 20 by starting from the enantiomers of
piperitone.18 Unfortunately in Japan, pure enantiomers
of piperitone were unavailable. Another preparative meth-
od for (1S,4S)-20 was reported by Schenck et al., who
1
by comparing their H NMR data as depicted in Scheme

2136
K. Mori / Tetrahedron: Asymmetry 17 (2006) 2133–2142
HO
5. Unfortunately, 15a and 15b could not be purified due to
their poor separation by SiO2 chromatography. The de-
sired isomer 15c, however, could be purified by SiO2 chro-
matography to give pure 15c in 44% yield based on the
mixture of 14a and 14b. Although the H2O2 oxidation of
the mixture of 15a and 15b did not give useful results,
the oxidation of 15c with H2O2 could be carried out suc-
HO
a
(S)-18
(1R,2S,4S)-19
δ = 3.36
cessfully in the presence of pyridine in THF to give
H
dd, J = 4, 11 Hz
OH
22
(1R,4R)-2, ½aꢁD ¼ þ10:3 (hexane), in 61% yield. Its EI-
MS was identical with that of the minor component of
the frass volatiles of P. quercivorus. In the same manner,
OH
(+)-limonene oxide 130 was converted to (1S,4S)-20,
26
½aꢁD ¼ ꢀ10:2 (hexane). The enantiomeric purities of
HO
(1R,4R)-2 and (1S,4S)-20 were analyzed by GC on a chiral
stationary phase by Dr. S. Tamogami, and found to be
98.3–98.7% ee and 97.8–98.2% ee, respectively. The overall
yield of (1R,4R)-2 was 25% based on 13 (three steps).
HO
b
(R)-18'
(1S,2R,4R)-19'
It is worthy of note that the presence of pyridine was essen-
tial for the success of the selenoxide elimination reaction
(15c ! 2). The product obtained in the absence of pyridine
was shown to be a mixture of all the four compounds 1, 2,
16, and 17 in a ratio of 12.2%, 66.8%, 8.5%, and 7.5%
together with some impurities (5%). In the presence of
pyridine, (1R,4R)-2 and (1S,4S)-20 were obtained with the
purities of 94.3% and 94.5%, respectively, as analyzed by
GC–MS. In the absence of pyridine, the acidity of the phen-
ylselenenic acid generated causes an allylic rearrangement
of 2 (Scheme 6). Accordingly, (1R,4R)-2 gives the delocal-
ized cation A, which affords a mixture of (1R,4R)-2,
(1S,4R)-1, (1S,6R)-16, and (1R,6R)-17.
Scheme 7. Asymmetric dihydroxylation of the enantiomers 18 and 180 of
dihydrolimonene. Reagents and conditions: (a) AD-mix-aꢂ, MeSO2NH2,
t-BuOH, H2O, 42%; (b) AD-mix-bꢂ, MeSO2NH2, t-BuOH, H2O, 40%.
21
½aꢁD ¼ þ9:3 (CHCl3) (Ref. 23: +8.2). Attempts were made
to convert 19 to 2 by tosylation followed by elimination or
by phenylselenenylation (PhSeCN, Bu3P) followed by oxi-
dation. Neither of these attempts were successful.
2.4. Synthesis of (R)-cryptone and its conversion to (1S,4R)-
4-isopropyl-1-methyl-2-cyclohexen-1-ol, the pheromone of P.
quercivorus
(R)-Cryptone 3 was isolated from the essential oil of Euca-
lyptus cneorifolia in Australia, and reported to possess an
[a]D value of ꢀ119.3 (EtOH)24 or ꢀ91.7 (EtOH).25 Laven-
OH
OH
der oil also contains enantiomerically impure (R)-cryptone,
21
½aꢁD ¼ ꢀ27 (CHCl3).26 Various syntheses of optically
active cryptone have been reported to date. Kato et al.
recorded a multi-step conversion of (+)-nopinone 12 into
(R)-cryptone (3, 86% ee)27 Asymmetric deprotonation of
4-isopropylcyclohexanone enabled Koga et al. to prepare
(S)-3 in 67% ee.28 Fuchs et al. synthesized (R)-3 of 94.7%
ee ([a]D not reported) employing Jacobsen’s asymmetric
epoxidation as the key step.29 Very recently, Ho¨gberg
(1R,4R)-2
(1S,4R)-1
+
A
et al. used lipase-catalyzed kinetic resolution for the prep-
20
aration of (R)-3 {76% ee; ½aꢁD ¼ ꢀ69:7 (EtOH)} and (S)-
20
3 {98% ee; ½aꢁD ¼ þ89:9 (EtOH)}.30 All of these published
OH
OH
methods, however, seem to be unsuitable for preparing (R)-
3 in gram quantities due to low overall yield and/or exper-
imental difficulty in a large-scale preparation.
(1S,6R)-16
(1R,6R)-17
Scheme 6. Phenylselenenic acid-catalyzed allylic rearrangement of
(1R,4R)-2.
It appeared that a slight modification of the method devel-
oped by Stevens and Albizati for the preparation of 4-iso-
propenyl-2-cyclohexenone31 might be useful for a gram-
scale preparation of (R)-3, because the starting (S)-perillyl
alcohol is commercially available. As shown in Scheme 8,
work along this line was successful to enable a gram-scale
synthesis of (R)-cryptone 3 and its conversion to the
desired pheromone (1S,4R)-1.
Another attempt was made to prepare the enantiomers 2
and 20 via the enantiomers of diol 19 (Scheme 7). Sharpless
asymmetric dihydroxylation21 of (S)-dihydrolimonene 18
afforded crystalline (1R,2S,4S)-4-isopropyl-1-methylcyclo-
hexane-1,2-diol 19 in 42% yield. The assigned structure
1
19 was consistent with the observed H NMR signal due
to CHOH (d = 3.36, dd, J 4, 11 Hz) and the [a]D value
[observed: ꢀ10.3 (CHCl3); Ref. 22: ꢀ10.1]. Similarly, asym-
metric dihydroxylation of (R)-dihydrolimonene 180 gave 190,
(S)-Perillyl alcohol 20 was epoxidized and silylated to give
the known unsaturated epoxide 21.31 This was hydro-

K. Mori / Tetrahedron: Asymmetry 17 (2006) 2133–2142
2137
multi-gram-scale synthetic route for (R)-cryptone 3 was
developed. Racemates of 1 and 2 were also prepared for
their biological evaluation. The pheromone activity of
these compounds against P. quercivorus will be tested and
reported in due course. The biological study will hopefully
enable us to develop practical pheromone traps against
that pest insect.
CH2OTBS
O
CH2OH
c
a, b
lit.29
(S)-20
21
CH2OTBS
O
CH2OR
OH
SePh
4. Experimental
4.1. General
f
d
23 R = TBS
24 R = H
22
Melting points (Yanaco MP-S3) and boiling points are
uncorrected values. Optical rotations were measured on a
Jasco DIP-320 polarimeter. IR spectra were recorded on
e
O
OH
a
Horiba FT-720 spectrometer. 1H NMR spectra
g
(300 MHz, TMS at d = 0.00 or CHCl3 at d = 7.26 as inter-
nal standard) and 13C NMR spectra (75 MHz, CDCl3 at
d = 77.0 as internal standard) were recorded on a Varian
Mercury-300 spectrometer. Column chromatography was
carried out on Merck Kieselgel 60 Art 1.07734.
(R)-cryptone (3)
(1S,4R)-1
Scheme 8. Synthesis of (R)-cryptone
3 and its conversion to the
pheromone (1S,4R)-1, Reagents and conditions: (a) t-BuOOH, VO(acac)2,
toluene, room temp, 2.5 h, quant.; (b) TBSCl, imidazole, DMF, quant.; (c)
H2, PtO2, hexane, EtOAc (1:1), quant.; (d) Ph2Se2, NaH, THF, HMPA,
reflux, 3 h; (e) TBAF, THF, room temp; (f) NaIO4, THF, H2O, room temp,
1.5 h, 28% based on 22 (three steps); (g) MeLi, LiBr, Et2O, THF, 44%.
4.2. 4-Isopropyl-3-cyclohexenone 6
To a solution of 5 (6.0 g, 39.5 mmol) in MeOH (40 mL)
was added a solution of oxalic acid dihydrate (0.7 g,
5.6 mmol) in H2O (9 mL). The mixture was stirred for
40 min at room temp, diluted with H2O, and then extracted
with Et2O. The extract was washed with H2O, NaHCO3
(aq solution), and brine, dried over MgSO4, and concen-
trated in vacuo to give 4.3 g (74%) of crude 6. This was dis-
tilled in vacuo to furnish 3.5 g (64%) of 6 as a colorless oil,
bp 70–71 ꢁC/4 Torr; n2D4 ¼ 1:4699; Ref. 7: n2D0 ¼ 1:4710;
Ref. 8: n2D2 ¼ 1:4817. mmax (film): 1720 (s, CO), 1465 (m),
1195 (m), 802 (m); dH (CDCl3): 1.04 (6H, d, J 6.9,
CH(CH3)2), 2.24–2.30 (1H, m, CH(CH3)2), 2.30–2.43
(2H, m, C@CCH2), 2.45–2.51 (2H, m, CH2CH2CO) 2.83–
2.87 (2H, m, C@CHCH2CO), 5.46 (1H, t-like, J 2, C@CH);
dC (CDCl3): 21.0, 26.3, 29.5, 34.7, 38.8, 39.5, 115.4, 144.5,
211.4. Anal. Calcd for C9H14O (138.2): C, 78.21; H, 10.21.
Found C, 75.45; H, 9.98. This ketone was so volatile that
correct analytical data could not be obtained.
genated over PtO2, and the resulting saturated epoxide 22
treated with NaSePh (prepared from Ph2Se2 and
NaH32,33) in THF and HMPA to give phenylselenide 23.
The reactivity of NaSePh prepared in this manner was
higher than that prepared from Ph2Se2 and NaBH4 in
EtOH.32,33 Desilylation of 23 with tetrabutylammonium
fluoride (TBAF) in THF furnished diol 24. Intermediates
21–24 were prepared and used as stereoisomeric mixtures.
Oxidation of 24 with sodium periodate in aqueous THF
19
gave (R)-cryptone 3, ½aꢁD ¼ ꢀ86:8 (EtOH), after chro-
matographic purification and distillation. The overall yield
of (R)-3 was 28% based on (S)-20 (six steps), and its enan-
tiomeric purity was 91.5–93% ee as determined by GC
analysis on a chiral stationary phase.
Finally, methylation of (R)-3 with methyllithium was
4.3. ( )-4-Isopropyl-1-methyl-3-cyclohexen-1-ol 7
followed by chromatographic purification and distillation
19
19
to give (1S,4R)-1, ½aꢁD ¼ ꢀ68:7 (hexane); ½aꢁD ¼ ꢀ65:9
(CHCl3) {Ref. 19: [a]D = +69 (CHCl3) for (1R,4S)-1}, in
44% yield. Its enantiomeric purity was determined as
93.3% ee by GC analysis. Details of the GC analysis of 1,
2, and 3 are described in the Experimental. 2,3-Di-
methoxymethyl-6-tert-butyldimethylsilyl-c-cyclodextrin or
Chiramixꢂ34 was employed as the chiral stationary phase
to achieve base-peak separations of the enantiomers of 1,
2, and 3.
A solution of 6 (2.76 g, 20 mmol) in dry Et2O (10 mL) was
added dropwise to a stirred and ice-cooled solution of the
Grignard reagent prepared from MeI (4.3 g, 30 mmol)
and Mg (0.72 g, 30 mmol) in dry Et2O (10 mL). The mix-
ture was stirred at 0–5 ꢁC for 30 min, at room temperature
for 5 h, then poured into ice and NH4Cl (aq solution) and
extracted with Et2O. The extract was washed with a diluted
aqueous solution of Na2S2O4, NaHCO3 (aq solution), and
brine, dried (K2CO3), and concentrated in vacuo to give
2.72 g (88%) of crude 7. This was chromatographed over
SiO2 (40 g). Elution with hexane/EtOAc (10:1) gave puri-
fied 7, which was distilled to give pure 7 (900 mg, 22%)
as a colorless oil, bp 80–81 ꢁC/4 Torr; n2D4 ¼ 1:4748, mmax
(film): 3370 (s, OH), 1130 (s, C–O), 1100 (s, C–O), 922
(m), 880 (m); dH (CDCl3): 1.10 (6H, d, J 6.9, CH(CH3)2),
1.57 (3H, s, C(OH)CH3), 1.60–1.75 (3H, m), 1.96–2.26
3. Conclusion
(1S,4R)-4-Isopropyl-1-methyl-2-cyclohexen-1-ol 1 and its
(1R,4R)- and (1S,4S)-isomers 2 and 20 were synthesized
in amounts sufficient for their biological evaluation. A

2138
K. Mori / Tetrahedron: Asymmetry 17 (2006) 2133–2142
(5H, m), 5.30 (1H, m, C@CH); dC (CDCl3): 21.41, 21.49,
23.7, 28.2, 34.7, 35.6, 39.8, 68.7, 115.9, 142.8 MS (70 eV,
EI): m/z (%): 154 (2) [M+]. 136 (34), 121 (43), 107
(29), 93 (34), 81 (100). GC (TC-WAX at 100–190 ꢁC,
+3 ꢁC/min): tR 15.8 min (92.2%). Anal. Calcd for
C10H18O (154.2): C, 77.86; H, 11.76. Found C, 77.56; H,
11.89.
4.6. ( )-Cryptone 3 by organoselenium chemistry
To a stirred and ice-cooled solution of ( )-11 (3.0 g,
10 mmol) in THF (40 mL) was added dropwise 30%
H2O2 (7 mL, 62 mmol). The stirring was continued for
2 h at room temp. The mixture was then concentrated in
vacuo, diluted with H2O, and extracted with Et2O. The ex-
tract was washed with NaHCO3 (aq solution), and brine,
dried over MgSO4, and concentrated in vacuo. The residue
was chromatographed over SiO2 (50 g). Elution with hex-
ane/EtOAc (20:1) afforded 1.0 g (70%) of crude ( )-3. This
was distilled to give pure ( )-3 (435 mg, 31%) as a colorless
oil, bp 70–71 ꢁC/3 Torr; n2D7 ¼ 1:4852; mmax (film): 3032 (w),
2958 (s), 2873 (m), 1682 (s, CO), 1466 (m), 1388 (m), 1245
(m), 956 (w), 833 (m); dH (CDCl3): 0.95 (3H, d, J 6.9,
CHCH3), 0.97 (3H, d, J 6.9, CHCH3), 1.69–1.87 (2H, m,
CH2CH2), 1.95–2.05 (1H, m, CHCH3), 2.25–2.40 (2H, m,
COCH2), 2.46–2.55 (1H, m, C@CHCH), 6.00 (1H, ddd, J
10.2, 2.7, 0.9, COCH@CH), 6.91 (1H, ddd, J 10.2, 2.4,
1.8, COCH=CH); dC (CDCl3): 19.4, 19.6, 25.2, 31.5,
37.4, 42.4, 129.7, 154.4, 200.2. Anal. Calcd for C9H14O
(138.2): C, 78.21; H, 10.21 Found C, 75.52; H, 9.87. Due
to the high volatility of ( )-3, correct analytical data could
not be obtained.
4.4. ( )-Cryptone 3 by Stork’s enamine procedure
Enamine 8 (bp 102–103 ꢁC/35 Torr) was prepared from
isovaleraldehyde and piperidine according to Stork
et al.12 Methyl vinyl ketone (6.7 g, 96 mmol) was added
dropwise to stirred ice-cooled enamine 8 (14.5 g, 95 mmol)
over 45 min. The mixture was then stirred overnight at
room temp. After 1 day, it was acidified with 10% HCl
(185 mL), and the mixture was stirred for 3 days under
Ar at room temperature. The stirred mixture was then
heated at reflux for 30 min. After cooling, it was extracted
with Et2O. The extract was washed with dil HCl, H2O, and
brine, dried over MgSO4, and concentrated in vacuo. The
residue was distilled to give 7.1 g (54%) of ( )-3 contami-
nated with 6, bp 83–86 ꢁC/4 Torr; n2D7 ¼ 1:4773. Acid treat-
ment causes isomerization of ( )-3 to 6. Their ratio could
be analyzed by 1H NMR measurement comparing the
areas of the signals [C@CH and CH(CH3)2] due to ( )-3
and 6, respectively, and found to be 85:15–75:25. mmax
(film): 1720 (m, CO of 6), 1682 (s, CO of 3), 833 (m), dH
(CDCl3): 0.95 (3H, d, J 6.9, CHCH3), 0.97 (3H, d, J 6.9,
CHCH3), 1.04 [d, J 6.9, CH(CH3)2 of 6], 1.69–1.87 (2H,
m, CH2CH2), 1.95–2.05 (1H, m, CHCH3), 2.25–2.40 (2H,
m, COCH2), 2.46–2.55 (1H, m, C@CHCH), 2.83–2.87
(m, C@CHCH2CO of 6), 5.46 (t-like, J 2, C@CH of 6),
6.00 (1H, ddd, J 10.2, 2.7, 0.9, COCH@CH), 6.91 (1H,
ddd, J 10.2, 2.4, 1.8, COCH=CH). Anal. Calcd for
C9H14O (138.2): C, 78.21; H, 10.21. Found C, 77.03; H,
10.09. Due to the high volatility of ( )-3 and 6, correct
analytical data could not be obtained.
4.7. ( )-Cryptone 3 from (+)-nopinone 12
Powdered AlCl3 (10.0 g, 72.5 mmol) was added to a stirred
and ice-cooled solution of (+)-nopinone (12, Aldrich, 5.3 g,
38 mmol) in CH2Cl2 (50 mL) at 0–5 ꢁC under Ar. The reac-
tion was exothermic, and the mixture was warmed up to
20 ꢁC for several seconds. Stirring was continued for
70 min at 0–5 ꢁC. The mixture was then poured into ice
and dil HCl, and extracted with CH2Cl2. The organic solu-
tion was washed with H2O and brine, dried over MgSO4,
and concentrated in vacuo. The residue was distilled to give
4.7 g (89%) of ( )-3 contaminated with 15–20% of 6. Its
IR, 1H and 13C NMR data were almost identical with those
of ( )-3 prepared by other methods. GC (TC-WAX 100–
190 ꢁC, +3 ꢁC/min): tR 13.85 min (19.5%, 6), 16.73 min
(80.5%, 3). MS (70 eV, EI) of 3: m/z (%): 138 (17) [M+],
96 (83), 95 (100), 81 (20), 67 (52), 66 (23), 65 (23), 53
(18); MS (70 eV, EI) of 6: m/z (%): 138 (41) [M+], 96
(22), 95 (21), 81 (100), 67 (40), 53 (24).
4.5. ( )-4-Isopropyl-2-phenylselenenylcyclohexanone 11
4-Isopropylcyclohexanone 10 was prepared from commer-
cially available p-isopropylphenol, by its hydrogenation
over PtO2 in AcOH followed by Jones oxidation, as a col-
orless oil, bp 62–64 ꢁC/3 Torr; n2D4 ¼ 1:4574. mmax (film):
1716 (s, CO), 1176 (m); dH (CDCl3): 0.93 (6H, d, J 6.6,
CH(CH3)2), 1.38–1.65 (5H, m), 1.95–2.06 (1H, m), 2.25–
2.44 (4H, m); dC (CDCl3): 19.9, 29.6, 31.7, 41.0, 42.5, 212.6.
4.8. (1S*,4R*)-( )-4-Isopropyl-1-methyl-2-cyclohexen-1-ol 1
and its (1R*,4R*)-isomer 2
A solution of MeLi in Et2O (containing LiBr, 1.0 M,
60 mL, 60 mmol) was added dropwise to a stirred and
cooled (dry ice–acetone) solution of ( )-3 (containing
19.5% of 6, 4.6 g, 33 mmol) in THF (50 mL) at ꢀ40 ꢁC un-
der Ar. The mixture was stirred for 30 min at ꢀ40 to 0 ꢁC,
and then for 1 h at room temp. It was then poured into ice
and NH4Cl (aq solution), and extracted with Et2O. The
extract was washed with brine, dried over K2CO3, and
concentrated in vacuo. The residue was chromatographed
over SiO2 (120 g). Elution with hexane/EtOAc (15:1) first
gave ( )-2 (0.8 g, 16%) and then ( )-1 (2.7 g, 53%) contam-
inated with small amounts of ( )-2 and ( )-7. Crude ( )-2
was distilled in vacuo to give 0.50 g (10%) of ( )-2, bp 73–
74 ꢁC/4 Torr; n2D6 ¼ 1:4722; mmax (film): 3340 (s, OH), 2958
PhSeCl (5.0 g, 26 mmol) was added to a stirred solution of
10 (3.2 g, 23 mmol) in EtOAc (75 mL) at room tempera-
ture. With the exothermic reaction, the color of the red
reaction mixture turned yellow within 5 min. Stirring was
continued for 40 min, and the mixture then partitioned be-
tween hexane and H2O. The organic layer was separated,
washed with H2O, NaHCO3 (aq solution), and brine, dried
over MgSO4, and concentrated in vacuo. The residue was
chromatographed over SiO2 (100 g). Elution with hexane/
EtOAc (10:1) yielded 3.1 g (46%) of ( )-11 as a slightly yel-
lowish oil, n2D4 ¼ 1:5012; mmax (film): 1708 (s, CO), 740 (s).
Anal. Calcd for C15H20OSe (295.3); C, 61.01; H, 6.83.
Found C, 61.10; H, 6.54.

K. Mori / Tetrahedron: Asymmetry 17 (2006) 2133–2142
2139
(s), 2873 (s), 1678 (w), 1461 (m), 1369 (m), 1122 (m), 906
4.10. 4-Isopropyl-1-methyl-2-phenylselenenylcyclohexan-1-
ol 15c and 15c0
(m), 733 (m), dH (CDCl3): 0.88 (3H, d, J 6.9, CHCH3)
0.90 (3H, d, J 6.9, CHCH3), 1.26 (3H, s, C(OH)CH3),
1.38–1.70 (5H, m), 1.80–1.92 (2H, m), 5.66 (2H, s-like,
CH@CH); dC (CDCl3): 19.2, 19.6, 21.6, 29.6, 31.7, 37.2,
42.1, 67.4, 133.2, 133.5. GC (TC-Wax, 100–190 ꢁC,
+3 ꢁC/min): tR 12.94 min [91.5% ( )-2]; MS (70 eV, EI):
m/z (%): 154 (13) [M+], 139 (78), 121 (50), 111 (72), 95
(61), 94 (73), 93 (79), 79 (100), 77 (73), 69 (51), 67 (49),
55 (53). Anal. Calcd for C10H18O (154.2): C, 77.86; H,
11.76. Found C, 77.79; H, 11.43. Distillation of crude
( )-1 gave 2.23 g (44%) of ( )-1 [92% purity with 6% of
( )-7 and 2% of ( )-2 as analyzed by GC], bp 78–79 ꢁC/
4 Torr; n2D8 ¼ 1:4728; mmax (film): 3367 (s, OH), 2958 (s),
2870 (s), 1651 (w), 1462 (m), 1369 (m), 1122 (s), 984 (m),
918 (m), 806 (w); dH (CDCl3): 0.87 (3H, d, J 6.6, CHCH3),
0.89 (3H, d, J 6.6, CHCH3), 1.27 (3H, s, C(OH)CH3), 1.30–
2.10 (7H, m), 5.60 (2H, s-like, CH@CH); dC (CDCl3): 19.4,
19.7, 23.5, 28.5, 31.7, 38.0, 41.7, 69.6, 131.3, 134.6. GC
(TC-WAX, 100–190 ꢁC, +3 ꢁC/min): tR 17.36 min (92%).
MS (70 eV, EI): m/z (%): 154 (9) [M+], 139 (100), 136
(46), 121 (73), 111 (62), 95 (58), 93 (87), 91 (56), 83 (64),
81 (58), 79 (62), 77 (78), 69 (71), 67 (53), 55 (71). Anal.
Calcd for C10H18O (154.2): C, 77.86; H, 11.76. Found C,
77.71; H, 11.48.
4.10.1. (1R,2R,4S)-Isomer 15c. NaBH4 (1.7 g, 45 mmol)
was added portionwise to a stirred and ice-cooled suspen-
sion of Ph2Se2 (7.0 g, 22 mmol) in 95% EtOH (100 mL)
at 0–5 ꢁC under Ar. The mixture was stirred for 30 min
to dissolve solid Ph2Se2, giving a homogeneous solution.
To this stirred solution of NaSePh was added a solution
of (ꢀ)-dihydrolimonene oxides 14a and 14b (5.7 g,
37 mmol) in 95% EtOH (20 mL) at room temp. The mix-
ture was stirred and heated at reflux for 2 h. White semi-
solid precipitates were generated at the end of this period.
The mixture was then concentrated in vacuo to remove
EtOH, and the residue was diluted with water. The result-
ing mixture was extracted with hexane. The extract was
washed with water and brine, dried (MgSO4), and concen-
1
trated in vacuo to give about 12.15 g of the residue. Its H
NMR analysis revealed the presence of 15a, 15b, and 15c in
a ratio of approximately 2:1:3 as estimated by the compar-
ison of the signals due to their CHOH or CHSePh proton
as shown in Scheme 5. The residue (12.15 g) was purified by
chromatography over SiO2 (150 g). Elution with hexane/
EtOAc (20:1) first gave 4.6 g of a mixture of 15a and 15b
contaminated with a small amount of 15c, then 3.6 g of
15c contaminated with a small amount of 15a and 15b,
and finally 15c (4.1 g). It was impossible to separate 15a
from 15b cleanly by open column SiO2 chromatography.
The middle fraction was rechromatographed over SiO2
(80 g) to give 0.9 g of pure 15c. The combined yield of
If the chromatographic purification was omitted and the
product purified by distillation only, then 7.55 g (86%) of
82% pure ( )-1 (contaminated with 10% of 7 and 4% of
2) was obtained by starting from 8.0 g of 80% pure ( )-3.
GC (TC-WAX, 100–190 ꢁC, +3 ꢁC/min): tR 13.04 (4%,
2), 13.26 (10%, 7), 14.65 (82%, 1). Calcd for C10H18O
(154.2): C, 77.86; H, 11.76. Found C, 77.35; H, 11.26.
15c was 5.0 g (44%), which was obtained as a yellowish
21
oil, n2D4 ¼ 1:5062; ½aꢁD ¼ ꢀ103:2 (c 3.83, hexane). mmax
(film): 3352 (s, OH), 3058 (w), 1577 (m), 737 (s), 690 (m);
dH (CDCl3): 0.80 (3H, d, J 6.6, CHCH3), 0.85 (3H, d, J
6.6, CHCH3), 1.26 (2H, m), 1.37 (3H, s, C(OH)-
CH3), 1.40–2.08 (7H, m), 3.40 (1H, t-like, CHSePh) 7.24–
7.27 (3H, m, arom-H) 7.50–7.60 (2H, m, arom-H); dC
(CDCl3): 14.1, 20.2, 22.6, 24.7, 31.6, 32.5, 35.2, 39.1,
54.9, 72.8, 127.4, 129.0, 130.8, 134.3. Anal. Calcd for
C16H22OSe (309.3): C. 62.13; H, 7.17. Found C, 61.64;
H, 7.58.
4.9. Enantiomers of dihydrolimonene oxide 14 and 140
4.9.1. (R)-(ꢀ)-Isomer 14. Adams’s PtO2 (50 mg) was
added to a solution of (ꢀ)-limonene oxide 13 (Aldrich,
99% ee; 6.4 g, 42 mmol) in MeOH (30 mL). The mixture
was stirred under H2 (balloon) for 2 h at room tempera-
ture. The hydrogenation was exothermic, and about 1 L
of H2 was consumed. The mixture was then diluted with
hexane and filtered through Celite. The filtrate was concen-
trated in vacuo, and the residue was distilled to give 6.0 g
4.10.2. (1S,2S,4R)-Isomer 15c0. In the same manner, (+)-
dihydrolimonene oxides 14a0 and 14b0 (6.1 g, 40 mmol)
(92%) of 14, bp 87–88 ꢁC/24 Torr; n2D4 ¼ 1:4490;
afforded 5.2 g (43%) of 15c0 as
a yellowish oil,
21
19
½aꢁD ¼ ꢀ65:5 (c 3.05, hexane); mmax (film): 2958 (s), 2873
n2D4 ¼ 1:5062, ½aꢁD ¼ þ110:5 (c 2.84, hexane). Its spectral
data were identical with those of 15c. Anal. Calcd for
C16H22OSe (309.3); C, 62.13; H, 7.17. Found C, 61.80;
H, 7.58.
(s), 1018 (m), 841 (m), 760 (m), 671 (m): dH (CDCl3):
0.83 (3.2H, d, J 6.9, CHCH3), 0.84 (1.4H, d, J 6.9,
CHCH3), 0.85 (1.4H, d, J 6.6, CHCH3), 0.90–1.20 (2H,
m), 1.30 [3H, s, C(OH)CH3], 1.32–1.68 (4H, m), 1.80–
2.14 (2H, m), 2.97 (0.6H, d, J 5.4, OCH of 14b), 3.02
(0.4H, t, J 1.5, OCH of 14a); dC (CDCl3): 19.3, 19.7,
22.5, 23.1, 24.4, 24.9, 27.9, 29.2, 30.9, 31.6, 32.3, 35.1,
39.2, 57.6, 57.8, 59.6, 61.0. Anal. Calcd for C10H18O
(154.2): C, 77.86; H, 11.76. Found C, 77.82; H, 11.97.
4.11. 4-Isopropyl-1-methyl-2-cyclohexen-1-ol 2 and 20
4.11.1. (1R,4R)-Isomer 2. H2O2 (30%, 17 mL, 150 mmol)
was added dropwise to a stirred and ice-cooled solution
of 15c (7.6 g, 24.6 mmol) in a mixture of THF (50 mL)
and pyridine (10 mL). The reaction was exothermic. The
mixture was stirred for 1 h at room temp, and then stirred
and heated under reflux for 1 h. Subsequently, it was con-
centrated in vacuo, diluted with H2O, and extracted with
hexane. The hexane solution was washed with K2CO3 (aq
solution), CuSO4 (aq solution), and brine, dried over
K2CO3, and concentrated in vacuo. The residue (about
4.9.2. (S)-(+)-Isomer 140. (+)-Limonene oxide (130, Al-
drich, 98% ee; 6.4 g, 42 mmol) yielded 5.4 g (83%) of (S)-
19
(+)-140, bp 87–88 ꢁC/25 Torr; nD24 ¼ 1:4490; ½aꢁD ¼ þ64:4
(c 2.39, hexane). Its spectral data were identical with those
of 14. Anal. Calcd for C10H18O (154.2): C, 77.86; H, 11.76.
Found C, 77.66; H, 12.32.

2140
K. Mori / Tetrahedron: Asymmetry 17 (2006) 2133–2142
5 g) was chromatographed over SiO2 (100 g). Elution with
hexane/EtOAc (30:1) afforded 3.4 g of crude 2 in later frac-
tions. This was distilled to give 2.3 g (61%) of (1R,4R)-2 as
and for 2 days at room temperature causing the mixture
to turn yellow in color. Subsequently, Na2SO3 (30 g) was
added, and the mixture was stirred for 30 min at room
temp. It was then concentrated in vacuo to remove t-
BuOH. The residue was diluted with H2O and extracted
with Et2O. The Et2O solution was washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was
tritulated with hexane to give 3.2 g (42%) of crude 19.
a
colorless oil, bp 66–68 ꢁC/3 Torr; n2D4 ¼ 1:4718;
22
20
½aꢁD ¼ þ10:3 (c 4.28, hexane); ½aꢁD ¼ þ11:4 (c 1.67,
CHCl3). Its spectral data were identical with those of
( )-2. GC (TC-WAX, 100–190 ꢁC, +3 ꢁC/min): tR =
15.91 min [94.3%, (1R,4R)-2]. Anal. Calcd for C10H18O
(154.2): C, 77.86; H, 11.76. Found C, 77.61; H, 11.84.
Recrystallization from hexane yielded 1.96 g of pure 19
22
as needles, mp 72–73 ꢁC; ½aꢁD ¼ ꢀ10:3 (c 2.28, CHCl3)
{Ref. 22 mp 82–83 ꢁC; [a]D = ꢀ10.1 (CHCl3)}. mmax
(nujol): 3336 (s, OH), 1165 (m), 1068 (m), 926 (m), 737
(m). dH (CDCl3): 0.88 [6H, d, J 6.6, CH(CH3)2],
1.04–1.20 (1H, br), 1.26 [3H, s, C(OH)CH3], 1.27–1.54
(5H, m) 1.60–1.86 (5H, m), 3.36 (1H, dd, J 4, 11, CHOH);
dC (CDCl3): 19.8, 19.9, 24.2, 27.1, 32.4, 34.0, 37.3, 42.7,
71.0, 75.5. Anal. Calcd for C10H20O2 (172.3): C, 69.72;
H, 11.70. Found C, 69.46; H, 12.11.
4.11.2. (1S,4S)-Isomer 20. In the same manner, 15c0 (3.8 g,
12.3 mmol) was oxidized with 30% H2O2 (10 mL, 88 mmol)
in THF (50 mL) and pyridine (10 mL). The crude product
was purified by SiO2 chromatography and distillation to
give 1.5 g (79%) of (1S,4S)-20 as a colorless oil, bp 73–
26
74 ꢁC/4 Torr; n2D4 ¼ 1:4712; ½aꢁD ¼ ꢀ10:2 (c 4.12, hexane);
20
½aꢁD ¼ ꢀ12:0 (c 2.06, CHCl3). Its spectral data were identi-
cal with those of ( )-2. GC (TC-WAX, 100–190 ꢁC, +3 ꢁC/
min): tR = 15.81 min [94.5%, (1S,4S,)-20]. Anal. Calcd for
C10H18O (154.2): C, 77.86; H, 11.76. Found C, 77.80; H,
11.89.
4.12.2. (1S,2R,4R)-Isomer 190. Similarly, 7.0 g of (R)-180
was oxidized with 30 g of AD-mix bꢂ in the presence of
MeSO2NH2 (3.2 g) in t-BuOH (100 mL) and H2O
(100 mL) to give 3.5 g (40%) of crude 190. This was recrys-
tallized from hexane to give 2.5 g of pure 190 as needles, mp
4.11.3. Isomerization in the absence of pyridine. If the
above reaction was executed in the absence of pyridine,
isomerization of (1R,2R)-2 took place due to the acidity
of the generated phenylselenenic acid to give a mixture of
(1R,4R,)-2 (tR = 16.13 min; 66.8%), (1S,4R)-1 (tR =
18.04 min; 12.2%), (1S,6R)-16 (tR = 19.69 min; 8.5%), and
(1R,6R)-17 (tR = 21.79 min; 7.5%) together with 5% of
six unidentified compounds as analyzed by GC–MS (TC-
WAX 100–190 ꢁC, +3 ꢁC/min). In the case of (1S,4S)-20,
the reaction in the absence of pyridine furnished a mixture
of (1S,4S)-20 (tR = 16.16 min; 51.2%), (1R,4S)-10 (tR =
18.09 min; 23.9%), (1R,6S)-160 (tR = 19.71 min; 7.6%),
and (1S,6S)-170 (tR = 21.82 min; 13.3%) together with 4%
of seven unidentified compounds. Addition of pyridine to
avoid the acid-catalyzed allylic rearrangement was there-
fore the key to the success of the synthesis. The four alco-
hols 1, 2, 16, and 17 were identified by their MS. MS
(70 eV, EI) of 16: m/z: 154 (6.3) [M+], 139 (49), 84 (100),
83 (56), 79 (25), 77 (26), 55 (31). MS (70 eV, EI) of 17:
m/z: 154 (9) [M+], 139 (43), 91 (19), 84 (100), 83 (56), 79
(24), 77 (61), 55 (37). The retention time of 17
(17.98 min) was longer than that of 16 (15.88 min) due to
the presence of the equatorial OH at C-2 of 17.
21
74.5–75.0 ꢁC; ½aꢁD ¼ þ9:3 (c 3.30, CHCl3) {Ref. 23 mp 82–
29
83 ꢁC; ½aꢁD ¼ þ8:2}. Its spectral properties were identical
with those of 19. Anal. Calcd for C10H20O2 (172.3): C,
69.72; H, 11.70. Found C, 69.50; H, 12.12.
4.13. (4S)-1-tert-Butyldimethylsilyloxymethyl-1,2-epoxy-4-
isopropylcyclohexane 22
(S)-Perillyl alcohol 20 (Aldrich, 30 g) was oxidized with t-
BuOOH to give 37.7 g of crude epoxy alcohol, which was
silylated with TBSCl to furnish 57.3 g (quant.) of the
known 21 after SiO2 chromatography.31 Adams’s PtO2
(300 mg) was added to a solution of 21 (57.3 g, 0.2 mol)
in hexane (100 mL) and EtOAc (100 mL), and the mixture
vigorously stirred under H2 for 2 h at room temp, allowing
the consumption of about 5 L of H2. The hydrogenation
was exothermic. The mixture was then filtered through Cel-
ite to remove Pt, and the Celite layer was washed with hex-
ane. The combined filtrate and washings were concentrated
in vacuo to give 56.9 g (quant.) of 22 as a colorless oil,
19
17
n2D2 ¼ 1:4572; ½aꢁD ¼ ꢀ25:7 (c 2.64, EtOH); ½aꢁD ¼ ꢀ23:3
(c 3.12, CHCl3); mmax (film): 1255 (m), 1100 (m), 837 (s),
780 (s); dH (CDCl3): 0.04 and 0.05 (6H, each s, SiCH3),
0.82 (3H, d, J 6, CHCH3), 0.83 (3H, d, J 6, CHCH3),
0.88 [9H, s, C(CH3)3], 1.20–1.70 (6H, m), 1.90–2.12 (4H,
m), 3.13 (1H, br s), 3.56 (2H, d, J 5, CH2O), 3.62 (1H, br
s); dC (CDCl3): ꢀ5.4, ꢀ5.3, 18.3, 19.6, 24.8, 25.8, 25.9,
25.95, 26.8, 31.7, 35.8, 58.0, 60.1, 67.1. Anal. Calcd for
C16H32O2Si: (284.5): C, 67.55; H, 11.34. Found C, 66.81;
H, 11.72.
4.12. 4-Isopropyl-1-methylcyclohexane-1,2-diols 19 and 190
4.12.1. (1R,2S,4S)-Isomer 19. (S)-(ꢀ)-Dihydrolimonene
was prepared from (S)-(ꢀ)-limonene (Aldrich, 6.0 g) by
partial hydrogenation over PtO2 (130 mg) in MeOH
(15 mL). After dilution with hexane, the mixture was fil-
tered through Celite to remove Pt, and the filtrate concen-
trated in vacuo to give crude 18 (6.0 g). AD-mix aꢂ
(Aldrich, 30 g) and MeSO2NH2 (3.2 g) were added to a
mixture of t-BuOH (90 mL) and H2O (100 mL), and the
red mixture was stirred for 30 min at 0–5 ꢁC to generate
a biphasic (red and colorless) oxidant for AD. A solution
of 18 (6.0 g, 44 mmol) in t-BuOH (10 mL) was added to
the mixture, and stirring was continued for 3 h at 0–5 ꢁC
4.14. (4S)-1-tert-Butyldimethylsilyloxymethyl-4-isopropyl-2-
phenylselenenylcyclohexan-1-ol 23
To a stirred suspension of NaH (50% in mineral oil, 3.4 g,
71 mmol) in dry THF (70 mL) was added slowly a solution
of Ph2Se2 (10.7 g, 34 mmol) in THF (30 mL) at gentle re-

K. Mori / Tetrahedron: Asymmetry 17 (2006) 2133–2142
2141
flux under Ar. With exothermic H2 evolution, the orange
solution turned to white and voluminous suspension of Na-
SePh. CAUTION. Care should be taken not to make the
reaction too vigorous to control. After stirring and heating
under reflux for 1.5 h, HMPA (7 mL) was added to the
mixture to dissolve NaSePh. To the resulting homogeneous
solution was added dropwise with stirring a solution of 22
(15.4 g, 54 mmol) in dry THF (35 mL), and the mixture
was stirred and heated under reflux for 3 h under Ar. Sub-
sequently, the mixture was cooled, diluted with ice-water,
and extracted with hexane. The extract was washed with
water and brine, dried over MgSO4, and concentrated in
4.18. Determination of the enantiomeric purities of 1, 2, and
3 by GC analysis
4.18.1. GC analysis of 1 and 2. Instrument: Agilent 6890.
Column: Chiramixꢂ34 (0.25 mm i.d. · 30 m). Column
temp: 40–180 ꢁC (+0.7 ꢁC/min). Carrier gas: N2, 0.7 mL/
min. Detector: FID. Injection temp: 230 ꢁC. Detector
temp: 250 ꢁC.
( )-1: tR 113.54 min [(1S,4R)-1], 114.54 min [(1R,4S)-10]
(base peak separation).
(1S,4R)-1: 96.67% of (1S,4R)-1 and 3.33% of (1R,4S)-10
(93.34% ee).
vacuo to give crude 23 (25 g, quant.) as an oil,
15
nD22 ¼ 1:5132; ½aꢁD ¼ þ12:2 (c 2.79, CHCl3); mmax (film):
( )-2: tR 108.43 min [(1S,4S)-20], 109.50 min [(1R,4R)-2]
(base peak separation).
3433 (m), 1577 (w), 1253 (m), 1084 (m), 837 (s), 779 (m),
737 (m), 690 (m). Anal. Calcd for C22H38O2SeSi; (441.5):
C, 59.84; H, 8.67. Found C, 59.11; H, 8.25.
(1R,4R)-2: 99.16% of (1R,4R)-2 and 0.84% of (1S,4S)-20
(98.32% ee) or 99.33% of (1R,4R)-2 and 0.67% of
(1S,4S)-20 (98.66% ee).
4.15. (4S)-1-Hydroxymethyl-4-isopropyl-2-phenylselenenyl-
cyclohexan-1-ol 24
(1S,4S)-2: 99.11% of (1S,4S)-20 and 0.89% of (1R,4R)-2
(98.22% ee) or 98.92% of (1S,4S)-20 and 1.08% of
(1R,4R)-2 (97.84% ee).
A solution of TBAF in THF (1 M, 70 mL, 70 mmol) was
added to a stirred solution of crude 23 (25 g, 54 mmol) in
THF (70 mL) and the dark-colored mixture was left to
stand overnight at room temperature. It was then diluted
with H2O and extracted with Et2O. The extract was washed
with H2O and brine, dried over MgSO4, and concentrated
in vacuo to give a crude oil (25 g) containing 24, mmax
(film): 3430 (s), 1577 (w), 1253 (s), 1064 (s), 837 (s), 779
(s). This was employed in the next step without further
purification.
4.18.2. GC analysis of 3. Instrument: Agilent 6890. Col-
umn:
2,3-dimethoxymethyl-6-tert-butyldimethylsilyl-c-
cyclodextrin (50% MOMTBDMSGC, 0.25 mm i.d. ·
30 m). Column temp: 70–180 ꢁC (+0.7 ꢁC/min). Carrier
gas, N2, 0.7 mL/min. Detector: FID. Injection temp:
230 ꢁC. Detector temp: 250 ꢁC.
( )-3: tR 94.95 min [(S)-3], 96.88 min [(R)-3].
(R)-3: 95.74% of (R)-3 and 4.26% of (S)-3 (91.48% ee).
4.16. (R)-Cryptone (4-isopropyl-2-cyclohexenone) 3
Acknowledgments
Solid sodium periodate (50 g, 234 mmol) was added in one
portion to a stirred and ice-cooled solution of crude 24
(25 g, 54 mmol) in THF (300 mL) and H2O (60 mL). The
resulting solution soon became pasty with precipitated
NaIO3. After stirring for 1.5 h at room temp, the mixture
was diluted with Et2O and NaHCO3 (aq solution). The
Et2O layer was separated and the aq layer was extracted
with Et2O. The combined Et2O solution was washed with
H2O and brine, dried with MgSO4, and concentrated in va-
cuo to give 21.3 g of an oil. This was chromatographed
over SiO2 (110 g). Elution with hexane/EtOAc (15:1)
yielded fractions with mmax (film): 1682. These were com-
bined and distilled in vacuo to give 2.1 g (28% based on
I thank Professor N. Kamata (the University of Tokyo),
Dr. T. Nakashima (Forestry and Forest Products Research
Institute), Professor T. Mitsunaga (Gifu University), Mr.
H. Takemoto (Kyoto University), and Professor H. Honda
(University of Tsukuba) for discussion. Thanks are due to
Dr. S. Tamogami (T. Hasegawa Co.) for chiral GC analy-
sis, Dr. S. Muto (Fuji Flavor Co.) for analytical help, Pro-
fessor T. Nukada (Tokyo University of Agriculture) for
MO calculation, and Dr. T. Tashiro (RIKEN) for prepar-
ing the Schemes.
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22, three steps) of (R)-3, bp 80–82 ꢁC/6 Torr; nD22
¼
19
1:4816; ½aꢁD ¼ ꢀ86:8 (c 1.06, EtOH). Its spectral properties
were identical with those of ( )-3.
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19
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