3700 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 12
Bezenc¸on et al.
(1R,5S)-7-{4-[3-(tert-Butyldimethylsilanyloxy)propyl]phenyl}-6-
[cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-3,9-diaza-
bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic Acid 3-tert-butyl Ester
9-(2,2,2-Trichloro-1,1-dimethylethyl) Ester (22a). A solution of acid
21a (23.9 g, 33.2 mmol), HOBt (5.50 g, 39.9 mmol), EDC ·HCl
(16.2 g, 83.0 mmol), DIPEA (17.5 g, 132.8 mmol), and DMAP
(1.0 g, 8.3 mmol) in CH2Cl2 (530 mL) was stirred at room
temperature for 30 min. N-Cyclopropyl-N-(2,3-dichlorobenzy-
l)amine (21.5 g, 99.6 mmol) was added, and the reaction mixture
was stirred at room temperature for 7 days. The mixture was diluted
with CH2Cl2 (300 mL) before aq 1 M HCl (400 mL) was added.
The org layer was concentrated under reduced pressure, and the
residue was purified by FC (3-7% gradient acetone in heptane) to
provide the title compound (18.7 g, 35% over two steps). 1H NMR
(CDCl3) 7.36 (d, J ) 7.6 Hz, 1H), 7.17-6.99 (m, 5H), 6.96 (d, J
) 7.6 Hz, 1H), 6.85 (d, J ) 7.6 Hz, 1HR), 4.78 (broad, d, J ≈ 15.2
Hz, 2H), 4.73-4.44 (m, 2H and 4HR), 4.35 (d, J ) 15.4 Hz, 1H),
4.23 (d, J ) 13.0 Hz, 1H), 4.09 (d, J ) 13.0 Hz, 1HR), 3.70-3.57
(m, 2H), 3.31-2.98 (m, 1H and 3HR), 3.16 (broad, d, J ≈ 12.8
Hz, 1H), 3.04 (d, J ) 12.5 Hz, 1H), 2.77-2.58 (m, 2H), 2.34 (d,
J ≈ 18.2 Hz, 1H), 2.27 (d, J ≈ 18.0 Hz, 1HR), 2.01 (s, 3H), 1.97
(s, 3H), 1.92-1.57 (m, 3H and 1HR), 1.54 (broad, s, 9HR), 1.48
(broad, s, 9H), 0.94 (s, 9H), 0.96-0.74 and 0.68-0.17 (m, 1H and
1HR), 0.07 (s, 6H). IR (film) ν 2928, 2856, 1698 cm-1. Anal. Calcd
for C43H58N3O6Cl5Si: C, 56.24; H, 6.37; N, 4.58. Found: C, 56.79;
H, 6.59; N, 4.65. [R]2D5 +139.9 (0.98, MeOH). LC-MS: tR ) 1.45
min. MS (ESI): m/z 917.87 (M + 1)+.
) 7.7 Hz, 1H), 4.74 (s, 1H and 1HR), 4.72 (broad, d, J ≈ 14.9 Hz,
1H), 4.68 (broad, d, J ≈ 16.3 Hz, 1H), 4.65-4.00 (m, 1H and 2HR,
H-1), 4.48 (broad, d, J ) 12.8 Hz, 1H), 4.41 (d, J ) 15.9 Hz,
1HR), 4.38 (d, J ) 15.7 Hz, 1H), 3.73-3.61 (m, 2H), 3.46 (d, J )
14.7 Hz, 1H), 3.22 (dd, J ) 18.3, 7.5 Hz, 1H), 3.13 (d, J ) 18.1,
7.4 Hz, 1HR), 2.88 (broad, d, J ) 12.8 Hz, 1H), 2.70 (q, J ) 7.4
Hz, 2H), 2.38-2.21 (m, 1H and 1HR), 2.29 (s, 3H), 2.27 (s, 3HR),
2.03 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3HR), 1.93-1.60 (m, 3H and
1HR), 0.95-0.77, 0.73-0.51, 0.45-0.31 and 0.29-0.19 (m, 4H
and 4HR). 13C NMR (CDCl3) 173.07, 172.87, 171.24, 171.21 (CO
and COR), 151.59 (Cq), 150.61 (CqR), 142.59 (Cq), 142.44 (CqR),
138.49 (Cq), 138.22 (CqR), 137.14 (Cq), 137.07 (CqR), 133.06 (Cq),
133.00 (CqR), 131.30 (CqR), 131.00 (Cq), 129.04 (CHarom), 129.02
(CHarom), 128.79 (CHarom), 128.70 (CHarom), 128.60 (CHRarom),
128.53 (CHRarom), 127.42 (CHRarom), 127.26 (CHarom), 127.15
(CHarom), 127.07 (CHarom), 126.73 (CHRarom), 126.56 (CHarom),
126.47 (CHarom), 126.36 (CHarom), 126.18 (CHRarom), 125.42 (Cq),
106.65 (CCl3), 106.53 (CRCl3), 89.32 (Me2C-O), 88.95 (Cq,
Me2CR-O), 62.02 (C12), 51.00, 49.54 (C5 and C5R), 50.52 (C4),
49.97 (C4R), 49.33, 49.02 (C14 and C14R), 47.55, 45.82 (C1 and
C1R), 46.92, 46.77 (C2 and C2R), 34.23 (C11R), 33.97 (C11), 33.17,
32.83 (C8 and C8R), 31.73 (C10), 31.21, 31.12 (C15 and C15R),
21.77, 21.69, 21.61, 21.32, and 21.29 (CH3CO, CRH3CO,
(CH3)2C-O, (CRH3)2C-O), 10.72, 10.54, 6.58, 6.00 (C16 and
C16R). IR (film) ν 2925, 2159, 2025, 1703, 1620 cm-1. Anal. Calcd
for C34H38N3O5Cl5: C, 54.75; H, 5.13; N, 5.63. Found: C, 54.52;
H, 5.15; N, 5.34. [R]2D5 +177.0 (1.02, MeOH). LC-MS: tR ) 1.15
min. MS (ESI): m/z 746.43 (M + 1)+.
(1R,5S)-7-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-6-
[cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-3,9-
diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic Acid 3-tert-Butyl Es-
ter 9-(2,2,2-Trichloro-1,1-dimethylethyl) Ester (22b). A solution of
acid 21b (40 g, 55.4 mmol), HOBt (9.9 g, 72.0 mmol), EDC ·HCl
(28.4 g, 145.2 mmol), DIPEA (29.2 g, 221.5 mmol), and DMAP
(1.7 g, 13.8 mmol) in CH2Cl2 (650 mL) was stirred at room
temperature for 30 min. N-Cyclopropyl-N-(2,3-dichlorobenzy-
l)amine (34.0 g, 157.3 mmol) was added, and the reaction mixture
was stirred at room temperature for 7 days. The mixture was diluted
with CH2Cl2 (650 mL) before aq 1 M HCl (450 mL) was added.
The org layer was concentrated under reduced pressure, and the
residue was purified by FC (3-20% gradient acetone in heptane)
(1R,5S)-3-Acetyl-6-[cyclopropyl(2,3-dichlorobenzyl)carbamoyl]-
7-[4-(2-hydroxyethoxy)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-9-
carboxylic Acid 2,2,2-Trichloro-1,1-dimethylethyl Ester (23b). A
solution of starting material 22b (20.4 g, 22.2 mmol) in CH2Cl2
(250 mL) was cooled to 0 °C. HCl (4 M in dioxane, 75 mL) was
added, and the mixture was stirred 0 °C for 20 min and at room
temperature for 3 h. The mixture was diluted with CH2Cl2 (150
mL) before aq 1 M NaOH (100 mL) was carefully added. The org
layer was concentrated under reduced pressure, the residue was
dissolved under N2 in THF (250 mL), and the solution was cooled
to -78 °C. DIPEA (15.2 mL, 88.7 mmol), DMAP (0.27 g, 2.2
mmol), and AcCl (1.6 mL, 22.2 mmol) were added, and the mixture
was stirred at -78 °C for 15 min. MeOH (250 mL) was added,
and the mixture was allowed to warm to room temperature. The
mixture was diluted with EtOAc (200 mL) before aq 1 M HCl
(200 mL) was added. The org layer was concentrated under reduced
pressure, and the residue was purified by FC (EtOAc) to provide
1
to provide the title compound (21.0 g, 41% over two steps). H
NMR (CDCl3) 7.33 (broad, s, 1H), 7.17-7.02 (m, 3H), 6.85-6.69
(m 3H), 4.81-4.32 (m, 5H and 5HR), 4.23 (d, J ) 13.5 Hz, 1H),
4.13-3.93 (m, 4H and 1HR), 3.28-3.0 (m, 2H and 3HR), 3.04
(broad, d, J ≈ 12.6 Hz, 1H), 2.32 (d, J ≈ 18.0 Hz, 1H), 2.26 (d, J
≈ 18.1 Hz, 1HR), 2.17 (broad, d, J ≈ 21.7 Hz, 1HR), 2.01 (s, 3H),
1.97 (s, 3H), 1.82-1.59 (m, 1H and 1HR), 1.53 (broad, s, 9HR),
1.48 (broad, s, 9H), 0.94 (s, 9H), 0.94-0.73 and 0.68-0.17 (m,
1H and 1HR), 0.13 (s, 6H). IR (film) ν 2928, 2856, 1698, 1608
cm-1. Anal. Calcd for C42H56N3O7Cl5: C, 54.82; H, 6.13; N, 4.57.
Found: C, 55.02; H, 6.09; N, 4.56. [R]2D5 +126.0 (1.0, MeOH).
LC-MS: tR ) 1.34 min. MS (ESI): m/z 920.65 (M + 1)+.
1
the title compound (11.8 g, 71%). H NMR (CDCl3) 7.36 (t, J )
6.7 Hz, 1H), 7.18-7.02 (m, 3H), 6.83 (d, J ) 8.4 Hz, 1H), 6.77
(d, J ) 8.4 Hz, 1H), 6.69 (t, J ) 9.7 Hz, 1H), 4.74 (s, 1H and
1HR), 4.72 (broad, d, J ≈ 14.4 Hz, 1H), 4.62 (broad, d, J ≈ 16.0
Hz, 1H and 2HR), 4.58-4.47 (m, 1H and 2HR), 4.46 (broad, d, J
) 10.4 Hz, 1H and 1HR), 4.40 (d, J ) 12.4 Hz, 1HR), 4.36 (d, J )
16.2 Hz, 1H), 4.11-4.02 (m, 2H), 4.01-3.92 (m, 2H), 3.48 (d, J
) 14.1 Hz, 1HR), 3.44 (d, J ) 14.0 Hz, 1H), 3.20 (dd, J ) 18.1,
7.4 Hz, 1H), 3.10 (d, J ) 17.9, 7.4 Hz, 1HR), 2.88 (broad, d, J ≈
11.1 Hz, 1H), 2.38-2.20 (m, 1H and 1HR), 2.29 (s, 3H), 2.27 (s,
3HR), 2.03 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3HR), 1.97 (s, 3H),
1.82-1.66 (m, 1H and 1HR), 0.92-0.77, 0.72-0.50, 0.47-0.30,
and 0.29-0.19 (m, 4H and 4HR). IR (film) ν 2925, 1703, 1607
cm-1. Anal. Calcd for C33H36N3O6Cl5: C, 52.99; H, 4.85; N, 5.62.
Found: C, 54.21; H, 5.30; N, 5.25. [R]2D5 +117.3 (1.0, MeOH).
LC-MS: tR ) 1.12 min. MS (ESI): m/z 748.36 (M + 1)+.
(1R,5S)-3-Acetyl-6-[cyclopropyl(2,3-dichlorobenzyl)carbamoyl]-
7-[4-(3-hydroxypropyl)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-9-
carboxylic Acid Trichloromethyl Ester (23a). A solution of starting
material 22a (18.5 g, 20.1 mmol) in CH2Cl2 (180 mL) was cooled
to 0 °C. HCl (4 M in dioxane, 68 mL) was added, and the mixture
was stirred 0 °C for 20 min and at room temperature for 3 h. The
mixture was diluted with CH2Cl2 (100 mL) before aq 1 M NaOH
(100 mL) was carefully added. The org layer was concentrated
under reduced pressure, the residue was dissolved under N2 in THF
(380 mL), and the solution was cooled to -78 °C. DIPEA (13.8
mL, 80.5 mmol), DMAP (0.246 g, 2.0 mmol), and CH3COCl (1.36
mL, 19.1 mmol) were added, and the mixture was stirred at -78
°C for 15 min. MeOH (100 mL) was added, and the mixture was
allowed to warm to room temperature. The mixture was diluted
with EtOAc (150 mL) before aq 1 M HCl (150 mL) was added.
The org layer was concentrated under reduced pressure, and the
residue was purified by FC (CH2Cl2/MeOH 98.2) to provide the
General Conditions for the Preparation of Compounds 24a-k
and 25a-l. To a solution of alcohol 23a (1.0 g, 1.3 mmol) or 23b
(1.66 g, 2.2 mmol), 1,1′-(azodicarbonyl)dipiperidine (2.7 mmol/
4.5 mmol), and the desired phenol (2.7 mmol/4.4 mmol) in toluene
(30 mL) was added PBu3 (85%, 4.0 mmol/6.7 mmol) at room
temperature, and the reaction mixture was stirred at 80 °C for 12 h.
Heptane (75 mL) was added, and the mixture was filtered. The
solvents were removed under reduced pressure, and the residue was
dissolved in CH2Cl2 (40 mL). At 0 °C aq H2O2 (25% in water, 8
mL) was added and the mixture was stirred at 0 °C for 5 min and
1
title compound (12.7 g, 84%). H NMR (CDCl3) 7.36 (t, J ) 6.6
Hz, 1H), 7.18-7.00 (m, 4H), 6.77 (d, J ) 7.7 Hz, 1H), 6.72 (d, J