2448 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10
Ali et al.
MHz): δ 7.53 (td, J ) 7.5, 1.3 Hz, 1H), 7.43-7.46 (m, 3 H),
7.24 (m, 1H), 7.12-7.18 (m, 3H), 7.02 (m, 1H), 6.10 (d, J ) 2.3
Hz, 1H), 5.48 (s, 1H), 3.16 (d, J ) 15.3 Hz, 1H), 2.83 (d, J )
15.3 Hz, 1H), 2.40 (m, 1H), 2.27 (bd, J ) 15.1 Hz, 1H), 1.81
(m, 1H), 1.68-1.76 (m, 2H), 1.61 (m, 1H), 1.26 (s, 3H), 1.20
(m, 1H). HRMS for C25H25F2N2O (M + 1)+: calcd, 407.1935;
found, 407.1896.
(R)-(4-F lu or o-3-m eth oxyp h en yl)[(4a R,5S)-1-(4-flu or o-
p h en yl)-4a -m et h yl-4,4a ,5,6,7,8-h exa h yd r o-1H -b en zo[f]-
in d a zol-5-yl]m eth a n ol (16). From 9 using 4-bromo-1-fluoro-
2-methoxybenzene. Final purification on AD chiral column
(20% IPA/heptanes), yield 52%. Rf ) 0.07 (25% EtOAc/
1
hexanes). H NMR (CDCl3, 600 MHz): δ 7.44-7.46 (m, 3H),
7.14-7.17 (m, 2H), 7.05 (dd, J ) 11.4, 8.4 Hz, 1H), 6.98 (dd, J
) 7.8, 1.8 Hz, 1H), 6.84 (m, 1H), 6.12 (d, J ) 2.2 Hz, 1H), 5.15
(s, 1H), 3.91 (s, 3H), 3.18 (d, J ) 15 Hz, 1H), 2.75 (d, J ) 15
Hz, 1H), 2.41 (m, 1H), 2.29 (bd, J ) 15.0 Hz, 1H), 1.57-1.84
(m, 4H), 1.26 (s, 3H), 1.20 (m, 1H). Anal. (C26H26F2N2O2) C,
H, N.
(R)-(4-Flu or o-3-m eth ylph en yl)[(4aR,5S)-1-(4-flu or oph en -
yl)-4a -m eth yl-4,4a ,5,6,7,8-h exa h yd r o-1H-ben zo[f]in d a zol-
5-yl]m eth a n ol (17). From 9 using 4-bromo-1-fluoro-2-meth-
ylbenzene. Final purification on AD chiral column (15% IPA/
heptanes), yield 53%. Rf ) 0.24 (25% EtOAc/hexanes). 1H NMR
(CDCl3, 600 MHz): δ 7.43-7.45 (m, 3H), 7.10-7.16 (m, 4H),
6.97 (t, J ) 8.8 Hz, 1H), 6.10 (d, J ) 2.1 Hz, 1H), 5.11 (s, 1H),
3.15 (d, J ) 15.1 Hz, 1H), 2.74 (d, J ) 15.1 Hz, 1H), 2.40 (m,
1H), 2.28 (s, 3H), 2.27 (m, 1H), 1.81 (m, 1H), 1.65-1.72 (m,
2H), 1.59 (m, 1H), 1.25 (s, 3H), 1.19 (m, 1H). Anal. (C26H26F2N2O);
C: calcd 74.26, found 73.00; H: calcd 6.23, found 6.29; N: calcd
6.66, found 6.45.
(R)-(3,4-Diflu or o-5-m eth oxyp h en yl)[(4a R,5S)-1-(4-flu o-
r op h en yl)-4a -m eth yl-4,4a ,5,6,7,8-h exa h yd r o-1H-ben zo[f]-
in d a zol-5-yl]m eth a n ol (18). From 9 using 5-bromo-1,2-
difluoro-3-methoxybenzene. Final purification by PTLC with
45/35/20 CH2Cl2/hexanes/Et2O, yield 67%. Rf ) 0.11 (25%
EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz): δ 7.44-7.47 (m,
3H), 7.14-7.18 (m, 2H), 6.73-6.79 (m, 2H), 6.13 (d, J ) 2.3
Hz, 1H), 5.12 (d, J ) 3.4 Hz, 1H), 3.92 (s, 3H), 3.18 (d, J )
14.9 Hz, 1H), 2.75 (d, J ) 14.9 Hz, 1H), 2.41 (m, 1H), 2.29 (bd,
J ) 15.1 Hz, 1H), 1.83 (m, 1H), 1.78 (d, J ) 3.9 Hz, 1H), 1.66-
1.71 (m, 2H), 1.54 (m, 1H), 1.26 (s, 3H), 1.21 (m, 1H). Anal.
(C25H25F2N2O) C, H, N.
(4-F lu or op h en yl)[(4aR,5S)-1-(4-flu or op h en yl)-4a -m eth -
yl-4,4a ,5,6,7,8-h exa h yd r o-1H-ben zo[f]in d a zol-5-yl]m eth a -
n on e (19). Compound 11 (23.0 mg, 0.057 mmol) was dissolved
in CH2Cl2 (2 mL), cooled to 0 °C, and NMO (10 mg, 0.085
mmol) was added. After 5 min, TPAP (2 mg, 0.0057 mmol)
was added. The reaction was stirred for 3 h at 0 °C and then
loaded directly onto a column of silica gel. Elution with 100%
CH2Cl2 followed by 25% EtOAc/hexanes afforded 19.2 mg (84%)
of 19. Rf ) 0.34 (25% EtOAc/hexanes). LCMS ) 405 (M + 1)+.
(S)-(4-F lu or op h en yl)[(4a R,5S)-1-(4-flu or op h en yl)-4a -
m eth yl-4,4a ,5,6,7,8-h exa h yd r o-1H-ben zo[f]in d a zol-5-yl]-
m eth a n ol (20). Compound 19 (19.2 mg, 0.048 mmol) was
dissolved in MeOH (2 mL) and cooled to 0 °C. NaBH4 (10 mg,
0.238 mmol) was added and the reaction was stirred at 0 °C
for 15 min. The reaction was quenched with saturated NH4Cl
(1 mL), diluted with EtOAc (25 mL), and washed with H2O
and brine (10 mL each). The organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. Purification of the
residue by flash chromatography on silica gel (40% EtOAc/
hexanes) followed by chiral HPLC (AD column with 12% IPA/
heptanes) gave 12.6 mg (65%) of 20. Rf ) 0.16 (25% EtOAc/
hexanes). 1H NMR (CDCl3, 600 MHz): δ 7.45 (dd, J ) 9.0, 4.8
Hz, 2H), 7.40 (s, 1H), 7.32 (dd, J ) 8.4, 5.4 Hz, 2H), 7.14 (t, J
) 8.4 Hz, 2H), 7.04 (t, J ) 8.4 Hz, 2H), 6.15 (s, 1H), 4.64 (d, J
) 9.0 Hz, 1H), 3.63 (d, J ) 16.2 Hz, 1H), 2.78 (d, J ) 16.2 Hz,
1H), 2.27-2.29 (m, 2H), 2.07 (bs, 1H), 1.89 (m, 1H), 1.68 (m,
1H), 1.05-1.25 (m, 2H), 1.13 (s, 3H). Anal. (C25H24F2N2O); C:
calcd 73.87, found 72.44; H: calcd 5.95, found 5.82; N: calcd
6.89, found 6.51. HRMS for C25H24F2N2O (M + 1)+: calcd,
407.1935; found, 407.1920.
3-[(R)-[(4a R,5S)-1-(4-F lu or op h en yl)-4a -m eth yl-4,4a ,5,-
6,7,8-hexahydro-1H-benzo[f]indazole-5-yl](hydroxy)methyl]-
p h en ol (13). A solution of (3-bromophenoxy)(triisopropyl)-
silane (220 mg, 0.667 mmol) in Et2O (8 mL) was cooled to -78
°C, and t-BuLi (785 µL of a 1.7 M solution in pentanes, 1.335
mmol) was added dropwise by syringe. The yellow reaction was
stirred for 30 min at - 78 °C, and then a solution of 9 (20.7
mg, 0.067 mmol) in THF (2 mL) was added by cannula. The
reaction was stirred at -78 °C for 30 min. Isopropyl alcohol
(1 mL) was added to quench the reaction at -78 °C, and the
reaction was poured into saturated NH4Cl. The mixture was
extracted with EtOAc (100 mL), and the organic layer was
washed with water and brine (25 mL each). The organic layer
was dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography on silica gel (5 to 15%
EtOAc/hexanes) gave 27.8 mg of desired product contaminated
with small amounts of minor diastereomers. Further purifica-
tion by chiral HPLC (AD column, 2% ethanol/heptanes) gave
14.0 mg (37%) of pure 3-[(R)-[(4aR,5S)-1-(4-fluorophenyl)-4a-
methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]{3-[(tri-
isopropylsilyl)oxy]phenyl}methanol. Rf ) 0.40 (25% EtOAc/
1
hexanes). H NMR (CDCl3, 500 MHz): δ 7.44-7.47 (m, 3H),
7.14-7.21 (m, 3H), 6.89-6.90 (m, 2H), 6.77 (m, 1H), 6.11 (d,
J ) 1.9 Hz, 1H), 5.13 (d, J ) 2.3 Hz, 1H), 3.16 (d, J ) 15.1 Hz,
1H), 2.73 (d, J ) 15.1 Hz, 1H), 2.41 (m, 1H), 2.8 (bd, J ) 15.1
Hz, 1H), 1.61-1.82 (m, 4H), 1.16-1.30 (m, 7H) 1.10-1.11 (m,
18H).
The silyl ether intermediate (7.8 mg, 0.0139 mmol) was
dissolved in THF (1 mL), cooled to 0 °C, and treated with TBAF
(70 µL of a 1 M solution in THF, 0.0696 mmol). After 30 min,
the reaction was quenched with 50 µL of HOAc. The reaction
was diluted with EtOAc (25 mL) and washed with H2O (5 mL)
and brine (5 mL). The organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo. Purification by flash
chromatography with 50% EtOAc/hexanes gave 2.0 mg (36%)
of 13 as a white solid. Rf ) 0.23 (40% EtOAc/hexanes). 1H NMR
(DMSO, 500 MHz): δ 9.32 (bs, 1H), 7.50-7.53 (m, 3 H), 7.32-
7.36 (m, 2H), 7.07 (t, J ) 7.8 Hz, 1H), 6.78 (s, 1H), 6.72 (d, J
) 7.6 Hz, 1H), 6.56 (dd, J ) 8.0, 2.0 Hz, 1 H), 6.16 (s, 1H),
4.95 (m, 2H), 3.16 (d, J ) 13.6 Hz, 1H), 2.66 (d, J ) 15.3 Hz,
1H), 2.26-2.33 (m, 1H), 1.60-1.72 (m, 2H), 1.51 (dd, J ) 12.4,
2.5 Hz, 1H), 1.41 (bd, J ) 13.5 Hz, 1H), 1.14 (s, 3H), 1.05 (m,
1H). HRMS for C25H26FN2O2 (M + 1)+: calcd, 405.1978; found,
405.1957.
4-[(R)-[(4a R,5S)-1-(4-F lu or op h en yl)-4a -m eth yl-4,4a ,5,-
6,7,8-h exah ydr o-1H-ben zo[f] in dazol-5-yl](h ydr oxy)m eth -
yl]p h en ol (14). Prepared in the same manner as 13 starting
with (4-bromophenoxy)(triisopropyl)silane and 9. Yield 28% (2
1
steps). Rf ) 0.15 (40% EtOAc/hexanes). H NMR (DMSO, 500
MHz): δ 9.14 (s, 1H), 7.50-7.52 (m, 3 H), 7.12 (d, J ) 8.5 Hz,
2H), 6.69 (d, J ) 8.5 Hz, 1H), 6.15 (s, 1H), 4.93 (d, J ) 4.8 Hz,
1H), 4.84 (d, J ) 4.2 Hz, 1H), 3.14 (d, J ) 15.5 Hz, 1H), 2.67
(d, J ) 15.5 Hz, 1H), 2.25-2.35 (m, 2H), 1.58-1.71 (m, 2H),
1.39-1.48 (m, 2H), 1.14 (s, 3H), 1.03 (m, 1H). HRMS for C25H26
-
FN2O2 (M + 1)+: calcd, 405.1978; found, 405.1969.
(R)-(4-Ch lor op h en yl)[(4a R,5S)-1-(4-flu or op h en yl)-4a -
m eth yl-4,4a ,5,6,7,8-h exa h yd r o-1H-ben zo[f]in d a zol-5-yl]-
m eth a n ol (15). From 9 using 4-bromochlorobenzene. Final
purification on AD chiral column (10% IPA/heptanes), yield
56%. Rf ) 0.14 (25% EtOAc/hexanes). 1H NMR (CDCl3, 600
MHz): δ 7.44-7.46 (m, 3H), 7.29-7.33 (m, 2H), 7.27 (d, J )
9.2 Hz, 2H), 7.14-7.17 (m, 2H), 6.11 (d, J ) 2.2 Hz, 1H), 5.17
(s, 1H), 3.17 (d, J ) 15.1 Hz, 1H), 2.74 (d, J ) 15.1 Hz, 1H),
2.40 (m, 1H), 2.28 (bd, J ) 15.1 Hz, 1H), 1.89 (bs, 1H), 1.81
(m, 1H), 1.54-1.72 (m, 3H), 1.26 (s, 3H), 1.17 (m, 1H). Anal.
(C25H24ClFN2O) C, H, N.
(1S)-1-(4-F lu or op h en yl)-1-[(4aR,5S)-1-(4-flu or op h en yl)-
4a -m eth yl-4,4a ,5,6,7,8-h exa h yd r o-1H-ben zo[f]in d a zol-5-
yl]eth a n ol (21). Compound 19 (6.0 mg, 0.015 mmol) was
dissolved in Et2O (2 mL) and cooled to -40 °C. MeLi (93 µL of
a 1.6 M solution in Et2O, 0.15 mmol) was added, and the
reaction was stirred at -40 °C for 45 min. The reaction was
quenched with IPA (1 mL), poured into saturated NH4Cl (10
mL), extracted with EtOAc (25 mL), and washed with H2O