Synthesis of Isoplagiochin A
J . Org. Chem., Vol. 62, No. 11, 1997 3669
8.5 Hz, 1 H, 5-H), 7.08 (d, J ) 8.5 Hz, 1 H, 4′-H), 7.24 (d, J )
2.1 Hz, 1 H, 2-H), 7.37 (dd, J ) 8.5 and 2.1 Hz, 1 H, 6-H), 7.78
(d, J ) 2.1 Hz, 1 H, 6′-H), 7.88 (dd, J ) 8.5 and 2.1 Hz, 1 H,
3′-H), 9.91 (s, 1 H, CHO). Anal. Calcd for C21H24O5: C, 70.77;
H, 6.79. Found: C, 70.52; H, 6.61.
-(CH2)3-), 3.55 (mc, 1 H, OCHACHB), 3.9 (mc, 1 H, OCHACHB),
3.62, 3.72, 3.73, 3.74, 3.75, 3.76, 3.83, 3.85 and 3.86 (8×s, 12
H, 4×(Z)-OMe, 4×(E)-OMe), 4.4-4.5 (m) and 4.7-4.8 (m) (3
H, ArCHACHBO, OCHO), 6.40 and 6.53 (2×d, J ) 12 Hz, (Z)-
CH ) CH-), 6.75-7.7 (m, Ar-H). Anal. Calcd for C37H38O8:
C, 72.77; H, 6.27. Found: C, 72.65; H, 6.33.
Meth yl 3-(2-F or m yl-4-m eth oxyp h en oxy)ben zoa te (9).
A mixture of 2-bromo-4-methoxybenzaldehyde (7.3 g, 34
mmol),15 methyl 3-hydroxybenzoate (6.7 g, 44 mmol), CuO (0.9
g), and dry K2CO3 (8.0 g) in pyridine (80 mL) was refluxed
with stirring for 48 h. Dilution with 10% HCl (200 mL) and
extraction with CH2Cl2, drying the extract over MgSO4,
evaporation, and chromatography (eluant hexane/acetone (5:
1)) gave 9 (2.5 g, 25%): 1H NMR (CDCl3, 400 MHz) δ ) 3.87
(s, CO2Me), 3.90 (s, 4′-OMe), (6 H), 6.94 (d, J ) 9.1 Hz, 1 H,
6′-H), 7.15 (dd, J ) 3.3 and 9.1 Hz, 1 H, 5′-H), 7.21 (ddd, J )
8.2, 2.7 and 1.2 Hz, 1 H, 4-H), 7.42 (d, J ) 3.3 Hz, 1 H, 3′-H),
7.43 (dd, J ) 8.2 and 7.8 Hz, 1 H, 5-H), 7.62 (dd, J ) 2.5 and
1.5 Hz, 1 H, 2-H), 7.80 (ddd, J ) 7.8, 1.5 and 1.2 Hz, 1 H,
6-H);30 13C NMR (100 MHz, CDCl3) δ ) 52.35 (CO2Me), 55.86
(4′-OMe), 110.09 (C-3′), 122.47 (C-4), 123.81 (C-5′), 124.59 (C-
6), 128.08 (C-2′), 130.04 (C-5), 132.11 (C-1), 152.68 (C-1′),
156.24 (C-4′), 158.03 (C-3), 166.26 (COMe).31 Anal. Calcd for
C16H14O5: C, 67.13; H, 4.93. Found: C, 66.97; H, 5.01.
Meth yl (2-(Hyd r oxym eth yl)-4-m eth oxyp h en oxy)ben -
zoa te (10). To a solution of 9 (2.5 g, 8.7 mmol) in EtOH (60
mL) was added NaBH4 (0.45 g). After the disappearance of
10 the mixture was acidified with AcOH and the solution
evaporated. The residue was treated with water and extracted
with CH2Cl2. Evaporation gave 10 as an oil (2.33 g, 92%): 1H
NMR (CDCl3, 500 MHz) δ ) 3.84 and 3.89 (2×s, 6 H, OMe),
4.67 (s, 2 H, CH2), 6.83 (dd, J ) 8.8 and 3 Hz, 1 H, 5′-H), 6.89
(d, J ) 8.8 Hz, 1 H, 6′-H), 7.07 (d, J ) 2.0 Hz, 1 H, 3′-H), 7.12
(ddd, J ) 8.1, 2.5 and 1 Hz, 1 H, 4-H), 7.37 (t, J ) 8.0 Hz, 1 H,
5-H), 7.54 (dd, J ) 2.5 and 1.5 Hz, 1 H, 2-H), 7.74 (ddd, J )
7.5, 1.5 and 1 Hz, 1 H, 6-H). Anal. Calcd for C16H16O5: C,
66.66; H, 5.59. Found: C, 66.73; H, 5.52.
1-[5-Meth oxy-2-(3-(m eth oxycar bon yl)ph en oxy)ph en yl]-
2-[4-m et h oxy-3-(2-m et h oxy-5-(((t et r a h yd r op yr a n -2-yl)-
oxy)m eth yl)p h en yl)p h en yl]eth a n e (14). Hydrogenation of
12 (280 mg) in EtOH over Pd/C followed by the usual workup
gave 14 (250 mg, 89%) as a resin: 1H-NMR (400 MHz, CDCl3)
δ ) 1.5-1.9 (m, 6 H, -(CH2)3-), 2.84 (s, 4 H, Ar(CH2)2Ar),
3.55 (mc, 1 H, OCHACHB), 3.73, 3.74, 3.78 and 3.87 (4×s, 12
H, 4×OMe), 4.45 (d, J ) 11.5 Hz, 1 H, ArCHACHBO), 4.72 (mc,
1H, OCHO), 4.74 (d, J ) 11.5 Hz, 1 H, ArCHACHBO), 6.75 (dd,
J ) 8.6 and 3 Hz, 1 H, 4′′′-H), 6.78 (d, J ) 8.5 Hz, 1 H, 6′′′-H),
6.83 (d, J ) 8.3 Hz, 1 H, 3′′-H), 6.88 (d, J ) 8 Hz, 1 H, 3′′′-H),
6.93 (d, J ) 8 Hz, 1 H, 5′-H), 7.00 (d, J ) 2.5 Hz, 1 H, 6′′-H),
7.03 (dd, J ) 8.3 and 2.4 Hz, 1 H, 4′′-H), 7.06 (ddd, J ) 8, 2.5
and 1.0 Hz, 1 H, 6′′′′-H), 7.17 (d, J ) 2 Hz, 1 H, 2′-H), 7.32
(dd, J ) 8.4 and 2.2 Hz, 1 H, 6′-H), 7.32 (t, J ) 8 Hz, 1 H,
5′′′′-H), 7.51 (dd, J ) 2.5, and 1.5 Hz, 1 H, 2′′′′-H), 7.67 (ddd,
J
) 7.5, 1.5, and 1 Hz, 1 H, 4′′′′-H). Anal. Calcd for
C37H40O8: C, 72.53; H, 6.58. Found: C, 72.41; H, 6.48.
1-[5-Meth oxy-2-(3-(h yd r oxym eth yl)p h en oxy)p h en yl]-
2-[4-m et h oxy-3-(2-m et h oxy-5-(((t et r a h yd r op yr a n -2-yl)-
oxy)m eth yl)p h en yl)p h en yl]eth a n e (15). Compound 14
(250 mg, 0.41 mmol) was reduced in dry Et2O (30 mL) with
LiAlH4 (50 mg). Excess reagent was destroyed with a satu-
rated aqueous solution of Seignettes’s salt. Evaporation,
extraction of the product with CH2Cl2, and evaporation gave
15 (220 mg, 92%) as a resin: 1H-NMR (400 MHz, CDCl3) δ )
1.5-1.9 (m, 6 H, -(CH2)3-), 2.83 (s, 4 H, Ar(CH2)2Ar), 3.55
(mc, 1 H, OCHACHB), 3.72, 3.73 and 3.78 (3×s, 9 H, 3×OMe),
3.93 (mc, 1 H, OCHACHB), 4.45 (d, J ) 11.5 Hz, 1 H,
5′′-CHACHBO), 4.55 (s, 2 H, 3′′′-CH2), 4.73 (mc, 1 H, OCHO),
4.74 (d, J ) 11.5 Hz, 1 H, 5′′-CHACHBO), 6.73 (dd, J ) 9 and
3 Hz, 1 H, 4′′′′-H), 6.735 (ddd, J ) 9, 3 and <1 Hz, 1 H, 6′′′′-
H), 6.78 (d, J ) 3.0 Hz, 1 H, 6′′′-H), 6.83 (d, J ) 8.5 Hz, 1 H,
3′′-H), 6.85 (t, J ) 2.5 Hz, 1 H, 2′′′′-H), 6.90 (d, J ) 9 Hz, 1 H,
3′′′-H), 6.92 (d, J ) 8.5 Hz, 1 H, 5′-H), 6.94 (d, J ) 2.5 Hz, 1
H, 6′′-H). 6.96 (ddd, J ) 8.5 ∼2 and <1 Hz, 1 H, 4′′′′-H), 7.04
(dd, J ) 8.5 and 2.5 Hz, 1 H, 4′′-H), 7.12 (d, J ) 2.0 Hz, 1 H,
2′-H), 7.21 (t, J ) 8 Hz, 1 H, 5′′′′-H), 7.32 (dd, J ) 8.5 and 2.5
Hz, 1 H, 6′-H). Anal. Calcd for C36H40O7: C, 73.95; H, 6.90.
Found: C, 74.02; H, 6.95.
Meth yl 3-(2-(Br om om eth yl)-4-m eth oxyp h en oxy)ben -
zoa te (11). To a solution of 9 (0.16 g, 0.55 mmol) in DME (2
mL) was added PBr3 (0.15 g, 0.55 mmol) in DME (2.75 mL).
After a few hours the mixture was diluted with Et2O, the
solution extracted several times with water, dried over MgSO4,
and evaporated, and the crude product purified by chroma-
tography (benzene/EtOAc (8:1) to give 11 (0.124 g, 64%): 1H
NMR (CDCl3, 400 MHz) δ ) 3.82 and 3.89 (2×s, 6 H, OMe),
4.48 (s, 2 H, CH2), 6.85 (m, 2 H, 5′,6′-H), 6.99 (d, J ) 2.5 Hz,
1 H, 3′-H), 7.14 (ddd, J ) 8.0, 2.5 and 1 Hz, 1 H, 4-H), 7.38 (t,
J ) 8 Hz, 1 H, 5-H), 7.60 (dd, J ) 2.5 and 1.5 Hz, 1 H, 2-H),
7.74 (ddd ) 7.5 1.5 and 1 Hz, 1 H, 6-H). Anal. Calcd for
C16H15BrO4: C, 54.72; H, 4.31. Found: C, 54.64; H, 4.40.
Meth yl 3-(2-(P h osp h on iom eth yl)-4-m eth oxyp h en oxy)-
ben zoa te (12). A solution of 11 (1.44 g, 4.1 mmol) and Ph3P
(1.18 g, 4.5 mmol) in MeCN (50 mL) was refluxed for 2 h.
Evaporation and treatment of the residue with hot hexane
1-[2-(3-Car bon ylph en oxy)-5-m eth oxyph en yl]-2-[4-m eth -
oxy-3-(2-m eth oxy-5-(((tetr a h ydr opyr a n -2-yl)oxy)m eth yl)-
p h en yl)p h en yl]eth a n e (16). To a suspension of pyridinium
chlorochromate (360 mg, 1.7 mmol) and NaOAc in dry
CH2Cl2 (20 mL) was added 15 (640 mg, 1.1 mmol) in CH2Cl2.
After stirring for 1 h the solution was evaporated and the
residue chromatographed (eluant: benzene/EtOAc (8:1)) to
give 16 (330 mg, 51%) as a resin: 1H NMR (CDCl3, 500 MHz):
δ ) 1.5-1.9 (m, 6 H, -(CH2)3-), 2.84 (s, 4 H, Ar(CH2)2Ar),
3.50-3.65 (m, 1 H, OCHACHB), 3.74, 3.76 and 3.83 (3×s, 9 H,
3×OMe), 3.93 (mc, 1 H, OCHACHB), 4.46 (d, J ) 11.5 Hz, 1 H,
5′′-CHACHBO), 4.74 (mc, 1 H, OCHO), 4.77 (d, J ) 11.5 Hz, 1
H, 5′′-CHACHBO), 6.77 (dd, J ) 8.7 and 3.0 Hz, 1 H, Hxb), 6.82
(d, J ) 2.9 Hz, 1 H, Hxc), 6.83 (d, J ) 8.3 Hz, 1 H, Hya), 6.95
(d, J ) 8.7 Hz, 1 H, Hxa), 6.93 (d, J ) 8.3 Hz, 1 H, Hza), 6.99
1
gave 12 (2.1 g, 83%): mp 152-154 °C; H NMR (CDCl3, 400
MHz): δ ) 3.60 and 3.91 (2×s, 6 H, OMe), 5.35 (d, J ) 14.5
Hz, 2 H, CH2), 6.53 (dd, J ) 9 and 1 Hz, 1 H, 6′-H), 6.75 (dd,
J ) 9 and 2.8 Hz, 1 H, 5′-H), 6.75 (ddd, J ) 8.0, 2.5 and 1.0
Hz, 1 H, 4-H), 7.08 (dd, J ) 2.5 and 1.5 Hz, 1 H, 2-H), 7.23
(dd, J ) 3 and 2.5 Hz, 1 H, 3′-H), 7.31 (t, J ) 7.5 Hz, 4 H,
5-H), 7.61-7.68 (m, 2 H, Ar-H), 7.72 (ddd, J ) 7.5, 1.5 and 1
Hz, 1 H, 6-H), 7.73-7.82 (m, 10 H, Ar-H). Anal. Calcd for
C34H30BrO4P: C, 66.57; H, 4.93. Found: C, 66.40; H, 4.88.
1-[5-Meth oxy-2-(3-(m eth oxycar bon yl)ph en oxy)ph en yl]-
2-[4-m et h oxy-3-(2-m et h oxy-5-(((t et r a h yd r op yr a n -2-yl)-
oxy)m eth yl)p h en yl)p h en yl]eth en e (13). To a solution of
12 (495 mg, 0.87 mmol) in dry MeOH (5 mL) was added 1 N
NaOMe (1.5 mL) under argon. After 1 h 7 (240 mg, 0.67 mmol)
dissolved in MeOH (5 mL) was added and stirring continued
for 1 h. The usual workup and chromatography (eluant
benzene/EtOAc (8:1)) gave 13 (152 mg, 37%) as an E/Z
mixture: 1H-NMR (400 MHz, CDCl3) δ ) 1.5-1.9 (m, 6H,
c
(d, J ) 2.1 Hz, 1 H, Hz ), 7.03 (dd, J ) 8.3 and 2.1 Hz, 1 H,
Hzb), 7.15 (d, J ) 1.7 Hz, 1 H, Hyc), 7.16 (dd, J ) 9.1 and 2.1
Hz, 1 H, Hyb), 7.27 (br. s, 1 H, 2′′′′-H), 7.31 (dd, J ) 8.4 and
2.0 Hz, 1 H, 6′′′′-H), 7.43 (t, J ) 7.8 Hz, 1 H, 5′′′′-H), 7.51 (d,
J ) 7.6 Hz, 1 H, 4′′′′-H), 9.91 (s, 1 H, CHO). Anal. Calcd for
C36H38O7: C, 74.21; H, 6.57. Found: C, 74.15; H, 6.39.
1-[2-(3-Car bon ylph en oxy)-5-m eth oxyph en yl]-2-[4-m eth -
oxy-3-(2-m e t h oxy-5-(h yd r oxym e t h yl)p h e n yl)p h e n yl]-
eth a n e (17). A solution of 16 (230 mg, 0.40 mmol) in EtOH
(5 ml) was refluxed for 1 h in the presence of Amberlite IR
120 strongly acidic ion exchange resin. Filtration, evaporation,
and chromatography (eluant: benzene/EtOAc (8:1)) afforded
17 (70 mg, 36%): 1H NMR (CDCl3, 500 MHz) δ ) 2.83 (s, 4 H,
Ar-(CH2)2-Ar) 3.74, 3.76 and 3.81 (3×s, 9 H, 3×OMe), 4.65 (s,
2 H, CH2O), 6.78 (dd, J ) 8.5 and 3.0 Hz, 1 H, Hxb), 6.81 (d, J
(30) Assignments were confirmed by NOEs on H-6′ and CHO, H-2′
and H-5′, on irradiation of H-2 and 4′-OMe, respectively.
(31) Protonated carbons were assigned by 1D HETCOR, quaternary
carbons by 1D long range correlations (INEPTL).