Asymmetric Diels-Alder reactions of 2-fluoroacrylic acid derivatives. Part 1: The construction of fluorine substituted chiral tertiary carbon

Article abstract of DOI:10.1016/S0957-4166(98)00195-5

For the construction of chiral monofluorinated tertiary carbons, we have examined the asymmetric Diels-Alder reaction of 2-fluoroacrylic acid derivatives beating a chiral oxazolidinone moiety. Under diethylaluminum chloride catalyzed conditions at - 100°C

Full text of DOI:10.1016/S0957-4166(98)00195-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1979–1987
Asymmetric Diels–Alder reactions of 2-fluoroacrylic acid
derivatives. Part 1: The construction of fluorine substituted chiral
tertiary carbon
Hisanaka Ito, Akio Saito and Takeo Taguchi ∗
Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 27 April 1998; accepted 15 May 1998
Abstract
For the construction of chiral monofluorinated tertiary carbons, we have examined the asymmetric Diels–Alder
reaction of 2-fluoroacrylic acid derivatives bearing a chiral oxazolidinone moiety. Under diethylaluminum chloride
catalyzed conditions at −100°C, the reaction of 1 with isoprene proceeded smoothly with high diastereoselectivity.
© 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Development of an efficient construction method for enantiomerically pure fluorine-substituted tertiary
carbons is of importance for the synthesis of biologically active fluorinated compounds.1 The asymmetric
Diels–Alder reaction of 2-fluoroacrylic acid derivatives could be one of the general approaches for the
construction of such molecules. Although there have been a few reports on the Diels–Alder reaction
of 2-fluoroacrylic derivatives,2 the asymmetric version has not been reported. We report herein the
Diels–Alder reaction of chiral 2-fluoroacrylic acid derivatives under Lewis acid catalyzed conditions
(Scheme 1).
2. Results and discussion
The synthesis of chiral 2-fluoroacrylic acid derivatives bearing an oxazolidinone as a chiral auxiliary
can be accomplished in three steps from methyl 2-fluoroacrylate 1 as illustrated in Scheme 2. Methyl
2-fluoroacrylate 13 was converted to acid chloride 2 according to the literature procedure [(a) 2 N
∗
Corresponding author.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00195-5

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H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1979–1987
Scheme 1.
NaOH/EtOH; (b) BzCl, hydroquinone, 160°C].4 The reaction of 2 with the oxazolidinone moiety was
achieved according to the Evans’ procedure.5 Thus, the treatment of chiral oxazolidinones 3a and 3b
with methylmagnesium bromide and the following addition of 2 gave the desired compounds 4a and 4b
in 76% and 61% yield (from 2), respectively.
Scheme 2.
The Lewis acid promoted Diels–Alder reactions of 4a and 4b with isoprene are summarized in Table 1.
In the presence of 1.5 equivalents of diethylaluminum chloride, the Diels–Alder reaction of 4a and 4b
proceeded at −78°C to give cycloadducts 5a in 60% yield with 70% de and 5b in 40% yield with 59% de,
respectively (entries 1, 2).6 As in the case of non-fluorinated N-enoyloxazolidinone, these results indicate
the importance of an aromatic group in the substituent (R) for π interaction in the transition state to
achieve higher diastereoselectivity.5 Determination of the diastereoselectivity was accomplished by the
conversion of the cycloadduct to its benzyl ester (BnOLi/THF) and following HPLC analysis by using a
chiral column. We also examined the effect of Lewis acid and reaction temperature. In all cases examined
here, diastereomeric preference was not affected by the Lewis acid employed. The diastereoselectivity
was significantly increased at low temperature in the presence of 1.5 equivalents of diethylaluminum
chloride (entries 2, 4, and 5). The best result was obtained when 1.5 equivalents of diethylaluminum
chloride was used at −100°C (entry 5, 59% yield, 90% de).
To examine the influence of the fluorine atom on exo/endo selectivity, the Diels–Alder reactions of 4a
with cyclopentadiene were conducted and the results are summarized in Table 2. Although the chemical
yield of cycloadduct 6 was satisfactory in the presence of certain kinds of Lewis acid, the exo/endo
selectivity was not as high as expected. Among the Lewis acids examined, titanium tetrachloride gave the
exo-adduct in slight predominance. Both exo- and endo-adducts were obtained in higher diastereofacial
selectivity (entry 3, exo; 96% de, endo; 95% de) than with isoprene.
The absolute stereochemistry of the adduct 6 was determined as shown in Scheme 3. After the
Diels–Alder reaction of 4a with cyclopentadiene at −100°C in the presence of 1.5 equivalents of
diethylaluminum chloride and the separation of endo/exo isomers of 6, 6-endo and 6-exo were con-
verted to (−)-10 and (−)-11, respectively. The known compound 8 ([α]D25=59.3) was prepared by the
asymmetric Diels–Alder reaction of 7 with cyclopentadiene at −78°C followed by benzyl esterification

H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1979–1987
1981
Table 1
The Diels–Alder reaction of 4a and 4b with isoprene
Table 2
The Diels–Alder reaction of 4a with cyclopentadiene

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H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1979–1987
(lit.5 [α]D25=125, in the literature, the Diels–Alder reaction was carried out at −100°C). Fluorination at
the α-position of the carbonyl group in 8 was achieved by the following procedure. After conversion of
8 to its silyl enol ether, a fluorination reaction with N-fluoro-2,4,6-trimethylpyridinium triflate7 afforded
the fluoro ester 9 as an endo:exo isomeric mixture (2:1) in 70% yield. The endo/exo mixture could
be separated by the iodolactonization. Through the determination of the specific rotation of the four
compounds (Scheme 3), we could determine the absolute stereochemistries of the cycloadducts and
reveal the nearly equal diastereofacial selectivity for both endo- and exo-adducts 6 in the Diels–Alder
reaction of 4a in the presence of 1.5 equivalents of diethylaluminum chloride at −100°C.
Scheme 3.
The mechanism of stereoselectivity could be considered as Fig. 1. Although we expected an abnormal
facial selectivity caused by the fluorine–aluminum interaction,8 the direction of asymmetric induction
was similar to the Evans’ result with non-fluorinated substrates.5 That is, in the presence of more than 1
equivalent of diethylaluminum chloride, an aluminum atom coordinates to two carbonyl groups to form
a six membered cyclic intermediate. The Re face of the fluorine-bearing carbon–carbon double bond of
4a is sterically crowded by the benzyl group on the oxazolidinone moiety through a π interaction. In
accordance with this hypothesis, the cycloaddition occurs selectively from the Si face on the dienophile
4a.
Fig. 1.

H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1979–1987
1983
In summary, we have demonstrated that the Diels–Alder reaction of 2-fluoroacrylic acid bearing chiral
oxazolidinone moieties provides an efficient construction method for chiral fluorine-substituted tertiary
carbons. Along these lines, the synthesis of a fluorinated biologically active compound is currently under
investigation.
3. Experimental
3.1. General
Melting points are uncorrected. Infrared absorption spectra were recorded using a Perkin–Elmer FTIR-
1
1710. H, and 13C NMR spectra were obtained using Varian Gemini 300 (300 MHz), Bruker dpx 400
(400 MHz), and Bruker drx 500 (500 MHz). 19F NMR spectra were obtained using a Bruker dpx 400. In
the 1H, 13C, and 19F NMR spectra, chemical shifts are expressed in δ (ppm) downfield from CHCl3 (7.26
ppm), CDCl3 (77.01 ppm), and benzotrifluoride (0 ppm), respectively. Mass spectra were recorded using
HITACHI M-80, Finnigan MAT TSQ700, and VG Auto Spec. Column chromatography was performed
on silica gel, Fuji silysia silica gel BW80S. All nonaqueous reactions were carried out under an argon
atmosphere with freshly distilled solvents. Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled
from sodium benzophenone ketyl. Dichloromethane (CH2Cl2) and toluene were distilled from calcium
hydride.
3.2. (4S)-3-(2-Fluoropropenoyl)-4-(phenylmethyl)-2-oxazolidinone 4a
Under an argon atmosphere, to a solution of oxazolidinone 3a (1.9 g, 10.7 mmol) in THF (100 ml)
was added a solution of methylmagnesium bromide in THF (3 M, 3.6 ml, 10.8 mmol) at −78°C and the
mixture was stirred for 10 min at −78°C, then for 10 min at 0°C. A solution of 2 (1.34 g, 12 mmol) in
THF (5 ml) was added to the reaction mixture and recooled to −78°C. After being stirred for 45 min at
−78°C, 2 h at 0°C, and 3 h at r.t., saturated aqueous ammonium chloride was added. The mixture was
extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate,
and concentrated under vacuum. After purification by silica gel column chromatography (hexane/ethyl
acetate, 6/1), the compound 4a (2.29 g, 9.13 mmol) was obtained in 85% yield (based on 3a).
4a: Mp 80–82°C; [α]D 82.1 (c 1.05, CHCl3); IR (KBr) 1783, 1686 cm−1; H NMR (CDCl3) δ
7.19–7.34 (5H, m), 5.45 (1H, dd, J=44.2, 3.9 Hz), 5.34 (1H, dd, J=14.7, 3.9 Hz), 4.67 (1H, m), 4.29 (1H,
dd, J=9.0, 7.8 Hz), 4.21 (1H, dd, J=9.0, 4.8 Hz), 3.40 (1H, dd, J=13.5, 3.6 Hz), 2.84 (1H, dd, J=13.5,
9.4 Hz); 13C NMR (CDCl3) δ 37.3, 55.7, 67.1, 102.0 (d, J=14.6 Hz), 127.5, 129.0, 129.3, 134.6, 152.3,
155.8 (d, J=267.5 Hz), 161.6 (d, J=35.9 Hz); 19F NMR (CDCl3) δ −44.7 (dd, J=44.2, 14.7 Hz). Anal.
calcd for C13H12FNO3: C, 62.65; H, 4.85; N, 5.62. Found: C, 62.71; H, 4.84; N, 5.66.
25
1
3.3. (4S)-3-(2-Fluoropropenoyl)-4-(i-propyl)-2-oxazolidinone 4b
According to a similar procedure for the preparation of 4a, the isopropyl derivative 4b was prepared
in 68% yield from oxazolidinone 3b (927 mg, 7.2 mmol) and acid chloride 2 (1.17 g, 8.1 mmol), and the
final purification by silica gel column chromatography (hexane/ethyl acetate, 8/1).
4b: Mp 67–71°C; [α]D28 106.8 (c 1.57, CHCl3); IR (KBr) 1800, 1694 cm−1; 1H NMR (CDCl3) δ 5.38
(1H, dd, J=42.2, 3.9 Hz), 5.28 (1H, dd, J=12.9, 3.9 Hz), 4.45 (1H, ddd, J=8.8, 8.6, 4.9 Hz), 4.36 (1H, dd,
J=8.7, 8.6 Hz), 4.23 (1H, dd, J=8.7, 4.9 Hz), 2.40 (1H, dqq, J=7.0, 7.0, 4.9 Hz), 0.92 (3H, d, J=7.0 Hz),

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H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1979–1987
0.88 (3H, d, J=7.0 Hz); 13C NMR (CDCl3) δ 15.1, 18.2, 28.3, 59.1, 64.4, 102.1 (d, J=14.4 Hz), 152.9,
156.0 (d, J=233.0 Hz), 161.9 (d, J=35.8 Hz); 19F NMR (CDCl3) δ −45.6 (dd, J=42.2, 12.9 Hz). Anal.
calcd for C9H12FNO3: C, 53.72; H, 6.01; N, 6.96. Found: C, 53.82; H, 5.95; N, 7.10.
3.4. Typical procedure of the Lewis acid mediated Diels–Alder reaction of 4. (4S)-3-[(40S)-40-Fluoro-
1-methylcyclohexene-40 -carbonyl]-4-(phenylmethyl)-2-oxazolidinone 5a
Under an argon atmosphere, to a solution of 4a (100 mg, 0.4 mmol) in CH2Cl2 (4 ml) was added a
solution of diethylaluminum chloride (0.95 M in hexane, 0.63 ml, 0.6 mmol) at −100°C. After being
stirred for 5 min, isoprene (0.8 ml, 8.0 mmol) was added to the reaction mixture at −100°C and the
mixture was stirred at the same temperature for 1.5 h. After addition of saturated aqueous ammonium
chloride, the mixture was extracted with ethyl acetate. The organic layer was washed with brine,
dried over magnesium sulfate, and concentrated under vacuum. After purification by silica gel column
chromatography (hexane/ethyl acetate, 8/1), the compound 5a (75.7 mg, 0.237 mmol) was obtained in
59% yield.
5a: [α]D25 97.3 (c 2.47, CHCl3); IR (neat) 1792, 1697 cm−1; 1H NMR (CDCl3) δ 7.20–7.37 (5H, m),
5.32 (1H, bs), 4.66 (1H, m), 4.25 (1H, dd, J=9.0, 7.3 Hz), 4.18 (1H, dd, J=9.0, 2.8 Hz), 3.31 (1H, dd,
J=13.3, 3.0 Hz), 2.84 (1H, dd, J=13.3, 9.6 Hz), 2.48–2.93 (2H, m), 2.00–2.44 (4H, m), 1.73 (3H, s); 13
C
NMR (CDCl3) δ 23.7, 26.3, 29.3 (d, J=22.8 Hz), 32.5 (d, J=23.5 Hz), 38.1, 57.5, 67.0, 95.4 (d, J=187.8
Hz), 115.8, 127.8, 129.4, 129.8, 133.9, 135.5, 151.9, 173.2 (d, J=28.1 Hz); 19F NMR (CDCl3) δ −99.2
(m). Anal. calcd for C18H20FNO3: C, 68.12; H, 6.35; N, 4.41. Found: C, 68.20; H, 6.50; N, 4.42.
3.5. (4S)-3-{(30S,40S,60S)-40-Fluoro-bicyclo[2.2.1]heptene-40 -carbonyl}-4-(phenylmethyl)-2-
oxazolidinone 6-exo and (4S)-3-{(30R,40S,60R)-40-fluoro-bicyclo[2.2.1]heptene-40 -carbonyl}-4-
(phenylmethyl)-2-oxazolidinone 6-endo
According to a similar procedure for the preparation of 5a, the Diels–Alder reaction of 4a (100 mg,
0.4 mmol) with cyclopentadiene (1.06 ml, 11 mmol) in the presence of diethylaluminum chloride (0.95
M in hexane, 0.63 ml, 0.6 mmol) was carried out at −100°C for 45 min. After extractive workup and
purification by silica gel column chromatography (hexane/ethyl acetate, 8/1), a mixture of 6-endo and 6-
exo (100.3 mg, 0.32 mmol) was obtained in 80% yield. Each isomer was separated by medium pressure
liquid chromatography (hexane/ethyl acetate, 6/1).
22
6-exo: Mp 91–94°C; [α]D −66.9 (c 1.05, CHCl3); IR (KBr) 1796, 1690 cm−1; 1H NMR (CDCl3) δ
7.21–7.37 (5H, m), 6.51 (1H, dd, J=5.6, 3.0 Hz), 6.33 (1H, dd, J=5.6, 3.0 Hz), 4.67 (1H, m), 4.26 (1H,
dd, J=9.0, 7.4 Hz), 4.19 (1H, dd, J=9.0, 3.3 Hz), 3.62 (1H, bs), 3.32 (1H, dd, J=13.4, 3.6 Hz), 2.96 (1H,
bs), 2.88 (1H, dd, J=13.4, 9.3 Hz), 2.54 (1H, dt, J=13.6, 3.6 Hz), 1.50–1.80 (3H, m); 13C NMR (CDCl3)
δ 37.8, 40.3 (d, J=20.2 Hz), 41.8, 48.4, 50.6 (d, J=20.6 Hz), 56.5, 66.6, 102.7 (d, J=197.7 Hz), 127.4,
128.9, 129.4, 132.1, 135.1, 140.8, 151.3, 171.8 (d, J=32.7 Hz); 19F NMR (CDCl3) δ −93.9 (dd, J=25.1,
14.1 Hz). HRMS calcd for C18H18FNO3 315.1271, found 315.1279.
6-endo: Mp 110–113°C; [α]D23 103.5 (c 1.02, CHCl3); IR (KBr) 1783, 1691 cm−1; 1H NMR (CDCl3)
δ 7.21–7.36 (5H, m), 6.35 (1H, dd, J=5.6, 2.8 Hz), 6.03 (1H, dd, J=5.6, 2.8 Hz), 4.59 (1H, m), 4.22 (1H,
dd, J=9.0, 6.9 Hz), 4.18 (1H, dd, J=9.0, 2.8 Hz), 3.65 (1H, bs), 3.27 (1H, dd, J=13.5, 3.3 Hz), 2.96 (1H,
bs), 2.81 (1H, dd, J=13.5, 9.6 Hz), 2.17–2.31 (2H, m), 1.97 (1H, d, J=8.6 Hz), 1.75 (1H, d, J=8.6 Hz);
13C NMR (CDCl3) δ 37.5, 40.9, 41.0 (d, J=20.9 Hz), 48.0, 51.2 (d, J=21.8 Hz), 56.6, 66.3, 104.0 (d,
J=198.8 Hz), 127.3, 128.9, 129.4, 132.0, 135.1, 141.3, 151.2, 169.5 (d, J=31.5 Hz); 19F NMR (CDCl3)
δ −86.5 (dd, J=32.4, 19.0 Hz). HRMS calcd for C18H18FNO3 315.1271, found 315.1254.

H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1979–1987
1985
3.6. (3R,4S,6R)-4-Benzyloxycarbonyl-4-fluoro-bicyclo[2.2.1]heptene 9-endo
Under an argon atmosphere, to a solution of BnOLi (prepared from 1.54 mmol of benzylalcohol and
1.19 mmol of n-BuLi) in THF (6 ml) was added a solution of 6-endo (162 mg, 0.75 mmol) in THF (2 ml)
at 0°C. After being stirred for 4 h, saturated aqueous ammonium chloride was added and the mixture was
extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate,
and concentrated under vacuum. After purification by silica gel column chromatography (hexane/ethyl
acetate, 25/1), the compound 9-endo (123 mg, 0.526 mmol) was obtained in 70% yield.
26
9-endo: [α]D 30.4 (c 0.44, CHCl3); IR (neat) 1745 cm−1; 1H NMR (CDCl3) δ 7.42–7.30 (5H, m),
6.33 (1H, dd, J=5.4, 3.0 Hz), 5.84 (1H, dd, J=5.4, 3.0 Hz), 5.21 (1H, d, J=12.4 Hz), 5.18 (1H, d, J=12.4
Hz), 3.15 (1H, bs), 2.97 (1H, bs), 2.13–1.85 (3H, m), 1.76–1.68 (1H, m); 13C NMR (CDCl3) δ 39.8 (d,
J=21.1 Hz), 41.7, 48.9, 52.0 (d, J=22.8 Hz), 67.4, 102.2 (d, J=195.3 Hz), 128.5, 128.7, 129.0, 131.5,
135.9, 142.3, 166.5 (d, J=34.3 Hz); 19F NMR (CDCl3) δ −86.5 (ddd, J=32.0, 18.0, 4.0 Hz). HRMS
calcd for C15H15FO2 246.1056, found 246.1064.
3.7. (3S,4S,6S)-4-Benzyloxycarbonyl-4-fluoro-bicyclo[2.2.1]heptene 9-exo
The compound 9-exo was obtained from 6-exo according to the above mentioned procedure.
23
9-exo: [α]D −135.5 (c 0.67, CHCl3); IR (neat) 1739 cm−1; 1H NMR (CDCl3) δ 7.42–7.39 (5H, m),
6.48 (1H, dd, J=5.6, 3.0 Hz), 6.10 (1H, dd, J=5.6, 3.0 Hz), 5.27 (2H, s), 3.22 (1H, bs), 2.98 (1H, bs),
2.40 (1H, ddd, J=13.1, 13.1, 3.6 Hz), 1.85 (1H, bd, J=9.1 Hz), 1.62–1.42 (1H, m), 1.47 (1H, ddd, J=24.3,
13.1, 4.1 Hz); 13C NMR (CDCl3) δ 40.4 (d, J=20.0 Hz), 42.6, 49.3, 51.9 (d, J=21.5 Hz), 67.7, 101.4 (d,
J=195.5 Hz), 128.6, 128.8, 129.0, 132.8, 135.8, 140.6, 166.4 (d, J=27.3 Hz); 19F NMR (CDCl3) δ −94.6
(dd, J=24.3, 13.1 Hz). HRMS calcd for C15H15FO2 246.1056, found 246.1063.
3.8. (3S,30S,5R,6R,60R)-3-Fluoro-6-iodohexahydro-3,5-methano-2H-cyclopenta[b]-furan-2-one 10
To a solution of 9-endo (20.9 mg, 0.086 mmol) in acetonitrile (2 ml) was added iodine (44 mg, 0.17
mmol) at ambient temperature and the mixture was stirred at the same temperature overnight. After
addition of an aqueous Na2S2O3 solution, the reaction mixture was extracted with ethyl acetate. The
organic layer was washed with brine dried over magnesium sulfate and concentrated under vacuum.
After purification by silica gel column chromatography (hexane/ethyl acetate, 15/1), the compound 10
(17.2 mg, 0.061 mmol) was obtained in 71% yield.
10: Mp 59–63°C; [α]D −105.6 (c 0.66, CHCl3); IR (KBr) 1805 cm−1; 1H NMR (CDCl3) δ 5.12 (1H,
22
dd, J=4.2, 4.2 Hz), 3.83 (1H, d, J=2.6 Hz), 3.29 (1H, dd, J=7.1, 4.2 Hz), 2.79 (1H, bs), 2.45 (1H, dd,
J=11.9, 1.3 Hz), 2.30 (1H, ddd, J=14.2, 4.7, 2.3 Hz), 2.14 (1H, bd, J=11.9 Hz), 2.06 (1H, ddd, J=14.2,
14.2, 4.2 Hz); 13C NMR (CDCl3) δ 26.7, 35.6, 42.1 (d, J=22.9 Hz), 46.6, 49.9 (d, J=20.0 Hz), 85.1, 93.0
(d, J=218.0 Hz), 172.8 (d, J=28.8 Hz); 19F NMR (CDCl3) δ −111.3 (m). HRMS calcd for C8H8FIO2
281.9553, found 281.9549.
3.9. (−)-(3R,4R,6R)-4-Carboxyl-4-fluoro-bicyclo[2.2.1]heptene 11
To a solution of 9-exo (19.0 mg, 0.0785 mmol) in THF (1 ml) was added 0.3 ml of 1 N NaOH at
ambient temperature and the mixture was stirred at the same temperature for 4 h. The reaction mixture
was acidified to pH 4 by the addition of 10% HCl and then sodium chloride was added. The mixture
was extracted with ethyl acetate three times. The organic layer was dried over magnesium sulfate and

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H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1979–1987
concentrated under vacuum. After purification by silica gel column chromatography (ethyl acetate only),
the compound 11 (9.2 mg, 0.059 mmol) was obtained in 75% yield.
11: [α]D −109.8 (c 0.54, CHCl3); IR (neat) 1717 cm−1; 1H NMR (CDCl3) δ 6.50 (1H, dd, J=5.5,
22
3.0 Hz), 6.12 (1H, dd, J=5.5, 3.0 Hz), 3.27 (1H, bs), 3.03 (1H, bs), 2.42 (1H, ddd, J=13.1, 13.1, 3.5 Hz),
1.95 (1H, bd, J=8.1 Hz), 1.63–1.56 (1H, m), 1.51 (1H, ddd, J=23.0, 13.1, 4.0 Hz); 13C NMR (CDCl3)
δ 39.6 (d, J=19.7 Hz), 41.5, 48.4, 51.1 (d, J=21.1 Hz), 100.0 (d, J=193.6 Hz), 131.8, 139.6, 177.7 (d,
J=30.0 Hz); 19F NMR (CDCl3) δ −94.0 (dd, J=23.0, 13.1 Hz). HRMS calcd for C8H9FO2 156.0587,
found 156.0582; Anal. calcd for C8H9FO2: C, 61.53; H, 5.81. Found: C, 61.78; H, 5.94.
3.10. 4-Benzyloxycarbonyl-4-fluoro-bicyclo[2.2.1]heptene 9 (fluorination of compound 8)
Under an argon atmosphere, to a solution of LDA (prepared from 0.99 mmol of diisopropylamine
and 0.82 mmol of n-BuLi) in THF (4 ml) was added a solution of 8 (162 mg, 0.75 mmol) in THF (2
ml) at −43°C. After being stirred for 30 min, chlorotrimethylsilane (0.13 ml, 1.02 mmol) was added to
the reaction mixture at −43°C and the mixture was stirred at ambient temperature for 1 h. The reaction
mixture was concentrated under vacuum. The residue was diluted with ether and filtered through a Celite
pad and the filtrate was concentrated under vacuum. After addition of saturated aqueous ammonium
chloride, the mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried
over magnesium sulfate, and concentrated under vacuum. A solution of the residue in CH2Cl2 (3 ml)
was added to a mixture of N-fluoro-2,4,6-trimethylpyridinium triflate (261.8 mg, 0.91 mmol), anhydrous
potassium carbonate (104 mg, 0.75 mmol) in CH2Cl2 (4.5 ml) at ambient temperature and the mixture
was stirred under reflux overnight. The mixture was poured onto brine and extracted with ether. The
organic layer was dried over magnesium sulfate and concentrated under vacuum. After purification by
silica gel column chromatography (hexane/ethyl acetate, 25/1), compound 9 (123 mg, 0.53 mmol) was
obtained as an exo:endo mixture (1:2) in 70% yield.
3.11. Preparation of (−)-10 and (+)-11 from the exo/endo mixture of 9
To a solution of an exo/endo mixture of 9 (123 mg, 0.53 mmol) in THF (0.1 ml) was added 4×0.5 ml of
1 N NaOH at ambient temperature over 4 h. The reaction mixture was acidified to pH 4 by the addition
of 10% HCl and then sodium chloride was added. The mixture was extracted with ethyl acetate five
times. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue
was treated with aqueous sodium bicarbonate (600 mg in 10 ml of water) at ambient temperature for 5
min. The mixture was washed with ether and the aqueous layer was cooled to 0°C. Powdered potassium
iodide (1.1 g, 6.5 mmol) and iodine (305 mg, 1.2 mmol) were added to the aqueous reaction mixture and
the mixture was stirred at ambient temperature for 18 h. Aqueous Na2S2O3 was added to the reaction
mixture which was then extracted with ether. The organic layer was dried over magnesium sulfate
and concentrated under vacuum. After purification by silica gel column chromatography (hexane/ethyl
acetate, 15/1), compound 10 (42.7 mg, 0.15 mmol) was obtained in 29% yield. The water layer was
treated with 10% HCl until the pH of solution was 4 and sodium chloride was then added. The mixture
was extracted with ethyl acetate five times. The organic layer was dried over magnesium sulfate and
25
concentrated under vacuum to afford compound 11 (10.3 mg, 0.066 mmol) in 13% yield. (−)-10: [α]D
−52.7 (c 1.01, CHCl3). (+)-11: [α]D25 54.2 (c 0.54, CHCl3).

H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1979–1987
1987
Acknowledgements
A generous donation of methyl 2-fluoroacrylate by Daikin Industries Co. is gratefully acknowledged.
We also thank F-TECH, Inc. for the generous donation of N-fluoro-2,4,6-trimethylpyridinium triflate.
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