Chemistry of Heterocyclic Compounds 2017, 53(4), 434–445
The combined organic layers were washed with saturated
(KBr), ν, cm–1: 3355 (O–H), 2961 (C–H), 1653 (C=O),
1589, 1455, 1401 (CH3, CH2), 1143, 1066 (C–O), 754, 724
(CH3, CH2). UV spectrum (MeCN), λmax, nm (log ε): 197.5
(4.47), 220.5 (4.53), 244.5 (4.42), 252.5 (4.46), 290.0
(3.83), 332.5 (3.92), 367.5 (4.25). 1H NMR spectrum
(300 MHz, CDCl3), δ, ppm (J, Hz): 0.84 (3H, t, J = 7.0,
CH2CH3); 1.71–1.91 (1H, m) and 1.91–2.10 (1H, m,
2'-CH2); 3.23–3.38 (4H, m, H-1', OCH3); 3.45 (3H, s,
OCH3); 4.00 (1H, mc, OH); 4.58 (1H, d, J = 7.4,
CH(OCH3)2); 4.69–4.80 (1H, m) and 4.89–5.01 (1H, m,
CH2OH); 5.27 (2H, s, 11-CH2); 7.30 (1H, s, H-6); 7.64
(1H, mc, H-2); 7.81 (1H, mc, H-3); 7.92 (1H, d, J = 8.1, H-1);
8.22 (1H, d, J = 8.5, H-4); 8.36 (1H, s, H-12). Mass
spectrum (ESI), m/z (Irel, %): 381 [M+H]+ (100). Found, m/z:
381.1808 [M+H]+, 403.1628 [M+Na]+. C22H24N2O4. Calcu-
lated, m/z: 381.1808, 403.1628.
Synthesis of compounds 32 and 33. A mixture of com-
pound 31 (3.2 mg, 8.4 μmol, 1.0 equiv) and LiBF4 (6.7 mg,
71 μmol, 8.5 equiv) in MeCN–H2O (50:1, 0.3 ml) was
stirred at room temperature for 30 min and then at 65°C for
70 min. After slight cooling, LiBF4 (5.8 mg, 62.0 μmol,
7.4 equiv) and a mixture of MeCN–H2O (50:1, 0.1 ml)
were added. The reaction mixture was then stirred at 65°C
for 30 min. Aqueous 5% NaHCO3 solution (1 ml) was
added, the aqueous phase was extracted with CH2Cl2
(3×10 ml), and the combined organic layers were dried
over anhydrous Na2SO4. After the removal of solvent, the
residue was purified by silica gel column chromatography
(EtOAc–NEt3, 40:3 → EtOAc–MeOH, 20:1), providing
two products – enol ether 33 and lactol 32.
aqueous Na2SO3 solution (25 ml) and saturated aqueous
NaCl solution (25 ml), dried over anhydrous MgSO4, and
the solvent was removed under reduced pressure. Silica gel
column chromatography (CH2Cl2–MeOH, 100:1) provided
the title compound 1. Yield 5 mg, (32%), pale-yellow solid.
20
[α]D
+14.4° (c 0.34, CHCl3–MeOH, 4:1). HPLC
(Chiralpak IA, (n-hexane–MeOH–CH2Cl2 4:2:1)–CH2Cl2,
80:20, flow rate 0.6 ml/min, 254 nm): tR 13.7 min (R)-(1),
tR 14.6 min (S)-(1), 37% ee. ([α]D20 +14.2° (c 0.34, CHCl3–
MeOH, 4:1)13b). The remaining analytical data correspond
to the racemic compound.
Methyl 7-(1,1-dimethoxybutan-2-yl)-9-oxo-9,11-dihydro-
indolizino[1,2-b]quinoline-8-carboxylate (30). A mixture
of compound 4ba (10 mg, 27 μmol, 1.0 equiv),
RuCl3·nH2O (2 mg, 9.6 μmol), trimethyl orthoformate
(3.5 mg, 33 μmol, 1.2 equiv) in methanol (1 ml) was stirred
in a pressure flask at 60°C for 3.5 h. Aqueous 5% NaHCO3
solution (5 ml) was added, the aqueous phase was extracted
with CH2Cl2 (3×10 ml), and the combined organic layers
were dried over Na2SO4. After removal of the solvent, the
residue was purified by silica gel column chromatography
(pentane–EtOAc, 1:1) to give the acetal intermediate. Yield
6.0 mg (54%), white solid. A mixture of the acetal (14 mg,
34 μmol, 1.0 equiv) and DDQ (15 mg, 68 μmol, 2.0 equiv)
in 1,4-dioxane (2 ml) was stirred at 65°C for 1 h. After
cooling to room temperature, the precipitate was removed
by filtration, washed with CH2Cl2, and the filtrate was
concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc–
NEt3, 20:1) to obtain compound 30. Yield 11 mg (79%),
yellow solid. Rf 0.38 (EtOAc–NEt3, 20:1). 1H NMR
spectrum (300 MHz, CDCl3), δ, ppm (J, Hz): 0.87 (3H, t,
J = 7.4, CH2CH3); 1.70–1.88 (1H, m) and 1.88–2.06 (1H,
m, 2'-CH2); 3.04–3.16 (1H, m, 1'-CH); 3.32 (3H, s, OCH3);
3.41 (3H, s, OCH3); 3.96 (3H, s, CO2CH3); 4.58 (1H, d,
J = 6.5, CH(OCH3)2); 5.28 (2H, s, 11-CH2); 7.34 (1H, s,
H-6); 7.66 (1H, mc, H-2); 7.83 (1H, mc, H-3); 7.93 (1H, d,
J = 8.1, H-1); 8.23 (1H, d, J = 8.5, H-4); 8.38 (1H, s,
H-12). Mass spectrum (ESI), m/z (Irel, %): 431.1 [M+Na]+
(100). Found, m/z: 409.1757 [M+H]+, 431.1576 [M+Na]+,
447.1316 [M+K]+. C23H24N2O5. Calculated, m/z: 409.1758,
431.1577, 447.1316.
7-(1,1-Dimethoxybutan-2-yl)-8-(hydroxymethyl)-
indolizino[1,2-b]quinolin-9(11H)-one (31). DIBAL-H
(1.0 M in CH2Cl2, 54 μl, 54 μmol, 2.0 equiv) was added
dropwise to a solution of compound 30 (11 mg, 27 μmol,
1.0 equiv) in dichloromethane (1.5 ml) at −78°C and stirred
at this temperature for 1.5 h. Subsequently, methanol
(2 ml) and NaBH4 (12 mg, 0.32 mmol, 12 equiv) were
added at −78°C and stirred for 1 h. The reaction mixture
was warmed to room temperature and stirred for 40 min.
Aqueous 1 M NaOH solution (5 ml) was added, the
aqueous phase was extracted with CH2Cl2 (3×10 ml), and
the combined organic layers were dried over anhydrous
Na2SO4. After removal of the solvent, the residue was
purified by silica gel column chromatography (EtOAc–
MeOH, 20:1), providing alcohol 31. Yield 7.3 mg (71%),
yellow solid. Rf 0.20 (EtOAc–MeOH, 30:1). IR spectrum
4-Ethyl-3-hydroxy-1,3,4,12-tetrahydro-14H-pyrano-
[3',4':6,7]indolizino[1,2-b]quinolin-14-one (32). Yield
1.1 mg (40%), light-yellow solid, Rf 0.13 (EtOAc–NEt3,
1
20:1) or 0.22 (EtOAc–MeOH, 40:1). H NMR spectrum
(300 MHz, CDCl3), δ, ppm (J, Hz): 1.07 (3H, t, J = 7.5,
CH2CH3); 1.80 (2H, mc, CH2CH3); 2.67 (1H, t, J = 6.6,
4-CH); 2.97 (1H, br. s, OH); 4.85 (2H, mc, 1-CH2); 5.24
(2H, s, 12-CH2); 5.35–5.44 (1H, m, 3-CH); 7.19 (1H, s,
H-5); 7.63 (1H, mc, H-9); 7.80 (1H, mc, H-8); 7.91 (1H, d,
J = 8.3, H-10); 8.20 (1H, d, J = 8.6, H-7); 8.34 (1H, s,
H-11). Mass spectrum (ESI), m/z (Irel, %): 335 [M+H]+
(100). Found, m/z: 335.1390 [M+H]+. C20H18N2O3. Calcu-
lated, m/z: 335.1390.
8-(Hydroxymethyl)-7-(1-methoxybut-1-en-2-yl)-
indolizino[1,2-b]quinolin-9(11H)-one (33). Yield 1.7 mg
1
(60%), white solid, Rf 0.31 (EtOAc–NEt3, 20:1). H NMR
spectrum (300 MHz, CDCl3, isomer A/B ratio 1:1), δ, ppm
(J, Hz): 1.04–1.17 (3H, m, CH2CH3); 1.72–1.87 (1.5H, m,
2'-CH2, isomer A and 2'-CHAHB, isomer B); 2.62 (0.5H,
mc, 2'-CHAHB, isomer B); 2.89 (1H, br. s, OH); 3.50 (1.5H,
s, OCH3, isomer A); 3.54 (1.5H, s, OCH3, isomer B); 4.65
(0.5H, dd, J = 17.1, J = 1.4, CHAHBOH, isomer A); 4.77–
4.95 (2.5H, m, CHAHBOH, isomer A and CHOCH3); 5.25
(2H, s, 11-CH2); 7.19 (0.5H, s, H-6, isomer A); 7.32 (0.5H,
s, H-6, isomer B); 7.63 (1H, mc, H-2); 7.81 (1H, mc, H-3);
7.92 (1H, d, J = 8.1, H-1); 8.20 (1H, d, J = 8.5, H-4); 8.35
(1H, s, H-12). Mass spectrum (ESI), m/z (Irel, %): 349
[M+H]+ (100). Found, m/z: 349.1547 [M+H]+. C21H20N2O3.
Calculated, m/z: 349.1546.
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