Inactivators of γ-Aminobutyric Acid Aminotransferase
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 717
DAST (0.35 g, 2.2 mmol) affording 49 (0.37, 63%) as a colorless
solid: 1H NMR (300 MHz, CDCl3) δ 7.15 (2H, m, ArH), 6.88
(2H, m, ArH), 4.92 (1/2H, m, H7), 4.74 (1/2H, m, H7), 4.49 (1H,
dd, J 2.4, 14.7 Hz, ArCH2), 4.10 (1H, d, J 14.7 Hz, ArCH2),
3.86 (1H, m, H6), 3.81 (3H, s, OCH3), 3.79 (1H, m, H1), 2.99
(1H, m, H4), 2.37-2.55 (2H, m, H5) ppm; m/z (EI) 327, 248,
aqueous portion was extracted with ethyl acetate (3 × 30 mL).
The combined organic layers were washed with saturated
NaHCO3 and brine, dried over anhydrous MgSO4, and con-
centrated under reduced pressure. The residue was purified
by column chromatography on silica gel, eluting with ethyl
acetate/hexane (2:3), giving 55 (0.94 g, 92%) as a colorless
solid: 1H NMR (300 MHz, CDCl3) δ 7.18 (2H, m, ArH), 6.91
(2H, m, ArH), 4.60 (1H, d, J 14.8 Hz, ArCH2), 4.27 (1H, d, J
1.3 Hz, H7), 3.93 (3H, s, OCH3), 3.91 (1H, d, J 14.6 Hz, ArCH2),
3.73 (1H, m, H1), 2.99 (1H, m, H4), 2.45 (2H, m, H5), 2.23 (2H,
m, H5) ppm; m/z (EI) 327, 325, 201, 199, 121, 77. HRMS (EI)
calcd for C14H1579BrNO3D M 326.0376, found M 326.0368; calcd
for C14H1581BrNO3 M 328.0357, found M 328.0390.
6-exo-7-a n ti-Dibr om o-6-d eu ter iu m -2-(4′-m eth oxyben -
zyl)-2-a za bicyclo[2.2.1]h ep ta n -3-on e (56). Triphenylphos-
phine (1.41 g, 5.4 mmol), carbon tetrabromide (1.80 g, 5.4
mmol), and terta-n-butylammonium bromide (100 mg) were
added to a stirred solution of 55 (0.90 g, 2.7 mmol) in
anhydrous THF (20 mL). The resultant solution was heated
at reflux for 9 h. The organic solvents were concentrated under
reduced pressure, and the residue was purified by column
chromatography on silica gel, eluting with ethyl acetate/hexane
(1:4), yielding 56 (0.95 g, 90%) as a colorless solid: 1H NMR
(300 MHz, CDCl3) δ 7.19 (2H, m, ArH), 6.91 (2H, m, ArH),
4.62 (1H, d, J 14.8 Hz, ArCH2), 4.25 (1H, d, J 1.3 Hz, H7),
4.00 (1H, d, J 14.8 Hz, ArCH2), 3.89 (1H, m, H1), 3.84 (3H, s,
-OCH3), 2.99 (1H, m, H4), 2.52-2.71 (2H, m, H5) ppm; m/z
(EI) 390, 311, 309, 121. HRMS (EI) calcd for C14H14NO279Br2D
M 387.9532, found M 387.9549; calcd for C14H14NO279Br81BrD
M 389.9512, found M 389.9515; calcd for C14H15NO281Br2D M
391.9493, found M 391.9466.
7-a n t i-Br om o-6-d e u t e r iu m -2-(4′-m e t h oxyb e n zyl)-2-
a za bicyclo[2.2.1]h ep t-5-en -3-on e (57). Following the prepa-
ration of 36 from 35, dibromolactam 56 (0.80 g, 2.1 mmol) was
treated with neat DBN (2 g) to afford 57 (0.48 g, 89%) as a
colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.11 (2H, m,
ArH), 6.87 (2H, m, ArH), 6.47 (1H, m, H6), 4.66 (1H, m, H7),
4.32 (1H, d, J 14.5 Hz, ArCH2), 4.16 (1H, d, J 14.5 Hz, ArCH2),
4.12 (1H, m, H1), 3.82 (3H, s, -OCH3), 3.55 (1H, m, H4) ppm;
m/z (EI) 311, 309, 241, 243, 229, 199, 163, 121. HRMS (EI)
calcd for C14H1379BrNO2D M 308.0271, found M 308.0279; calcd
for C14H1381BrNO2D M 310.0252, found M 310.0299.
6-Deu ter iu m -2-(4′-m eth oxyben zyl)-2-a za bicyclo[2.2.1]-
h ep t-5-en -3-on e (58). As described in the preparation of 21
from 20, compound 57 (0.46 g, 1.5 mmol) was allowed to react
with tributyltin hydride (0.65 g, 2.23 mmol) in the presence
of AIBN (20 mg), giving 58 (0.22 g, 68%) as a colorless oil: 1H
NMR (300 MHz, CDCl3) δ 7.11 (2H, m, ArH), 6.87 (2H, m,
ArH), 6.47 (1H, dd, J 1.38, 3.2 Hz, H6), 4.3 (1H, d, J 14.8 Hz,
ArCH2), 4.00 (1H, d, J 14.8 Hz, ArCH2), 4.05 (1H, m, H1), 3.82
(3H, s, -OCH3); 3.40 (1H, m, H4), 2.30 (1H, m, H7), 2.09 (1H,
m, H7) ppm; m/z (EI) 230, 163, 121, 69. HRMS (EI) calcd for
162, 136, 121, 78. HRMS (EI) calcd for C14H1579BrFNO2
327.02706, found M 327.02702; calcd for C14H1581BrFNO2
329.0250, found M 329.0227.
M
M
(1R,2S,3S,4S)-3-Am in o-4-br om o-2-flu or ocyclop en ta n e-
1-ca r boxylic Acid ((+)-15). In the general deprotection
procedure by CAN, the protected lactam 49 (0.37 g, 1.1 mmol)
was treated with CAN (1.8 g, 3.4 mmol), giving 50 as a solid.
Without further purification, the solid was hydrolyzed by the
general acid hydrolysis procedure with a basic elution from
an ion-exchange column, giving (+)-15 (0.08 g, 35%) as a
colorless solid. The product was further purified by recrystal-
lization from methanol/ether.
For 50: 1H NMR (300 MHz, D2O) δ 5.17 (1/2H, m, H7), 4.97
(1/2H, m, H7), 4.21 (1H, m, H6), 4.14 (1H, m, H1), 2.85 (1H, m,
H4), 2.30-2.60 (2H, m, H5); 19F NMR (300 MHz, D2O) -182.38
(dd, J 59.5, 37.5 Hz) ppm; m/z (EI) 207, 127, 108, 82, 59. HRMS
(EI) calcd for C6H779BrFNO M 206.9695, found M 206.9696;
calcd for C6H781BrFNO M 208.9675, found M 208.9679.
For (+)-15: mp 126 °C (decomp.); [R]23.5 ) + 45.7° (c, 1.36,
H2O); 1H NMR (300 MHz, D2O) δ 5.16 (1/2H, t, J 6.0 Hz, H2),
4.99 (1/2H, t, J 6.0 Hz, H2), 4.12 (1H, quart., J 8.4 Hz, H4),
3.90 (1H, m, H3), 3.06 (1H, m, H1), 2.38-2.53 (2H, m, H5);
19F NMR (300 MHz, D2O) -179.85 (dt, J 55.8, 21.6 Hz)
ppm; m/z (EI) 199, 201, 162, 121, 74, 56. HRMS (ES) calcd for
C6H979BrFNO2H M + H 225.9879, found M + H 225.9889;
calcd for C6H981BrFNO2H M + H 227.9859, found M + H
227.9845.
6-exo-Br om o-2-(4′-m eth oxyben zyl)-7-oxo-2-a za bicyclo-
[2.2.1]h ep ta n -3-on e (51). Following the same oxidation pro-
cedure from 23 to 24, compound 45 (20 mg) was treated with
excess of NMO in the presence of TPAP to afford crude 51.
Purification by flash column chromatography yielded pure (()-
51 (14 mg, 70%) as a solid: 1H NMR (300 MHz, CDCl3) δ 7.22
(2H, m, ArH), 6.92 (2H, m, ArH), 4.64 (1H, d, J 14.7 Hz,
ArCH2), 4.40 (1H, d, J 14.7 Hz, ArCH2), 3.84 (3H, s, OCH3),
3.74 (1H, m, H6), 3.72 (1H, m, H1), 3.04 (1H, dd, J 4.1, 1.2 Hz,
H4), 2.62 (1H, dd, J 14.3, 9.1 Hz, H5-endo or H5-exo), 2.49 (1H,
m, H5-endo or H5-exo) ppm.
5-en do-Br om o-2-(4′-m eth oxyben zyl)-6-oxo-2-azabicyclo-
[2.2.1]h ep ta n -3-on e (52). Following the same procedure as
for the preparation of 45 (20 mg), compound 48 was treated
with excess TBAF to afford crude 46. Without any purification,
compound 46 was oxidized to form 52 (10 mg, 50%) by the
same method as for the preparation of 51: 1H NMR (400 MHz,
CDCl3) δ 7.17 (2H, m, ArH), 6.86 (2H, m, ArH), 4.70 (1H, d, J
14.8 Hz, ArCH2), 4.29 (1H, d, J 4.0 Hz, H5), 3.89 (1H, d, J
14.8 Hz, ArCH2), 3.78 (3H, s, OCH3), 3.68 (1H, s, H1), 3.25 (1H,
m, H4), 2.50 (1H, m, H7-syn), 2.02 (1H, m, H7-anti) ppm.
7-a n ti-Br om o-2-(4′-m eth oxyben zyl)-6-oxo-2-a za bicyclo-
[2.2.1]h ep ta n -3-on e (54). Following the same oxidation pro-
cedure used to convert 23 to 24, 7-anti-bromo-6-exo-hydroxyl-
2-(4′-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (53)11 (2.3
g, 7.0 mmol) was treated with NMO (1.64 g, 14 mmol) in
the presence of a catalytic amount of TPAP (5 mg) to afford
54 (1.8 g, 78%) as a colorless solid: 1H NMR (300 MHz, CDCl3)
δ 7.16 (2H, m, ArH), 6.88 (2H, m, ArH), 4.72 (1H, d, J 14.6
Hz, ArCH2), 4.37 (1H, m, H7), 3.90 (1H, d, J 14.6 Hz, ArCH2),
3.81 (3H, s, OCH3), 3.68 (1H, m, H1), 3.17 (1H, m, H4), 2.72
(2H, d, J 17.8, 4.1 Hz, H5), 2.23 (2H, d, J 17.8, 2.5 Hz, H5)
ppm; m/z (EI) 323, 325, 244, 216, 121. HRMS (EI) calcd for
C
14H14NO2D M 230.1166, found M 230.1166.
6-exo-7-a n ti-Dibr om o-1-d eu ter iu m -2-(4′-m eth oxyben -
zyl)-2-a za bicyclo[2.2.1]h ep ta n -3-on e (59). Bromine (0.15 g,
0.94 mmol) was added to a stirred solution of 58 (0.18 g, 0.78
mmol) in dichloromethane (10 mL) at 0 °C. After being stirred
for 1 h, the reaction mixture was diluted with dichloromethane
(50 mL) and washed with a saturated Na2SO3 solution (20 mL)
and brine (20 mL). The organic solution was dried over MgSO4
and concentrated under reduced pressure to afford 59 (0.29 g,
95%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.19
(2H, m, ArH), 6.91 (2H, m, ArH), 4.60 (1H, d, J 14.8 Hz,
ArCH2), 4.24 (1H, t, J 1.5 Hz, H7), 4.00 (1H, d, J 14.8 Hz,
ArCH2), 3.84 (3H, s, -OCH3), 3.78 (1H, m, H6), 2.99 (1H, m,
H4), 2.68 (1H, m, H5), 2.52 (1H, m, H5) ppm. HRMS (ES) calcd
for C14H14NO279Br2D + H 388.9600, found M + H 388.9648;
calcd for C14H14NO279Br81BrD + H 390.9590, found M + H
390.9620; calcd for C14H14NO281Br2D + H 392.9570, found M
+ H 392.9598.
C
C
14H1479BrNO3 M 323.0157, found M 323.0153; calcd for
14H1481BrNO3 M 325.0138, found M 323.0134.
7-a n ti-Br om o-6-d eu t er iu m -6-h yd r oxy-2-(4′-m et h oxy-
ben zyl)-2-a za bicyclo[2.2.1]h ep ta n -3-on e (55). NaBD4 (0.13
g, 3.1 mmol) was added to a stirred solution of 54 (1.02 g, 3.1
mmol) in EtOD (10 mL). After being stirred for 1 h, the
reaction mixture was concentrated under reduced pressure.
The residue was treated with 0.5 N HCl (10 mL), and the
3r-Am in o-2â,4â-d ibr om o-3â-d eu t er iu m cyclop en t a n e-
1r-ca r boxylic Acid (61). Following the general deprotection
procedure by CAN, compound 59 (0.22 g, 0.45 mmol) was
treated with CAN (0.92 g, 1.7 mmol) to afford crude 60.