Synthesis and Anti-HIV Activity of Cosalene Analogs
J . Org. Chem., Vol. 64, No. 16, 1999 5865
zinc dust (3.0 g). The zinc was removed by filtration through
a pad of Celite, and acidification of the aqueous solution with
concentrated HCl to pH 1 gave a white solid (0.256 g, 77%).
The solid was air-dried to give the product: mp 263-265 °C;
ketone. This material was immediately esterified by stirring
a solution of the crude ketone in acetone (50 mL) containing
dimethyl sulfate (2 mL) and K2CO3 for 3 h at room tempera-
ture. The solid mass was filtered off, and the solvents were
evaporated at reduced pressure to give an oil. The oil was flash
chromatographed on SiO2 (25 g, 230-400 mesh), eluting with
hexanes/ethyl acetate (1:1, v/v), to give 24 (0.12 g, 45%) as an
oil: IR (neat) 2950, 2828, 1731, 1659 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.08 (d, J ) 2.2 Hz, 2 H), 7.73 (d, J ) 2.2 Hz, 2 H),
7.49 (d, J ) 2.2 Hz, 2 H), 7.32 (d, J ) 2.2 Hz, 2 H), 3.98 (s, 4
H), 3.87 (s, 6 H), 3.85 (s, 6 H), 3.84 (s, 6 H), 3.79 (s, 6 H). Anal.
Calcd for C39H36Cl3O13‚H2O: C, 58.43; H, 4.78. Found: C,
58.50; H, 4.53.
1
IR (KBr) 2936, 1660, 1613 cm-1; H NMR (300 MHz, DMSO)
δ 11.27 (s, 1 H), 7.25 (dd, J ) 1.5, 7.9 Hz, 1 H), 7.19 (d, J )
1.9 Hz, 1 H), 7.12 (d, J ) 1.9 Hz, 1 H), 7.01 (dd, J ) 1.1, 7.3
Hz, 1 H), 6.44 (t, J ) 7.7 Hz, 1 H), 3.44 (s, 2 H). Anal. Calcd
for C15H11ClO6‚0.7H2O: C: 53.73; H: 3.73. Found: C: 53.76.
H: 4.00
1,1-Bis[3-ch lor o-4,6′-d ih yd r oxy-5,5′-d im eth oxyca r bon -
yld ip h en yl]m eth a n e (21). A mixture of 20 (2.62 g, 8.1 mmol)
in methanol (200 mL) containing sulfuric acid (20 mL) was
heated to 80 °C for 1.5 days. The solvents were concentrated
to one-half the initial volume, and the solution was allowed
to stand at room temperature overnight. The solid product (1.9
g, 65%) was collected by filtration: mp 108-109 °C; IR (neat)
3139, 2952, 1675 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.73 (dd,
J ) 1.5, 8.0 Hz, 1 H), 7.65 (d, J ) 2.0, 1 H), 7.43 (d, J ) 2.0
Hz, 1 H), 7.26 (m, 1 H), 6.81 (t, J ) 7.7 Hz, 1 H), 3.93 (s, 3 H),
3.92 (s, 3 H). Anal. Calcd for C17H15ClO6: C, 58.21; H, 4.31.
Found: C, 58.26; H, 4.25.
3â-(3-Oxop r op a n yl)-5a -ch olesta n e (26). The alcohol 252
(0.32 g, 0.75 mmol) was dissolved in CH2Cl2 (5 mL), and
neutral alumina (0.5 g) was added. Solid pyridinium chloro-
chromate (0.22 g, 1 mmol) was then added, and the mixture
was stirred at room temperature for 6 h. The residue produced
was placed atop a column of silica gel (30.0 g, 230-400 mesh)
and flash chromatographed using ethyl acetate/hexanes (4:1)
to give the aldehyde as an oil that crystallized to afford a solid
(0.22 g, 69%) upon cooling: mp 58-60 °C; IR (neat) 2717, 1723
1
1,1-Bis[3,3-(3′-ch lor o-4′-h yd r oxy-5′-m eth oxyca r bon yl-
ben zyl)-4-h yd r oxy-5-m eth oxyca r bon ylp h en yl)]-2-ch lor o-
eth a n e (22). A mixture of 21 (2.34 g, 7.2 mmol), chloroace-
taldehyde dimethyl acetal (1.14 mL, 10 mmol), and acetic acid
(15 mL) was stirred at 0 °C while concentrated sulfuric acid
(60 mL) was added dropwise. The mixture slowly became red.
After stirring overnight while warming to room temperature,
the brown mixture was poured into ice (200 g), and the grayish
solid produced was filtered and air-dried. Flash chromatog-
raphy on SiO2 (200 g, 230-400 mesh) eluting with hexane/
ethyl acetate (4:1, v/v) gave recovered 21 (0.31 g, 0.9 mmol)
followed by 22 (0.82 g, 1.1 mmol, 30%) as a glass: IR (neat)
cm-1; H NMR (300 MHz, CDCl3) δ 9.76 (s, 1 H, CHO), 2.43
(td, J ) 7.53, 1.7 Hz, 2 H), 1.34 (m, 6 H), 1.2 (m, 6 H), 0.7 (s,
3 H), 0.64 (s, 5 H); 13C NMR (75 MHz, CDCl3) δ 203.1, 56.6,
56.3, 54.6, 46.5, 41.6, 40.1, 39.5, 38.4, 37.6, 36.2, 39.5, 38.4,
37.6, 36.2, 35.8, 35.5, 35.4, 32.1, 29.3, 28.9, 28.7, 28.2, 28.0,
24.2, 23.8, 22.8, 22.5, 21.0, 18.7, 12.3, 12.1. Anal. Calcd for
C
30H52O: C, 84.04; H, 12.23. Found: C, 84.00; H, 12.49.
5r,3â-[4′,4′-(3′′,3′′-Bis[3′′′-m eth oxy-4′′′-m eth oxyca r bon -
ylben z-a m id o]-4′′,4′′-d im eth oxy-5′′,5′′-d im eth oxyca r bon -
yld ip h en yl)-3′-bu ten yl]ch olesta n e (27). A suspension of
TiCl4‚2THF (0.5 g, 1.5 mmol) and zinc dust (0.1 g, 1.5 mmol)
in dry THF (5 mL) was heated to reflux under Ar for 30 min.
A solution of ketone 14 (0.231 g, 0.3 mmol) and aldehyde 26
(0.183 g, 0.4 mmol) dissolved in dry THF (5 mL) was added
by cannulation. The mixture was heated for 1 h at reflux
temperature and then cooled to room temperature. Ethyl
acetate (50 mL) was added, and the suspension was filtered
through silica gel (10.0 g, 230-400 mesh). The silica gel was
washed with ethyl acetate (50 mL), and the filtrate was
concentrated to an oil. The oil was chromatographed (30.0 g
SiO2, 230-400 mesh), eluting with benzene/THF (10:1), to give
the product as a glassy solid (0.120 g, 25%): IR (neat) 3423,
3332, 1738, 1731, 1714, 1681 cm-1; 1H NMR (300 MHz, CDCl3)
δ 8.63 (s, 1 H, NH), 8.59 (d, J ) 1.6 Hz, 1 H), 8.54 (s, 1 H,
NH), 8.52 (d, J ) 1.7 Hz, 1 H) 8.31 (d, J ) 2.4 Hz, 2 H), 8.03
(s, 1 H), 8.01 (s, 1 H), 7.45 (d, J ) 1.4 Hz, 1 H), 7.31 (d, J )
1.9 Hz, 1 H), 7.06 (d, J ) 8.8 Hz, 2 H), 6.11 (t, J ) 7.4 Hz, 1
H), 4.03 (s, 3 H), 3.97 (s, 3 H), 3.89 (s, 3 H), 3.83 (s, 3 H), 2.12
(q, J ) 7.5 Hz, 2 H), 1.60-1.00 (m, 40 H), 0.86 (s, 3 H), 0.71
(s, 3 H), 0.54 (s, 3 H); FABMS m/z (relative intensity) 1169.25
(MH+, 77.3), 1152.25 (50.4), 1151.25 (64.2), 945.25 (54.5), 757.0
(60.4), 565 (100). Anal. Calcd for C69H88N2O14‚H2O: C, 69.79;
H, 7.64; N, 2.36. Found: C, 69.91; H, 7.50; N, 2.22.
3140, 2958, 1677, 1610 cm-1 1H NMR (300 MHz, CDCl3) δ
;
11.15 (s, OH), 11.03 (s, OH), 7.60 (d, J ) 1.98 Hz, 2 H), 7.54
(d, J ) 2.1 Hz, 2 H), 7.33 (d, J ) 1.9 Hz, 2 H), 7.03 (d, J ) 1.8
Hz, 2 H), 4.19 (t, J ) 7.43, 1 H), 3.93 (d, J ) 7.5 Hz, 2 H), 3.90
(s, 12 H), 3.85 (s, 4 H). Anal. Calcd for C36H31Cl3O12: C, 56.75;
H, 4.10. Found: C, 56.71; H, 3.99.
1,1-Bis[3,3-(3′-ch lor o-4′-m eth oxy-5′-m eth oxyca r bon yl-
ben zyl)-4-m eth oxy-5-m eth oxyca r bon ylp h en yl]-2-ch lor o-
eth a n e (23). A mixture of 22 (0.8 g, 1.1 mmol), K2CO3 (1.0 g),
and dimethyl sulfate (2 mL, 48 mmol) was stirred in DMF (25
mL) overnight at room temperature. The solution was poured
into water, extracted with ethyl acetate (2 × 100 mL), washed
with brine, and dried over Na2SO4. The solvents were removed
at reduced pressure, and the oil was flash chromatographed
on SiO2 (100 g, 230-400 mesh), eluting with hexanes/ethyl
acetate (3:1, v/v), to give the product as an oil (0.51 g, 56.8%):
IR (neat) 2950, 2828, 1729, 1600 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 7.54 (s, 2 H), 7.47 (s, 2 H), 7.26 (s, 2 H), 7.12 (s, 2 H),
4.25 (t, 1 H, J ) 7.4 Hz), 3.88 (m, 20 H), 3.69 (s, 6 H). Anal.
Calcd for C40H39Cl3O12‚CHCl3: C, 52.53; H, 4.30. Found: C,
52.39; H, 4.27.
3,3′-Di(3′-ch lor o-4′-m eth oxy-5′-m eth oxyca r bon yl-ben -
zyl)-4,4′-d im et h oxy-5,5′-d im et h oxyca r b on ylb en zop h e-
n on e (24). A solution of 23 (0.51 g, 0.62 mmol) in MeOH (50
mL) containing KOH (1.0 g) was heated to reflux temperature
for 12 h. The solvents were removed at reduced pressure, and
the solid material was triturated in 1 N HCl (100 mL),
extracted with ethyl acetate (100 mL), and dried over MgSO4.
The solvents were evaporated to give the product as a glass
(0.398 g, 90% recovery). This material was inspected by NMR,
which indicated the presence of the desired compound 23 with
the following shifts: 1H NMR (300 MHz, acetone-d6) δ 7.72
(d, J ) 2.3 Hz, 2 H), 7.63 (d, J ) 2.0 Hz, 2 H), 7.50 (d, J ) 1.9
Hz, 2 H), 7.48 (d, J ) 2.2 Hz, 2 H), 5.50 (s, 2 H), 4.07 (s, 4 H),
3.85 (s, 6 H), 3.83 (s, 6 H). The crude material was dissolved
in MeOH (200 mL), and ozonized air was bubbled through the
solution at -78 °C for 1 h. The reaction was quenched at -78
°C with the addition of 5% KI solution (2 mL). The solvents
were removed in vacuo, and the residue was partitioned
between ethyl acetate (100 mL) and 5% Na2SO3. The organic
layer was dried over MgSO4 and evaporated to give crude
5r,3â-4′,4′-[3′′,3′′-Bis(3′′′-car boxy-4′′′-m eth oxyben zam ido)-
5′′,5′′-d ica r b oxy-4′′,4′′-d im et h oxyd ip h en yl]-3′-b u t en yl]-
ch olesta n e (4). Alkene 27 (0.1 g, 0.08 mmol) was stirred in
0.5 N NaOH (2 mL, 1 mmol) and THF (2 mL) overnight in an
argon atmosphere. The solution was acidified by the addition
of TFA (1 mL), and the solvents were removed in vacuo. The
residue was chromatographed on SiO2 (20.0 g, 230-400 mesh),
eluting with CH2Cl2/MeOH/TFA (100:10:1, v/v), to give the
product (87 mg, 90%) as a glass. IR (KBr) 3287, 2554 (b), 1733,
1720, 1702, 1686, 1653 cm-1; 1H NMR (300 MHz, acetone-d6)
δ 8.50 (m, J ) 2.25, 2.25 Hz, 5 H), 8.21 (t, J ) 8.3 Hz, 1 H),
8.20 (t, J ) 8.6 Hz, 1 H), 7.50 (d, J ) 2.1 Hz, 1 H), 7.48 (d, J
) 2.2 Hz, 1 H), 7.34 (d, J ) 8.8 Hz, 1 H), 7.32 (d, J ) 8.8 Hz,
1 H), 6.22 (t, J ) 7.6 Hz, 1 H), 4.05 (s, 3 H), 4.03 (s, 3 H), 4.01
(s, 3 H), 3.92 (s, 3 H) 2.2 (q, J ) 7.1 Hz, 2 H), 1.60-1.00 (m,
40 H), 0.90 (s, 3 H), 0.69 (s, 3 H), 0.55 (s, 3 H). Anal. Calcd for
C
65H80N2O14‚H2O: C, 69.01; H, 7.31; N, 2.48. Found: C, 69.04;
H, 7.64; N, 2.11. The tetrasodium salt was obtained as a glass
that decomposed slowly upon heating above 100 °C: FTIR
(KBr) 3419, 2925, 1658, 1613, 1573 cm-1. Anal. Calcd for