Y. Terao et al.
Bull. Chem. Soc. Jpn., 76, No. 12 (2003) 2397
yield). 1H-NMR (270 MHz, CDCl3) ꢁ 1.52 (3H, d, J ¼ 7:1 Hz),
3.68 (3H, s), 3.75 (1H, q, J ¼ 7:1 Hz), 7.07–7.52 (8H, m); IR
ꢂmax cmꢃ1: 2982, 2951, 1737, 1642, 1582, 1563, 1515, 1484,
1418, 1376, 1333, 1198, 1132, 1073, 1010, 974, 920, 875, 834,
767, 725, 699, 577.
was determined by HPLC: Column, Chiralcel OJ (Daicel); Solvent,
hexane/2-propanol = 9/1; Flow rate, 0.5 mL/min; Retention time,
(R)-form 20.0 min, (S)-form 22.0 min.
This work was partially supported by ‘‘Science and Technol-
ogy Program on Molecules, Supra Molecules, and Supra-Struc-
tured Materials’’ of the Academic Frontier Promotional Project
and Special Coordination Funds for Promoting Science and
Technology by Japan’s Ministry of Education, Culture, Sports,
Science and Technology. The financial support by the ‘‘Re-
search for the Future’’ Program (JAPS-RFTF 97100302) from
Japan Society for the Promotion of Science is also acknowl-
edged.
Preparation of Dimethyl 2-(2-Fluoro-4-biphenylyl)-2-meth-
ylmalonate (5). To a solution of diisopropylamine (3.39 mL,
24.2 mmol) in dry THF (20 mL) was added a solution of n-BuLi
ꢄ
in hexane (1.56 M, 15.6 mL, 24.2 mmol) with stirring at ꢃ78 C
over a period of 50 min. 4 (3.12 g, 12.1 mmol) in THF (10 mL)
was added at ꢃ78 ꢄC and the mixture was stirred for 50 min. Then
methyl chloroformate (2.11 mL, 24.2 mmol) was added and the
stirring was continued for 2 h at 0 ꢄC. The mixture was quenched
with 2 M HCl and extracted with ethyl acetate. The organic layer
was washed with brine and dried over anhydrous Na2SO4. After
filtration and removal of the solvent, the residue was purified by re-
crystallization from ethyl acetate/hexane to afford 3.44 g of 5 as
colorless crystals (90% yield). Mp 116–117 ꢄC; 1H-NMR (270
MHz, CDCl3) ꢁ 1.89 (3H, s), 3.78 (6H, s), 7.07–7.52 (8H, m);
IR ꢂmax cmꢃ1: 3465, 2958, 1707, 1583, 1485, 1408, 1267, 1176,
1128, 940, 764, 724, 697, 578.
References
1
2
M. Simonyi, Med. Res. Rev., 4, 359 (1984).
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3
Preparation of 2-(2-Fluoro-4-biphenylyl)-2-methylmalonic
Acid (6). Dimethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate
(5, 3.44 g, 10.9 mmol) was added to a mixture of 4 M aqueous
KOH (20 mL) and EtOH (100 mL), and the resulting mixture
4
W. J. Wechter, D. D. Leipold, E. D. Murray, Jr., D. Quiggle,
J. D. McCracken, R. S. Barrios, and N. M. Greenberg, Cancer Res.,
60, 2203 (2000).
ꢄ
was stirred for 1 h at 0 C. After the mixture was acidified with
5
J. D. McCracken, Y. Liu, R. L. Chase, D. Kantoci, E. D.
conc. HCl, EtOH was evaporated and the residue was extracted
with diethyl ether. The ether layer was washed with brine and
dried over anhydrous Na2SO4. After removal of the solvent, the
residue was purified by recrystallization from ethyl acetate/hexane
to afford 2.68 g of 6 as colorless crystals (85% yield). Mp 155–156
Murray, Jr., D. D. Quiggle, Y. Mineyama, and W. J. Wechter, J.
Clin. Pharmacol., 36, 540 (1996).
6
R. Morrone, G. Nicolosi, A. Patti, and M. Piattelli, Tetrahe-
dron: Asymmetry, 7, 1773 (1995).
K. Takahashi and T. Takeda, Jpn. Kokai Tokkyo Koho, JP
2000-143580 (2000).
7
1
ꢄC; H-NMR (270 MHz, CD3OD) ꢁ 1.76 (3H, s), 7.16–7.47 (8H,
m); IR ꢂmax cmꢃ1: 3442, 1707, 1409, 1128, 937, 767, 751, 722,
697, 579, 457.
8 J. A. Walker, U. S. Patent 4266069; Chem. Abstr., 95,
80497 (1981).
Enzymatic Decarboxylation. The substrate 6 (576 mg, 2
mmol) was dissolved in water (100 mL) and the pH of the mixture
was adjusted to 8.0 with 2 M HCl and 2 M NaOH. To a 20-mL
round-bottomed flask was added 1 mL of the 10 mM Tris–HCl
buffer (pH = 8.0), 2 mL of the substrate solution (11.5 mg,
40 mmol) and 1 mL of AMDase solution. The reaction mixture
9
Abstr., 95, 203560 (1981).
10 O. Toussaint, P. Capdevielle, and M. Maumy, Tetrahedron
Lett., 28, 539 (1987).
11 L. Verbit, T. Halbert, and R. B. Patterdon, J. Org. Chem.,
40, 1649 (1965).
12 K. Miyamoto and H. Ohta, J. Am. Chem. Soc., 112, 4077
(1990).
13 H. Ohta, Bull. Chem. Soc. Jpn., 70, 2895 (1997).
14 K. Miyamoto, H. Ohta, and Y. Osamura, Bioorg. Med.
Chem., 2, 469 (1994).
15 M. Miyazaki, H. Kakidani, S. Hanzawa, and H. Ohta, Bull.
Chem. Soc. Jpn., 70, 2765 (1997).
T. A. Hylton and J. A. Walker, Eur. Patent 32620; Chem.
ꢄ
was stirred at 30 C for 40 min. The mixture was quenched with
1 mL of 2 M HCl and filtered through a pad of celite. The filtrate
was extracted with diethyl ether. The ether layer was washed with
brine and dried over anhydrous Na2SO4. After filtration and re-
moval of the solvent, the residue was purified by preparative thin
layer chromatography (hexane/ethyl acetate/acetic acid = 33/
66/1) to affordꢄ 8.79 mg of (R)-1 as colorless crystals (90%
yield). Mp 114 C; 1H-NMR (270 MHz, CD3OD) ꢁ 1.49 (3H, d,
J ¼ 7:0 Hz), 3.72 (1H, q, J ¼ 7:0 Hz), 7.16–7.47 (8H, m); IR
ꢂmax cmꢃ1: 2935, 1700, 1622, 1580, 1482, 1461, 1417, 1324,
1257, 1216, 1129, 1075, 1012, 959, 925, 874, 802, 766, 725,
16 For (R)-(ꢃ)-2-fluoro-ꢀ-methyl-4-biphenylacetic acid:
27
½ꢀꢂD ꢃ43ꢄ (c 1, CHCl3) (Aldrich Handbook of Fine Chemicals
and Laboratory Equipment).
17 K. Nakamura, M. Fujii, and Y. Ida, J. Chem. Soc., Perkin
Trans. 1, 2000, 3205.
20
698, 625, 574; ½ꢀꢂD ꢃ30:5ꢄ (c 0.10, CHCl3). The e.e. of (R)-1