Brief Articles
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5479
water, 65:35, 5.01 min; Column B methanol-water, 50:20, 4.93
Hz, 1 H, H-2), 6.92 (d, J ) 7.93 Hz, 1 H, H-6), 6.87 (dd, J )
7.93, 1.84 Hz, 1 H, H-5), 6.03 (d, J ) 8.54 Hz, 1 H, H-7), 5.72
(s, 1 H, 4-OH), 4.30 (d, J ) 8.54 Hz, 1 H, H-8), 3.98 (s, 3 H,
3′-OCH3), 3.87 (s, 3 H, 3-OCH3), 3.81 (s, 3 H, 9-OCH3), 3.68 (s,
3 H, 9′-OCH3), 2.91 (t, J ) 7.78 Hz, 2 H, H-7′), 2.62 (t, J )
7.78 Hz, 2 H, H-8′); 13C NMR (acetone-d6) δ 173.21 (C-9′),
171.73 (C-9), 146.68 (C-4′), 146.43 (C-3), 145.92 (C-4), 144.57
(C-3′), 136.12 (C-8′), 134.19 (C-1′), 131.97 (C-1), 130.85 (C-7′),
125.25 (C-5′), 119.40 (C-6), 116.50 (C-6′), 114.44 (C-5), 113.16
(C-2′), 108.86 (C-2), 86.75 (C-7), 77.32 (C-8), 77.00 (3-OCH3),
76.68 (3′-OCH3), 52.53 (9-OCH3), 51.50 (9′-OCH3); DCI-MS
(NH3) m/z 417 (MH+). HPLC analysis: Column A methanol-
water, 65:35, 3.88 min; Column B methanol-water, 50:20, 3.51
min.
min. Anal. (C22H22O8) C, H.
Met h yl (E)-3-[2-(3,4-d im et h oxyp h en yl)-7-m et h oxy-3-
m eth oxyca r bon yl-2,3-d ih yd r o-1-ben zofu r a n -5-yl]p r op -2-
en oa te (2d ) was prepared using the method of Lemie`re et
al.2 using an improved workup. After evaporation of the
reaction mixture, the resulting yellow oil was dissolved in
methanol. The solution was left to stand overnight. Crystals
(75%) were formed, filtered, and washed with cold methanol:
1
White crystals, mp 135 °C; H NMR (acetone-d6) δ 7.65 (d, J
) 15.91 Hz, 1 H, H-7′), 7.19 (s, 1 H, H-6′), 7.03 (s, 1 H, H-2′),
6.97 (dd, J ) 15.91, 1.99 Hz, 1 H, H-6), 6.92 (d, J ) 1.99 Hz,
1 H, H-2), 6.84 (d, J ) 8.35 Hz, 1 H, H-5), 6.32 (d, J ) 15.91
Hz, 1 H, H-8′), 6.13 (d, J ) 8.15 Hz, 1 H, H-7), 4.35 (d, J )
8.15 Hz, 1 H, H-8), 3.87 (s, 3 H, 4-OCH3), 3.86 (s, 3 H, 3-OCH3),
3.84 (s, 3 H, 9-OCH3), 3.80 (s, 3 H, 9′-OCH3), 3.92 (s, 3 H, 3′-
OCH3); 13C NMR (acetone-d6) δ 170.74 (C-9), 167.55 (C-9′),
150.14 (C-4′), 149.62 (C-4), 149.49 (C-3), 144.85 (C-3′), 144.72
(C-6′), 132.18 (C-1), 128.76 (C-1′), 125.88 (C-5′), 118.82 (C-6),-
117.99 (C-6′), 115.76 (C-8′), 112.53 (C-2′), 111.46 (C-5), 109.56
(C-2), 87.41 (C-7), 56.09 (3′-OCH3), 56.09 (4-OCH3), 56.05 (3-
OCH3), 52.83 (9-OCH3), 51.56 (9′-OCH3); DCI-MS (NH3) m/z
429 (MH+). HPLC analysis: Column A methanol-water, 65:
35, 5.06 min; Column B methanol-water, 50:20, 5.61 min.
Anal. (C23H24O8) C, H.
Meth yl 3-[2-(3,4-d im eth oxyp h en yl)-7-m eth oxy-3-m eth -
o x y c a r b o n y l -2 ,3 -d i h y d r o -1 -b e n z o fu r a n -5 -y l ]p r o -
p a n oa te (3d ) was prepared according to the method of
Lemie`re et al.2 The reaction was improved by using a Parr
apparatus at 60 psi hydrogen pressure for 20 min. Workup
was performed identically, resulting in a white powder (81%);
1
mp 97-99 °C; H NMR (CDCl3) δ 7.80 (s, 1 H, H-6′), 7.70 (s,
1 H, H-2′), 6.97 (dd, J ) 8.09, 1.99 Hz, 1 H, H-6), 6.95 (d, J )
1.84 Hz, 1 H, H-2), 6.83 (d, J ) 8.09 Hz, 1 H, H-6), 6.05 (d, J
) 8.39 Hz, 1 H, H-7), 5.70 (s, 1 H, 4-OH), 4.31 (d, J ) 8.39 Hz,
1 H, H-8), 3.98 (s, 3 H, 3′-OCH3), 3.86 (s, 3 H, 3-OCH3), 3.85
(s, 3 H, 9-OCH3), 3.68 (s, 3 H, 9′-OCH3), 2.91 (t, J ) 7.75 Hz,
2 H, H-7′), 2.62 (t, J ) 7.78 Hz, 2 H, H-8′); 13C NMR (CDCl3)
δ 173.16 (C-9′), 171.24 (C-9), 149.66 (C-4), 149.65 (C-3), 146.74
(C-4′), 144.50 (C-3′), 134.37 (C-1′), 133.04 (C-1), 125.51 (C-5′),
118.83 (C-6), 116.76 (C-6′), 113.74 (C-2′), 111.90 (C-5), 110.25
(C-2), 86.72 (C-7), 56.45 (3′-OCH3), 56.23 (C-8), 56.20 (4-OCH3),
56.15 (3-OCH3), 52.52 (9-OCH3), 51.46 (9′-OCH3), 36.17 (C-
7′), 30.96 (C-8′); DCI-MS (NH3) m/z 431 (MH+). HPLC analy-
sis: Column A methanol-water, 65:35, 4.50 min; Column B
methanol-water, 50:20, 4.26 min.
Meth yl (E)-3-[2-(4-h yd r oxyp h en yl)- 3-m eth oxyca r bo-
n yl-2,3-d ih yd r o-1-ben zofu r a n -5-yl]p r op a n oa te (3a ) was
prepared by dissolving 418 mg (1.18 mmol) of 2a in 30 mL of
acetone to which 220 mg of 5% Pd/C was added. The mixture
was put in a Parr apparatus under 60 psi hydrogen pressure
and was shaken for 20 min. After filtration and evaporation,
the crude oil was purified by column chromatography (3 × 20
cm, silica gel 60, 0.040-0.063 mm) with ethyl acetate-heptane
(3:1) as the eluent, resulting in a colorless oil (85%): 1H NMR
(CDCl3) δ 7.26 (d, J ) 8.70 Hz, 2 H, H-2, H-6), 7.17 (d, J )
1.83 Hz, 1 H, H-6′), 7.05 (dd, J ) 8.24, 1.83 Hz, 1 H, H-2′),
6.81 (d, J ) 8.70 Hz, 2 H, H-3, H-5), 6.74 (d, J ) 8.24 Hz, 1 H,
H-3′), 5.45 (s, 1 H, 4-OH), 4.24 (d, J ) 7.78 Hz, 1 H, H-7), 3.81
(s, 3 H, 9-OCH3), 3.68 (s, 3 H, 9′-OCH3), 2.91 (t, J ) 7.78 Hz,
2 H, H-8′), 2.61 (t, J ) 7.78, 2 H, H-7′); 13C NMR (CDCl3) δ
173.55 (C-9′), 171.46 (C-9), 157.89 (C-4), 155.97 (C-4′), 132.70
(C-1′), 129.55 (C-2′), 127.51 (C-2, C-6), 124.93 (C-6′), 124.24
(C-5′), 115.63 (C-3, C-5), 109.74 (C-3′), 85.78 (C-7), 55.74 (C-
8), 52.66 (C-9), 51.64 (C-9′), 36.22 (C-8′), 30.50 (C-7′); DCI-MS
(NH3) m/z 357 (MH+). HPLC analysis: Column A methanol-
water, 65:35, 4.02 min; Column B methanol-water, 60:40, 9.22
min.
Methyl(E)-3-[2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methoxy-
ca r bon yl-2,3-d ih yd r o-1-ben zofu r a n -5-yl]p r op a n oa te (3b)
was prepared from 2b using the same method and concentra-
tions as for the synthesis of 3a . The crude oil was purified by
column chromatography (3 × 20 cm, silica gel 60, 0.040-0.063
mm) with ethyl acetate-n-heptane (1:2) as the eluent, result-
ing in a colorless oil (95%): 1H NMR (acetone-d6) δ 7.95 (s, 2
H, 3-OH, 4-OH), 6.88 (d, J ) 1.98 Hz, 1 H, H-2), 6.82 (d, J )
8.08 Hz, 1 H, H-5), 6.76 (dd, J ) 8.08, 1.98 Hz, 1 H, H-6), 6.71
(s, 1 H, H-2′), 6.68 (s, 1 H, H-6′), 5.88 (d, J ) 7.48 Hz, 1 H,
H-7), 4.24 (d, J ) 7.53 Hz, 1 H, H-8), 3.76 (s, 3 H, 9-OCH3),
3.60 (s, 3 H, 9′-OCH3), 2.80 (t, J ) 7.63 Hz, 2 H, H-7′), 2.55 (t,
J ) 7.63 Hz, 2 H, H-8′); 13C NMR (acetone-d6) δ 173.45 (C-9′),
172.06 (C-9), 146.18 (C-4′), 146.08 (C-3), 145.41 (C-4), 142.00
(C-3′), 135.26 (C-1′), 133.36 (C-1), 126.48 (C-5′), 118.60 (C-6),
117.78 (C-6′), 116.20 (C-2′), 116.13 (C-5′), 113.9 (C-2), 87.95
(C-7), 56.40 (C-8), 52.94 (9-OCH3), 51.53 (9′-OCH3), 36.54 (C-
8′), 31.20 (C-7′); DCI-MS (NH3) m/z 389 (MH+). HPLC analy-
sis: Column A methanol-water, 65:35, 6.25 min; Column B
methanol-water, 60:40, 3.45 min.
3-[2-(4-Hyd r oxyp h en yl)-3-h yd r oxym eth yl-2,3-d ih yd r o-
1-ben zofu r a n -5-yl]p r op a n -1-ol (4a ) was prepared from 3a
according to the method of Lemie`re et al.2 In the workup the
crude green oil was dissolved in a few drops of ethyl acetate
and left to stand overnight at 0 °C, resulting in the formation
of white crystals (40%); mp 122-125 °C; 1H NMR (acetone-
d6) δ 8.32 (s, 1 H, 4-OH), 7.68 (m, J ) 1.40 Hz, 1 H, H-6′), 7.24
(d, J ) 8.24 Hz, 2 H, H-2, H-6), 6.95 (dd, J ) 8.08, 1.40 Hz, 1
H, C-2′), 6.89 (d, J ) 8.08 Hz, 1 H, H-2′), 6.81 (d, J ) 8.24 Hz,
2 H, H-3, H-5), 6.69 (d, J ) 8.08 Hz, 1 H, H-3′), 5.50 (d, J )
6.10 Hz, 1 H, H-7), 4.37 (m, J ) 6.10 Hz, 1 H, H-8), 3.85 (m,
J ) 10.83, 5.34 Hz, 1 H, H-9a), 3.78 (m, J ) 10.83, 7.02 Hz, 1
H, H-9b), 2.89 (s, 2 H, 9-OH, 9′-OH), 2.61 (t, J ) 7.98 Hz, 2 H,
H-7′), 1.78 (m, J ) 7.94, 6.24 Hz, 2 H, H-8′); 13C NMR (acetone-
d6) δ 159.09 (C-4), 157.95 (C-4′), 135.49 (C-5′), 134.45 (C-1),
129.19 (C-2′), 128.87 (C-1′), 127.97 (C-2, C-6), 125.69 (C-6′),
116.06 (C-3, C-5), 109.35 (C-3′), 87.70 (C-7), 81.87 (C-9′), 65.09
(C-9), 54.79 (C-8), 35.99 (C-8′), 32.33 (C-7′); DCI-MS (NH3) m/z
301(MH+); DCI-MS (NH3) m/z 283 (MH+)-H2O. HPLC analy-
sis: Column A methanol-water, 65:35, 4.17 min; Column B
methanol-water, 60:40, 2.53 min.
3-[2-(3,4-Dih yd r oxyp h e n yl)-3-h yd r oxym e t h yl-7-h y-
dr oxy-2,3-dih ydr o-1-ben zofu r an -5-yl]pr opan -1-ol (4b) was
prepared from 3b according to the method of Lemie`re et al.2
In the workup the crude oil was dissolved in 3 mL of ethyl
acetate and left to stand overnight at 0 °C, resulting in the
formation of white crystals (20%); mp 123 °C; 1H NMR (CDCl3)
δ 6.84 (m, 1 H, H-2), 6.72 (m, 2 H, H-5, H-6), 6.60 (s, 1 H,
H-6′), 6.56 (s, 1 H, H-2′), 5.53 (d, J ) 5.95 Hz, 1 H, H-7), 3.81
(m, J ) 10.99, 5.49 Hz, 1 H, H-9a), 3.73 (m, J ) 10.99, 7.32
Hz, 1 H, H-9b), 3.56 (t, J ) 6.57 Hz, 2 H, H-9′), 2.56 (t, J )
7.47 Hz, 2 H, H-7′), 1.80 (m, J ) 7.48, 6.57 Hz, 2 H, H-8′); 13
C
Meth yl 3-[2-(4-h yd r oxy-3-m eth oxyp h en yl)-7-m eth oxy-
3-m et h oxyca r bon yl-2,3-d ih yd r o-1-ben zofu r a n -5-yl]p r o-
p a n oa te (3c) was prepared from 2c using the same method
and concentrations as for the synthesis of 3a . Workup was
performed identically, resulting in a white powder (95%); mp
85-87 °C; H NMR (acetone-d6) δ 7.79 (s, 1 H, H-2′), 7.69 (s,
1 H, H-6′), 6.93 (d, J ) 1.84 Hz, 1 H, H-2), 6.92 (d, J ) 1.84
NMR (CDCl3) δ 146.56 (C-4′), 146.37 (C-3), 146.14 (C-4), 141.76
(C-3′), 136.61 (C-1′), 135.34 (C-1), 129.88 (C-5′), 118.59 (C-6),
116.98 (C-2′), 116.71 (C-6′), 116.22 (C-5), 114.01 (C-2), 88.64
(C-7), 65.26 (C-9), 61.52 (C-9′), 55.68 (C-8), 35.73 (C-8′), 32.70
(C-7′); DCI-MS (NH3) m/z 333 (MH+); DCI-MS (NH3) m/z 315
(MH+)-H2O. HPLC analysis: Column A methanol-water, 65:
35, 3.01 min; Column B; methanol-water, 60:40, 2.41 min.
1