Asymmetric Diels-Alder reactions of 2-fluoroacrylic acid derivatives. Part 2: A remarkable effect of fluorine substituent on the diastereoselectivity

Article abstract of DOI:10.1016/S0957-4166(98)00196-7

An efficient construction of a chiral monofluorinated tertiary carbon was achieved by a highly exo- and diastereofacial selective Diels-Alder reaction of a 2-fluoroacrylic acid derivative derived from 8-phenylmenthol, and cyclopentadiene. The substituent effect of the fluorine on the selectivities is remarkable as compared with the other substituents at the α-position of the acrylate.

Full text of DOI:10.1016/S0957-4166(98)00196-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1989–1994
Asymmetric Diels–Alder reactions of 2-fluoroacrylic acid
derivatives. Part 2: A remarkable effect of fluorine substituent on
the diastereoselectivity
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
An efficient construction of a chiral monofluorinated tertiary carbon was achieved by a highly exo- and
diastereofacial selective Diels–Alder reaction of a 2-fluoroacrylic acid derivative derived from 8-phenylmenthol,
and cyclopentadiene. The substituent effect of the fluorine on the selectivities is remarkable as compared with the
other substituents at the α-position of the acrylate. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The importance of organofluorine compounds, in particular in the field of medicinal chemistry, requires
the development of an efficient method for the construction of chiral molecules in enantiomerically pure
form.1 In the preceding paper, for the construction of chiral monofluorinated tertiary carbon, we described
the Lewis acid mediated asymmetric Diels–Alder reaction of 2-fluoroacrylic acid derivatives bearing a
chiral oxazolidinone moiety.2 Although high diastereoselectivities could be achieved in the reactions
with isoprene and cyclopentadiene, the exo/endo-selectivity was not satisfactory and the requirement of
an extremely low temperature to obtain a high diastereoselectivity was also problematic. Therefore, it
was necessary to find a more effective chiral auxiliary. The efficiency of the 8-phenylmenthyl group in
asymmetric reactions has been well documented for the asymmetric Diels–Alder reaction.3 We report
herein the Diels–Alder reaction of chiral 2-fluoroacrylic acid derivatives 1a under Lewis acid catalyzed
conditions (Scheme 1). We also examined the Diels–Alder reaction of the α-substituted acrylic acid
derivatives 1b and 1c to reveal the effect of the fluorine-substituent on the reactivity and selectivity.
∗
†
Corresponding author.
E-mail: itohisa@ps.toyaku.ac.jp
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00196-7

1990
H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1989–1994
Scheme 1.
2. Results and discussion
The Lewis acid promoted Diels–Alder reactions of 1a4 with cyclopentadiene are summarized in
Table 1 (entries 1–3). In the presence of 1.5 equivalents of diethylaluminum chloride, the Diels–Alder
reaction of 1a proceeded at between 0°C and ambient temperature to give the cycloadduct 2a in 79% yield
with high diastereoselectivity (95% de, entry 1). The exclusive formation of the exo-adduct observed in
this system should also be noted, while no appreciable endo/exo-selectivity was realized in the case of
the oxazolidinone derivative.2 The absolute stereochemistry of the newly formed stereogenic center of
2a was determined, after conversion to its benzyl ester, by comparing the specific rotation with that of the
authentic sample.2 We also examined the effect of the Lewis acid. In the case of titanium tetrachloride,
the reaction proceeded in a highly diastereo- and exo-selective manner as in the case of diethylaluminum
chloride (entry 2). On the other hand, in the case of trimethylaluminum, which has one coordination site,
the diastereoselectivity decreased (entry 3). In all cases examined here, the direction of chiral induction
was not affected by the Lewis acid employed.
To examine the influence of the fluorine substituent on the diastereo- and exo/endo-selectivity, the
Diels–Alder reactions of 1b5 and 1c with cyclopentadiene were conducted and the results are summarized
in Table 1 (entries 4–9), also the results of the hydrogen-substituted substrate 1d reported by Oppolzer et
al.3b also shown (entries 10 and 11). Regarding the exo/endo-selectivity, introduction of a substituent at
the α-position (1b, 1c) resulted in an exo-predominant reaction as commonly observed in the Diels–Alder
reaction of acrylate derivatives with cyclopentadiene. With the chlorinated compound 1b (entries 4–6),
the best selectivity was obtained with the use of titanium tetrachloride, but both the diastereo- and
exo/endo-selectivities were lower than those of the fluorinated compound 1a. The Diels–Alder reaction
of the methyl substituted compound 1c also showed an exo-selectivity similar to that of 1b but the
diastereoselectivity was moderate (entries 7–9).
Determination of the absolute stereochemistry of compound 2b-exo (X=8-phenylmenthyloxy, 93% de)
and 2c-exo (X=8-phenylmenthyloxy, 74% de) was easily accomplished as shown in Scheme 2. Reduction
of compound 2b-exo was achieved in a two step procedure to afford the alcohol 3 (exo/endo, 1/3.2).
This isomeric mixture could be separated after conversion to the benzoyl derivatives. By comparing the
specific rotation of 3-endo with the reported value (lit.3b [α]D25 67.7 for ent-3-endo, 70% ee), the absolute
chemistry of compound 2b-exo was unambiguously established. To determine the stereochemistry of
compound 2c-exo, this was converted to the known compound 5 (lit.6 [α]D25 16.8 for ent-5, 72% ee).
The mechanism of the diastereoselectivity could be considered as shown in Fig. 1. The α-
fluoroacrylate 1a showed higher diastereoselectivity than the acrylate 1d. The ab initio-based force field
modelling study of the transition state by Houk et al. indicates the preference of the s-trans conformer
in the case of the Lewis acid mediated Diels–Alder reaction of acrylic acid 8-phenylmenthyl ester,7 due
to the steric repulsion between the Lewis acid and the β-proton on the acrylic ester moiety in the s-cis

H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1989–1994
1991
Table 1
The Diels–Alder reaction of 1a, 1b, 1c, and 1d with cyclopentadiene
Scheme 2.
conformer (C, X=H). In the case of the α-fluoroacrylate 1a, the facial selectivity of the double bond in
the Diels–Alder reaction was similar to that with the acrylate 1d. This suggests that the α-fluoroacryloyl
moiety would have s-trans conformation because of the small steric difference of the fluorine and

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H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1989–1994
Fig. 1.
hydrogen atoms. Recently, Maruoka et al. reported a significant interaction between a fluorine atom
and aluminum metal.8 One of the speculative mechanisms for the observed high diastereoselectivity,
formation of the five-membered intermediate (A) based on the interaction of the fluorine atom with
aluminum metal possibly plays an important role. On the other hand, the steric bulkiness of α-chloro or
α-methyl substituents should result in the s-trans conformer being more unfavourable than in the case
of the α-fluoro or α-hydrogen substituent thus resulting in the decrease in diastereoselectivity as shown
in Fig. 1.
In summary, we have demonstrated that the Diels–Alder reaction of 2-fluoroacrylic acid bearing the
8-phenylmenthyl group provides an efficient constructive method of chiral fluorine-substituted tertiary
carbons.
3. Experimental
3.1. General
Melting points are uncorrected. Infrared absorption spectra were recorded using Perkin–Elmer FTIR-
1
1710. H and 13C NMR spectra were obtained using Varian Gemini 300 (300 MHz), Brucker 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.

H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1989–1994
1993
3.2. (1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)-cyclohexyl 2-fluoropropenoate 1a
Under an argon atmosphere, to a solution of (−)-8-phenylmenthol (633 mg, 2.7 mmol) and triethyl-
amine (0.58 ml, 4.2 mmol) in CH2Cl2 (2 ml) was added a solution of 2-fluoroacryloyl chloride (426 mg,
3.8 mmol) in CH2Cl2 (2 ml) at 0°C. After being stirred for 3 h at 0°C, 4-dimethylaminopyridine (158
mg, 1.1 mmol) was added to the reaction mixture and then stirred for 8 h at ambient temperature. After
addition of water, 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, 7/2), the compound 1a (2.29 g, 9.13 mmol) was obtained
in 64% yield (based on 8-phenylmenthol).
25
1
1a: [α]D −43.7 (c 1.43, CHCl3); IR (neat) 1734 cm−1; H NMR (CDCl3) δ 7.30–7.00 (5H, m),
5.00 (1H, dd, J=12.8, 3.2 Hz), 4.98 (1H, dd, J=44.3, 3.2 Hz), 4.94 (1H, ddd, J=10.8, 10.8, 4.4 Hz),
2.20–0.78 (8H, m), 1.32 (3H, s), 1.22 (3H, s), 0.88 (3H, d, J=6.1 Hz); 13C NMR (CDCl3) δ 22.0, 25.4,
26.8, 28.2, 31.5, 34.7, 39.8, 41.6, 50.5, 76.3, 102.3 (d, J=15.0 Hz), 125.4, 125.5, 128.3, 151.3, 153.3 (d,
J=258.2 Hz), 159.6 (d, J=36.8 Hz); 19F NMR (CDCl3) δ −54.6 (dd, J=44.3, 12.8 Hz). HRMS calcd for
C19H25FO2 304.1839, found 304.1822.
3.3. Typical procedure for the Lewis acid mediated Diels–Alder reaction of 1a with cyclopentadiene
Under an argon atmosphere, to a solution of 1a (102.6 mg, 0.335 mmol) in CH2Cl2 (4 ml) was added
a solution of diethylaluminum chloride (0.95 M in hexane, 0.53 ml, 0.504 mmol) at 0°C. After being
stirred for 30 min, cyclopentadiene (1.0 ml, 10.3 mmol) was added to the reaction mixture at 0°C and
the mixture was stirred at ambient temperature for 8 h. 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. After purification by silica gel column
chromatography (hexane/chloroform, 7/2), 2a-exo (98.3 mg, 0.264 mmol) was obtained in 79% yield.
3.4. 4-(1R,2S,5R,30S,40S,60S)-[5-Methyl-2-(1-methyl-1-phenylethyl)-cyclohexyloxycarbonyl]-4-fluoro-
bicyclo[2.2.1]heptene 2a-exo
[α]D −57.7 (c 3.46, CHCl3); IR (neat) 1728 cm−1; H NMR (CDCl3) δ 7.40–7.20 (4H, m),
7.20–7.10 (1H, m), 6.43 (1H, dd, J=5.6, 3.0 Hz), 6.06 (1H, dd, J=5.6, 3.0 Hz), 4.98 (1H, dd, J=10.6,
10.6, 4.3 Hz), 3.08 (1H, bs), 2.87 (1H, bs), 2.20–0.7 (12H, m), 1.39 (3H, s), 1.27 (3H, s), 0.88 (3H, d,
J=6.4 Hz); 13C NMR (CDCl3) δ 21.7, 26.2, 27.0, 27.6, 31.3, 34.4, 39.3 (d, J=20.1 Hz), 40.0, 41.5, 42.0,
48.8, 50.0, 51.2 (d, J=21.2 Hz), 76.3, 100.6 (d, J=195.8 Hz), 125.3, 125.5, 128.0, 132.4 (d, J=5.7 Hz),
140.0, 150.7, 171.8 (d, J=29.0 Hz); 19F NMR (CDCl3) δ −94.2 (dd, J=24.0, 13.0 Hz). HRMS calcd for
C24H31FO2 370.2308, found 370.2290.
25
1
3.5. 4-(1R,2S,5R,30S,40S,60S)-[5-Methyl-2-(1-methyl-1-phenylethyl)-cyclohexyloxycarbonyl]-4-
chloro-bicyclo[2.2.1]heptene 2b-exo
[α]D −34.9 (c 3.46, CHCl3); IR (neat) 1727 cm−1; H NMR (CDCl3) δ 7.35–7.26 (4H, m),
7.20–7.10 (1H, m), 6.38 (1H, dd, J=5.5, 3.0 Hz), 6.15 (1H, dd, J=5.5, 3.0 Hz), 4.90 (1H, dd, J=10.7,
10.7, 4.3 Hz), 3.22 (1H, bs), 2.89 (1H, bs), 2.10–1.90 (2H, m), 1.70–0.70 (10H, m), 1.37 (3H, s), 1.26
(3H, s), 0.87 (3H, d, J=6.3 Hz); 13C NMR (CDCl3) δ 21.8, 25.3, 27.2, 28.7, 31.3, 34.5, 40.1, 41.0, 41.1,
26
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H. Ito et al. / Tetrahedron: Asymmetry 9 (1998) 1989–1994
42.5, 48.2, 48.8, 50.1, 51.9, 71.9, 77.3, 125.3, 125.6, 128.1, 133.6, 139.4, 150.7, 170.6. HRMS calcd for
C24H31ClO2 386.2013, found 386.2008.
3.6. 4-(1R,2S,5R,30S,40R,60S)-[5-Methyl-2-(1-methyl-1-phenylethyl)-cyclohexyloxycarbonyl]-4-
methyl-bicyclo[2.2.1]heptene 2a-exo
25
1
[α]D −26.3 (c 1.34, CHCl3); IR (neat) 1716 cm−1; H NMR (CDCl3) δ 7.32–7.26 (4H, m),
7.18–7.10 (1H, m), 6.20 (1H, dd, J=5.6, 3.0 Hz), 6.04 (1H, dd, J=5.6, 3.0 Hz), 4.88 (1H, dd, J=10.6,
10.6, 4.3 Hz), 2.88 (1H, bs), 2.78 (1H, bs), 2.29 (1H, dd, J=12.1, 4.0 Hz), 2.20–1.80 (2H, m), 1.60–0.70
(8H, m), 1.35 (3H, s), 1.25 (3H, s), 1.00 (3H, s), 0.85 (3H, d, J=6.4 Hz), 0.66 (1H, dd, J=12.1, 2.4 Hz);
13C NMR (CDCl3) δ 21.8, 24.1, 25.2, 27.2, 28.8, 31.3, 34.5, 36.8, 40.1, 41.6, 42.8, 48.8, 49.6, 50.0,
50.4, 75.2, 125.2, 125.5, 128.0, 133.6, 138.7, 151.0, 177.9. HRMS calcd for C25H34O2 366.2559, found
366.2537.
Acknowledgements
The generous donation of methyl 2-fluoroacrylate by Daikin Industries Co. is gratefully acknowledged.
References
1. (a) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of Fluorine Chemistry; Elsevier Biomedical Press and Kodansha
Ltd, 1982. (b) Welch, J. T. Tetrahedron 1987, 43, 3123. (c) Resnati, G. Tetrahedron 1993, 49, 9385. (d) Fluoroorganic
Chemistry: Synthetic Challenges and Biomedical Rewards; Tetrahedron Symposium-in Print No. 58; Guest Editors: G.
Resnati and V. A. Soloshonok, Tetrahedron 1996, 52, 1. (e) Biomedical Frontiers of Fluorine Chemistry, Ojima, I.;
McCarthy, J. R.; Welch, J. T. Eds., ACS Symposium Series 639, American Chemical Society: Washington, D.C., 1996. (f)
O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 645.
2. Ito, H.; Saito, A.; Taguchi, T. Tetrahedron: Asymmetry 1998, 9, 1979–1987.
3. (a) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908. (b) Oppolzer, W.; Kurth, M.; Reichlin, D.; Moffatt, F.
Tetrahedron Lett. 1981, 22, 2545. (c) Oppolzer, W.; Kurth, M.; Reichlin, D.; Chapuis, C.; Mohnhaupt, M.; Moffatt, F. Helv.
Chim. Acta 1981, 64, 2802. (d) Whitesell, J. K.; Liu, C.-L.; Buchanam, C. M.; Chen, H.-H.; Minton, M. A. J. Org. Chem.
1986, 51, 551.
4. 8-Phenylmenthyl ester 1a was prepared in 64% yield by reaction of 2-fluoroacryloyl chloride with 8-phenylmenthol in the
presence of triethylamine and a catalytic amount of 4-dimethylaminopyridine in CH2Cl2.
5. Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A. Syn. Commun. 1992, 22, 1205.
6. (a) Hashimoto, S.; Komeshima, N.; Koga, K. J. Chem. Soc., Chem. Commun. 1979, 437. (b) Takemura, H.; Komeshima,
N.; Takahashi, I.; Hashimoto, S.; Ikota, N.; Tomioka, K.; Koga, K. Tetrahedron Lett. 1987, 28, 5687.
7. Pascual-Teresa, B.; Gonzalez, J.; Asensio, A.; Houk, K. N. J. Am. Chem. Soc. 1995, 117, 4347.
8. (a) Ooi, T.; Kagoshima, N.; Maruoka, K. J. Am. Chem. Soc. 1997, 119, 5754. (b) Ooi, T.; Uraguchi, D.; Kagoshima, N.;
Maruoka, K. Tetrahedron Lett. 1997, 38, 5679. (c) Plenio, H. Chem. Rev. 1997, 97, 3363.