A R T I C L E S
Kamiya et al.
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the eluent to give 12 as a red powder (22.7 mg, 70%). H NMR (300
MHz, CD3OD): δ 7.82 (d, 2H, J ) 9.2 Hz), 7.32 (d, 2H, J ) 2.4 Hz),
7.24 (dd, 2H, J ) 9.2 Hz, 2.4 Hz), 7.18 (d, 1H, J ) 8.3 Hz), 6.76 (d,
1H, J ) 2.0 Hz), 6.70 (dd, 1H, J ) 8.3 Hz, 2.0 Hz), 3.70 (s, 3H).
HRMS (ESI+): calcd for [M + H]+, 335.091 95; found, 335.
088 62.
1H, J ) 8.25, 2.20 Hz), 6.66-6.72 (m, 4H), 4.52 (s, 2H), 3.73 (s, 3H).
HRMS (ESI-): calcd for [M - H]-, 391.081 78; found, 391.079 47.
Synthesis of 9-{1-[4-(4-Methoxycarbonylbutyloxy)-2-methylphe-
nyl]}-6-hydroxy-3H-xanthen-3-one (17). To a mixture of 3 (63.8 mg,
0.20 mmol) and Cs2CO3 (400 mg, 1.2 mmol) in dry dimethylformamide
(2 mL) methyl 5-bromovalerate (21 µL, 0.18 mmol) was added. The
reaction mixture was stirred at room temperature under argon overnight.
The inorganic precipitate was filtered off, and the filtrate was
concentrated under reduced pressure. The residue was diluted with water
and extracted with CH2Cl2 three times. The combined organic solution
was washed with water and saturated aq. NaCl, dried over Na2SO4,
and evaporated. The residue was chromatographed on silica gel with
CH2Cl2-MeOH (100:5) as the eluent to give 17 as a red powder (53.7
Synthesis of 9-[1-(2-Methoxy-4-methoxycarbonylmethoxyphe-
nyl)]-6-hydroxy-3H-xanthen-3-one (13). A mixture of 12 (22.7 mg,
68 µmol), bromomethyl acetate (6.27 µL, 68 µmol), and Cs2CO3 (66.5
mg, 204 µmol) was stirred at room temperature under argon overnight.
The inorganic precipitate was filtered off, and the filtrate was
concentrated under reduced pressure. The residue was diluted with water
and extracted with CH2Cl2 three times. The combined organic solution
was washed with water and saturated aq. NaCl, dried over Na2SO4,
and evaporated. The residue was chromatographed on silica gel with
CH2Cl2-MeOH (100:5) as the eluent to give 13 as an orange powder
1
mg, 62%). H NMR (300 MHz, CDCl3) δ 7.10 (d, 2H, J ) 9.2 Hz),
7.07 (d, 1H, J ) 8.3 Hz), 6.91-6.84 (m, 4H), 6.81 (dd, 2H, J ) 9.2
Hz, 2.0 Hz), 4.06 (m, 2H), 3.70 (s, 3H), 2.45 (m, 2H), 2.02 (s, 3H),
1.88 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 175.04, 174.08, 159.73,
157.43, 152.90, 137.67, 130.77, 130.21, 124.47, 121.80, 116.42, 115.57,
111.84, 103.68, 67.41, 53.35, 33.58, 28.54, 21.55, 19.83. HRMS
(ESI+): calcd for [M + H]+, 433.165 11; found, 433.168 53.
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(17.4 mg, 63%). H NMR (300 MHz, CDCl3) δ 7.16 (d, 2H, J ) 9.0
Hz), 7.10 (d, 1H, J ) 8.3 Hz), 6.81 (m, 3H), 6.75 (dd, 2H, J ) 9.0 Hz,
2.0 Hz), 6.59 (dd, 1H, J ) 8.3 Hz, 2.2 Hz,), 4.74 (s, 2H), 3.87 (s, 3H),
3.69 (s, 3H). HRMS (ESI+): calcd for [M + H]+, 407.113 08; found,
407.110 06.
Synthesis of 9-{1-[4-(4-methoxycarbonylbutyloxy)-2-methylphe-
nyl]}-6-hydroxy-3H-xanthen-3-one Mono(2′,3′,4′,6′-tetra-O-acetyl-
â-D-galactopyranoside) (18). A mixture of 17 (18.2 mg, 42 µmol),
Cs2CO3 (250 mg, 0.77 mmol), and 2,3,4,6-tetra-O-acetyl-R-D-galacto-
pyranosyl bromide (100 mg, 0.25 mmol) in dry dimethylformamide (1
mL) was stirred at room temperature under argon overnight. The
inorganic precipitate was filtered off, and the filtrate was concentrated
under reduced pressure. The residue was diluted with water and
extracted with CH2Cl2 three times. The combined organic solution was
washed with water and saturated aq. NaCl, dried over Na2SO4, and
evaporated. The residue was chromatographed on silica gel with AcOEt
as the eluent to give 18 as an orange powder (25 mg, 78%). 1H NMR
(300 MHz, CDCl3) δ 7.08-6.80 (m, 7H), 6.57 (dd, 1H, J ) 9.7 Hz,
2.0 Hz), 6.39 (d, 1H, J ) 2.0 Hz), 5.56-5.48 (m, 2H), 5,18-5.12 (m,
2H), 4.22-4.11 (m, 3H), 4.06 (m, 2H), 3.70 (s, 3H), 2.19 (s, 3H), 2.13
(s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 1.88 (m, 4H). HRMS (ESI+): calcd
for [M + H]+, 763.260 19; found, 763.255 43.
Synthesis of 9-[1-(2-Methoxy-4-methoxycarbonylmethoxyphe-
nyl)]-6-hydroxy-3H-xanthen-3-one Mono(2′,3′,4′,6′-tetra-O-acetyl-
â-D-galactopyranoside) (14). A mixture of 13 (3.8 mg, 9.3 µmol),
Cs2CO3 (38.4 mg, 117 µmol), and 2,3,4,6-tetra-O-acetyl-R-D-galacto-
pyranosyl bromide (100 mg, 0.25 mmol) in dry DMF (2 mL) was stirred
at room temperature under argon for 4.5 h. The inorganic precipitate
was filtered off, and the filtrate was concentrated under reduced
pressure. The residue was diluted with water and extracted with CH2-
Cl2 three times. The combined organic solution was washed with water
and saturated aq. NaCl, dried over Na2SO4, and evaporated. The residue
was chromatographed on silica gel with CH2Cl2-MeOH (100:3) as
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the eluent to give 14 as an orange powder (6.4 mg, 94.2%). H NMR
(300 MHz, CDCl3) δ 7.13-7.06 (m, 4H), 6.81 (dd, 1H, J ) 8.8 Hz,
2.4 Hz), 6.74 (d, 1H, J ) 2.3 Hz), 6.59 (dd, 1H, J ) 8.2 Hz, 2.3 Hz),
6.57 (dd, 1H, J ) 9.7 Hz, 1.8 Hz), 6.39 (d, 1H, J ) 1.8 Hz), 5.56-
5.49 (m, 2H), 5.18-5.13 (m, 2H), 4.74 (s, 2H), 4.25-4.17 (m, 3H),
3.86 (s, 3H), 3.70 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H), 2.07 (s, 3H),
2.03( s, 3H). HRMS (ESI+): calcd for [M + H]+, 737.208 16; found,
737.208 60.
Synthesis of 9-{1-[4-(4-methoxycarbonylbutyloxy)-2-methylphe-
nyl]}-6-hydroxy-3H-xanthen-3-one Mono-â-D-galactopyranoside (19).
To a solution of 18 (28 mg, 37 µmol) in methanol (5 mL) a 5 M
methanol solution of NaOMe (10 µL, 50 µmol) was added. The mixture
was stirred at room temperature for 1 h and then neutralized with
Amberlite IR-120 (H+). The Amberlite IR-120 was filtered off, and
the filtrate was evaporated. The residue was subjected to reversed-
phase preparative TLC (RP18W) with acetonitrile/water (1:1) as the
Synthesis of 9-[1-(2-Methoxy-4-methoxycarbonylmethoxyphe-
nyl)]-6-hydroxy-3H-xanthen-3-one Mono-â-D-galactopyranoside)
(15). To a solution of 14 (2 mg, 2.7 µmol) in methanol (1 mL) a 5 M
methanol solution of NaOMe (2 µL, 5 µmol) was added. The mixture
was stirred at room temperature for 1 h and then neutralized with
Amberlite IR-120 (H+). The Amberlite IR-120 was filtered off, and
the filtrate was evaporated. The residue was chromatographed on silica
gel with CHCl3-MeOH (100:10) as the eluent to give 15 as an orange
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eluent to give 19 as an orange powder (7.4 mg, 34%). H NMR (300
MHz, CD3OD) δ 7.37 (d, 1H, J ) 2.4 Hz), 7.19 (dd, 1H, J ) 8.8 Hz),
7.16 (d, 1H, J ) 9.7 Hz), 7.15 (d, 1H, J ) 8.3 Hz), 7.10 (d, 1H, J )
8.3 Hz, 2.4 Hz), 7.03 (d, 1H, J ) 1.8 Hz), 6.99 (dd, 1H, J ) 8.3 Hz,
1.8 Hz), 6.61 (dd, 1H, J ) 9.7 Hz, 2.0 Hz), 6.47 (d, 1H, J ) 2.0 Hz),
4.10 (m, 2H), 5.10 (dd, 1H, J ) 7.7 Hz, 3.0 Hz), 3.92 (d, 1H, J ) 3.5
Hz), 3.88-3.74 (m, 4H), 3.62 (dd, 1H, J ) 9.5 Hz, 3.1 Hz), 3.67 (s,
3H), 2.45 (m, 2H), 2.06 (s, 3H), 1.88 (m, 4H). HRMS (ESI+): calcd
for [M + H]+, 595.217 94; found, 595.218 62.
Synthesis of 9-{1-[4-(4-Carboxybutyloxy)-2-methylphenyl]}-6-
hydroxy-3H-xanthen-3-one (20). To a solution of 17 (9.3 mg, 21.5
µmol) in methanol (2 mL) 2 M aq. NaOH (0.5 mL, 1 mmol) was added.
The mixture was stirred at room temperature for 4 h and then neutralized
with 2 N aq. HCl. The methanol was evaporated off, and the residue
was diluted with H2O and then extracted with CH2Cl2. The combined
organic layer was evaporated, and the residue was chromatographed
on silica gel with CH2Cl2-MeOH (100:5) as the eluent to give 20 as
an orange powder (7 mg, 78%). 1H NMR (300 MHz, CD3OD) δ 7.11-
7.16 (m, 3H), 7.03 (d, 1H, J ) 2.6 Hz), 6.98 (dd, 1H, J ) 8.4, 2.6 Hz),
6.70-6.75 (m, 4H), 4.10 (t, 2H, J ) 5.6 Hz), 2.40 (t, 2H, J ) 6.8 Hz),
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powder (0.74 mg, 48%). H NMR (400 MHz, CD3OD): δ 7.35 (d,
1H, J ) 2.4 Hz), 7.30 (d, 1H, J ) 9.3 Hz), 7.27 (d, 1H, J ) 9.8 Hz),
7.19 (d, 1H, J ) 8.3 Hz), 7.11 (dd, 1H, J ) 9.3, 2.4 Hz), 6.88 (d, 1H,
J ) 2.2 Hz), 6.77 (dd, 1H, J ) 8.3, 2.2 Hz), 6.62 (dd, 1H, J ) 9.8, 2.0
Hz), 6.46 (d, 1H, J ) 2.0 Hz), 5.10 (dd, 1H, J ) 7.3, 1.5 Hz), 4.78 (s,
2H), 3.93 (d, 1H, J ) 2.4 Hz), 3.89-3.75 (m, 4H), 3.73 (s, 3H), 3.70-
3.69 (m, 1H), 3.65 (s, 3H). HRMS (ESI+): calcd for [M + H]+,
569.165 90; found, 569.168 46.
Synthesis of 9-[1-(4-Carboxymethoxy-2-methoxyphenyl)]-6-hy-
droxy-3H-xanthen-3-one (16). To a solution of 13 (4.1 mg, 10 µmol)
in methanol (1 mL) 2 N aq. NaOH (0.1 mL, 0.2 mmol) was added.
The mixture was stirred at room temperature for 4 h and then neutralized
with 2 N aq. HCl. The solvent was evaporated off, and the residue
was subjected to reversed-phase preparative TLC (RP18W) with
acetonitrile/water (1:1) as the eluent to give 16 as an orange powder
1
(3 mg, 76%). H NMR (300 MHz, CD3OD) δ 7.25 (d, 2H, J ) 9.17
Hz), 7.12 (d, 1H, J ) 8.25 Hz), 6.84 (d, 1H, J ) 2.20 Hz), 6.74 (dd,
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3928 J. AM. CHEM. SOC. VOL. 129, NO. 13, 2007