N. Hirata et al. / Bioorg. Med. Chem. 17 (2009) 3775–3781
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dimethylsilyloxypentane (31.2 g, 110 mmol) followed by stirring
at room temperature for overnight. The reaction was quenched
with saturated aqueous NaHCO3 and extracted with EtOAc. The
combined organic layer was washed with brine, dried over anhy-
drous MgSO4, filtered, concentrated under reduced pressure. The
residue was purified by flash column chromatography (silica gel,
EtOAc–hexane = 1:10) to give the title compound (10.6 g, 38%
yield). A yellow oil; Rf = 0.74 (50% EtOAc–hexane); 1H NMR
(400 MHz, CDCl3) d 7.55 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H),
6.80 (dd, J = 2.4, 8.9 Hz, 1H), 3.99 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H),
3.60 (s, 3H), 3.59 (t, J = 6.6 Hz, 2H), 2.67 (s, 3H), 1.78 (m, 2H),
1.50 (m, 4H), 0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 166.6, 155.1, 145.3, 131.6, 127.3, 112.1, 109.6, 104.7, 103.4, 68.6,
63.1, 50.6, 32.6, 29.7, 29.2, 26.0, 22.4, 18.4, 12.0, ꢀ5.3; FABMS m/z
419 [M+]; HRMS calcd for C23H38NO4Si [(M+H)+] 420.2565, found
420.2580.
(4.61 g, 85% yield). An off-white solid; mp 90–91 °C; Rf = 0.91
(80% EtOAc–hexane); 1H NMR (300 MHz, DMSO-d6) d 6.80 (d,
J = 8.6 Hz, 1H), 6.56 (d, J = 8.6 Hz, 1H), 5.68 (bs, 2H), 3.86 (m, 2H),
3.58 (s, 3H), 3.56 (m, 5H) 3.28 (s, 3H), 2.57 (s, 3H), 1.69 (m, 2H),
1.46 (m, 4H), 0.83 (s, 9H), 0.01 (s, 6H); 13C NMR (75.5 MHz,
DMSO-d6), d 166.7, 144.0, 139.2, 133.6, 131.0, 113.5, 111.0, 102.9,
96.6, 69.7, 62.4, 51.0, 32.1, 29.8, 29.0, 25.8, 22.0, 17.9, 12.7, -5.3;
FABMS m/z 435 [(M+H)+]; HRMS calcd for C23H39N2O4Si [(M+H)+]
435.2674, found 435.2673.
4.2.5. {4-Amino-5-[5-(tert-butyldimethylsilanyloxy)pentoxy]-
1,2-dimethyl-1H-indole-3-yl}methanol (6)
To a solution of the ester 5 (4.61 g, 11 mmol) in THF (50 mL)
cooled in ice-water bath (0 °C) was added lithium aluminium hy-
dride (800 mg, 21 mmol) followed by stirring at the same tem-
perature for 30 min. The reaction was quenched by ice-water.
The reaction mixture was extracted with EtOAc. The combined
organic layer was washed with brine, died over anhydrous
MgSO4, filtered, concentrated under reduced pressure. The given
compound was immediately reacted for the next step without
purification.
4.2.2. 5-(5-Hydroxypentoxy)-1,2-dimethyl-4-nitro-1H-indole-
3-carboxylic acid methyl ester (3)
To a solution of the indole 2 (4.33 g, 10 mmol) and acetic acid
(1.8 mL, 30 mmol) in CH2Cl2 (50 mL) cooled in ice-water bath
(0 °C) was added 61% nitric acid (1.2 mL, 15 mmol) followed by
stirring at room temperature for 4 h. The reaction was quenched
with saturated aqueous NaHCO3 and extracted with CHCl3. The
combined organic layer was washed brine, dried over MgSO4, fil-
tered and concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica gel, EtOAc–hex-
ane = 4:1) to give the title compound (2.22 g, 63% yield). A brown
solid; mp 83–87 °C; Rf = 0.09 (50% EtOAc–hexane); 1H NMR
(400 MHz, DMSO-d6) d 7.73 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 9.0 Hz,
1H), 4.35 (t, J = 5.0 Hz, 1H), 4.09 (t, J = 6.4 Hz, 2H), 3.76 (s, 3H),
3.63 (s, 3H), 3.38 (q, J = 6.1 Hz, 2H), 2.66 (s, 3H), 1.66 (m, 2H),
1.44–1.38 (4H); 13C NMR (100 MHz, DMSO-d6) d 164.0, 147.7,
145.5, 132.2, 116.7, 113.3, 109.5, 101.3, 101.1, 70.2, 60.6, 50.0,
32.0, 30.2, 28.5, 21.8, 11.7; FABMS m/z 350 [M+]; HRMS calcd for
C17H23N2O6 [(M+H)+] 351.1551, found 351.1554.
4.2.6. 5-[5-(tert-Butyldimethylsilanyloxy)pentoxy]-3-
hydroxymethyl-1,2-dimethyl-1H-indole-4,7- dione (7)
To a solution of the 4-aminoindole 6 (4.31 g, crude) and trio-
ctylmethylammonium chloride (8.6 g, 21 mmol) in THF (22 mL)
cooled in ice-water bath (0 °C) was added potassium nitrosodisulf-
onate (Fremy’s salt) (7.18 g, 27 mmol) in aqueous sodium dihydro-
genphosphate (0.3 M, 22 mL) followed by stirring at the same
temperature for 20 min. The reaction was quenched saturated
aqueous NaHCO3, extracted with EtOAc. The combined organic
layer was washed with brine, dried over anhydrous MgSO4,
filtered, concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica gel, EtOAc–hex-
ane = 1:2) to give the title compound (3.52 g, 79% yield in two
steps).
A
red oil; Rf = 0.63 (80% EtOAc–hexane); 1H NMR
(400 MHz, DMSO-d6), d 5.68 (s, 1H), 4.58 (d, J = 4.9 Hz, 1H), 4.54
(s, 2H), 3.88 (t, J = 6.3 Hz, 2H), 3.80 (s, 3H), 3.56 (t, J = 6.0 Hz, 2H),
2.20 (s, 3H), 1.74–1.68 (2H), 1.48–1.39 (4H), 0.83 (s, 9H), 0.00 (s,
6H); 13C NMR (100 MHz, DMSO-d6) d 177.5, 159.0, 154.7, 135.0,
126.0, 122.5, 120.4, 104.5, 69.4, 62.3, 54.4, 31.9, 31.8, 27.6, 25.8,
21.8, 17.9, 9.2, -5.3; FABMS m/z 421 [M+]; HRMS calcd for
C22H36NO5Si [(M+H)+] 422.2357, found 422.2354.
4.2.3. 4-Amino-5-(5-hydroxypentoxy)-1,2-dimethyl-1H-indole-
3-carboxylic acid methyl ester (4)
To a solution of 3 (2.21 g, 6.3 mmol) in EtOH (50 mL) were
added Sn (3.75 g, 32 mmol) and 35% HCl (13 mL, 147 mmol). The
reaction was refluxed with stirring at 80 °C for 2 h. The reaction
was quenched with saturated aqueous NaHCO3 and extracted with
EtOAc. The combined organic layer was washed with brine, dried
over anhydrous MgSO4, filtered, concentrated under reduced pres-
sure to give the title compound (1.91 g, 95% yield). An off-white so-
lid; mp 103–105 °C; Rf = 0.50 (80% EtOAc–hexane); 1H NMR
(300 MHz, DMSO-d6) d 6.83 (d, J = 8.8 Hz, 1H), 6.59 (d, J = 8.6 Hz,
1H), 5.72 (bs, 2H), 4.35 (t, J = 5.2 Hz, 1H), 3.89 (t, J = 6.5 Hz, 2H),
3.80 (s, 3H), 3.58 (s, 3H), 3.41 (m, 2H), 2.60 (s, 3H), 1.72 (m, 2H),
1.48–1.45 (4H); 13C NMR (75.5 MHz, DMSO-d6) d 166.7, 144.1,
139.2, 133.6, 131.0, 113.5, 111.0, 102.9, 96.6, 69.8, 60.6, 51.0,
32.3, 29.8, 29.1, 22.2, 12.7; FABMS m/z 320 [M+]; HRMS calcd for
C17H25N2O4 [(M+H)+] 321.1809, found 321.1804.
4.2.7. Indolequinone derivatives conjugated with biotin (8)
To a solution of the indolequinone 7 (1.73 g, 4.1 mmol) and bio-
tin (2.03 g, 8.3 mmol) in DMF (23 mL) cooled in ice-water bath
(0 °C) were added O-(7-azabenzotriazol-1-yl)-N,N,N0,N0-tetrameth-
yluronium tetrafluoroborate (2.71 g, 8.4 mmol), 4-(dimethyl-
amino)pyridine (612 mg, 5 mmol), and N,N0-diisopropylethyl-
amine (1.44 mL, 8.2 mmol) followed by stirring at room tempera-
ture for overnight. The reaction was quenched with saturated
aqueous NaHCO3 and extracted with CHCl3. The combined organic
layer was washed with brine, dried over anhydrous MgSO4, fil-
tered, concentrated under reduced pressure. The residue was puri-
fied by flash column chromatography (silica gel, MeOH–
CHCl3 = 1:20) to give the title compound (2.48 g, 93% yield). An or-
ange solid, mp 109–110 °C; Rf = 0.54 (9% MeOH–CHCl3); 1H NMR
(400 MHz, DMSO-d6) d 6.37 (s, 1H), 6.32 (s, 1H), 5.72 (s, 1H), 5.10
(s, 2H), 4.26 (t, J = 7.6 Hz, 1H), 4.08 (m, 1H), 3.89 (t, J = 6.3 Hz,
2H), 3.81 (s, 3H), 3.81 (m, 2H), 3.02 (m, 1H), 2.67 (dd, J = 12.4,
5.1 Hz, 1H), 2.53 (d, J = 12.4 Hz, 1H), 2.24–2.21 (5H), 1.72–1.69
(2H), 1.49–1.41 (8H), 1.27 (m, 2H), 0.82 (s, 9H), 0.00 (s, 6H); 13C
NMR (100 MHz, DMSO-d6) d 178.3, 177.1, 172.7, 162.6, 158.5,
138.4, 128.1, 120.8, 114.8, 106.9, 69.1, 62.3, 61.0, 59.1, 56.0, 55.3,
40.1, 33.3, 32.1, 31.9, 27.91, 27.89, 27.6, 25.8, 24.6, 21.8, 17.9,
4.2.4. 4-Amino-5-[5-(tert-butyldimethylsilanyloxy)pentoxy]-
1,2-dimethyl-1H-indole-3-carboxylic acid methyl ester (5)
To a solution of the alcohol 4 (4.0 g, 12.5 mmol) and imidazole
(1.84 g, 27 mmol) in DMF (50 mL) cooled in ice-water bath (0 °C)
was added tert-butyldimethylsilylchloride (3.94 g, 26 mmol) fol-
lowed by stirring at room temperature for 3.5 h. The reaction
was quenched with saturated aqueous NaHCO3 and extracted with
EtOAc. The combined organic layer was washed with brine, dried
over anhydrous MgSO4, filtered, concentrated under reduced pres-
sure. The residue was purified by flash column chromatography
(silica gel, EtOAc–hexane = 1:4) to give the title compound