Enzyme-assisted synthesis of (S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one, the male-produced aggregation pheromone of the Colorado potato beetle, and its (R)-enantiomer

Article abstract of DOI:10.1016/j.tetasy.2005.03.030

(S)-1,3-Dihydroxy-3,7-dimethyl-6-octen-2-one, the male-produced aggregation pheromone of the Colorado potato beetle (Leptinotarsa decemlineata), and its (R)-isomer were synthesized by employing lipase-catalyzed asymmetric acetylation of (±)-2,3-epoxynerol as the key step.

Full text of DOI:10.1016/j.tetasy.2005.03.030

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1801–1806
Enzyme-assisted synthesis of (S)-1,3-dihydroxy-3,7-dimethyl-6-
octen-2-one, the male-produced aggregation pheromone of the
Colorado potato beetle, and its (R)-enantiomerq
Takuya Tashiroa and Kenji Moria,b,
*
aGlycosphingolipid Synthesis Group, RIKEN Research Center for Allergy and Immunology, c/o Seikagaku Corporation,
Tateno 3-1253, Higashiyamato-shi, Tokyo 207-0021, Japan
bInsect Pheromone and Traps Division, Fuji Flavor Co., Ltd, Midorigaoka 3-5-8, Hamura-shi, Tokyo 207-8503, Japan
Received 21 February 2005; accepted 23 March 2005
Abstract—(S)-1,3-Dihydroxy-3,7-dimethyl-6-octen-2-one, the male-produced aggregation pheromone of the Colorado potato beetle
(Leptinotarsa decemlineata), and its (R)-isomer were synthesized by employing lipase-catalyzed asymmetric acetylation of ( )-2,3-
epoxynerol as the key step.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
monoterpene 1.5 Bioassay of the synthetic samples
revealed that (S)-1 was attractive for both male and
female L. decemlineata, while (R)-1 was inactive, and
its presence in ( )-1 abolished the response to (S)-1.5
The Colorado potato beetle, Leptinotarsa decemlineata,
is a major pest of potatoes and related solanaceous
plants, such as tomatoes and eggplants throughout the
world. Heavy use of pesticides for control has led to
the development of insecticide resistance in this insect.
It is therefore important to study the attractants and
pheromones of L. decemlineata to make its biorational
control possible.
This kind of inhibitory action of the incorrect enantio-
mer is well known in pheromone science.6 Pheromones
belonging to this category must be prepared in enantio-
merically pure or highly enriched form prior to its bio-
logical test.
In 1926, McIndoo was the first to study the attractancy
of volatiles emitted by mature potato plants against
L. decemlineata.2 Subsequently, Dickens identified five
volatile components of potatoes, which caused anten-
nal response of the potato beetle.3 More importantly,
in 2002, Dickens isolated about 1 mg of its male-pro-
duced aggregation pheromone.4
At this stage, Dickens of the US Department of Agricul-
ture requested one of us (K.M.) to synthesize gram
quantities of (S)-1 required for its field test. Because Oli-
ver et al. started their synthesis of (S)-1 from scarcely
available (S)-linalool, they were unable to prepare (S)-
1 in a sufficient amount.5 Their synthesis of ( )-1, how-
ever, employed readily available ( )-2,3-epoxygeraniol
(20, trans-epoxide, Table 1) as the starting material,
and well-designed to give ( )-1 smoothly. Accordingly,
development of a practical method for the preparation
of enantiomerically highly enriched 2 [2,3-epoxynerol
(cis-epoxide) or 20 (2,3-epoxygeraniol)] enables us to
obtain (S)-1 in gram quantities.
The pheromone was identified as (S)-1,3-dihydroxy-3,7-
dimethyl-6-octen-2-one 1 (Scheme 1) by Oliver et al. on
the basis of MS and NMR analysis of the isolated mate-
rial coupled with the synthesis and bioassay of the race-
mate and enantiomers of this highly oxygenated
Optically active 2,3-epoxygeraniol or 2,3-epoxynerol is
usually prepared by the Sharpless asymmetric epoxida-
tion of geraniol or nerol.7–9 Their enantiomeric purities,
however, are not perfect: 94–95% ee,7 86–91% ee,8 or
q Pheromone synthesis, Part 231. For Part 230, see: Ref. 1.
*
Corresponding author. Fax: +81 3 3813 1516; e-mail: kjk-mori@
arion.ocn.ne.jp
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.030

1802
T. Tashiro, K. Mori / Tetrahedron: Asymmetry 16 (2005) 1801–1806
C-3 of 2,3-epoxynerol 2 or 2,3-epoxygeraniol 20 was re-
OH
O
quired, because the stereogenic center at C-2 would later
be destroyed to give the target 2-ketone (S)-1. We there-
fore decided to examine both 2 and 20 concerning their
suitabilities as the substrate for asymmetric acetylation.
These two epoxy alcohols 2 and 20 could readily be
prepared from nerol and geraniol, respectively, by their
oxidation with tert-butyl hydroperoxide in refluxing
benzene in the presence of vanadyl acetylacetonate
[VO(acac)2] according to Sharpless and Michaelson.11
OH
Pheromone of the Colorado potato beetle (S)-1
b
O
OAc
OH
O
a
(2S,3R)-3
(2R,3S)-2
Esterases and lipases are known to catalyze asymmetric
hydrolysis of 2,3-epoxyalkyl acetates12 and also asym-
metric acetylation of 2,3-epoxy alcohols.13 We therefore
screened various lipases for the asymmetric acetylation
of 2,3-epoxy alcohols 2 and 20 as shown in Table 1.
All the lipases tested showed enantioselectivity in the
acetylation reaction with vinyl acetate in diethyl ether:
( )-2,3-Epoxynerol 2 yielded (2S,3R)-2,3-epoxyneryl
acetate 3, and ( )-2,3-epoxygeraniol 20 afforded
(2R,3R)-2,3-epoxygeranyl acetate 30. Assignment of the
above absolute configuration was made possible by
comparing the sign of the specific rotation of these prod-
ucts with those reported previously.7–9 Thus, lipases do
not discriminate the stereoisomers at C-2, which is adja-
cent to the hydroxy group, but recognize the absolute
configuration at C-3. Both 2 and 20 were good substrates
for acetylation, and lipase PS (Amano) was selected as
the enzyme of choice. Since lipase PS did not work
efficiently at ꢀ18 ꢁC, the reaction temperature was set
at 0 ꢁC. Under these conditions, both 2 and 20 were
half-acetylated within 3 h to give the products in 72–
74% ee. It was therefore evident that the repetition of
the above lipase-catalyzed acetylation would give epoxy
acetate 3 or 30 and epoxy alcohol 2 or 20 in satisfactory
enantiomeric purity.
OH
( )-2
O
OH
OH
OH
d
OR
OR
O
(2S,3S)-4 R = H
(S)-6 R = TBDPS
(S)-1 R = H
c
e
(2S,3S)-5 R = TBDPS
Similarly
OH
O
OH
O
OR
(R)-1
(2R,3S)-2 R = H
(2R,3S)-3 R = Ac
f
Scheme 1. Synthesis of the male-produced aggregation pheromone
of the Colorado potato beetle (S)-1 and its (R)-isomer. Reagents and
conditions: (a) lipase PS (Amano), CH2@CHOAc, Et2O, 0 ꢁC, 4 h,
three times, 10–16% for (2S,3R)-3 and 11–22% for (2R,3S)-2 based on
( )-2; (b) 60% HClO4, DMF, 0 ꢁC–room temp, 12 h; then K2CO3,
MeOH, room temp, 20 h, 77–92%; (c) TBDPSCl, Et3N, DMAP,
CH2Cl2, room temp, 24 h, 93–97%; (d) SO3ÆC5H5N, DMSO, Et3N,
CH2Cl2, 0 ꢁC–room temp, 24 h, 78–91%; (e) TBAF, THF, 0 ꢁC, 5 min,
65%-quant.; (f) Ac2O, DMAP, C5H5N, 30 min, 86–92%.
2.2. Synthesis of the pheromone (S)-1 and its (R)-isomer
The synthesis of pheromone (S)-1 is summarized in
Scheme 1. The synthesis started from nerol, which we
had in quantity. ( )-2,3-Epoxynerol 214 was subjected
to the enzymatic kinetic resolution three times with
lipase PS and vinyl acetate to give, in 16% yield based
on ( )-2, (2S,3R)-2,3-epoxyneryl acetate 3. It was
enantiomerically almost pure (98.8% ee) as determined
by its HPLC analysis on Chiralcel-ODꢂ. Unreacted
alcohol (2R,3S)-2 (98.6% ee) was obtained in 22% yield.
Through this enzyme reaction, a sufficient amount
(about 5 g) of both (2S,3R)-3 and (2R,3S)-2 could be
secured, and the former was further processed to give
the pheromone (S)-1 essentially according to Oliver et al.5
62–81% ee.9 Although recrystallization of their p-nitro-
benzoates can afford enantiomerically pure materials,
this purification is cumbersome and inefficient.7,8 We
therefore envisaged to employ enzymatic and asymmet-
ric acetylation of ( )-2 as the key step to prepare enan-
tiomerically highly enriched acetate 3. Herein we report
the lipase-catalyzed asymmetric acetylation of ( )-2 to
give (2S,3R)-3, as well as its conversion to (S)-1 via
(2S,3S)-4. The synthesis of (R)-1 is also reported.
Inversion of the (3R)-configuration of (2S,3R)-3 was
achieved by treating epoxide 3 with aqueous perchloric
acid in N,N-dimethylformamide (DMF) at 0 ꢁC, fol-
lowed by treatment of the resulting 1,2,3-triol-1-ace-
tate-2-formate with potassium carbonate in methanol
to give triol (2S,3S)-4 in 86% yield.5,15 Inversion of con-
figuration at C-3 of epoxide 3 under these conditions
had been studied conclusively by Hanson.15 The enan-
tiomeric purity of (2S,3S)-4, as determined at the stage
of (S)-6 (vide infra), was 93.2% ee. When the ring
2. Results and discussion
2.1. Lipase-catalyzed asymmetric acetylation of
2,3-epoxynerol and 2,3-epoxygeraniol
Lipase-catalyzed asymmetric acetylation of racemic
alcohols with vinyl acetate is one of the most established
methods for kinetic resolution of racemic alcohols.10 In
the present case, enantiomer discrimination only at the

T. Tashiro, K. Mori / Tetrahedron: Asymmetry 16 (2005) 1801–1806
1803
a
Table 1. Lipase-catalyzed asymmetric acetylation of ( )-2,3-epoxynerol 2 and ( )-2,3-epoxygeraniol 20
O
O
Lipase
(2S,3R)-3
(2R,3R)-3'
OAc
CH2=CHOAc
OH
Et2O
O
(2R*,3S*)-2 (2,3-epoxynerol)
(2R*,3R*)-2' (2,3-epoxygeraniol)
(2R,3S)-2
(2S,3S)-2'
OH
2,3-Epoxygeranyl acetateb
Lipase
Temperature
2,3-Epoxyneryl acetateb
Yield (%)d
Time (min)c
ee (%)e
Time (min)c
Yield (%)d
ee (%)e
AK
AH
PS
Rt
Rt
70
25
23
25
30
21
26
24
50
59
72
42
60
20
20
26
31
23
21
50
46
60
74
26
Rt
125
165
15
120
160
15
PS
PS-C
0 ꢁC
Rt
a Conditions: To a solution of 2,3-epoxy alcohol (100 mg) in diethyl ether (2 mL) and vinyl acetate (0.5 mL) was added lipase (50 mg) at the shown
temperature. The enzymes were a generous gift of Amano Enzyme, Inc. (Lipase AK from Pseudomonas fluorescens; Lipase AH from Burkholderia
cepacia; Lipase PS from B. cepacia; PS-C = PS on Celite).
b The absolute configuration of the resulting 2,3-epoxyneryl acetate 3 was 2S,3R, while that of 2,3-epoxygeranyl acetate (30) was 2R,3R.7–9
c The acetylation was monitored by TLC.
d Yields were based on the starting racemates 2 or 20.
e Determined by HPLC analysis of 3 and 30.
opening of epoxide 3 was performed at room tempera-
ture (about 20 ꢁC), partial racemization at C-3 took
place to give (2S,3S)-4 of only 83% ee. The epoxide
cleavage did not occur at ꢀ18 ꢁC.
3. Conclusion
Lipase-catalyzed asymmetric acetylation of ( )-2,3-
epoxynerol 2 enabled us to prepare (2S,3R)-2,3-epoxy-
neryl acetate 3 in a substantial amount, which afforded
(S)-2,3-dihydroxy-3,7-dimethyl-6-octen-2-one 1, the
male-produced aggregation pheromone of the Colorado
potato beetle in an amount sufficient for its field test.
The unnatural (R)-1 was also synthesized, and supplied
for further biological study. The field trial to catch adult
Colorado potato beetles in pitfall traps baited with (S)-1
was successfully conducted in Virginia, USA. However,
more research is necessary to optimize the release rate of
(S)-1 and incorporate control methods for cohabiting
pests. Details of the field test will be reported in due
course.17
Prior to the oxidation of the secondary hydroxy group
at C-2 of (2S,3S)-4, the terminal hydroxy group at
C-1 was selectively protected by treatment with
1.1 equiv of tert-butyldiphenylsilyl chloride (TBDPSCl)
and triethylamine in the presence of a catalytic amount
of 4-N,N-dimethylaminopyridine (DMAP) to give
(2S,3S)-5 in 97% yield. Subsequent oxidation of
(2S,3S)-5 with dimethyl sulfoxide (DMSO) and sulfur
trioxide-pyridine complex in the presence of triethyl-
amine16 yielded (S)-6 in 85% yield. HPLC analysis of
(S)-6 on Chiralcel-ODꢂ revealed its enantiomeric purity
as 93.2% ee.
Final deprotection of the TBDPS group of (S)-6 by
short treatment (0 ꢁC, 5 min) with tetra-n-butylammo-
nium fluoride (TBAF) in THF furnished oily (S)-1 in a
quantitative yield after chromatographic purification,
4. Experimental
4.1. General
25
25
½aꢁ ¼ þ3:8 (c 0.79, CHCl3) {lit.5 ½aꢁ ¼ þ0:7
All boiling points (bp) data are uncorrected. Refractive
indices (nD) were measured by an Atago 1T refracto-
meter. Optical rotation values were measured by a Jasco
DIP-1010 instruments. IR spectra were recorded by Jas-
co FT/IR-460 plus spectrometer. 1H NMR spectra were
recorded by Jeol JNM-90A (90 MHz), JNM-AL300
(300 MHz) and Jeol JNM-LA500 (500 MHz) spectro-
meters (TMS at dH = 0.00, CHCl3 at dH = 7.26, or benz-
ene at dH = 7.15 as an internal standard). Coupling con-
stants (J) were reported in hertz. 13C NMR spectra were
recorded by Jeol JNM-LA500 (126 MHz) spectrometer
(CHCl3 at dC = 77.0, or benzene at 128.0 as an internal
standard). Mass spectra were recorded by Jeol JMS-
SX102A and Hitachi M-80B instruments. Column
chromatography was carried out with Merck Kieselgel
D
D
(CHCl3)}. Its 1H NMR spectrum (500 MHz, CDCl3)
was identical to that reported for the natural phero-
mone.5 A longer reaction time at room temperature over
the course of the TBAF treatment resulted in a drasti-
cally reduced yield (about 12% after 16 h) due to the
isomerization followed by retroaldol reaction caused
by the basicity of TBAF. This decomposition is similar
to that of D-fructose under basic conditions. Through
the present synthesis, about 2.5 g of (S)-1 was synthe-
sized in 71% overall yield based on (2S,3R)-3 (four
steps). For the synthesis of (R)-1, (2R,3S)-2 was acetyl-
ated to give (2R,3S)-3 (99.3% ee), which was converted
to (R)-1 (2.0 g) in 42% overall yield based on (2R,3S)-
2 (five steps).

1804
T. Tashiro, K. Mori / Tetrahedron: Asymmetry 16 (2005) 1801–1806
60 Art 1.07734, and TLC was carried out with 0.25 mm
Merck silica gel plates (60F-254).
(M+) 170.1307, found 170.1301. This was immediately
used in the next step without further purification.
4.2. (2S,3R)-3,7-Dimethyl-2,3-epoxy-6-octenyl acetate 3,
and (2R,3S)-3,7-dimethyl-2,3-epoxy-6-octen-1-ol 2
4.3. (2R,3S)-3,7-Dimethyl-2,3-epoxy-6-octenyl acetate
(2R,3S)-3
To a stirred solution of ( )-2 (23.6 g, 162 mmol) and
vinyl acetate (60 mL) in Et2O (230 mL) was added
lipase-PS (Amano Enzyme, Inc., 4.6 g) at 0 ꢁC. The
mixture was stirred at 0 ꢁC for 4 h. It was then filtered
through a bed of Celite and the filtrate concentrated in
vacuo. The residue was purified by chromatography
on silica gel [1.1 kg, hexane/ethyl acetate = 5:1 for
(2S,3R)-3, and 2:1 for (2R,3S)-2] to give (2S,3R)-3 and
(2R,3S)-2.
To a stirred solution of (2R,3S)-2 (5.17 g, 30.4 mmol) in
pyridine (50 mL) were added acetic anhydride (8.40 mL,
88.9 mmol) and a catalytic amount of 4-N,N-dimethyl-
aminopyridine (DMAP, 0.04 g) at 0 ꢁC. The mixture
was stirred for 30 min at room temperature. It was then
poured into water and extracted with EtOAc
(20 mL · 2). The combined organic solution was succes-
sively washed with water (50 mL · 2), saturated CuSO4
solution (20 mL · 5), water (20 mL), saturated NaHCO3
solution (30 mL), and brine (30 mL), dried over MgSO4,
and concentrated in vacuo. The residue was purified by
chromatography on silica gel (100 g, hexane/EtOAc
30:1) to give (2R,3S)-3 (5.93 g, 92%, 98.6% ee) as a col-
orless oil; HPLC analysis (Chiralcel-ODꢂ, n-hexane/
i-PrOH = 200:1, 0.5 mL/min, detection at 210 nm): tR
The separated (2S,3R)-3 (16.8 g, 79.1 mmol) was then
methanolyzed with K2CO3 (1.09 g, 7.89 mmol) in
MeOH (200 mL) at room temperature for 4 h. The
resulting mixture was concentrated in vacuo. The resi-
due was diluted with Et2O, and filtered through a bed
of Celite. The filtrate was concentrated in vacuo to give
the enantiomerically enriched crude alcohol (2S,3R)-2
(ca. 15 g). This procedure, enzymatic resolution fol-
lowed by methanolysis as described above, was repeated
for the resulting alcohol (2S,3R)-2 for additional two
times to give (2S,3R)-3 [first: 10.1 g, 92.9% ee; second:
5.49 g, 98.8% ee; 16% based on ( )-2, two steps] as a
colorless oil. For (2R,3S)-2, enzymatic acetylation
described above was repeated twice more to give unre-
acted (2R,3S)-2 [first: 8.42 g; 92.7% ee; second: 5.19 g,
98.6% ee, 22%, based on ( )-2, two steps] as a color-
less oil. The enantiomeric purity of (2R,3S)-2 was deter-
mined by HPLC analysis after acetylation to (2R,3S)-3.
(2S,3R)-3: HPLC analysis (Chiralcel-ODꢂ, n-hexane/i-
PrOH 200:1, 0.25 mL/min, detection at 210 nm): tR
13.6 min [(2R,3S)-3, 99.3%], 16.7 min [(2S,3R)-3,
23
0.7%]; n2D3 1:4580; ½aꢁ ¼ þ27:0 (c 0.86, CHCl3); Its
D
IR, 1H NMR, and MS were identical with those of
(2S,3R)-3; HRMS calcd for C12H20O3 (M+) 212.1412,
found 212.1409. This was immediately used in the next
step without further purification.
4.4. (2S,3S)-3,7-Dimethyl-6-octene-1,2,3-triol (2S,3S)-4
To a stirred solution of (2S,3R)-3 (8.00 g, 37.7 mmol)
in DMF (80 mL) was added slowly an aqueous
solution of HClO4 (60%, 6.2 mL) at 0 ꢁC. The mixture
was gradually warmed to room temperature with
stirring. After stirring for 12 h, the mixture was diluted
with EtOAc (150 mL), and the resulting mixture
successively washed with saturated NaHCO3 solution
(50 mL), water (50 mL), and brine (50 mL), dried with
MgSO4, and concentrated in vacuo. The residue was
dissolved in MeOH (70 mL). To the mixture was added
K2CO3 (588 mg, 4.25 mmol) at room temperature. The
mixture was stirred for 20 h. It was then concentrated
in vacuo, and the residue purified by chromatography
on silica gel (150 g, CHCl3/MeOH 20:1) to give
13.3 min [(2R,3S)-3, 0.6%], 16.0 min [(2S,3R)-3,
23
D
99.4%]; n2D0 1:4570; ½aꢁ ¼ ꢀ25:7 (c 0.58, CHCl3) {lit.9
25
D
½aꢁ ¼ ꢀ23:4 (c 1.7, CHCl3)}; mmax (film): 1745 (s,
CO), 1675 (w, C@C), 1235 (s, C–O), 1035 (s, C–O),
880 (w); dH (90 MHz, CDCl3): 1.34 (3H, s, 3-Me), 1.61
(3H, br s, 7-Me), 1.68 (3H, br s, 7-Me), 1.41–1.76 (2H,
m, 4-H2), 2.10 (3H, s, Ac), 1.88–2.27 (2H, m, 5-H2),
2.98 (1H, dd, J 4.4, 7.1, 2-H), 4.00 (1H, dd, J 7.1, 12,
1-Ha), 4.34 (1H, dd, J 4.4, 12, 1-Hb), 5.09 (1H, br t, J
7.1, 6-H); MS (EI, 70 eV) m/z (%): 17 (7), 18 (32), 41
(46), 43 (100), 67 (23), 69 (47), 82 (20), 95 (15), 103
(13), 109 (52), 119 (6), 134 (7), 152 (3), 169 (1),
178 (1), 194 (1), 212 (M+, 1); HRMS calcd for
C12H20O3 (M+) 212.1412, found 212.1408. This was
immediately used in the next step without further
purification.
(2S,3S)-4 (6.08 g, 86%) as a colorless oil; n2D5 1:4815;
25
D
½aꢁ ¼ ꢀ1:5 (c 1.05, CHCl3); mmax (film): 3390 (s,
OH), 1085 (m, C–O), 1015 (m, C–O), 880 (m), 835
(w), 790 (w), 755 (w); dH (300 MHz, CDCl3): 1.18
(3H, s, 3-Me), 1.62 (3H, s, 7-Me), 1.68 (3H, s, 7-Me),
1.20–1.78 (2H, m, 4-H2), 1.78–2.14 (2H, m, 5-H2),
2.14–2.87 (3H, m, OH · 3), 3.42–3.61 (1H, m, 2-H),
3.76 (2H, br d, J 4.6, 1-H2), 5.12 (1H, br t, J 6.8, 6-
H). This was immediately used in the next step without
further purification.
28
D
(2R,3S)-2: n2D8 1:4702; ½aꢁ ¼ þ13:3 (c 1.09, CHCl3);
mmax (film): 3420 (s, OH), 1035 (s, C–O), 870 (m); dH
(90 MHz, CDCl3): 1.34 (3H, s, 3-Me), 1.62 (3H, br s,
7-Me), 1.69 (3H, br s, 7-Me), 1.35–1.93 (2H, m, 4-H2),
1.93–2.38 (2H, m, 5-H2), 2.96 (1H, dd, J 4.9, 6.4, 2-H),
3.51–3.82 (3H, m, 1-H2, OH), 5.10 (1H, br t, J 7.3,
6-H); MS (EI, 70 eV) m/z (%): 17 (44), 18 (100), 28
(20), 39 (21), 41 (80), 43 (58), 55 (27), 61 (26), 67 (45),
69 (69), 82 (38), 95 (25), 109 (83), 121 (6), 141 (2), 151
(3), 161 (1), 170 (M+, 1); HRMS calcd for C10H18O2
4.5. (2R,3R)-3,7-Dimethyl-6-octene-1,2,3-triol (2R,3R)-4
In the same manner as described above, (2R,3S)-3
(9.41 g, 44.3 mmol) was converted to (2R,3R)-4 (6.92 g,
25
83%) as a colorless oil; n2D5 ¼ 1:4822; ½aꢁ ¼ þ1:5 (c
D
1.37, CHCl3). Its IR and 1H NMR spectra were identical
with those of (2S,3S)-4. This was immediately used in
the next step without further purification.

T. Tashiro, K. Mori / Tetrahedron: Asymmetry 16 (2005) 1801–1806
1805
4.6. (2S,3S)-1-tert-Butyldiphenylsilyloxy-3,7-dimethyl-
6-octene-2,3-diol (2S,3S)-5
C–H), 1725 (s, C@O), 1590 (w, arom. C@C), 1115 (s,
C–O), 825 (s, C@C–H), 740 (m), 705 (s), 610 (m); dH
(300 MHz, CDCl3): 1.12 (9H, s, t-Bu), 1.21 (3H, s,
3-Me), 1.51 (3H, s, 7-Me), 1.63 (3H, s, 7-Me), 1.45–
1.77 (3H, m, 4-H2, 5-Ha), 1.88–2.12 (1H, m, 5-Hb),
3.47 (1H, s, OH), 4.51 (2H, s, 1-H2), 4.96 (1H, br t, J
6.9, 6-H), 7.38–7.50 (6H, m, Ph), 7.60–7.73 (4H, m,
Ph). Anal. Calcd for C26H36O3Si (424.65): C, 73.54; H,
8.54. Found: C, 73.67; H, 8.46. HRMS calcd for
C26H36O3Si (M+) 424.2434, found 424.2434.
To a stirred solution of (2S,3S)-4 (6.06 g, 32.2 mmol) in
CH2Cl2 (100 mL) were added Et3N (10 mL), tert-butyl-
chlorodiphenylsilane (9.20 mL, 36.9 mmol), and a cata-
lytic amount of DMAP (0.05 g) at 0 ꢁC. After stirring
for 24 h at room temperature, the reaction was
quenched by the addition of MeOH (2 mL). After
stirring for 30 min at room temperature, the mixture
was poured into water and extracted with CHCl3.
(30 mL · 2). The combined organic solution was succes-
sively washed with saturated NaHCO3 solution (30 mL),
water (40 mL), and brine (30 mL), dried over MgSO4,
and concentrated in vacuo. The residue was purified
by chromatography on silica gel (300 g, hexanes/EtOAc
4.9. (R)-1-tert-Butyldiphenylsilyloxy-3-hydroxy-3,7-
dimethyl-6-octen-2-one (R)-6
In the same manner as described above, (2R,3R)-5
(12.8 g, 30.0 mmol) was converted to (R)-6 (11.5 g,
91%, 92.0% ee) as a colorless oil; HPLC analysis
(Chiralcel-ODꢂ, n-hexane/i-PrOH = 50:1, 0.5 mL/min,
15:1) to give (2S,3S)-5 (13.3 g, 97%) as a colorless oil;
20
D
n2D1 1:5170; ½aꢁ ¼ ꢀ10:6 (c 1.01, CHCl3); mmax (film):
3460 (s, OH), 3070 (w, arom. C–H), 3050 (w, arom.
C–H), 1590 (w, arom. C@C), 1115 (s, C–O), 825 (s,
C@C–H), 740 (s), 705 (s), 615 (s); dH (300 MHz,
CDCl3): 1.07 (9H, s, t-Bu), 1.10 (3H, s, 3-Me), 1.49–
1.55 (2H, m, 4-H2), 1.60 (3H, s, 7-Me), 1.67 (3H, s,
7-Me), 1.96–2.03 (2H, m, 5-H2), 2.72 (1H, br s, OH),
2.92 (1H, br d, J 4.5, OH), 3.52 (1H, ddd, J 4.2, 4.5,
6.0, 2-H), 3.77 (1H, dd, J 6.0, 11, 1-Ha), 3.81 (1H, dd,
J 4.5, 11, 1-Hb), 5.09 (1H, br t, J 6.9, 6-H), 7.37–7.47
(6H, m, Ph), 7.65–7.69 (4H, m, Ph). Anal. Calcd for
C26H38O3Si (426.66): C, 73.19; H, 8.98. Found: C,
73.29; H, 9.02. HRMS calcd for C26H38O3Si (M+)
426.2590, found 426.2594.
detection at 254 nm): tR 15.4 min (R, 96.0%), 17.5 min
20
D
(S, 4.0%); n2D0 1:5175; ½aꢁ ¼ þ0:45 (c 1.17, CHCl3); Its
1
IR and H NMR spectra were identical with those of
(S)-6. Anal. Calcd for C26H36O3Si (424.65): C, 73.54;
H, 8.54. Found: C, 73.40; H, 8.59. HRMS calcd for
C26H36O3Si (M+) 424.2434, found 424.2445.
4.10. (S)-1,3-Dihydroxy-3,7-dimethyl-6-octen-2-one (S)-1
To a stirred solution of (S)-6 (5.64 g, 13.3 mmol) in THF
(60 mL) was added a solution of tetra-n-butylammo-
nium fluoride (TBAF) in THF (1.0 M, 20 mL, 20 mmol)
at 0 ꢁC. After stirring for 5 min, the mixture was poured
into water and extracted with EtOAc. The combined
organic solution was washed with water and brine, dried
over MgSO4, and concentrated in vacuo. The residue
was purified by chromatography on silica gel (100 g,
hexane/EtOAc 30:1) to give (S)-1 (2.47 g, quant.) as a
4.7. (2R,3R)-1-tert-Butyldiphenylsilyloxy-3,7-dimethyl-
6-octene-2,3-diol (2R,3R)-5
In the same manner as described above, (2R,3R)-4
(6.33 g, 33.7 mmol) was converted to (2R,3R)-5 (13.3 g,
colorless oil. An analytical sample was purified by distil-
20
25
D
93%) as a colorless oil; n2D0 1:5171; ½aꢁ ¼ þ10:5 (c
lation; bp = 103–105 ꢁC/1.2 Torr; n2D5 1:4745; ½aꢁ
¼
D
1.06, CHCl3); Its IR and 1H NMR spectra were identical
with those of (2S,3S)-5. Anal. Calcd for C26H38O3Si
(426.66): C, 73.19; H, 8.98. Found: C, 73.18; H, 9.02.
HRMS calcd for C26H38O3Si (M+) 426.2590, found
426.2588.
þ3:8 (c 0.79, CHCl3); mmax (film): 3425 (s, OH), 2970
(s, CH), 2920 (s, CH), 1720 (s, CO), 1450 (m, CH2),
1375 (m, CH3), 1265 (w), 1195 (m), 1135 (m, C–O),
1095 (m), 1035 (m, C–O), 1010 (m, C–O), 875 (w), 830
(w, C@C–H), 790 (w), 745 (w), 670 (w); dH (500 MHz,
CDCl3): 1.37 (3H, s, 3-Me), 1.58 (3H, s, 7-Me), 1.67
(3H, s, 7-Me), 1.71 (1H, br ddd, J 5.8, 10, 14, 4-Ha),
1.79 (1H, br ddd, J 6.1, 9.8, 14, 4-Hb), 1.90 (1H, br dt,
J 6.4, 14, 5-Ha), 2.09 (1H, br dt, J 6.4, 14, 5-Hb),
2.90–2.95 (2H, m, OH · 2), 4.48 (1H, d, J 4.9, 1-Ha),
4.50 (1H, d, J 4.9, 1-Hb), 5.04 (1H, br t, J 6.4, 6-H);
dC (126 MHz, CDCl3): 17.6, 22.1, 25.6, 26.0, 39.9,
64.6, 78.4, 122.9, 133.2, 214.2; dH (500 MHz, C6D6):
0.87 (3H, s, 3-Me), 1.33 (1H, ddd, J 5.5, 11, 14, 4-Ha),
1.44 (3H, br s, 7-Me), 1.45 (1H, ddd, J 6.0, 11, 14,
4-Hb), 1.59 (3H, d, J 0.5, 7-Me), 1.75–1.84 (1H, m,
5-Ha), 1.91–2.00 (1H, m, 5-Hb), 2.20 (1H, s, OH), 2.90
(1H, t, J 5.0, OH), 4.15 (1H, dd, J 5.0, 20, 1-Ha), 4.21
(1H, dd, J 5.0, 20, 1-Hb), 4.94 (1H, tquint. J 1.5, 7.0,
6-H); dC (126 MHz, C6D6): 17.5, 22.4, 25.7, 25.8,
40.2, 64.9, 78.2, 123.8, 132.5, 214.6; MS (EI, 70 eV)
m/z (%): 18 (22), 41 (32), 43 (45), 53 (6), 55 (8), 58 (7),
67 (8), 69 (100), 70 (7), 71 (12), 83 (11), 86 (10), 104
(20), 109 (77), 127 (28), 168 (4), 186 (M+, 1); HRMS
calcd for C10H18O3 (M+) 186.1256, found 186.1253.
4.8. (S)-1-tert-Butyldiphenylsilyloxy-3-hydroxy-3,7-
dimethyl-6-octen-2-one (S)-6
To a stirred solution of (2S,3S)-5 (13.0 g, 30.5 mmol) in
dry CH2Cl2 (40 mL), dimethyl sulfoxide (DMSO,
110 mL), and Et3N (30 mL) was added sulfur trioxide
pyridine complex (24.3 g, 153 mmol) at 0 ꢁC. After stir-
ring for 24 h at room temperature, the mixture was
poured into water and extracted with CH2Cl2
(40 mL · 3). The combined organic solution was succes-
sively washed with water (30 mL) and brine (40 mL),
dried over MgSO4, and concentrated in vacuo. The
residue was purified by chromatography on silica gel
(150 g, hexane/EtOAc 30:1) to give (S)-6 (11.0 g, 85%,
93.2% ee) as a colorless oil; HPLC analysis (Chiralcel-
ODꢂ, n-hexane/i-PrOH = 50:1, 0.5 mL/min, detection
at 254 nm): tR 15.8 min (R, 3.4%), 18.0 min (S, 96.6%);
21
D
3485 (s, OH), 3070 (w, arom. C–H), 3050 (w, arom.
n2D3 1:5176; ½aꢁ ¼ ꢀ0:5 (c 1.46, CHCl3); mmax (film):

1806
T. Tashiro, K. Mori / Tetrahedron: Asymmetry 16 (2005) 1801–1806
4. Dickens, J. C.; Oliver, J. E.; Hollister, B.; Davis, J. C.;
Klun, J. A. J. Exp. Biol. 2002, 205, 1925–1933.
5. Oliver, J. E.; Dickens, J. C.; Glass, T. E. Tetrahedron Lett.
2002, 43, 2641–2643.
6. Mori, K. Acc. Chem. Res. 2000, 33, 102–110.
7. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974–5976.
8. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780.
4.11. (R)-1,3-Dihydroxy-3,7-dimethyl-6-octen-2-one
(R)-1
In the same manner as described above, (R)-6 (7.11 g,
16.7 mmol) was converted to (R)-1 (2.02 g, 65%) as a col-
25
D
orless oil; bp = 94–97 ꢁC/ 0.7 Torr; n2D5 1:4742; ½aꢁ
¼
ꢀ4:0 (c 1.08, CHCl3); IR, 1H and 13C NMR and
mass spectra were identical with those of (S)-1; HRMS
calcd for C10H18O3 (M+) 186.1256, found 186.1255.
9. Nacro, K.; Baltas, M.; Escudier, J.-M.; Gorrichon, L.
Tetrahedron 1996, 52, 9047–9056.
10. Mori, K. Chemoenzymatic Synthesis of Pheromones,
Terpenes, and Other Bioregulators. In Stereoselective
Biocatalysis; Patel, R. N., Ed.; Marcel Dekker: New
York, 2000, pp 59–85.
11. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc.
1973, 95, 6136–6137.
12. Brevet, J.-L.; Mori, K. Synthesis 1992, 1007–1012.
13. Muto, S.; Mori, K. Eur. J. Org. Chem. 2003, 1300–
1307.
Acknowledgements
We thank Dr. J. C. Dickens (US Department of Agricul-
ture) for his cooperation. Our thanks are due to Dr. Y.
Hirose (Amano Enzyme, Inc.) for his supply of lipases.
We are grateful to Ms. N. Hirai, Messres Y. Imamura
and T. Yamauchi for their technical assistance.
14. Davis, C. E.; Bailey, J. L.; Lockner, J. W.; Coates, R. M.
J. Org. Chem. 2003, 68, 75–82.
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