8092 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24
Høg et al.
tubes and are uncorrected or using a SRS MPA100 OptiMelt
automated melting point system. NMR spectra were recorded on a
300 MHz Varian spectrometer in CDCl3 solutions using TMS as
an internal standard, in D2O solutions using 1,4-dioxane as an
internal standard, or in CD3OD, acetone-d6, or DMSO-d6 solutions.
Elemental analyses were performed at Analytical Research Depart-
ment, H. Lundbeck A/S Denmark or by Mr. J. Theiner, Department
of Physical Chemistry, University of Vienna, Austria, and are within
(0.4% of the calculated values, unless otherwise stated. Optical
rotations were measured in thermostatted cuvettes on a Perkin-Elmer
241 polarimeter.
temperature overnight completed the lactonization, except for 8a,
which was stirred for 6 days to complete the lactonization. The
reaction mixture was washed with saturated aqueous NaHCO3 (3×)
followed by H2O (2×), and the aqueous layers were extracted with
CH2Cl2 (1×). The combined organic layers were dried using MgSO4
and concentrated in vacuo to give the crude lactonized 4-hydroxy
acid.
(RS)-5-(Biphen-4-yl)dihydrofuran-2(3H)-one (8a).34 8a was
prepared from 4-(biphen-4-yl)-4-oxobutanoic acid (748 mg, 2.94
mmol) following the general procedure for reduction and lacton-
ization of 4-oxo acids. The crude product was subjected to DCVC
(petroleum ether f EtOAc), giving a white solid (691 mg), which
was further purified by recrystallization (EtOAc/petroleum ether)
providing 8a as white crystals (465 mg, 66%); mp 105-106 °C
(lit.34 mp 105 °C). 1H NMR (CDCl3): δ 2.12-2.32 (m, 1H),
2.59-2.75 (m, 3H), 5.50-5.59 (m, 1H), 7.28-7.49 (m, 5H),
7.51-7.67 (m, 4H). 13C NMR (CDCl3): δ 29.0, 31.0, 81.0, 125.6,
126.9, 127.3, 127.4, 128.7, 138.1, 140.2, 141.2, 176.7. Anal.
(C16H14O2) C, H.
4-(4-Benzylphenyl)-4-oxobutanoic acid (7b).33 Anhydrous
AlCl3 (5.34 g, 40 mmol) was added to a solution of succinic
anhydride (2.24 g, 22 mmol) and diphenylmethane (3.36 g, 20
mmol) in CH2Cl2 (100 mL). The reaction mixture was stirred at
room temperature for 70 h and concentrated in vacuo. H2O (30
mL) was added and the mixture cooled to 0 °C and acidified with
HCl (37%, 15 mL). The mixture was allowed to warm to room
temperature and stirred for 30 min. The pale-yellow solid was
filtered off and dried. The crude product was subjected to FC
(petroleum ether/EtOAc 5:1, AcOH 2%) giving 7b as a white solid
(2.99 g, 56%); mp 124 °C (lit.33 mp 124-125 °C). 1H NMR
(CDCl3): δ 2.78 (t, 2H, J ) 6.5 Hz), 3.26 (t, 2H, J ) 6.5 Hz), 4.02
(s, 2H), 7.06-7.41 (m, 7H), 7.90 (d, 2H, J ) 8.2 Hz). 13C NMR
(CDCl3): δ 28.1, 33.1, 41.9, 126.3, 128.2, 128.5, 128.8, 129.0, 134.3,
139.8, 146.9, 178.9, 197.2. Anal. (C17H16O3) C, H.
General Procedure for Hydrolysis of Lactones (9a-d, 12a-g,
and 17a-l). The lactone was dissolved in THF (2-10 mL/mmol).
A solution of LiOH ·H2O (1 equiv) in H2O (1-10 mL/mmol) was
added, and the mixture stirred overnight at room temperature. If
the reaction was not completed after 16 h, additional LiOH (0.1
equiv) was added and the mixture was stirred overnight to complete
the reaction. The mixture was concentrated in vacuo to give the
crude lithium salt of the 4-hydroxybutanoic acid, which was
essentially pure by TLC. The crude lithium salt was recrystallized
to obtain an analytically pure sample for use in binding studies.
Lithium (RS)-4-(Biphen-4-yl)-4-hydroxybutanoate (9a). 9a
was prepared from 8a (295 mg, 1.24 mmol) following the general
procedure for hydrolysis of lactones. Recrystallization (EtOH/Et2O)
of the crude product gave 9a as white crystals (256 mg, 79%); mp
4-(4-Phenethylphenyl)-4-oxobutanoic acid (7c).34 Anhydrous
AlCl3 (2.97 g, 22 mmol) was added to a solution of succinic
anhydride (1.30 g, 13 mmol) and 1,2-diphenylethane (2.03 g, 11
mmol) in CH2Cl2 (50 mL) at 0 °C. The reaction mixture was
allowed to warm to room temperature and stirred for 6 days. H2O
(40 mL) was added to the reaction mixture at 0 °C, followed by
HCl (37%, 18 mL). The mixture was allowed to warm to room
temperature and stirred for 1 h. The mixture was concentrated in
vacuo to evaporate CH2Cl2, and the aqueous solution was filtered
giving a brown solid. The crude product was subjected to FC
(petroleum ether/EtOAc 3:1, AcOH 2%) giving 7c as a white solid
(1.24 g, 40%). An analytical sample for microanalysis was
recrystallized (toluene); mp 129-130 °C (lit.34 mp 125-127 °C).
1H NMR (CDCl3): δ 2.80 (t, 2H, J ) 6.5 Hz), 2.87-3.04 (m, 4H),
3.29 (t, 2H, J ) 6.5 Hz), 7.09-7.31 (m, 7H), 7.87 (d, 2H, J ) 8.2
Hz). 13C NMR (CDCl3): δ 28.1, 33.1, 37.4, 37.9, 126.0, 128.1,
128.3, 128.3, 128.6, 134.1, 140.9, 147.5, 178.9, 197.2. Anal.
(C18H18O3) C, H.
1
> 230 °C. H NMR (D2O): δ 1.93-2.12 (m, 2H), 2.13-2.27 (m,
2H), 4.68-4.74 (m, 1H), 7.34-7.57 (m, 5H), 7.58-7.75 (m, 4H).
13C NMR (D2O): δ 34.3, 34.9, 73.7, 127.08, 127.14, 127.3, 127.9,
129.4, 140.1, 140.4, 143.0, 182.9. Anal. (C16H15LiO3 ·1H2O) C, H.
General Procedure for Heck Reactions (10a-g). The alkene
(1.2 equiv) was added to a mixture of 8d, Pd(OAc)2 (0.01 equiv),
and dry K3PO4 (1.4 equiv) in dry THF (3.0 mL). The vial was
sealed, stirred for 1 min at room temperature, and subsequently
irradiated in a microwave at 190 °C for 15 min.
(E,RS)-5-(4-Styrylphenyl)dihydrofuran-2(3H)-one (10a). 10a
was prepared from 8d (503 mg, 2.09 mmol) and styrene following
the general procedure for Heck reactions. The reaction mixture was
concentrated in vacuo and the crude product was subjected to FC
(petroleum ether/EtOAc 2:1) providing 10a as a white solid (430
mg, 78%). An analytical sample for microanalysis was recrystallized
4-(4-Bromophenyl)-4-oxobutanoic acid (7d).35 Anhydrous
AlCl3 (25.0 g, 188 mmol) was added to a stirred mixture of succinic
anhydride (10.1 g, 101 mmol) in bromobenzene (50 mL, 475 mmol)
at room temperature. The reaction mixture was stirred at 80 °C for
45 min. H2O (150 mL) was added at 0 °C under stirring, followed
by HCl (37%, 100 mL), and the mixture was stirred for 1 h at
room temperature. The yellow solid was filtered off, washed with
H2O, and dried, giving a pale-yellow solid (25.8 g). The crude
product was dissolved in hot toluene, filtered, and recrystallized
from hot toluene to give 7d as white crystals (18.3 g, 70%); mp
1
(EtOAc/Et2O); mp 152-155 °C. H NMR (CDCl3): δ 2.08-2.30
(m, 1H), 2.56-2.80 (m, 3H), 5.43-5.57 (m, 1H), 7.09 (s, 2H),
7.20-7.42 (m, 4H), 7.43-7.64 (m, 5H). 13C NMR (CDCl3): δ 29.0,
31.0, 81.0, 125.6, 126.4, 126.7, 127.6, 127.7, 128.6, 129.2, 136.9,
137.4, 138.3, 176.7. Anal. (C18H16O2 ·0.1H2O) C, H.
4-(4-Phenethylphenyl)butanoic acid (11a). 10a (193 mg, 0.73
mmol) and Pd-C (0.023 g, 0.011 mmol) was added to a dry flask,
which was charged with N2. EtOH (99.9%, 30 mL) was added under
N2. H2 was bubbled through the solution for a few minutes, and
the reaction mixture was stirred under H2 for 2 h. The reaction
mixture was filtered through celite, and the solvent was evaporated
giving 11a as a white solid (182 mg, 93%). An analytical sample
for microanalysis was recrystallized (EtOAc/petroleum ether); mp
85 °C. 1H NMR (CDCl3): δ 1.95 (pentet, 2H, J ) 7.5 Hz), 2.37 (t,
2H, J ) 7.5 Hz), 2.64 (t, 2H, J ) 7.5 Hz), 2.89 (s, 4H), 7.05-7.13
(m, 4H), 7.14-7.21 (m, 2H), 7.23-7.30 (m, 3H). 13C NMR
(CDCl3): δ 26.3, 33.4, 34.6, 37.5, 38.0, 125.7, 128.2, 128.3, 128.3,
128.3, 138.5, 139.3, 141.6, 180.2. Anal. (C18H20O2) C, H.
145-146 °C (lit.35 mp 146-149.5 °C). H NMR (acetone-d6): δ
1
2.72 (t, 2H, J ) 6.3 Hz), 3.31 (t, 2H, J ) 6.3 Hz), 7.70 (d, 2H, J
) 8.4 Hz), 7.95 (d, 2H, J ) 8.4 Hz). 13C NMR (acetone-d6): δ
28.1, 33.9, 130.0, 130.4, 132.4, 136.5, 173.7, 197.5. Anal.
(C10H9BrO3) C, H.
General Procedure for Reduction and Lactonization of
4-Oxo Acids (8a-d). NaBH4 (4 equiv) was added slowly to a
solution of the 4-oxo acid in EtOH (99.9%, 5-10 mL/mmol) at 0
°C. The reaction mixture was allowed to warm to room temperature
and stirred for 1 h. The mixture was concentrated in vacuo, H2O
was added, and pH adjusted to 2 using aqueous HCl (2N). The
mixture was extracted with EtOAc (3×), and the combined organic
phases were washed with brine, dried using MgSO4, and concen-
trated in vacuo.
4-(4-Hydroxyphenyl)-4-oxobutanoic acid (14).36 4-(4-Meth-
oxyphenyl)-4-oxobutanoic acid (13) (7.29 g, 35 mmol) and pyridine
hydrochloride (21 g, 180 mmol) were heated in an oil bath at 200
°C for 4 h. The reaction mixture was allowed to cool to room
temperature and H2O (400 mL) was added. The mixture was filtered
The resulting crude mixture of the 4-hydroxyacid and the
corresponding lactone was dissolved in CH2Cl2 and cooled to 0 °C
followed by the addition of a few drops of TFA. Stirring at room