Catalytic asymmetric synthesis of the Colorado potato beetle pheromone and its enantiomer

Article abstract of DOI:10.1016/j.tetasy.2013.12.018

An efficient catalytic asymmetric synthesis of the CPB pheromone [(S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one] and its enantiomer was accomplished with 99% ee and in gram quantities from geraniol. The key steps in this procedure involve Sharpless asymmetric epoxidation and recrystallization of the 4-bromobenzoate from the CPB pheromone to improve its enantiomeric purity. Furthermore, the absolute configuration of the CPB pheromone enantiomer was confirmed as (R) for the first time by the X-ray crystallographic structure of its benzoate.

Full text of DOI:10.1016/j.tetasy.2013.12.018

Tetrahedron: Asymmetry 25 (2014) 591–595
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Catalytic asymmetric synthesis of the Colorado potato beetle
pheromone and its enantiomer
Shuo-Ning Li, Ling-Lan Fang, Jiang-Chun Zhong, Jun-Jian Shen, Hao Xu, Yan-Qing Yang,
⇑
⇑
Shi-Cong Hou , Qing-hua Bian
Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient catalytic asymmetric synthesis of the CPB pheromone [(S)-1,3-dihydroxy-3,7-dimethyl-6-
octen-2-one] and its enantiomer was accomplished with 99% ee and in gram quantities from geraniol.
The key steps in this procedure involve Sharpless asymmetric epoxidation and recrystallization of the
4-bromobenzoate from the CPB pheromone to improve its enantiomeric purity. Furthermore, the
absolute configuration of the CPB pheromone enantiomer was confirmed as (R) for the first time by
the X-ray crystallographic structure of its benzoate.
Received 1 December 2013
Accepted 27 December 2013
Available online 2 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
accomplished from 2-fluoronerol or 2-fluorogeraniol, and involved
a 6-endo epoxide ring-opening with ester participation.8
The Colorado potato beetle (CPB), Leptinotarsa decemlineata
(Say), is the most severe defoliator of potatoes worldwide and
potatoes are the most important non-grain food crop in the world.1
The heavy use of synthetic insecticides for controlling CPB has led
to insecticide resistance,2 which prompted us to seek new strate-
gies to combat CPB infestations. The use of insect pheromones is
a viable, safe, and environmentally friendly alternative to insecti-
cides. A recent discovery of a male-produced aggregation phero-
mone of CPB (S)-7 has made it possible for the pest management
of CPB.3
A growing awareness of environmentally friendly pest control
and some disadvantages in earlier synthetic strategies prompted
us to study an efficient asymmetric synthesis of the CPB phero-
mone in high enantiomeric purity and in gram quantities. Herein,
CPB pheromone (99% ee) and its enantiomer were synthesized
from known geraniol via Sharpless asymmetric epoxidation as
the key step; furthermore, the absolute configuration of its enan-
tiomer was confirmed as (R) for the first time by the X-ray crystal-
lographic structure of the benzoate (R)-8.
In 2002, the pheromone was isolated and identified as (S)-1,3-
dihydroxy-3,7-dimethyl-6-octen-2-one by Dickens.4 Meanwhile
the formal synthesis of the CPB pheromone and its enantiomer
was carried out from (S)-linalool and (R)-linalool.5 Preliminary bio-
assays revealed that (S)-7 was able to attract both sexes of L.
decemlineata, while (R)-7 was inactive.5 This result promoted the
stereoselective synthesis of the CPB pheromone. Shortly thereafter,
the CPB pheromone and its (R)-isomer were synthesized by
employing a lipase-catalyzed asymmetric acetylation of ( )-2,3-
epoxygeraniol as the key step.6 In 2009, a novel synthetic approach
to produce the CPB pheromone was developed, in which the
chirality at C3 was introduced by the stereoselective addition of
an organometallic reagent to a ketone.7 The latest example was
2. Results and discussion
The catalytic asymmetric synthesis of the CPB pheromone and
its enantiomer is outlined in Scheme 1.
The Sharpless asymmetric epoxidation of geraniol 19 afforded
(2R,3R)-2 with
D
-(ꢀ)-diethyl tartrate in 95% yield. After acetylation,
exposure of the epoxyacetate (2R,3R)-3 to aqueous perchloric acid
in N,N-dimethylformamide (DMF), followed by treatment with
potassium carbonate in methanol gave triol (2R,3S)-4. The specific
rotation measured for (2R,3S)-4 {½a D25
¼ þ5:0 (c 1.05, CHCl3)} was
ꢁ
consistent with the literature value {½a D25
ꢁ
¼ þ5:8 (c 0.97, CHCl3)},10
thereby providing confirmation of its absolute (3S)-configuration.
The inversion of the configuration at C-3 of the epoxyacetate
(2R,3R)-3 under these conditions was identical to the study re-
ported by Hanson.11
⇑
Corresponding authors. Tel.: +86 010 62731881; fax: +86 010 62820325
The selective protection of (2R,3S)-4 as its mono silyl ether
(2R,3S)-5 was achieved using tert-butyldiphenylsilyl chloride in
the presence of a catalytic amount of DMAP, subsequent oxidation
(S.-C.H); tel.: +86 010 62731356; fax: +86 010 62820325 (Q.-H.B).
E-mail addresses: houshc@cau.edu.cn (S.-C. Hou), bianqinghua@cau.edu.cn
(Q.-H. Bian).
http://dx.doi.org/10.1016/j.tetasy.2013.12.018
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

592
S.-N. Li et al. / Tetrahedron: Asymmetry 25 (2014) 591–595
D-(-)-DET
O
Ti(i-PrO)4
Ac2O, CH2Cl2
OH
OH
t-BuOOH
_30 to _10oC
95%
DMAP, Et3N
_ 5 to 25oC
(2R,3R)-2
1
94%
OH
O
(1) HClO4, DMF, 0 to 25oC
(2) K2CO3, MeOH, 25oC
77%
OAc
OH
OH
(2R,3R)-3
(2R,3S)-4
OH
TBDPSCl, E3N
SO3·C5H5N, DMSO
OTBDPS
DMAP, CH2Cl2
0 to 23oC
Et3N, CH2Cl2
0 to 25oC
82%
OH
94%
5
(2R,3S)-
OH
OH
TBAF,THF, 0oC
87%
OH
OTBDPS
O
O
(S)-7
(S)-6
CPB pheromone
L-(+)-DET
OH
O
O
OH
2
Ti(i-PrO)4
1
t-BuOOH
OH
_30 to _10oC
(2S,3S)-
93%
7
(R)-
Scheme 1. Synthesis of the CPB pheromone and its enantiomer.
of (2R,3S)-5 with dimethyl sulfoxide (DMSO), and the sulfur triox-
ide-pyridine complex gave (S)-6 in 82% yield.12 Desilylation with
tetra-n-butylammonium fluoride (TBAF) provided the desired
(S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one (S)-7 whose spec-
troscopic properties matched with the reported values of the
natural product.4 A similar procedure for the synthesis of (R)-7
was developed from the Sharpless asymmetric epoxidation of
{½a 2D5
ꢁ
¼ þ3:2 (c 0.4, CHCl3)}.8
A 4-bromobenzoate from the
enantiomer of CPB pheromone (R)-8 was obtained, and the
enantiomeric purity of (R)-7 was improved to 99% ee with
the same method.
To further confirm the absolute configuration of the CPB phero-
mone, the structural X-ray investigation of 4-bromobenzoate of
(R)-7 was carried out. Benzoate (R)-8 with 99% ee was carefully
crystallized from hexane–ether to give good crystals, and the
X-ray crystallographic structure of it (Fig. 1) indicating that the
absolute configuration was (R).
geraniol 1 with L-(+)-diethyl tartrate. The racemic material was
obtained by repeating the sequence described above and gave
( )-7 from ( )-2, being achieved with tert-butyl hydroperoxide
and vanadium acetylacetonate as described by Sharpless.13
Recrystallization of the 4-nitrobenzoates or 3,5-dinitrobenzo-
ates from chiral alcohols can improve the enantiomeric purity,14
unfortunately those benzoates of CPB pheromone were oils. After
careful experimentation, crystalline 4-bromobenzoate from CPB
pheromone (S)-8 was obtained with 86% ee determined by chiral
HPLC on an AD-H column. Slow recrystallization of benzoate
(S)-8 from hexanes–ether improved the enantiomeric purity to
99% ee, and then hydrolysis of it with potassium carbonate and
methanol offered nearly enantiomerically pure CPB pheromone
Figure 1. X-Ray crystallographic structure of (R)-8 (CCDC 958550).
(S)-7 (Scheme 2). The specific rotation of (S)-7 {½a D25
¼ þ3:3
ꢁ
(c 1.05, CHCl3)} was consistent with the literature value
3. Conclusion
O
Herein the pheromone secreted by the male Colorado potato
beetle and its enantiomer was prepared with high enantiomeric
purity (99% ee) and in gram quantities from Sharpless asymmetric
epoxidation of geraniol. Moreover, the absolute configuration of
the CPB pheromone enantiomer was confirmed as (R) for the first
time by the X-ray crystallographic structure of its benzoate.
Cl
Br
7
(S)-
Et3N, CH2Cl2, 0 to 25oC
80%
86% ee
Br
O
4. Experimental
4.1. General
K2CO3
O
7
(S)-
MeOH, 0oC
84%
99% ee
HO
O
(S)-8
All reactions were performed under an argon atmosphere.
Solvents were dried according to standard procedures and distilled
Scheme 2. Improvement of the enantiomeric purity of (S)-7.

S.-N. Li et al. / Tetrahedron: Asymmetry 25 (2014) 591–595
593
before use. All reagents were purchased commercially and used
without further purification, unless stated otherwise. Melting
points were recorded using a STUART-SMP3 Melt-Temp apparatus
and are uncorrected. 1H and 13C NMR spectra were recorded at 300
and 75 MHz, respectively. High-resolution mass spectra were
recorded on an Agilent instrument by the TOF MS technique.
Enantiomeric excesses (ee) were determined by chiral HPLC
analyses using a chiral column (Chiralpak AD-H), and elution with
isopropanol–hexanes. The optical rotations were measured on a
PERKIN ELMER 341 Polarimeter. Crystallographic data were ob-
tained using a Rigaku MM007HF Saturn724+ X-ray diffractometer.
CHCl3); 1H NMR (300 MHz, CDCl3) d: 1.31 (s, 3H), 1.43–1.53 (m,
1H), 1.61–1.74 (m, 1H), 1.64 (s, 3H), 1.71 (s, 3H), 2.05–2.11 (m,
2H), 2.12 (s, 3H), 2.99 (dd, J = 4.2, 6.9 Hz, 1H), 4.03 (dd, J = 6.9,
12.1 Hz, 1H), 4.32 (dd, J = 4.2, 12.1 Hz, 1H), 5.06–5.11 (m, 1H);
13C NMR (75 MHz, CDCl3) d: 16.77, 17.55, 20.70, 23.54, 25.57,
38.20, 59.57, 60.45, 63.34, 123.17, 132.10, 170.73; HRMS (TOF)
m/z calcd for C12H21O3 [M+H]+ 213.1491, found 213.1494.
4.2.4. Synthesis of ((2S,3S)-3-methyl-3-(4-methylpent-3-en-1-yl)
oxiran-2-yl)methyl acetate (2S,3S)-3
According to the similar procedure described above, (2S,3S)-2
(5.45 g, 32 mmol) was converted into (2S,3S)-3 (6.31 g, 93%) as a
4.2. Synthesis of the CPB pheromone and its enantiomer
colorless oil. ½a D25
ꢁ
¼ ꢀ20:2 (c 1.7, CHCl3), lit11
½
a 2D0
ꢁ
¼ ꢀ24 (c 1.5,
CHCl3); 1H NMR (300 MHz, CDCl3) d: 1.31 (s, 3H), 1.43–1.53 (m,
1H), 1.61 (s, 3H), 1.63–1.73 (m, 1H), 1.71 (s, 3H), 2.05–2.11 (m,
2H), 2.12 (s, 3H), 2.99 (dd, J = 4.3, 6.9 Hz, 1H), 4.03 (dd, J = 6.9,
12.1 Hz, 1H), 4.31 (dd, J = 4.2, 12.1 Hz, 1H), 5.06–5.11 (m, 1H);
13C NMR (75 MHz, CDCl3) d: 16.77, 17.55, 20.70, 23.54, 25.57,
38.20, 59.57, 60.45, 63.34, 123.17, 132.10, 170.73; HRMS (TOF)
m/z calcd for C12H21O3 [M+H]+ 213.1491, found 213.1494.
4.2.1. Synthesis of (2R,3R)-3-methyl-3-(4-methylpent-3-en-1-yl)-
oxiran-2-yl)methanol (2R,3R)-2
A solution of 4 Å molecular sieves (2.12 g) and CH2Cl2 (60 mL)
was cooled to ꢀ10 °C,
D
-(ꢀ)-diethyl tartrate (0.56 g, 2.7 mmol)
and Ti(i-PrO)4 (0.54 g, 1.9 mmol) were added sequentially. The
mixture was stirred and a solution of tert-butyl hydroperoxide
(11.6 mL, 5.5 M in heptane, 64 mmol) was added via a syringe at
a slow rate. The solution was cooled to ꢀ30 °C and stirred for
30 min, after which geraniol (5.0 g, 32 mmol) in CH2Cl2 (5 mL)
was added dropwise. The mixture was stirred for an additional
5 h at ꢀ30 to ꢀ10 °C, and the reaction was quenched with water
(24 mL). The mixture was allowed to warm to 23 °C, and a 30%
aqueous solution of NaOH (3 mL) was added. The mixture was stir-
red for 1 h, and filtered through a Celite pad. The aqueous phase
was extracted with CH2Cl2. The combined organic phases were
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(hexanes/ethyl acetate 5:1) to give (2R, 3R)-2 (5.16 g, 95%) as a col-
4.2.5. Synthesis of (2R,3S)-3,7-dimethyl-6-octene-1,2,3-triol
(2R,3S)-4
An aqueous solution of HClO4 (4.45 mL, 60%) was added slowly
to a stirred solution of (2R,3R)-3 (5.75 g, 27 mmol) in DMF (60 mL)
at 0 °C. After stirring for 12 h at room temperature, the mixture
was diluted with EtOAc (150 mL). The resulting mixture was
washed with saturated NaHCO3 solution, water and brine sequen-
tially, dried over anhydrous Na2SO4, and concentrated. The residue
was dissolved in MeOH (50 mL), and K2CO3 (0.42 g, 4.25 mmol)
was added. After an additional stirring for 20 h, the mixture was
concentrated under reduced pressure. The crude product was puri-
fied by silica gel chromatography (hexanes/ethyl acetate 3:1) to
orless oil. ½a 2D5
ꢁ
¼ þ4:5 (c 3.0, CHCl3); 1H NMR (300 MHz, CDCl3) d:
1.30 (s, 3H), 1.40–1.50 (m, 1H), 1.61 (s, 3H), 1.61–1.76 (m, 1H), 1.66
(s, 3H), 1.96 (br s, 1H), 2.05–2.13 (m, 2H), 2.98 (dd, J = 4.2, 6.7 Hz,
1H), 3.64–3.71 (m, 1H), 3.80–3.87 (m, 1H), 5.09 (t, J = 7.1 Hz, 1H);
13C NMR (75 MHZ, CDCl3) d: 16.68, 17.56, 23.61, 25.58, 38.43,
61.12, 61.38, 62.93, 123.29, 132.07; HRMS (TOF) m/z calcd for
yield (2S,3S)-4 (3.91 g, 77%) as a colorless oil. ½a D25
¼ þ5:0 (c 1.05,
ꢁ
CHCl3), lit10
½
a 2D5
ꢁ
¼ þ5:8 (c 0.97, CHCl3); 1H NMR (300 MHz, CDCl3)
d: 1.21 (s, 3H), 1.31–1.42 (m, 1H), 1.55–1.68 (m,1H), 1.61 (s, 3H),
1.68 (s, 3H), 1.97–2.15 (m, 2H), 3.29 (br s, 1H), 3.49 (br s, 1H),
3.67–3.73 (m, 2H), 3.95 (br s, 1H), 4.13–4.14 (m, 1H), 5.10 (t,
J = 6.9 Hz 1H); 13C NMR (75 MHz, CDCl3) d: 17.62, 22.10, 23.17,
25.61, 37.69, 63.10, 74.50, 76.86, 124.12, 131.89. HRMS (TOF) m/z
calcd for C10H19O3 [MꢀH]+ 187.1334, found 187.1333.
C
10H19O2 [M+H]+ 171.1385, found 171.1385.
4.2.2. Synthesis of (2S,3S)-3-methyl-3-(4-methylpent-3-en-1-yl)-
oxiran-2-yl)methanol (2S,3S)-2
According to the similar procedure described above, geraniol
(5.0 g, 32 mmol) was converted into (2S,3S)-2 (5.06 g, 93%) as a col-
4.2.6. Synthesis of (2S,3R)-3,7-dimethyl-6-octene-1,2,3-triol
(2S,3R)-4
orless oil with
L
-(+)-diethyl tartrate. ½a D25
ꢁ
¼ ꢀ4:2 (c 3.0, CHCl3), lit9c
According to the similar procedure described above, (2S,3S)-3
(5.75 g, 27 mmol) was converted into (2S,3R)-4 (3.87 g, 76%) as a
½
a 2D4
ꢁ
¼ ꢀ5:3 (c 3.0, CHCl3); 1H NMR (300 MHz, CDCl3) d: 1.30 (s,
3H), 1.42–1.52 (1H, m), 1.61 (s, 3H), 1.63–1.73 (m, 1H), 1.66 (s,
3H), 2.02–2.12 (m, 3H), 2.98 (dd, J = 4.2, 6.8 Hz, 1H), 3.64–3.72
(m, 1H), 3.80–3.87 (m, 1H), 5.06–5.11 (m, 1H); 13C NMR
(75 MHz, CDCl3) d: 16.68, 17.56, 23.61, 25.58, 38.44. 61.14, 61.36,
colorless oil. ½a D25
ꢁ
¼ ꢀ6:7 (c 1.05, CHCl3); 1H NMR (300 MHz, CDCl3)
d: 1.22 (s, 3H), 1.25–1.43 (m, 1H), 1.55–1.68 (m, 1H), 1.62 (s, 3H),
1.68 (s, 3H), 2.00–2.13 (m, 2H), 3.13 (br s, 1H), 3.48 (br s, 1H),
3.73–3.74 (m, 3H), 3.92–3.93 (m, 1H), 5.10 (t, J = 7.0 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d: 17.63, 22.13, 23.23, 25.63, 37.74, 63.14,
74.60, 76.73, 124.11, 131.97. HRMS (TOF) m/z calcd for C10H19O3
[MꢀH]+ 187.1334, found 187.1334.
63.02, 123.30, 132.07; HRMS (TOF) m/z calcd for
C10H19O2
[M+H]+ 171.1385, found 171.1381.
4.2.3. Synthesis of (2R,3R)-(3-methyl-3-(4-methylpent-3-en-1-
yl)oxiran-2-yl) methyl acetate (2R,3R)-3
4.2.7. Synthesis of (2R,3S)-1-tert-butyldiphenylsilyloxy-3,7-
dimethyl-6-octene-2,3-diol (2R,3S)-5
Triethylamine (5.40 mL, 38.4 mmol) and DMAP (0.39 g,
3.2 mmol) were added to a stirred solution of (2R,3R)-2 (5.45 g,
32 mmol) in CH2Cl2 (60 mL) at ꢀ5 °C. Acetic anhydride (3.63 mL,
38.4 mmol) was added via a syringe and the mixture was stirred
for 20 min. Water was poured into the mixture after an additional
stirring for 3 h at room temperature. The aqueous phase was ex-
tracted with EtOAc, and combined organic phases were washed
with saturated NaHCO3 solution and brine, successively, dried over
anhydrous Na2SO4, and concentrated. The crude product was puri-
fied by silica gel chromatography (hexanes/ethyl acetate 20:1) to
To a stirred solution of (2R,3S)-4 (5.6 g, 30 mmol) in CH2Cl2
(100 mL), triethylamine (9.3 mL, 66.1 mmol), tert-butylchloro-
diphenylsilane (8.5 mL, 34 mmol) and DMAP (47 mg, 0.38 mmol)
were added sequentially at 0 °C. The reaction mixture was main-
tained for 12 h at 23 °C, and quenched with water. The aqueous
phase was extracted with CH2Cl2. The combined organic phases
were washed with saturated aqueous NaHCO3 solution, water,
and brine consecutively, dried over anhydrous Na2SO4, and con-
centrated. The residue was purified by silica gel chromatography
(hexanes/ethyl acetate 5:1) to furnish (2S,3S)-5 (12.01 g, 94%) as
give (2R,3R)-3 (6.40 g, 94%) as a colorless oil. ½a D25
¼ þ25:0 (c 1.7,
ꢁ

594
S.-N. Li et al. / Tetrahedron: Asymmetry 25 (2014) 591–595
a colorless oil. ½a D25
ꢁ
¼ ꢀ1:92 (c 1.01, CHCl3); 1H NMR (300 MHz,
and brine consecutively, dried over anhydrous Na2SO4, and con-
centrated. The crude product was purified by silica gel chromatog-
raphy (hexanes/ethyl acetate 5:1) to give (S)-7 (0.85 g, 87%) as a
CDCl3) d: 1.07 (s, 9H), 1.09 (s, 3H), 1.19–1.39 (m, 1H), 1.32–1.61
(m, 2H), 1.50–1.62 (m, 2H), 1.56 (s, 3H), 1.66 (s, 3H), 1.94–1.95
(m, 1H), 2.07–2.09 (m, 1H), 2.70 (s, 1H), 2.91 (d, J = 5.0 Hz, 1H),
3.47–3.52 (m, 1H), 3.76–3.84 (m, 2H), 5.03–5.07 (m, 1H), 7.37–
7.48 (m, 6H), 7.65–7.69 (m, 4H); 13C NMR (75 MHz, CDCl3) d:
17.54, 19.09, 22.07, 23.12, 25.60, 26.80, 38.05, 64.84, 73.80,
75.80, 124.23, 127.81, 129.91, 131.65, 132.53, 132.67, 135.47,
135.50; HRMS (TOF) m/z calcd for C26H35O3Si [MꢀH]+ 425.2512,
found 425.2504.
colorless oil. ½a D25
ꢁ
¼ þ2:3 (c 0.79, CHCl3), lit8
½
a 2D5
ꢁ
¼ þ3:2 (c 0.4,
CHCl3); 1H NMR (300 MHz, CDCl3) d: 1.37 (s, 3H), 1.58 (s, 3H),
1.71 (s, 3H), 1.58–1.85 (m, 2H), 1.86–1.91 (m, 1H), 2.06–2.08 (m,
1H), 2.92 (s, 1H), 2.94 (t, J = 4.9 Hz, 1H), 4.48–4.51 (m, 2H), 5.02–
5.07 (m, 1H); 13C NMR (75 MHz, CDCl3) d: 17.64, 22.16, 25.60,
26.07, 39.93, 64.66, 78.47, 122.98, 133.25, 214.15. HRMS (TOF)
m/z calcd for C10H17O3 [MꢀH]+ 185.1178, found 185.1173.
4.2.8. Synthesis of (2S,3R)-1-tert-butyldiphenylsilyloxy-3,7-
dimethyl-6-octene-2,3-diol (2S,3R)-5
4.2.12. Synthesis of (R)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-
one (R)-7
According to the similar procedure described above, (2S,3R)-4
(5.6 g, 30 mmol) was converted into (2S,3R)-5 (12.03 g, 94%) as a
According to the similar procedure described above, (R)-6
(2.23 g, 5.25 mmol) was converted into (R)-7 (0.83 g, 85%) as a col-
colorless oil. ½a D25
ꢁ
¼ þ1:92 (c 1.01, CHCl3); 1H NMR (300 MHz,
orless oil. ½a 2D5
ꢁ
¼ ꢀ2:5 (c 0.79, CHCl3), lit6
½
a 2D5
ꢁ
¼ ꢀ4:0 (c 1.08,
CDCl3) d: 1.07 (s, 9H), 1.19 (s, 3H), 1.26–1.39 (m, 2H), 1.50 (s,
3H), 1.50–1.56 (m, 1H), 1.66 (s, 3H), 1.92–1.98 (m, 1H), 2.05–2.09
(m, 1H), 2.71 (s, 1H), 2.92 (d, J = 4.8 Hz, 1H), 3.49–3.52 (m, 1H),
3.79–3.81 (m, 2H), 5.03–5.05 (m, 1H), 7.37–7.45 (m, 6H), 7.66–
7.68 (m, 4H); 13C NMR (75 MHz, CDCl3) d: 17.54, 19.09, 22.07,
23.13, 25.60, 26.80, 38.05, 64.84, 73.80, 75.81, 124.24, 127.81,
129.91, 131.64, 132.54, 132.67, 135.47, 135.50; HRMS (TOF) m/z
calcd for C26H37O3Si [MꢀH]+ 425.2512 found 425.2497.
CHCl3); 1H NMR (300 MHz, CDCl3) d: 1.37 (s, 3H), 1.58 (s, 3H),
1.67 (s, 3H), 1.68–1.81 (m, 2H), 1.82–1.96 (m,1H), 2.03–2.13 (m,
1H), 3.13 (t, J = 4.9 Hz, 1H), 3.17 (s, 1H), 4.49–4.58 (m, 2H), 5.04
(t, J = 6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) d: 17.56, 22.07,
25.53, 25.93, 39.89, 64.65, 78.42, 122.96, 133.06, 214.22. HRMS
(TOF) m/z calcd for C10H17O3 [MꢀH]+ 185.1178, found 185.1177.
4.3. Improvement of the enantiomeric purity of (S)-7 and (R)-7
4.2.9. Synthesis of (S)-1-tert-butyldiphenylsilyloxy-3-hydroxy-
3,7-dimethyl-6-octen-2-one (S)-6
4.3.1. Synthesis of (S)-3-hydroxy-3,7-dimethyl-2-oxo-6-octenyl
4-bromobenzoate (S)-8
To a solution of (2R,3S)-5 (2.63 g, 6.1 mmol) in anhydrous CH2Cl2
(8 mL) at 0 °C, DMSO (22 mL), triethylamine (6 mL, 42.64 mmol)
and sulfur trioxide pyridine complex (4.86 g, 30.6 mmol) were
added sequentially. After stirring for 24 h at room temperature,
the reaction was quenched with water at 0 °C, and extracted with
CH2Cl2. The combined organic phases were successively washed
with water and brine, dried over anhydrous Na2SO4, and
concentrated. The crude product was purified by silica gel
chromatography (hexanes/ethyl acetate 5:1) to give (S)-6 (2.13 g,
To a stirred solution of (S)-7 (1.86 g, 10 mmol) and triethyl-
amine (3.1 mL, 22 mmol) in CH2Cl2 (10 mL) at 0 °C, a solution of
4-bromobenzoyl chloride (2.63 g, 12 mmol) in CH2Cl2 was added
dropwise over 15 min. After stirring overnight at room tempera-
ture, the reaction was quenched with water and extracted with
CH2Cl2. The organic phase was washed sequentially with water
and brine, dried over anhydrous Na2SO4, and concentrated. The
residue was purified by silica gel chromatography (hexanes/ethyl
acetate 10:1) to give (S)-8 (3.5 g, 95%, 86% ee) as a white solid. Slow
recrystallization of (S)-8 from hexanes-ether improved the enan-
tiomeric purity to 99% ee, and gave nearly enantiomerically pure
(S)-8 as colorless crystals. The overall yield of the parab-
romobenzoylation was 80% (2.95 g, 8 mmol). mp 85.1–85.2 °C;
82%) as
a
colorless oil.
½
a 2D5
ꢁ
¼ ꢀ0:52 (c 1.46, CHCl3), lit6
½
a 2D1
ꢁ
¼ ꢀ0:5 (c 1.46, CHCl3); 1H NMR (300 MHz, CDCl3) d: 1.07 (s,
9H), 1.09 (s, 3H), 1.51 (s, 3H), 1.54–1.74 (m, 3H), 1.63 (s, 3H),
1.96–2.01 (m, 1H), 3.46 (s, 1H), 4.52 (s, 2H), 4.93–4.99 (m, 1H),
7.36–7.47 (m, 6H), 7.65–7.68 (m, 4H); 13C NMR (75 MHz, CDCl3)
d: 17.61, 19.24, 22.08, 25.54, 25.59, 26.71, 39.46, 66.28, 78.31,
123.35, 127.82, 129.98, 132.46, 132.49, 135.51, 135.57, 135.58,
211.15. HRMS (TOF) m/z calcd for C26H35O3Si [MꢀH]+ 423.2355,
found 423.2358.
½
a 2D5
ꢁ
¼ þ5:7 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) d: 1.44 (s,
3H), 1.62 (s, 3H), 1.67 (s, 3H), 1.71–1.84 (m, 1H), 1.85–1.92 (m,
1H), 2.00–2.05 (m, 1H), 2.11–2.16 (m, 1H), 3.06 (s, 1H), 5.07–5.15
(m, 1H), 5.15–5.27 (m, 2H), 7.58–7.63 (m, 2H), 7.93–7.97 (m,
2H); 13C NMR (75 MHz, CDCl3) d: 17.69, 22.15, 25.65, 25.91,
39.72, 65.69, 79.03, 123.20, 128.20, 128.56, 131.38, 131.81,
133.15, 165.21, 207.05; HRMS (TOF) m/z calcd for C17H22BrO4
[M+H]+ 369.0701, found 369.0684. Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (90:10 n-hexanes/
isopropanol, 1.0 mL/min, 230 nm); minor (R)-enantiomer tr = 8.2
min, major (S)-enantiomer tr = 9.0 min.
4.2.10. Synthesis of (R)-1-tert-butyldiphenylsilyloxy-3-hydroxy-
3,7-dimethyl-6-octen-2-one (R)-6
According to the similar procedure described above, (2S,3R)-5
(2.63 g, 6.1 mmol) was converted into (R)-6 (2.15 g, 83%) as a col-
orless oil. ½a 2D5
ꢁ
¼ þ0:5 (c 1.46, CHCl3), lit6
½
a 2D0
ꢁ
¼ þ0:45 (c 1.17,
CHCl3); 1H NMR (300 MHz, CDCl3) d: 1.07 (s, 9H), 1.10 (s, 3H),
1.51 (s, 3H), 1.54–1.76 (m, 3H), 1.63 (s, 3H), 1.96–2.01 (m, 1H),
3.46 (s, 1H), 4.52 (s, 2H), 4.93–4.99 (m, 1H), 7.36–7.47 (m, 6H),
7.65–7.68 (m, 4H); 13C NMR (75 MHz, CDCl3) d: 17.63, 19.26,
22.09, 25.55, 25.60, 26.72, 39.47, 66.28, 78.32, 123.36, 127.84,
130.00, 132.46, 132.50, 132.52, 135.59, 135.60, 211.16. HRMS
(TOF) m/z calcd for C26H35O3Si [MꢀH]+ 423.2355, found 423.2366.
4.3.2. Hydrolysis of (S)-8 to (S)-7
To a solution of (S)-8 (1.92 g, 5 mmol) in methanol (10 mL) at
0 °C was added NaOH (25 mL, 1 mol/L, 25 mmol). After stirring
for 3 h, the mixture was extracted with Et2O. The organic phase
was washed with brine, dried over anhydrous Na2SO4, and concen-
trated. The residue was purified by silica gel chromatography
(hexanes/ethyl acetate 5:1) to give (S)-7 (0.78 g, 84%) as a colorless
4.2.11. Synthesis of (S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-
one (CPB pheromone) (S)-7
oil. ½a 2D5
ꢁ
¼ þ3:3 (c 1.7, CHC13), lit8
½
a 2D5
ꢁ
¼ þ3:2 (c 0.4, CHCl3).
To a stirred solution of (S)-6 (2.23 g, 5.25 mmol) in THF (25 mL)
was added tetra-n-butylammonium fluoride (7.9 mL, 1.0 M in THF,
7.9 mmol) slowly at 0 °C. After the reaction mixture was main-
tained for 40 min at 0 °C, it was poured into water and extracted
with EtOAc. The combined organic phases were washed with water
4.3.3. Synthesis of (R)-3-hydroxy-3,7-dimethyl-2-oxo-6-octenyl
4-bromobenzoate (R)-8
According to the similar procedure described above, (R)-7
(1.86 g, 10 mmol) was converted into (R)-8 (2.92 g, 79%, 99% ee)
as colorless crystals. mp 85.1–85.3 °C; ½a D25
¼ ꢀ5:4 (c 1.0, CHCl3);
ꢁ

S.-N. Li et al. / Tetrahedron: Asymmetry 25 (2014) 591–595
595
1H NMR (300 MHz, CDCl3) d: 1.44 (s, 3H), 1.62 (s, 3H), 1.68 (s, 3H),
1.71–1.84 (m, 1H), 1.85–1.92 (m, 1H), 2.00–2.05 (m, 1H), 2.11–2.16
(m, 1H), 3.08 (s, 1H), 5.07–5.12 (m, 1H), 5.15–5.28 (m, 1H), 7.58–
7.63 (m, 2H), 7.93–7.97 (m, 2H); 13C NMR (75 MHz, CDCl3) d:
17.69, 22.15, 25.65, 25.91, 39.72, 65.69, 79.03, 123.20, 128.20,
128.56, 131.38, 131.81, 133.15, 165.21, 207.05. HRMS (TOF) m/z
calcd for C17H22BrO4 [M+H]+ 369.0701, found 369.0696. Enantio-
meric excess was determined by HPLC with a Chiralpak AD-H
column (80:20 n-hexanes/isopropanol, 1.0 mL/min, 230 nm);
major (R)-enantiomer tr = 8.5 min, minor (S)-enantiomer tr = 9.6 min.
0.008(10). Therefore, the absolute configuration assigns the
(R)-chirality to the quaternary carbon center.
Acknowledgements
We thank the National Key Technology Research and
Development Program (No. 2012BAK25B03) for financial support.
References
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Patent 20056958360.
4.3.4. Hydrolysis of (R)-8 to (R)-7
According to the similar procedure described above, (R)-8
(1.92 g, 5 mmol) was converted into (R)-7 (0.75 g, 81%) as a color-
less oil. ½a 2D5
ꢁ
¼ ꢀ3:7 (c 1.0, CHCl3), lit6
½
a 2D5
ꢁ
¼ ꢀ4:0 (c 1.08, CHCl3).
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Baltas, M.; Escudier, J.-M.; Gorrichon, L. Tetrahedron 1996, 52, 9047–9056.
C17H21BrO4, crystal system: monoclinic; unit cell dimensions:
P1, a = 5.985 (2), b = 10.491 (4), c = 14.028 (5) Å; = 90,
a
b = 92.25(6),
c
= 90°; volume = 880.2 (5) Å3; Z = 2; calculated den-
sity: 1.393 mg/cm3; absorption coefficient: 2.349 mmꢀ1; F(000):
380; h range for data collection: 2.91–27.49°; refinement method:
full-matrixleast-squares on F2; data/parameters: 3930/203; good-
ness-of-fit on F2: 1.071; final R indices [I > 2
r(I)]: R1 = 0.0414,
wR2 = 0.0868; R indices (all data): R1 = 0.0445, wR2 = 0.0890.
The structure was solved by direct methods program SHELXL-
97. The chirality of the asymmetric carbon atom C3(C1) was deter-
mined by a Flack analysis, and absolute structure parameter is