Asymmetric synthesis of (S)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1-butanol, a key intermediate for (1S,5R)-(-)-frontalin via asymmetric bromolactonization

Article abstract of DOI:10.1016/S0957-4166(02)00071-X

A asymmetric synthesis of (S)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1-butanol, a key intermediate for (1S,5R)-(-)-frontalin, via asymmetric bromolactonization employing (S)-(-)-proline as a chiral auxiliary is described.

Full text of DOI:10.1016/S0957-4166(02)00071-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 155–159
Asymmetric synthesis of
(S)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1-butanol, a key
intermediate for (1S,5R)-(−)-frontalin via asymmetric
bromolactonization
Sang-sup Jew,* Doo-Yeon Lim, Jin-Yee Kim, Sung-ji Kim, Eun-young Roh, Hyo-Jeong Yi,
Jin-Mo Ku, Boon-saeng Park, Byeong-seon Jeong and Hyeung-geun Park*
Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
Received 25 December 2001; accepted 12 February 2002
Abstract—A asymmetric synthesis of (S)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1-butanol, a key intermediate for (1S,5R)-(−)-fron-
talin, via asymmetric bromolactonization employing (S)-(−)-proline as a chiral auxiliary is described. © 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
2. Results and discussion
(1S,5R)-(−)-Frontalin 1 is one of the aggregation
pheromones secreted from the southern pine beetle
(Dendroctonus frontalis), the western pine beetle (Den-
droctonus brevicomis), and the Douglas-fir beetle (Den-
droctonus pseudotsugae).1 Since these beetles destroy
large areas of pine forest each year, frontalin has been
used to exterminate the harmful insects. In terms of
environmental impact, the aggregation pheromone
method is very desirable as compared to the use of
general chemical pesticides. Studies on the biological
activities of 1 revealed that of the two possible enan-
tiomers, only the (1S,5R)-isomer shows aggregation
activity. A number of enantioselective synthetic meth-
ods for 1 have been presented, employing chiral build-
ing blocks,2 chiral auxiliaries,3 chiral reagents,4 and
Sharpless asymmetric dihydroxylation.5 Herein, we
introduce a new, efficient enantioselective synthetic
method for (1S,5R)-(−)-frontalin via bromolactoniza-
tion,6 using (S)-(−)-proline as a chiral auxiliary.
Although (1S,5R)-(−)-frontalin contains two stereo-
genic centers, only the configuration at C(1) needs to be
considered in the enantioselective synthesis because the
stereochemistry at C(5) can be controlled in forming
the ketal from the corresponding methyl ketone.
Based on the retrosynthetic analysis depicted in Scheme
1, we planned to prepare enantiomerically pure 2 by
asymmetric bromolactonization, which can be con-
verted to (1S,5R)-(−)-frontalin in four steps by a
known method.7,10 The a,b-unsaturated ester 7, the
substrate for asymmetric bromolactonization, was pre-
pared from the commercially available 4-benzyloxy-
butylbromide 5 (Scheme 2). The successive alkylation
of triethyl phosphonoacetate with 5 and Horner–
Wadsworth–Emmons reaction8 using formaldehyde,
followed by alkaline hydrolysis gave 7. Compound 7
was coupled with (S)-(−)-ethyl prolinate9 using diethyl
phosphorocyanidate (DEPC) in the presence of triethyl-
amine to give the (S)-a,b-unsaturated acyl proline ethyl
ester 8, [h]2D0=−41.3 (c 2.40, CHCl3), which was
hydrolyzed to the (S)-a,b-unsaturated acyl proline 9,
[h]2D0=−91.4 (c 0.91, CHCl3). Bromolactonization of 9
was performed with N-bromosuccinimide (NBS) in
N,N-dimethylformamide (DMF) to give 10 with 99%
e.e., [h]2D0=−93.9 (c 1.94, CHCl3) (vide infra).
O
1
5
O
1
(1S,5R)-(-)-Frontalin
The bromolactone 10 was then debrominated with n-
Bu3SnH to give lactone 11, [h]2D0=−101.7 (c 0.80,
* Corresponding authors.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00071-X

156
S. Jew et al. / Tetrahedron: Asymmetry 13 (2002) 155–159
Scheme 1.
H
H
a
c
e
N
CO2X
O
X
RBr
N
O
R
R
CO2X
O
O
5
6 X = Et
7 X = H
R
b
8 X = Et
9 X = H
10 X = Br
11 X = H
d
f
5 - 11
R = CH2(CH2)2CH2OBn
O
R
g
i
OH
O
OBn
OR
12 R = CO2H
13 R = CH2OH
14 R = Bn
2 R = H
h
j
Scheme 2. Reagents and conditions: (a) triethyl phosphonoacetate, NaH, DME, reflux, 20 h; (CH2O)n, NaH, DME, rt, 4 h, 55%.
(b) KOH, MeOH, H2O, rt, 6 h, quant. (c) (S)-(−)-Ethyl prolinate, DEPC, Et3N, DMF, rt, 2.5 h, 92%. (d) KOH, MeOH, H2O,
reflux, 4 h, quant. (e) NBS, DMF, 0°C to rt, 24 h, 60%. (f) n-Bu3SnH, benzene, reflux, 2 h, 95%. (g) 2N aq. KOH, reflux, 24 h.
(h) BH3·SMe2, THF, 0°C, 24 h, 80% (two steps from 11). (i) 2,2-Dimethoxypropane, PPTS, CH2Cl2, rt, 3 h, 95%. (j) H2, 10%
Pd/C, abs. EtOH, rt, 2 h, quant.
4. Experimental
CHCl3), which was hydrolyzed under basic conditions
to produce the a-hydroxy acid 12. Diol 13, [h]2D0=−5.3
(c 0.92, CHCl3), was prepared by reduction of 12 using
borane. The diastereoselectivity of the bromolactoniza-
tion step (10, 99% d.e.) was determined by HPLC
(Chiralcel OD column) of 13.11 Protection of the diol 13
gave the acetonide 14, [h]2D0=−1.9 (c 1.13, CHCl3), and
the subsequent removal of the benzyl group of 14 by
hydrogenolysis provided 2, [h]2D0=−2.43 (c 1.07,
CHCl3); lit.10 [h]D24=−2.57 (c 1.11, CHCl3). The abso-
lute configuration at C(1%) of 10 was assigned as S by
chemical correlation with 2. Compound 2 can be con-
verted to (1S,5R)-(−)-frontalin in four steps by a
known process.7,10
4.1. General
Optical rotations were measured with a JASCO DIP-
1000 digital polarimeter. Infrared spectra were taken on
a Perkin–Elmer 1710 FT-IR spectrometer. Mass spectra
and high resolution mass spectra were obtained on an
HP 5890 Series II. 1H and 13C NMR spectra were
measured with a JEOL JNM-LA 300, a JEOL JNM-
GCX 400 spectrometer using TMS as the internal stan-
dard. HPLC analysis was carried out on HITACHI
L-7420, L-7100 chromatography with Chiralcel OD
column from DAICEL. All reactions were carried out
under a nitrogen atmosphere using anhydrous solvents
except for those involving hydrolysis. Most reagents
were obtained from commercial suppliers and used
without further purification unless noted. Tetra-
hydrofuran was distilled from Na and benzophenone.
3. Conclusion
In summary, a new enantioselective synthetic method
for (S)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1-butanol
2, a key intermediate for (1S,5R)-(−)-frontalin, has
been developed via asymmetric bromolactonization
using (S)-proline as a chiral auxiliary from the a,b-
unsaturated acid 7 in eight steps (40% overall yield,
99% e.e.). Due to the high enantioselectivity and
the good chemical yield, we believe that this
synthetic method can be easily applied in an industrial
process.
4.2. Ethyl 2-[4-(benzyloxy)butyl]acrylate 6
To a suspension of NaH (95%, 579 mg, 22.9 mmol) in
1,2-dimethoxyethane (15 mL) was added a solution of
triethyl phosphonoacetate (4.13 mL, 20.8 mmol) in
1,2-dimethoxyethane (15 mL) at 0°C. The mixture was
allowed to warm to room temperature and stirred for 2
h then 4-benzyloxybutyl bromide (5.07 g, 20.8 mmol)
was added. The mixture was heated under reflux for 20

S. Jew et al. / Tetrahedron: Asymmetry 13 (2002) 155–159
157
1
h then cooled to room temperature. The reaction mix-
ture was cooled to 0°C and NaH (95%, 579 mg, 22.9
mmol) was added. The resulting suspension was
allowed to warm to room temperature, stirred for 1 h
and treated with paraformaldehyde (95%, 697 mg, 22
mmol) and then stirred for 4 h. The excess solvent was
then removed in vacuo and the residue was diluted with
ethyl acetate (600 mL). The ethyl acetate solution was
washed with water (2×30 mL) and brine (2×30 mL),
dried over anhydrous MgSO4, filtered and concentrated
in vacuo. The residue was purified by column chro-
matography (SiO2, ethyl acetate:n-hexane=1:30) to
give 6 as a colorless oil (3.02 g, 55% yield). IR (neat):
cm−1. H NMR (CDCl3, 300 MHz): l 7.35–7.21 (m,
5H), 5.24 (s, 1H), 5.21 (s, 1H), 4.41–4.57 (m, 3H), 4.16
(q, 2H, J=7.1 Hz), 3.65–3.55 (m, 2H), 3.46 (t, 2H,
J=6.1 Hz), 2.31 (t, 2H, J=7.1 Hz), 2.02–1.84 (m, 4H),
1.66–1.54 (m, 4H), 1.24 (t, 3H, J=7.1 Hz). 13C NMR
(CDCl3, 100 MHz): l 172.99, 170.78, 145.77, 139.02,
128.79, 128.67, 128.51, 128.29, 128.07, 115.95, 73.263,
70.462, 61.264, 59.368, 49.582, 33.934, 31.701, 29.760,
25.450, 24.553, 14.462. MS (EI): m/z 359 [M]+. HRMS
(CI): calcd for C21H30NO4, 360.2175 [M+1]+; found:
360.2178.
4.5. (2S)-1-2-[4-(Benzyloxy)butyl]acryloylpyrrolidine-2-
carboxylic acid 9
1
2937, 1714, 1455, 1151 cm−1. H NMR (CDCl3, 300
MHz): l 7.35–7.21 (m, 5H), 6.11 (s, 1H), 5.49 (s, 1H),
4.48 (s, 2H), 4.18 (q, 2H, J=7.1 Hz), 3.47 (t, 2H,
J=6.3 Hz), 2.30 (t, 2H, J=7.2 Hz), 1.68–1.49 (m, 4H),
1.28 (t, 3H, J=7.1 Hz). 13C NMR (CDCl3, 100 MHz):
l 167.31, 140.77, 138.62, 128.50, 128.20, 127.76, 127.64,
127.47, 127.36, 72.900, 70.141, 60.565, 31.595, 29.308,
25.007, 14.333. MS (EI): m/z 262 [M]+. HRMS (CI):
calcd for C16H23O3, 263.1647 [M+1]+; found: 263.1642.
A mixture of methanol–water (1:1, 75 mL), 8 (3.62 g,
10.1 mmol) and 85% potassium hydroxide (1.0 g, 15.1
mmol) was stirred at room temperature for 4 h. Excess
methanol was removed in vacuo and the water mixture
was acidified with 1N aqueous HCl solution and
extracted with ethyl acetate (5×200 mL). The combined
ethyl acetate solution was washed with water (2×25
mL) and brine (2×25 mL), then dried over anhydrous
MgSO4. The excess solvent was removed in vacuo to
give crude 9 as a colorless oil (3.35 g, 100% yield). [h]D20
−91.4 (c 0.91, CHCl3). IR (neat): 3444, 2924, 1732,
1645, 1455 cm−1. 1H NMR (CDCl3, 300 MHz): l
7.28–7.19 (m, 5H), 5.28 (s, 1H), 5.18 (s, 1H), 4.56–4.54
(m, 1H), 4.43 (s, 2H), 3.59–3.46 (m, 2H), 3.42 (t, 2H,
J=6.3 Hz), 2.28 (t, 2H, J=7.5 Hz), 2.05–1.76 (m, 4H),
1.61–1.45 (m, 4H). 13C NMR (CDCl3, 100 MHz): l
173.89, 172.21, 144.58, 138.48, 128.31 (×2), 127.61 (×2),
127.49, 116.42, 72.849, 62.920, 59.257, 49.648, 33.344,
29.213, 28.254, 24.889, 24.127. MS (EI): m/z 331 [M]+.
HRMS (CI): calcd for C19H26NO4, 332.1862 [M+1]+;
found: 332.1865.
4.3. 2-[4-(Benzyloxy)butyl]acrylic acid 7
A mixture of methanol–water (1:1, 60 mL), 6 (3 g, 11.5
mmol) and 85% potassium hydroxide (1.14 g, 17.2
mmol) was heated under reflux for 6 h. Excess
methanol was removed in vacuo and the water mixture
was acidified with a 5% aqueous HCl solution. The
solution was extracted with ethyl acetate (3×150 mL).
The combined ethyl acetate solution was washed with
brine (2×20 mL), dried over anhydrous MgSO4, filtered
and concentrated in vacuo to give crude 7 as a colorless
oil (2.68 g, 100% yield). IR (neat): 2921, 1696, 1445,
1
1103 cm−1. H NMR (CDCl3, 300 MHz): l 7.36–7.21
(m, 5H), 6.25 (s, 1H), 5.61 (s, 1H), 4.49 (s, 2H), 3.47 (t,
2H, J=6.3 Hz), 2.31 (t, 2H, J=7.2 Hz), 1.69–1.51 (m,
4H). 13C NMR (CDCl3, 100 MHz): l 172.71, 140.29,
138.97, 128.77, 128.06, 127.93, 127.53, 127.16, 122.90,
73.324, 70.465, 31.649, 29.677, 24.315. MS (EI): m/z
234 [M]+. HRMS (CI): calcd for C14H19O3, 235.1334
[M+1]+; found: 235.1335.
4.6. Bromolactone 10
To a solution of 9 (0.390 g, 2.35 mmol) in N,N-
dimethylformamide (4 mL) cooled at 0°C was added a
solution of NBS (0.42 g, 4.70 mmol) in N,N-dimethyl-
formamide (5 mL). The reaction mixture was stirred at
0°C for 2 h and then allowed to warm to room temper-
ature and stirred for 24 h. The excess solvent was
removed in vacuo and the residue was diluted with
ethyl acetate (150 mL). The ethyl acetate solution was
washed with a saturated aqueous NaHCO3 solution
(2×10 mL), water (5×10 mL), a 1N aqueous HCl solu-
tion (2×10 mL), brine (2×10 mL), dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, ethyl
acetate:n-hexane=2:3) to give bromolactone 10 as a
colorless oil (0.29 mg, 60% yield). [h]2D0 −93.9 (c 1.94,
CHCl3). IR (neat): 2921, 1748, 1682, 1455, 1104 cm−1.
1H NMR (CDCl3, 300 MHz): l 7.37–7.26 (m, 5H),
4.52–4.49 (m, 1H), 4.47 (s, 2H), 3.74 (ABq, 2H, J=11.2
Hz), 3.73–3.67 (m, 2H), 3.44 (t, 2H, J=6.3 Hz), 2.50–
4.4. Ethyl (2S)-1-2-[4-(benzyloxy)butyl]acryloyl-
pyrrolidine-2-carboxylate 8
To a solution of 7 (2.66 g, 11.4 mmol) and (S)-(−)-ethyl
prolinate (1.79 g, 12.5 mmol) in N,N-dimethylfor-
mamide (70 mL) was added diethyl phosphoro-
cyanidate (1.9 mL, 12.5 mmol) and triethylamine (1.74
mL, 12.5 mmol) at 0°C. The reaction mixture was
stirred at room temperature for 2.5 h. The excess
solvent was removed in vacuo and the residue was
diluted with ethyl acetate (500 mL). The ethyl acetate
solution was washed with a 1N aqueous HCl solution
(2×20 mL), a saturated aqueous NaHCO3 solution
(2×20 mL), water (5×20 mL) and brine (2×20 mL),
dried over anhydrous MgSO4, filtered and concentrated
in vacuo. The residue was purified by column chro-
matography (SiO2, ethyl acetate:n-hexane=1:2) to give
8 as a colorless oil (3.75 g, 92% yield). [h]2D0 −41.3 (c
2.40, CHCl3). IR (neat): 3479, 2935, 1746, 1651, 1186
2.46 (m, 2H), 2.24–1.75 (m, 4H), 1.63–1.45 (m, 4H). 13
C
NMR (CDCl3, 100 MHz): l 166.34, 163.44, 138.42,
128.29 (×2), 127.56 (×2), 127.46, 88.586, 72.756, 69.580,
57.933, 44.971, 37.939, 37.599, 29.877, 29.224, 21.472,
20.584. MS (EI): m/z 409 [M]+. HRMS (CI): calcd for
C19H25NO481Br, 412.0967 [M+1]+; found: 412.0937.

158
S. Jew et al. / Tetrahedron: Asymmetry 13 (2002) 155–159
4.7. (3S,8aS)-3-[4-(Benzyloxy)butyl]-3-methyltetra-
hydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,4(3H)-dione 11
4.10. Benzyl 4-[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]-
butyl ether 14
To a solution of 10 (144 mg, 0.35 mmol) in benzene (4
mL) was added n-Bu3SnH (283 mL, 1.05 mmol). The
reaction mixture was heated under reflux for 2 h. The
excess solvent was removed in vacuo and the residue
was purified by column chromatography (SiO2, ethyl
acetate:n-hexane=1:1) to give 11 as a white solid (110
mg, 95% yield). [h]D20 −101.7 (c 0.80, CHCl3). IR
To a solution of 13 in dichloromethane (6 mL) and
pyridinium p-toluenesulfonate (182 mg, 0.73 mmol)
was added 2,2-dimethoxypropane (0.54 mL, 4.36
mmol). The reaction mixture was stirred at room tem-
perature for 3 h. The excess solvent was removed in
vacuo and the residue was dissolved in ethyl acetate.
The ethyl acetate solution was washed with a satu-
rated aqueous NaHCO3 solution (2×15 mL), water
(2×15 mL), brine (2×10 mL), dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The
residue was purified by column chromatography (SiO2,
ethyl acetate:n-hexane=1:9) to give 14 as a colorless
oil (354 mg, 95% yield). [h]2D0 −1.9 (c 1.13, CHCl3). IR
1
(neat): 2925, 1754, 1667, 1454, 1106 cm−1. H NMR
(CDCl3, 300 MHz): l 7.34–7.23 (m, 5H), 4.49 (s, 2H),
4.24–4.19 (m, 1H), 3.67–3.55 (m, 2H), 3.46 (t, 2H,
J=6.0 Hz), 2.51–2.42 (m, 2H), 2.19–2.03 (m, 4H),
1.97–1.62 (m, 4H), 1.57 (s, 3H). 13C NMR (CDCl3, 75
MHz): l 168.21, 166.73, 138.63, 128.34 (×2), 127.64
(×2), 127.46, 86.30, 72.85, 70.13, 57.45, 45.39, 37.70,
37.55, 29.65, 23.92, 22.27, 20.23. MS (EI): m/z 331
[M]+. HRMS (CI): calcd for C19H26NO4, 332.1862
[M+1]+; found: 332.1862.
1
(neat): 2936, 1455 cm−1. H NMR (CDCl3, 300 MHz):
l 7.33–7.26 (m, 5H), 4.50 (s, 2H), 3.73 (ABq, 2H,
J=8.3 Hz), 3.48 (t, 2H, J=6.5 Hz), 1.65–1.42 (m,
6H), 1.39 (s, 3H), 1.37 (s, 3H), 1.26 (s, 3H). 13C NMR
(CDCl3, 75 MHz): l 138.63, 128.37, 127.65 (×2),
127.52 (×2), 109.00, 81.20, 73.99, 72.95, 70.19, 39.90,
30.22, 27.26, 27.13, 24.79, 21.22. MS (EI): m/z 277
[M−1]+. HRMS (CI): calcd for C17H27O3, 279.1960
[M+1]+; found: 279.1954.
4.8. (2S)-6-(Benzyloxy)-2-hydroxy-2-methylhexanoic
acid 12
A solution of 11 (92.4 mg, 0.279 mmol) in a 3N
aqueous KOH (2.5 mL) was heated under reflux for
24 h. The reaction mixture was acidified with a 1N
aqueous HCl solution and extracted with ethyl acetate
(5×10 mL). The combined ethyl acetate solution was
washed with brine (2×5 mL), dried over anhydrous
MgSO4. The excess solvent was removed in vacuo to
give the crude acid 12 as pale yellow oil (70 mg),
which was not purified further.
4.11. (S)-4-(2,2,4-Trimethyl-1,3-dioxolan-4-yl)-1-butanol
2
To a solution of 14 in absolute ethanol (7 mL) was
added 10% Pd/C (972 mg). The reaction mixture was
stirred at room temperature for 2 h under a hydrogen
atmosphere. The reaction mixture was filtered through
a Celite pad and the filtrate was concentrated in
vacuo. Then the residue was purified by column chro-
matography (SiO2, ethyl acetate:n-hexane=1:2) to give
2 as a colorless oil (180 mg, quant.). [h]2D0 −2.43 (c
1.07, CHCl3) (lit.10 −2.57 (c 1.11, CHCl3)). IR (neat):
4.9. (2S)-6-(Benzyloxy)-2-methyl-1,2-hexanediol 13
1
1117 cm−1. H NMR (CDCl3, 300 MHz): l 3.75 (ABq,
To a solution of 12 (847 mg, 3.36 mmol) in tetra-
hydrofuran (18 mL) was added BH3·SMe2 (2.0 M
solution in THF, 4.2 mL, 8.39 mmol). The reaction
mixture was stirred for 24 h at 0°C then the reaction
was quenched with a 5% aqueous AcOH solution (2–3
drops) and the excess solvent was removed in vacuo.
The residue was diluted with ethyl acetate (100 mL)
and the ethyl acetate solution was washed with a satu-
rated aqueous NaHCO3 solution (3×10 mL), water
(5×10 mL), brine (2×10 mL), dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The excess
solvent was removed in vacuo and the residue was
purified by column chromatography (SiO2, ethyl ace-
tate:n-hexane=1:1) to give 13 as a colorless oil (400
mg, 80% yield). [h]2D0 −5.3 (c 0.92, CHCl3). IR (neat):
2H, J=8.3 Hz), 3.66 (t, 2H, J=6.3 Hz), 1.64–1.42 (m,
6H), 1.40 (s, 3H), 1.38 (s, 3H), 1.28 (s, 3H). 13C NMR
(CDCl3, 75 MHz): l 109.02, 81.15, 73.93, 62.62, 39.72,
33.06, 27.17, 27.07, 24.73, 20.67. MS (EI): m/z 189
[M+1]+. HRMS (CI): calcd for C10H21O3, 189.1490
[M+1]+; found: 189.1494.
Acknowledgements
This paper was supported by grants from Aminogen
Co., Korea, via the Research Center of New Drug
Development of Seoul National University, and the
Korea Health 21 R&D Project, Ministry of Health &
Welfare, Republic of Korea (01-PJ2-PG6-01NA01-
0002).
1
2937, 1456, 1100 cm−1. H NMR (CDCl3, 300 MHz):
l 7.38–7.26 (m, 5H), 4.50 (s, 2H), 3.49 (t, 2H, J=6.3
Hz), 3.43 (ABq, 2H, J=10.7 Hz), 1.85 (br s,
2H), 1.69–1.42 (m, 6H), 1.16 (s, 3H). 13C NMR
(CDCl3, 75 MHz): l 138.51, 128.39, 127.77, 127.71,
127.66, 127.58, 72.96, 72.89, 70.16, 69.77, 38.33, 30.16,
23.21, 20.50. MS (EI): m/z 237 [M−1]+. HRMS
(CI): calcd for C14H23O3, 239.1647 [M+1]+; found:
239.1650.
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11. The enantioselectivity was determined by chiral HPLC
analysis (DAICEL Chiralcel OD, hexane:2-propanol=
90:10, flow rate=1.0 mL/min, 23°C, u=254 nm, reten-
tion time; R (minor) 15.8 min, S (major) 23.4 min, 99%
ee).