4584 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 18
4.52 (1 H, d, J ) 12.4 Hz), 4.60 (1 H, d, J ) 12.4 Hz), 7.34-
Nakazato et al.
lic a cid (-)-11bp : a white powder; mp >167 °C (dec); 1H NMR
(300 MHz, D2O, TMSP) δ 1.38 (3 H, d, J ) 6.4 Hz), 2.21 (1 H,
dd, J ) 2.7, 7.8 Hz), 2.24-2.32 (1 H, m), 2.39-2.59 (2 H, m),
3.73-3.86 (1 H, m), 4.54 (1 H, q, J ) 6.4 Hz), 7.30 (1 H, d, J
) 8.2 Hz), 7.55 (1 H, d, J ) 8.2 Hz), 7.56 (1H, s); MS (negative)
m/z 390 (M - 1)-; [R]27D ) -62.1° (c ) 1.39, 1 M NaOH). Anal.
(C16H16Cl2FNO5‚0.2H2O‚0.2Py)42 C, H, N.
7.44 (3 H, m); MS (negative) m/z 376 (M - 1)-; [R]27 ) -9.4°
D
(c ) 0.38, 1 M NaOH). Anal. (C15H14Cl2FNO5‚0.8 H2O) C, H, N.
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(2.3-d ich lor ob en zy-
loxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d ica r boxylic a cid
1
(-)-11bg: a white powder; mp >210 °C (dec); H NMR (300
MHz, D2O, TMSP) δ 2.28-2.62 (4 H, m), 4.13-4.23 (1 H, m),
4.70-4.85 (2 H, m), 7.31-7.56 (3 H, m); MS (negative) m/z
(+)-(1R,2R,3R,5R,6R)-2-Am in o-3-((R*)-1-(3,4-d ich lo-
r op h en yl)p r op oxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d i-
ca r boxylic a cid (+)-11bq: a white powder; mp >165 °C (dec);
1H NMR (300 MHz, D2O, TMSP) δ 0.78 (3 H, t, J ) 7.2 Hz),
1.50-1.68 (1 H, m), 1.70-1.89 (1 H, m), 2.03-2.37 (4 H, m),
2.38-2.62 (2 H, m), 3.83-3.95 (1 H, m), 4.34 (1 H, t, J ) 6.8
Hz), 7.26 (1 H, d, J ) 8.2 Hz), 7.51 (1 H, s), 7.55 (1 H, d, J )
376 (M - 1)-; [R]25 ) -37.8° (c ) 0.40, 1 M NaOH). Anal.
D
(C15H14Cl2FNO5‚0.1H2O) C, H, N.
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(2,4-d ich lor ob en zy-
loxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d ica r boxylic a cid
1
(-)-11bh : a white powder; mp >215 °C (dec); H NMR (300
MHz, D2O, TMSP) δ 2.28-2.60 (4 H, m), 4.13-4.19 (1 H, m),
8.2 Hz); MS (negative) m/z 404 (M - 1)-; [R]26 ) +68.4° (c )
4.62-4.84 (2 H, m), 7.37-7.54 (3 H, m); MS (negative) m/z
D
1.04, 1 M NaOH). Anal. (C17H18Cl2FNO5‚0.5H2O‚0.2Py)42 C,
376 (M - 1)-; [R]24 ) -21.1° (c ) 0.25, 1 M NaOH). Anal.
D
H, N.
(C15H14Cl2FNO5) C, H, N.
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-((S*)-1-(3,4-dich lor oph e-
n yl)p r op oxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d ica r box-
ylic a cid (-)-11br : a white powder; mp >170 °C (dec); 1H
NMR (300 MHz, D2O, TMSP) δ 0.81 (3 H, t, J ) 7.3 Hz), 1.52-
1.70 (1 H, m), 1.70-1.90 (1 H, m), 2.06-2.36 (2 H, m), 2.38-
2.62 (2 H, m), 3.70-3.82 (1 H, m), 4.28 (1 H, t, J ) 6.7 Hz),
7.30 (1 H, d, J ) 8.2 Hz), 7.56 (1 H, s), 7.57 (1 H, d, J ) 8.2
Hz); MS (negative) m/z 404 (M - 1)-; [R]29D ) -71.6° (c ) 1.21,
1 M NaOH). Anal. (C17H18Cl2FNO5‚1.2H2O) C, H, N.
(+)-(1R,2R,3R,5R,6R)-2-Am in o-3-((R*)-1-(3,4-d ich lo-
r op h en yl)bu toxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d ica r -
boxylic a cid (+)-11bs: a white powder; mp >188 °C (dec);
1H NMR (300 MHz, D2O, TMSP) δ 0.84 (3 H, t, J ) 7.4 Hz),
1.04-1.38 (2 H, m), 1.42-1.64 (1 H, m), 1.70-1.86 (1 H, m)
2.00-2.39 (4 H, m), 3.83-3.98 (1 H, m), 4.42 (1 H, t, J ) 6.8
Hz), 7.27 (1 H, d, J ) 9.5 Hz), 7.50-7.59 (2 H, m); MS
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(2,5-d ich lor ob en zy-
loxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d ica r boxylic a cid
(-)-11bi: a white powder; mp >195 °C (dec); 1H NMR (300
MHz, D2O, TMSP) δ 2.22-2.62 (4 H, m), 4.15-4.20 (1 H, m),
4.62-4.85 (2 H, m), 7.32-7.56 (3 H, m); MS (negative) m/z
376 (M - 1)-; [R]26 ) -22.0° (c ) 0.27, 1 M NaOH). Anal.
D
(C15H14Cl2FNO5‚0.5H2O) C, H, N.
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(2,6-d ich lor ob en zy-
loxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d ica r boxylic a cid
1
(-)-11bj: a white powder; mp >195 °C (dec); H NMR (300
MHz, D2O, TMSP) δ 2.22-2.59 (4 H, m), 4.17-4.24 (1 H, m),
4.76-4.85 (2 H, m), 4.96 (1 H, d, J ) 10.9 Hz), 7.29-7.48 (3
H, m); MS (negative) m/z 376 (M - 1)-; [R]26 ) -18.9° (c )
D
0.42, 1 M NaOH). Anal. (C15H14Cl2FNO5‚0.5H2O) C, H, N.
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(4-ch lor o-3-flu or oben -
zyloxy)-6-flu or obicyclo[3.1.0]h exan e-2,6-dicar boxylic acid
(negative) m/z 418 (M - 1)-; [R]30 ) +63.9° (c ) 0.82, 1 M
1
D
(-)-11bk : a white powder; mp >276 °C (dec); H NMR (300
NaOH). Anal. (C18H20Cl2FNO5‚0.3H2O) C, H, N.
MHz, D2O, TMSP) δ 2.22-2.45 (3 H, m), 2.51 (1 H, dd, J )
7.6, 13.4 Hz), 4.02-4.20 (1 H, m), 4.54 (1 H, d, J ) 12.1 Hz),
4.61 (1 H, d, J ) 12.1 Hz), 7.13-7.20 (1 H, m), 7.22-7.30 (1
H, m), 7.44-7.53 (1 H, m); MS (negative) m/z 360 (M - 1)-;
(-)-(1R ,2R ,3R ,5R ,6R )-2-Am in o-3-((S *)-1-(3,4-d ich lo-
r op h en n yl)b u t oxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d i-
ca r boxylic a cid (-)-11bt: a white powder; mp >190 °C (dec);
1H NMR (300 MHz, D2O, TMSP) δ 0.86 (3 H, t, J ) 7.2 Hz),
1.12-1.40 (2 H, m), 1.46-1.64 (1 H, m), 1.70-1.86 (1 H, m),
2.12-2.34 (2 H, m), 2.38-2.64 (2 H, m), 3.68-3.83 (1 H, m),
4.36 (1 H, t, J ) 6.6 Hz), 7.30 (1 H, d, J ) 8.4 Hz), 7.53-7.60
[R]27 ) -8.7° (c ) 0.43, 1 M NaOH). Anal. (C15H14ClF2NO5‚
D
0.3H2O) C, H, N.
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(3-ch lor o-4-flu or oben -
zyloxy)-6-flu or obicyclo[3.1.0]h exan e-2,6-dicar boxylic acid
(-)-11bl: a white powder; mp >174 °C (dec); 1H NMR (300
MHz, D2O, TMSP) δ 2.23-2.30 (2 H, m), 2.33-2.46 (1 H, m),
2.53 (1 H, dd, J ) 7.8, 13.7 Hz), 4.06-4.18 (1 H, m), 4.62-
4.73 (2 H, m), 7.16-7.23 (1 H, m), 7.35-7.43 (1 H, m), 7.45-
7.53 (1 H, m); MS (negative) m/z 360 (M - 1)-; [R]25D ) -17.6°
(c ) 0.45, 1 M NaOH). Anal. (C15H14ClF2NO5‚0.1H2O) C, H,
N.
(2 H, m); MS (negative) m/z 418 (M - 1)-; [R]26 ) -63.3° (c
D
) 1.07, 1 M NaOH). Anal. (C18H20Cl2FNO5‚2H2O) C, H, N.
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(d ip h en ylm eth oxy)-6-
flu or ob icyclo[3.1.0]h exa n e-2,6-d ica r b oxylic a cid (-)-
11bu : a white powder; mp >230 °C (dec); 1H NMR (300 MHz,
D2O, TMSP) δ 2.23-2.53 (4 H, m), 4.01-4.08 (1 H, m), 5.61 (1
H, s), 7.35-7.44 (10 H, m); MS (negative) m/z 384 (M - 1)-;
[R]26 ) -29.8° (c ) 1.04, 1 M NaOH). Anal. (C21H20FNO5‚
D
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(3,4,5-tr ich lor oben zy-
1.2H2O) C, H, N.
loxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d ica r boxylic a cid
1
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(bis(4-ch lor op h en yl)-
m et h oxy)-6-flu or ob icyclo[3.1.0]h exa n e-2,6-d ica r b oxyl-
ic a cid (-)-11bv: a white powder; mp >215 °C (dec); 1H NMR
(300 MHz, D2O, TMSP) δ 2.25-2.49 (4 H, m), 3.98-4.07 (1 H,
m), 5.59 (1 H, s), 7.34-7.44 (8 H, m); MS (negative) m/z 452
(-)-11bm : a white powder; mp >189 °C (dec); H NMR (300
MHz, D2O, TMSP) δ 2.28-2.29 (2 H, m), 2.36-2.43 (1 H, m),
2.50 (1 H, dd, J ) 13.4, 7.3 Hz), 4.05-4.11 (1 H, m), 4.51 (1 H,
d, J ) 13.4 Hz), 4.59 (1 H, d, J ) 13.4 Hz), 7.51 (2 H, s); MS
(negative) m/z 410 (M - 1)-; [R]29 ) -4.1° (c ) 0.39, 1 M
D
(M - 1)-; [R]25D ) -18.4° (c ) 0.17, 1 M NaOH). Anal. (C21H18
Cl2FNO5‚0.8H2O) C, H, N.
-
NaOH). Anal. (C15H13Cl3FNO5‚0.1H2O) C, H, N.
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(2,3,4,5,6-p en t a flu o-
r oben zyloxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d ica r box-
ylic a cid (-)-11bn : a white powder; mp >250 °C (dec); 1H
NMR (300 MHz, D2O, TMSP) δ 2.22-2.58 (4 H, m), 4.07-4.14
(1 H, m), 4.64-4.82 (2 H, m); MS (negative) m/z 398 (M - 1)-;
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(bis(4-flu or op h en yl)-
m et h oxy)-6-flu or ob icyclo[3.1.0]h exa n e-2,6-d ica r b oxyl-
ic a cid (-)-11bw : a white powder; mp >190 °C (dec); 1H NMR
(300 MHz, D2O, TMSP) δ 2.25-2.49 (4 H, m), 3.98-4.07 (1 H,
m), 5.59 (1 H, s), 7.34-7.44 (8 H, m); MS (negative) m/z 420
[R]28 ) -5.2° (c ) 0.42, 1 M NaOH). Anal. (C15H11F6NO5‚
D
(M - 1)-; [R]24 ) -24.5° (c ) 1.05, 1 M NaOH). Anal.
0.3H2O) C, H, N.
D
(C21H18F3NO5‚1H2O‚0.1Py)42 C, H, N.
(+)-(1R,2R,3R,5R,6R)-2-Am in o-3-((R*)-1-(3,4-d ich lo-
r op h en yl)eth oxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d ica r -
boxylic a cid (+)-11bo: a white powder; mp >186 °C (dec);
1H NMR (300 MHz, D2O, TMSP) δ 1.36 (3 H, d, J ) 6.1 Hz),
2.10-2.39 (4 H, m), 3.84-3.97 (1 H, m), 4.59 (1 H, q, J ) 6.1
Hz), 7.24 (1 H, d, J ) 7.2 Hz), 7.53 (1 H, s), 7.55 (1 H, d, J )
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-(bis(3,4-d ich lor op h en -
yl)m eth oxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d ica r boxy-
lic a cid (-)-11bx: a white powder; mp >206 °C (dec); 1H NMR
(300 MHz, D2O, TMSP) δ 2.26-2.47 (4 H, m), 3.96-4.10 (1 H,
m), 5.57 (1 H, s), 7.31 (1 H, d, J ) 8.2 Hz), 7.53 (1 H, d, J )
7.2 Hz); MS (negative) m/z 390 (M - 1)-; [R]27 ) +94.2° (c )
8.2 Hz), 7.55 (1 H, s); MS (negative) m/z 520 (M - 1)-; [R]31
D
D
0.95, 1 M NaOH). Anal. (C16H16Cl2FNO5‚0.2Py)42 C, H, N.
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-((S*)-1-(3,4-dich lor oph e-
n yl)eth oxy)-6-flu or obicyclo[3.1.0]h exa n e-2,6-d ica r boxy-
) -5.1° (c ) 0.42, 1 M NaOH). Anal. (C21H16Cl4FNO5) C, H, N.
(-)-(1R,2R,3R,5R,6R)-2-Am in o-3-((n a p h t h a len -1-yl)-
m et h oxy)-6-flu or ob icyclo[3.1.0]h exa n e-2,6-d ica r b oxyl-