Journal of Medicinal Chemistry
Article
DMSO-d ): δ/ppm 7.47 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.7 Hz, 2H),
additional 5 min and then heated at 110 °C for 1 h. Next, the reaction
mixture was cooled to room temperature and filtered through Celite.
The filtrate was concentrated and treated with ice-cold water, and the
resulting precipitate was collected by filtration. The crude product was
purified by silica gel column chromatography eluting with 90% ethyl
acetate in hexanes to afford rac-(1R,2R,3S,3aR,8bS)-6-cyano-1,8b-
dihydroxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-
tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide (rac-13) as an
off-white solid. Yield: 0.10 g (0.21 mmol, 25%), MS (ESI) m/z: 471.17
6
7
6
2
3
.34 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.06−6.96 (m, 7H),
.65 (s, 1H), 6.58 (d, J = 8.8 Hz 2H), 6.53 (d, J = 9.5 Hz, 1H), 5.11 (s,
H), 5.03 (s, 1H), 4.45 (d, J = 4.92 Hz, 1H), 4.02 (d, J = 13.2 Hz, 1H),
.60 (s, 3H), 3.51−3.42 (m, 1H).
rac-(1R,2R,3S,3aR,8bS)-6-(Benzyloxy)-1,8b-dihydroxy-3a-(4-me-
thoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-
cyclopenta[b]benzofuran-2-carboxamide (S26). To a solution of
rac-(1R,2R,3S,3aR,8bS)-6-(benzyloxy)-1,8b-dihydroxy-3a-(4-methox-
yphenyl)-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-
+
+
[
M + 1] ; UPLC: 96.39%; HRMS (ESI): calcd, 471.1914 [M + H] ;
2
-carboxylic acid (4.0 g, 7.6 mmol) in dichloromethane (40 mL), 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.38 g,
2.8 mmol), hydroxybenzotriazole (3.09 g, 20.2 mmol), and DIPEA
8.0 mL, 45.9 mmol) were added at 0 °C. This mixture was stirred for
min at 0 °C. Then, dimethylamine hydrochloride (3.09 g, 38.16
1
found, 471.1927; H NMR (400 MHz, DMSO-d ): δ/ppm 7.63 (d, J =
6
7
2
2
4
3
.7 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 8.6 Hz,
H), 7.04−6.98 (m, 3H), 6.80 (d, J = 7.1 Hz, 2H), 6.67 (d, J = 8.8 Hz,
H), 5.70 (d, J = 6.0 Hz, 1H), 5.66 (s, 1H), 4.91 (t, J = 7.0 Hz, 1H),
2
(
5
.15 (d, J = 13.1 Hz, 1H), 4.0 (dd, J = 7.88 Hz, 13.1 Hz, 1H), 3.64 (s,
mmol) was added, and the mixture was stirred for 8 h at room
temperature. Afterward, the mixture was diluted with dichloromethane
and washed with cold water. The organic layer was separated and dried
over sodium sulfate, filtered, and concentrated to give the crude
product which was purified by silica gel column chromatography
eluting with 70−90% ethyl acetate in hexane to afford rac-
13
H), 3.19 (s, 3H), 2.71 (s, 3H); C NMR (101 MHz, DMSO-d ): δ/
6
ppm 168.24, 157.79, 157.75, 138.51, 136.50, 129.71, 128.69, 127.74,
1
1
27.34, 127.31, 125.86, 124.67, 119.01, 113.79, 112.24, 111.75,
00.95, 91.06, 77.52, 54.82, 54.70, 47.05, 36.41, 35.10.
Synthesis of rac-(1R,2R,3S,3aR,8bS)-6-Cyano-3a-(4-cyanophen-
(
1R,2R,3S,3aR,8bS)-6-(benzyloxy)-1,8b-dihydroxy-3a-(4-methoxy-
phenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta-
b]benzofuran-2-carboxamide (S26) as a white solid. Yield: 4 g (7.2
[
+
1
mmol, 95% over two steps). MS (ESI) m/z: 552.25 [M + 1] ; H
NMR (400 MHz, DMSO-d ): δ/ppm 7.48 (d, J = 7.3 Hz, 2H), 7.43−
6
.29 (m, 4H), 7.07 (d, J = 8.4 Hz, 2H), 7.03−6.97 (m, 3H), 6.78 (d, J
(
s, 3H), 3.17 (s, 3H), 2.71 (s, 3H).
rac-(1R,2R,3S,3aR,8bS)-1,6,8b-trihydroxy-3a-(4-methoxyphenyl)-
1H-cyclopenta[b]benzofuran-2-carboxamide (rac-14). rac-Methyl
(1R,2R,3S,3aR,8bS)-6-(Benzyloxy)-3a-(4-cyanophenyl)-1,8b-dihy-
droxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]-
benzofuran-2-carboxylate (81). To a solution of rac-methyl
N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]-
benzofuran-2-carboxamide (S27). To a solution of
(
1R,2R,3S,3aR,8bS)-6-(benzyloxy)-3a-(4-bromophenyl)-1,8b-dihy-
(
1R,2R,3S,3aR,8bS)-6-(benzyloxy)-1,8b-dihydroxy-3a-(4-methoxy-
phenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta-
b]benzofuran-2-carboxamide (S26) (2.0 g, 3.6 mmol) in ethyl acetate
100 mL), palladium hydroxide (0.66 g, 4.7 mmol) was added. The
droxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-
carboxylate (78) (1.50 g, 2.55 mmol) in N,N-dimethylformamide (5.0
mL), zinc cyanide (0.899 g, 7.65 mmol) was added. The reaction
mixture was degassed with argon for 5 min. Then, tetrakis-
[
(
reaction mixture was stirred under a hydrogen atmosphere for 2 h at
room temperature and then filtered through Celite and concentrated
under vacuum to afford rac-(1R,2R,3S,3aR,8bS)-1,6,8b-trihydroxy-3a-
(triphenylphosphine)palladium (0.442 g, 0.382 mmol) was added.
The mixture was degassed for an additional 5 min and then incubated
at 100 °C for 1 h in a microwave reactor. The mixture was then filtered
through Celite and washed with ethyl acetate. The filtrate was
concentrated, ice water was added, and the resulting precipitate was
collected by filtration and washed with ethanol and pentane to afford
methyl (1R,2R,3S,3aR,8bS)-6-(benzyloxy)-3a-(4-cyanophenyl)-1,8b-
dihydroxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]-
benzofuran-2-carboxylate (81) as a white solid. Yield: 1.1 g (2.1 mmol,
(
4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-
cyclopenta[b]benzofuran-2-carboxamide (S27) as an off-white solid.
Yield: 1.5 g, crude. MS (ESI) m/z: 460.4 [M − 1] .
−
rac-(1R,2R,3S,3aR,8bS)-2-(dimethylcarbamoyl)-1,8b-dihydroxy-
a-(4-methoxyphenyl)-3-phenyl-2,3,3a,8b-tetrahydro-1H-
3
cyclopenta[b]benzofuran-6-yl Trifluoromethanesulfonate (S28).
To a solution of crude rac-(1R,2R,3S,3aR,8bS)-1,6,8b-trihydroxy-3a-
−
1
(
4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-
81%). MS (ESI) m/z: 332.3 [M − 1] ; H NMR (400 MHz, DMSO-
cyclopenta[b]benzofuran-2-carboxamide (S27) (1.4 g) in dichloro-
methane (100 mL) at 0 °C, DIPEA (1.28 mL, 7.35 mmol) was added.
Triflic anhydride (3.34 mmol) diluted in dichloromethane (10 mL)
was added dropwise to the reaction mixture while it was stirred at −40
d ): δ/ppm 7.51 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 7.2 Hz, 2H), 7.41 (t, J
6
= 7.1 Hz, 2H), 7.36−7.30 (m, 3H), 7.25 (d, J = 8.4 Hz, 1H), 7.07−
6.98 (m, 3H), 6.89 (d, J = 7.1 Hz, 2H), 6.76 (d, J = 1.9 Hz, 1H), 6.61
(d, J = 8.3 Hz, 1H), 5.73 (s, 1H), 5.57 (s, 1H), 5.13 (s, 2H). 4.71 (t, J =
6.5 Hz, 1H), 3.54 (s, 3H).
°C for 1 h. Then, the reaction mixture was neutralized with saturated
sodium bicarbonate solution and washed with cold water. The organic
layer was separated, dried over sodium sulfate, filtered, and
concentrated to afford (1R,2R,3S,3aR,8bS)-2-(dimethylcarbamoyl)-
rac-Methyl (1R,2R,3S,3aR,8bS)-3a-(4-Cyanophenyl)-1,6,8b-trihy-
droxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]-
benzofuran-2-carboxylate (S29). A flask containing ethyl acetate (10
mL) was charged with rac-methyl (1R,2R,3S,3aR,8bS)-6-(benzyloxy)-
1
1
,8b-dihydroxy-3a-(4-methoxyphenyl)-3-phenyl-2,3,3a,8b-tetrahydro-
H-cyclopenta[b]benzofuran-6-yl trifluoromethanesulfonate (S28) as
3
1
a-(4-cyanophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3a,8b-tetrahydro-
H-cyclopenta[b]benzofuran-2-carboxylate (81) (1.1 g, 2.1 mmol),
an off-white solid. Yield: 1.0 g (1.7 mmol, 56% over two steps). MS
−
and palladium hydroxide (50% wet, 0.579 g, 4.12 mmol) was added at
room temperature. The reaction mixture was purged with hydrogen
twice and stirred under hydrogen pressure for 16 h. Then, the reaction
mixture was filtered through Celite. The filtrate was concentrated
under reduced pressure to afford rac-methyl (1R,2R,3S,3aR,8bS)-3a-
(4-cyanophenyl)-1,6,8b-trihydroxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-
cyclopenta[b]benzofuran-2-carboxylate (S29) as a white solid. Yield:
(
ESI) m/z: 592.0 [M − 1] .
rac-(1R,2R,3S,3aR,8bS)-6-Cyano-1,8b-dihydroxy-3a-(4-methoxy-
phenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-
cyclopenta[b]benzofuran-2-carboxamide (rac-13). To a solution of
rac-(1R,2R,3S,3aR,8bS)-2-(dimethylcarbamoyl)-1,8b-dihydroxy-3a-
(4-methoxyphenyl)-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]-
benzofuran-6-yl trifluoromethanesulfonate (S28) (0.50 g, 0.84 mmol)
in N,N-dimethylacetamide (20 mL), zinc cyanide (0.3 g, 3 mmol) was
added. The reaction mixture was degassed with argon for 15 min.
Tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.084 mmol) was
added to the reaction mixture. The mixture was degassed for an
−
1
0.76 g (1.7 mmol, 81%). MS (ESI) m/z: 442.00 [M − 1] ; H NMR
(400 MHz, DMSO-d ): δ/ppm 9.52 (s, 1H), 7.49 (d, J = 8.1 Hz, 2H),
6
7.25 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.1 Hz, 1H), 7.06−6.99 (m, 3H),
6.87 (d, J = 7.2 Hz, 2H), 6.42 (d, J = 1.7 Hz, 1H), 6.37 (d, J = 8.32 Hz,
AD
J. Med. Chem. XXXX, XXX, XXX−XXX