8530 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 24
Pereira et al.
(3H, s); 13C NMR (CDCl3, 100 MHz) δ 164.5 (C), 153.2 (C),
152.8 (C), 123.6 (C), 118.6 (CH), 108.0 (CH), 100.8 (CH), 93.5
(C), 74.2 (C), 57.2 (CH3), 43.4 (CH2), 41.4 (CH2), 38.3 (C), 35.4
(CH2), 35.4 (CH), 34.1 (CH), 32.7 (CH3), 23.7 (CH2), 23.4
(CH3), 21.3 (CH3), 20.4 (CH2), 19.2 (CH3). HRESIMS calcd
for C22H31O3Na79Br ([M þ Na]þ): 445.1354; found 445.1366.
Compound 7c. The title compound (0.133 g, 30%) was pre-
pared as before, from hydroxy acid 5 (0.30 g, 1.31 mmol) and
phosphonium salt 6c (0.942 g, 1.97 mmol). Colorless oil.
[R]D21 -28° (c 0.24, CHCl3). 1H NMR (CDCl3, 600 MHz) δ 7.30
(1H, d, J = 8.9 Hz), 6.97 (1H, d, J = 2.7 Hz), 6.80 (1H, dd,
J = 2.6, 8.8 Hz), 6.35 (1H, s), 3.84 (3H, s), 2.92 (1H, m), 2.03
(1H, m), 1.74 (1H, m), 1.67 (1H, m), 1.54-1.36 (5H, m), 1.35
(1H, m), 1.33 (3H, d, J = 7.0 Hz), 1.20 (1H, td, J = 3.7, 13.1 Hz),
1.14 (1H, m), 1.12 (3H, s), 0.93 (3H, s), 0.78 (3H, s); 13C NMR
(CDCl3, 150 MHz) δ 165.2 (C), 155.9 (C), 149.7 (C), 129.7 (C),
111.5 (CH), 111.3 (CH), 103.4 (CH), 101.0 (CH), 74.5 (C), 57.6
(CH3), 56.2 (CH), 43.6 (CH2), 41.6 (C), 38.7 (CH2), 35.7 (CH2),
34.6 (CH), 33.0 (CH3), 24.1 (CH2), 23.6 (CH3), 21.6 (CH3), 20.7
(CH2), 19.4 (CH3). HRESIMS calcd for C22H32O3Na ([M þ
Na]þ): 367.2249; found 367.2251.
(C), 126.5 (C), 124.5 (C), 121.8 (CH), 107.7 (CH), 94.8 (C), 57.0
(CH3), 54.2 (CH), 42.7 (CH2), 41.1 (CH2), 40.5 (C), 35.5 (CH2),
35.4 (C), 34.3 (CH), 33.6 (CH3), 24.8 (CH2), 22.6 (CH3), 22.2
(CH3), 20.9 (CH3), 19.7 (CH2). HRESIMS calcd for C22H29O2-
Na79Br ([M þ Na]þ): 427.1249; found 427.1254.
Compound 8c. SnCl4 (240 μL, 2.04 mmol) was added dropwise
to a solution of 7c (0.13 g, 0.38 mmol) in 2-nitropropane (30 mL)
at -78 °C. The usual workup afforded a yellowish oil, which was
used without any further purification in the following deprotec-
tion reaction.
Compound 8d. SnCl4 (240 μL, 2.04 mmol) was added drop-
wise to a solution of 7d (0.18 g, 0.51 mmol) in 2-nitropropane
(30 mL) at -78 °C. The usual workup afforded a yellowish oil,
which was used without any further purification in the next step.
Compounds 9b, 10, and 11. To a solution of 8a (36 mg, 0.083
mmol) in CH2Cl2 (10 mL) at -78 °C was added BI3 (0.33 mL,
0.33 mmol, 1 M in CH2Cl2). The resulting mixture was warmed
to room temperature (2 h) and quenched with aqueous Na2S2O3.
The organic layer was separated and washed with HCl 0.1 M,
followed by Na2SO4 addition, filtration, and solvent evapora-
tion. Silica gel column chromatography (30% EtOAc/hexanes)
provided one main fraction (one spot by TLC), which was
additionally purified by reversed-phase HPLC (C18 Inertsil,
80% CH3CN/20% H2O þ 0.05% trifluoroacetic acid (TFA)), to
yield yellow fractions of 9b (1.1 mg, 3%), spiro compound 11
(1.2 mg, 13%), and quinone 10 (0.8 mg, 2%).
Compound 7d. The title compound (0.177 g, 39%) was pre-
pared using the previously reported methodology from hydroxy
acid 5 (0.30 g, 1.31 mmol) and phosphonium salt 6d (0.942 g,
1.97 mmol). Colorless oil. [R]D21 -26° (c 0.18, CHCl3). 1H NMR
(CDCl3, 600 MHz) δ 7.34 (1H, d, J = 8.3 Hz), 6.98 (1H, d, J =
1.9 Hz), 6.82 (1H, dd, J = 2.2, 8.4 Hz), 6.33 (1H, s), 3.85 (3H, s)
2.90 (1H, m), 2.02 (1H, m), 1.74 (1H, m), 1.68 (1H, m),
1.54-1.34 (5H, m), 1.32 (1H, m), 1.32 (3H, d, J = 6.9 Hz),
1.20 (1H, td, J = 3.8, 13.2 Hz), 1.14 (1H, m), 1.12 (3H, s), 0.93
(3H, s), 0.78 (3H, s); 13C NMR (CDCl3, 150 MHz) δ 163.3 (C),
157.3 (C), 155.6 (C), 122.4 (C), 120.5 (CH), 111.2 (CH), 100.5
(CH), 96.0 (CH), 74.5 (C), 57.6 (CH3), 56.0 (CH), 43.6 (CH2),
41.7 (CH2), 38.8 (CH2), 35.7 (C), 34.5 (CH), 33.0 (CH3), 24.1
(CH2), 23.6 (CH3), 21.6 (CH3), 20.7 (CH2), 19.4 (CH3). HRESIMS
calcd for C22H32O3Na ([M þ Na]þ): 367.2249; found 367.2258.
Compound 8a. To a solution of alcohol 7a (0.29 g, 0.65 mmol)
in 2-nitropropane (60 mL) at -78 °C was added SnCl4 (0.6 mL,
5.0 mmol). After being stirred for 20 min, the mixture was slowly
warmed to room temperature and water was then added. EtOAc
extractions were performed, and the organic phase was dried
over Na2SO4, filtered, and evaporated under reduced pressure.
Silica gel column chromatography (5% EtOAc/hexanes) of the
residue afforded 8a (0.074 g, 26%) as a colorless solid and a
slightly more polar fraction composed of a mixture of benzofu-
9b: CD (CH3CN, c 0.22) λ 343.0 nm (Δε þ0.078), 297.0
(-0.042). 1H NMR (C6D6, 600 MHz) δ 7.14 (1H, s), 4.85 (1H,
s, broad), 4.73 (1H, s, broad), 2.97 (1H, m), 2.42 (1H, m), 1.60
(1H, m), 1.56 (1H, m), 1.52 (1H, qt, J = 3.2, 13.9 Hz), 1.49 (1H,
m), 1.47 (1H, m), 1.37 (1H, m), 1.362 (1H, m), 1.360 (1H, m),
1.32 (3H, d, J = 6.9 Hz), 1.31 (1H, m), 1.24 (3H, s), 1.15 (1H, td,
J = 3.4, 13.3 Hz), 0.88 (3H, s), 0.86 (3H, s); 13C NMR (C6D6,
600 MHz) δ 156.1 (C), 146.0 (C), 141.0 (C), 138.5 (C), 125.9 (C),
122.5 (C), 107.3 (CH), 92.5 (C), 50.5 (CH), 42.7 (CH2), 40.5
(CH2), 39.9 (C), 36.2 (CH2), 34.9 (C), 34.2 (CH3), 31.6 (CH),
23.4 (CH2), 22.8 (CH3), 20.7 (CH3), 19.5 (CH2), 19.2 (CH3).
10: CD (CH3CN, c 0.08) λ 351.0 nm (Δε þ0.26), 323.0
(-0.026). 1H NMR (C6D6, 600 MHz) δ 7.36 (1H, s), 6.31 (1H,
s), 2.24 (1H, s, broad), 2.22 (1H, m), 1.84 (1H, d, J = 8.4 Hz),
1.71 (1H, m), 1.59 (1H, m), 1.33 (1H, qt, J = 2.9, 13.4 Hz), 1.22
(1H, m), 1.21 (1H, m), 1.179 (1H, m), 1.176 (1H, m), 1.07 (1H,
m), 1.01 (3H, s), 0.99 (1H, td, J = 2.5, 12.8 Hz), 0.98 (1H, m),
0.78 (3H, s), 0.64 (3H, s), 0.47 (3H, d, J = 6.9 Hz); 13C NMR
(C6D6, 150 MHz) δ 176.6 (C), 168.3 (C), 167.5 (C), 149.2 (C),
127.0 (C), 120.0 (C), 98.5 (CH), 91.0 (C), 49.7 (CH), 43.1 (CH2),
42.3 (C), 41.5 (CH2), 40.4 (CH), 34.9 (C), 33.7 (CH3), 32.8
(CH2), 22.3 (CH3), 22.3 (CH3), 21.4 (CH2), 19.8 (CH2), 14.0
(CH3). HRESIMS calcd for C21H28O479Br ([MþH]þ): 423.1171;
found 423.1160.
1
rans (around 0.080 mg). H NMR (CDCl3, 600 MHz) δ 7.11
(1H, s), 3.88 (3H, s), 3.86 (3H, s), 3.25 (1H, m), 2.55 (1H, m), 2.15
(1H, m), 1.83 (1H, m), 1.70 (1H, dt, J = 3.1, 13.6 Hz), 1.68 (1H,
m), 1.58 (3H, m), 1.51 (1H, m), 1.49 (1H, m), 1.43 (3H, d, J = 7.2
Hz), 1.35 (3H, s), 1.23 (1H, td, J = 3.3, 13.8 Hz), 0.97 (3H, s),
0.93 (3H, s); 13C NMR (CDCl3, 150 MHz) δ 158.0 (C), 149.0 (C),
146.0 (C), 144.0 (C), 126.0 (C), 124.1 (C), 105.3 (CH), 99.5 (C),
61.1 (CH3), 57.3 (CH3), 53.4 (CH), 41.9 (CH2), 40.1 (CH2), 38.9
(C), 36.0 (C), 34.8 (CH2), 33.5 (CH3), 33.3 (CH), 24.0 (CH2),
22.02 (CH3), 21.97 (CH3), 20.0 (CH3), 18.9 (CH2). HRESIMS
calcd for C23H32O379Br ([M þ H]þ): 435.1535; found 435.1529.
Compound 8b. To a solution of alcohol 7b (0.13 g, 0.31 mmol)
in 2-nitropropane (20 mL) at -78 °C was added SnCl4 (0.22 mL,
1.9 mmol). After being stirred for 20 min, the mixture was slowly
warmed to room temperature and water was then added. EtOAc
extractions were performed, and the organic phase was dried
over Na2SO4, filtered, and evaporated under reduced pressure.
Silica gel column chromatography (5% EtOAc/hexanes) of the
residue afforded 8b (0.073 g, 58%) as a colorless solid. 1H NMR
(C6D6, 600 MHz) δ 7.39 (1H, d, J = 8.6 Hz), 6.48 (1H, d, J = 8.8
Hz), 3.39 (3H, s), 3.06 (1H, m), 2.57 (1H, m), 1.86 (1H, m), 1.63
(1H, m), 1.61 (1H, m), 1.52 (1H, m), 1.44 (1H, m), 1.42 (1H, m),
1.38 (1H, m), 1.37 (3H, d, J = 7.2 Hz), 1.36 (1H, m), 1.31 (3H, s),
1.29 (1H, m), 1.13 (1H, td, J = 3.6, 13.5 Hz), 0.89 (3H, s), 0.88
(3H, s); 13C NMR (C6D6, 150 MHz) δ 157.6 (C), 154.1 (C), 153.4
1
11: CD (CH3CN, c 0.24) no absorbance; H NMR (CDCl3,
600 MHz) δ 7.18 (1H, s), 5.35 (1H, s, broad), 5.10 (1H, s, broad),
2.86 (1H, m), 2.57 (1H, dt, J = 3.7, 14.3 Hz), 2.51 (1H, td, J =
4.2, 13.7 Hz), 1.94 (1H, m), 1.91 (1H, m), 1.80 (1H, m), 1.61 (1H,
qt, J = 4.4, 17.8 Hz), 1.50 (1H, m), 1.48 (1H, m), 1.36 (1H, m),
1.35 (3H, d, J = 6.8 Hz), 1.27 (1H, m), 1.15 (1H, m), 1.03 (3H, s),
0.88 (3H, s), 0.85 (3H, d, J = 6.8 Hz); 13C NMR (CDCl3, 150
MHz) δ 159.1 (C), 145.8 (C), 139.6 (C), 137.1 (C), 122.7 (C),
118.1 (C), 108.3 (CH), 91.5 (C), 43.8 (C), 40.9 (C), 36.8 (CH),
36.5 (CH2), 32.1 (CH2), 31.2 (CH2), 30.2 (CH2), 29.3 (CH), 27.0
(CH3), 21.4 (CH2), 20.7 (CH3), 18.9 (CH3), 17.0 (CH3). HRE-
SIMS calcd for C21H27O3Na79Br ([M þ Na]þ): 429.1041; found
429.1050.
Compound 12. A solution of 8b (6.9 mg, 0.017 mmol) and
BBr3 SMe2 (26 mg, 0.081 mmol) was refluxed in clorobenzene
3
until TLC analysis showed the absence of starting material
(around 18 h). Once at room temperature, H2O was added
and the reaction mixture was stirred for 30 min. The aqueous
layer was extracted with EtOAc, dried (Na2SO4), and concentrated
in vacuo. Silica gel column chromatography (20% EtOAc/hexanes)