2408 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12
Bell et al.
ambient temperature for 30 min and then concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy on silica, with elution by CHCl3/2% MeOH/0.2% NH4-
OH, to yield (S)-{2-[3-(4-cyano-3-fluorobenzyl)-3H-imidazol-4-
yl]ethyl}-{1-[7-hydroxynaphthalen-1-yl]-2-oxopyrrolidin-3-
yl}carbamic acid tert-butyl ester as a white foam (870 mg,
95%): 1H NMR (CDCl3) δ 7.76 (1H, d, J ) 9.0 Hz), 7.71 (1H,
d, J ) 8.3 Hz), 7.57 (1H, dd, J ) 7.7, 6.9 Hz), 7.43 (1H, s),
7.29-7.13 (5H, m), 6.94 (1H, d, J ) 7.9 Hz), 6.84 (1H, d, J )
9.2 Hz), 6.14 (1H, br s), 5.27 (2H, s), 4.13 (1H, m), 3.88 (1H,
m), 3.68 (1H, t, J ) 9.4 Hz), 3.49 (1H, m), 3.13-2.96 (2H, m),
2.74 (1H, m), 2.54 (1H, m), 2.31 (1H, m), 1.49 (9H, s); HPLC
purity ) 100% (method B, 215 nm).
A mixture of (S)-{2-[3-(4-cyano-3-fluorobenzyl)-3H-imidazol-
4-yl]ethyl}-{1-[7-hydroxynaphthalen-1-yl]-2-oxopyrrolidin-3-
yl}carbamic acid tert-butyl ester (870 mg, 1.53 mmol) and
Cs2CO3 (1.15 g, 3.53 mmol) in dry, degassed DMF (300 mL)
was stirred at 45 °C for 18 h. Acetic acid (0.06 mL, 1.0 mmol)
was added and the solvent was removed under reduced
pressure. The residue was purified by flash column chroma-
tography on silica, with elution by CHCl3/2% MeOH/0.2% NH4-
OH, to yield (20S)-21-(tert-butoxycarbonyl)-19,20,22,23-tetra-
hydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-metheno-
benz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-
carbonitrile (65), which was dissolved in EtOAc (20 mL), cooled
to 0 °C, and then saturated with HCl (g). After standing at 0
°C for 15 min, the mixture was concentrated to dryness under
reduced pressure to yield the titled product as a white solid
(627 mg, 79%): 1H NMR (CD3OD) δ 9.19 (1H, d, J ) 1.3 Hz),
8.13 (1H, d, J ) 9.0 Hz), 8.01 (1H, d, J ) 7.5 Hz), 7.79 (1H, d,
J ) 8.1 Hz), 7.72 (1H, s), 7.66-7.55 (4H, m), 7.53 (1H, dd, J )
9.0, 2.4 Hz), 6.65 (1H, br s), 5.68-5.40 (2H, m), 4.63 (1H, m),
4.28-3.19 (4H, m), 3.20-2.97 (2H, m), 2.79 (1H, m), 2.42 (1H,
m); MS (ES) m/z ) 450 (M+ + H); HPLC purity ) 99.8%
(method B, 215 nm); e.e. ) 98.9%; Anal. (C27H23N5O2‚1.9HCl‚
0.8H2O‚0.4EtOAc) C, H, N.
Syn th esis of (17R, 20R)-19,20,21,22-Tetr a h yd r o-19-oxo-
17H -15,17:18,20-d ie t h a n o-6,10:12,16-d im e t h e n o-16H -
im id a zo[3,4-h ][1,8,11,14]oxa tr ia za cycloeicosin e-9-ca r bo-
n it r ile H yd r och lor id e (78): (i) 6-[(ter t-Bu t yld ip h en yl-
silyl)oxy]-1-in d a n ol (71). A mixture of 6-hydroxy-1-in-
danone22 (70) (5.00 g, 33.8 mmol), tert-butyldiphenylsilyl
chloride (23.1 g, 84.2 mmol), and imidazole (6.90 g, 101.4
mmol) in degassed DMF (100 mL) was heated at 60 °C for 18
h. The solvent was removed in vacuo and the residue was
purified by silica gel chromatography, with elution by hex-
ane/10% EtOAc, to yield 6-[(tert-butyldiphenylsilyl)oxy]-1-
indanone as an oil (12.8 g, 98%): 1H NMR (CDCl3) δ 7.69 (4H,
d, J ) 7.9 Hz), 7.43-7.33 (6H, m), 7.17-7.13 (2H, m), 6.96
(1H, dd, J ) 8.3, 2.4 Hz), 3.01-2.96 (2H, m), 2.66-2.61 (2H,
m), 1.10 (9H, s).
To a solution of 6-[(tert-butyldiphenylsilyl)oxy]-1-indanone
(12.6 g, 32.6 mmol) in MeOH (500 mL) was added NaBH4 (3.2
g, 84.6 mmol), portionwise, over 5 min. The resulting mixture
was stirred at ambient temperature for 1 h and then cooled
to 0 °C. The chilled solution was adjusted to pH ) 4.5 with
dilute aqueous HCl, and most of the MeOH was removed under
reduced pressure. The residue was partitioned between satu-
rated aqueous NaHCO3 (75 mL) and CHCl3 (150 mL). The
organic layer was removed, and the aqueous phase was
extracted further with CHCl3 (2 × 100 mL). The combined
organic extracts were washed with brine, then dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel chromatography, with elution by hexane/
10% EtOAc, to yield the titled product as a colorless oil (10.3
g, 81%): 1H NMR (CDCl3) δ 7.72 (4H, d, J ) 7.7 Hz), 7.45-
7.33 (6H, m), 6.92 (1H, d, J ) 8.2 Hz), 6.82 (1H, d, J ) 2.2
Hz), 6.63 (1H, dd, J ) 8.2, 2.3 Hz), 5.06 (1H, td, J ) 6.8, 5.7
Hz), 2.90 (1H, ddd, J ) 15.5, 8.5, 4.8 Hz), 2.67 (1H, m), 2.42
(1H, m), 1.88 (1H, m), 1.48 (1H, d, J ) 7.1 Hz), 1.10 (9H,
s).
99%): 1H NMR (CDCl3) δ 7.74-7.69 (4H, m), 7.45-7.34 (6H,
m), 6.95 (1H, d, J ) 8.2 Hz), 6.80 (1H, d, J ) 2.4 Hz), 6.67
(1H, dd, J ) 8.2, 2.4 Hz), 4.63 (1H, dd, J ) 7.1, 4.8 Hz), 2.92
(1H, m), 2.72 (1H, m), 2.38 (1H, m), 2.06 (1H, m), 1.10 (9H, s).
(iii) 6-[(ter t-Bu t yld ip h en ylsilyl)oxy]-1-in d a n yla m in e
(73). By the procedure for compound 6 but with 72 in place of
5, the titled compound was obtained as an oil (3.40 g, 59%):
1H NMR (CDCl3) δ 7.74-7.68 (4H, m), 7.45-7.33 (6H, m), 6.89
(1H, d, J ) 8.1 Hz), 6.70 (1H, d, J ) 2.1 Hz), 6.57 (1H, dd, J
) 8.1, 2.4 Hz), 4.17 (1H, t, J ) 7.5 Hz), 2.79 (1H, ddd, J )
15.4, 8.6, 3.2 Hz), 2.65 (1H, m), 2.42 (1H, m), 2.06 (1H, ddt, J
) 12.6, 7.9, 8.6 Hz), 1.46 (2H, br s), 1.10 (9H, s).
(iv) (2R)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-4-(m et h yl-
m er capto)-N-{6-[(ter t-bu tyldiph en ylsilyl)oxy]in dan -1-yl}-
bu tyr a m id e, Dia ster eom er s A a n d B (74). By the procedure
for compound 7 but with 73 in place of 6, the titled compounds
were obtained as a mixture of diastereomers (2.30 g, 85%):
1H NMR (CDCl3) δ 7.74-7.66 (4H, m), 7.46-7.33 (6H, m),
6.92-6.86 (1H, m), 6.71 (1H, one isomer, br s), 6.64 (1H, one
isomer, br s), 6.61-6.72 (1H, m), 6.20-6.09 (1H, m), 5.34-
5.25 (1H, m), 5.15 (1H, one isomer, br d), 5.06 (1H, one isomer,
br d), 4.25-4.13 (1H, m), 2.87-2.78 (1H, m), 2.75-2.66 (1H,
m), 2.60-2.44 (3H, m), 2.14-2.00 (1H, m), 2.11 (3H, one
isomer, s), 2.07 (3H, one isomer, s), 1.95-1.82 (1H, m), 1.80-
1.66 (1H, m), 1.46 (9H, one isomer, s), 1.44 (9H, one isomer,
s), 1.09 (9H, one isomer, s), 1.08 (9H, one isomer, s).
(v) (3R)-3-[(ter t-Bu t oxyca r b on yl)a m in o]-1-{6-[(ter t-
b u t yld ip h e n ylsilyl)oxy]in d a n -1-yl}-2-oxop yr r olid in e ,
Dia ster eom er s A a n d B (75 a n d 76). By the procedures for
compound 8 but with 74 in place of 7, the titled compounds
were obtained. The diastereomers were separated by flash
column chromatography on silica, with elution by a gradient
of hexane/20-35% EtOAc, to yield the titled compounds,
diastereomer A (75) (the isomer of higher Rf) (872 mg, 42%)
and diastereomer B (76) (the isomer of lower Rf) (820 mg,
39%): 1H NMR (CDCl3) δ 7.74-7.64 (4H, m), 7.47-7.31 (6H,
m), 6.99 (1H, d, J ) 8.4 Hz), 6.75 (1H, dd, J ) 8.2, 2.3 Hz),
6.36 (1H, d, J ) 1.9 Hz), 5.54 (1H, t, J ) 7.8 Hz), 5.00 (1H, br
s), 4.13 (1H, m), 2.96 (1H, td, J ) 10.1, 6.3 Hz), 2.86-2.71
(2H, m), 2.59 (1H, t, J ) 9.3 Hz), 2.46 (1H, m), 2.30 (1H, dtd,
J ) 12.9, 8.1, 4.2 Hz), 1.82 (1H, m), 1.49 (9H, s), 1.30 (1H, m),
1.08 (9H, s).
(vi) (R,R)-4-{[5-({[1-(6-Hyd r oxyin d a n -1-yl)-2-oxop yr r o-
lid in -3-yl]a m in o}m et h yl)im id a zol-1-yl]m et h yl}-2-flu o-
r oben zon itr ile (77). Pyrrolidinone 76 (the R,R isomer), (270
mg, 0.47 mmol) was dissolved in CH2Cl2 (5 mL), and TFA (0.72
mL, 9.4 mmol) was added dropwise. The resulting mixture was
stirred at ambient temperature for 18 h and then concentrated
under reduced pressure to afford (R,R)-3-amino-1-{6-[(tert-
butyldiphenylsilyl)oxy]indan-1-yl}-2-oxopyrrolidine trifluoro-
acetate as a white foam (275 mg, 99%): 1H NMR (CD3OD) δ
7.73 (2H, m), 7.67 (2H, m), 7.49-7.33 (6H, m), 7.03 (1H, d, J
) 8.2 Hz), 6.73 (1H, dd, J ) 8.2, 2.2 Hz), 6.49 (1H, d, J ) 1.9
Hz), 5.49 (1H, t, J ) 7.7 Hz), 4.00 (1H, dd, J ) 11.2, 8.4 Hz),
2.96 (1H, td, J ) 9.9, 6.3 Hz), 2.88 (1H, ddd, J ) 15.8, 9.0, 4.0
Hz), 2.78 (1H, m), 2.65 (1H, t, J ) 9.4 Hz), 2.43-2.27 (2H, m),
2.30 (1H, ddt, J ) 13.1, 8.6, 7.7 Hz), 1.59 (1H, m), 1.07 (9H,
s).
(R,R)-3-Amino-1-{6-[(tert-butyldiphenylsilyl)oxy]indan-1-yl}-
2-oxopyrrolidine trifluoroacetate (170 mg, 0.29 mmol) and 1-(4-
cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde (60 mg, 0.26
mmol) were stirred in MeOH (3 mL) for 30 min at ambient
temperature, and then NaCNBH3 (22 mg, 0.35 mmol) was
added and stirring was continued for 18 h. The solvent was
evaporated and the residue was dissolved in THF (5 mL). To
this solution was added TBAF (1.0 M in THF, 0.34 mL, 0.34
mmol); stirring was continued for 15 min, and then the solvent
was evaporated. The residue was partitioned between satu-
rated aqueous NaHCO3 (5 mL) and CHCl3 (10 mL). The
aqueous layer was extracted further with CHCl3 (2 × 5 mL).
The combined organic extracts were dried over MgSO4, filtered,
and concentrated in vacuo. The crude product was purified by
flash column chromatography on silica, with elution by CHCl3/
5% MeOH/0.5% NH4OH, to yield the titled product as a
(ii) 6-[(ter t-Bu t yld ip h en ylsilyl)oxy]-1-in d a n yl Azid e
(72). By the procedure for compound 5 but with 71 in place of
4, the titled product was obtained as a colorless oil (6.10 g,