X. Wang et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
to room temperature for 24 h before it was quenched with 2 M HCl
(20 mL). After an additional 1 h, the mixture was extracted with
CHCl3/methanol (10:1, v/v) (40 mL ꢂ 3), the organic phase com-
bined, dried over MgSO4, and the solvent was removed. The crude
product was triturated with THF (20 mL ꢂ 3) to afford 8 (5.6 g,
4.6. (40S)-40-Ethyl-40-hydroxy-3-phenyl-70,80-dihydrospiro[oxir-
ane-2,60-pyrano[3,4-f]indolizine]-30,100(10H,40H)-dione 11
The
a-hydroxylation reaction was carried out under the same
condition, the residue was purified by flash chromatography (pet-
roleum ether/ethyl acetate 1:2, v/v) to give 11 (0.25 g, 5%), the
compound 11 (0.25 g, 5%) was obtained by flash chromatography
(ethyl acetate) and the recovery of catalyst 14a (0.51 g, 80%) was
obtained by CH2Cl2/ methanol, 10:1, v/v). Mp = 219–221 °C. IR
(neat): mmax (cmꢀ1) 3225, 2965, 1656, 1584, 1552, 1399, 1107,
1015, 908, 763, 688. 1H NMR (400 MHz, DMSO-d6): d 7.34–7.56
(m, 6H), 6.88 (s, 1H), 6.56 (s, 1H), 4.83 (d, J = 13.2 Hz, 1H), 4.68
(d, J = 13.2 Hz, 1H), 4.11 (t, J = 6.8 Hz, 2H), 3.23 (m, 2H), 1.88 (q,
J = 7.2 Hz, 2H), 0.76 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, DMSO-
d6): d 156.9, 152.5, 150.4, 136.1, 134.8, 129.1, 128.9, 128.1, 125.5,
125.4, 110.5, 92.5, 79.3, 69.3, 46.5, 31.6, 27.3, 8.3. HRMS calcd for
89%) as a pale yellow solid. Mp >300 °C; IR (neat): mmax (cmꢀ1
)
2972, 1745, 1723, 1623, 1575, 1532, 1183, 1053, 689, 655; 1H
NMR (400 MHz, DMSO-d6): d 7.38–7.45 (m, 5H), 7.19 (br s, 1H),
5.26 (dd, J = 9.6, 16.0 Hz, 2H), 4.04 (dd, J = 4.0, 7.2 Hz, 2H), 3.55
(m, 1H), 3.19 (m, 2H), 1.83 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H); 13CNMR
(100 MHz, DMSO-d6): d 169.9, 167.3, 156.4, 145.8, 143.6, 135.4,
134.0, 130.0, 129.1, 128.7, 117.9, 107.0, 64.9, 46.5, 43.9, 27.4,
24.4, 11.7.; HRMS calcd for C21H19NO5 [M]+ m/z 365.1302, found
m/z 365.1311.
4.4. (E)-6-Benzylidene-4-ethyl-7,8-dihydro-1H-pyrano[3,4-f]indo-
lizine-3,10(4H,6H)-dione 4
C
19H20NO3 [MꢀCO2+H]+ m/z 310.1443, found m/z 310.1447.
4.7. (4S)-4-Ethyl-4-hydroxy-6-(hydroxy(phenyl)methyl)-7,8-dihy-
dro-1H-pyrano[3,4-f]indolizine-3,10(4H,6H)-dione 10
A stirred solution of benzylidene acid 8 (7.3 g, 20 mmol) in
48% hydrobromic acid (50 mL) was heated at 90 °C for 3 h. The
mixture was cooled to room temperature then the solvent was
removed in vacuo. The residue was dissolved in ethyl acetate
(100 mL), washed with Sat. NaHCO3 (20 mL ꢂ 3). The organic
phase was washed with brine (30 mL), dried over Na2SO4, filtered,
and concentrated in vacuo, the crude product was crystallized
from ethanol (25 mL) to afford benzylidene 4 (6.0 g, 93%) as a yel-
low crystals. Mp = 184.0–185.7 °C; IR (neat): mmax (cmꢀ1) 3579,
3367, 1723, 1645, 1576, 1471, 1375, 1042, 844, 758, 691; 1H
NMR (400 MHz, CDCl3): d 7.36–7.50 (m, 5H), 7.19 (br s, 1H),
6.45 (s, 1H), 5.47 (d, J = 16.0 Hz, 1H), 5.29 (d, J = 16.0 Hz, 1H),
4.29 (t, J = 4.0, 7.6 Hz, 2H), 3.50 (t, J = 6.4 Hz, 1H), 3.27 (dt,
J = 2.4, 5.6 Hz, 2H), 2.01 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H). 13C
Mp >300 °C. IR (neat): m
max (cmꢀ1) 3404, 2930, 1611, 1568, 1367,
1090, 989, 809, 683. 1H NMR (400 MHz, DMSO-d6): d 7.56 (d,
J = 7.6 Hz, 2H), 7.44(t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.23
(s, 1H), 7.20 (s, 1H), 6.00 (s, 1H), 5.69 (dd, J = 3.2, 4.0 Hz, 1H), 4.76
(dd, J = 3.2, 8.4 Hz, 1H), 4.47 (dd, J = 3.2, 8.8 Hz, 1H), 4.10–4.02 (m,
3H), 3.17 (t, J = 6.0 Hz, 2H), 2.07 (q, J = 7.2 Hz, 1H), 1.93 (q,
J = 7.2 Hz, 1H), 0.81 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 174.8, 161.9, 156.4, 144.8, 136.4, 135.7, 129.3, 129.0, 128.1,
126.8, 124.3, 98.5, 80.0, 56.0, 48.9, 47.1, 31.5, 27.1, 9.4. HRMS calcd
for C20H22NO5 [M+H]+ m/z 356.1498, found m/z 356.1490.
4.8. (S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indo-
lizine-3,6,10(4H)-trione 2
NMR (100 MHz, CDCl3):
d 171.3, 157.6, 149.2, 146.8, 136.1,
135.0, 129.4, 129.2, 128.5, 126.2, 117.6, 96.7, 65.5, 47.2, 45.3,
27.0, 23.8, 11.5. HRMS calcd for
C
20H20NO3 [M+H]+ m/z
A solution of
a-hydroxylation lactone 9 (3.37 g, 10 mmol) in
322.1443, found m/z 322.1436.
CH2Cl2 (100 mL) was cooled to–40 °C and a stream of ozone in oxy-
gen was bubbled through. After the starting material had virtually
disappeared (0.5 h), a stream of oxygen was bubbled through the
reaction mixture for 15 min. The reaction mixture was treated with
dimethyl sulfide (1.46 mL, 20 mmol) and allowed to warm to room
temperature over 2 h. The solvent was removed in vacuo and the
residue was taken up in ethyl acetate and water and extracted with
ethyl acetate. The combined extracts were washed with brine, dried
over Na2SO4, and concentrated in vacuo to give trione 2 (2.5 g, 96%)
as a brown solid. The ee of 2 was increased from 94% to 99% by a
single recrystallization using ethyl acetate, determined by HPLC
4.5. (S,E)-6-Benzylidene-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyra-
no[3,4-f]indolizine-3,10(4H,6H)-dione 9
To a solution of benzylidene 4 (3.21 g, 10 mmol) in mixed
solvent CHCl3/toluene (10 mL/ 90 mL) were added .catalyst 14a
(0.63 g, 1 mmol), 4 Å MS (50 mg) and K2CO3 (1.65 g, 12 mmol) at
room temperature. The mixture was cooled to 0 °C and stirred
for 0.5 h, then cumene hydroperoxide (2.85 g, 15 mmol) was
added. The mixture was heated to 20 °C for 48 h. The reaction
was quenched by Na2S2O3 solution, and the mixture was stirred
at room temperature for 2 h. The organic phase was separated
and the aqueous phase was extracted with ethyl acetate
(30 mL ꢂ 3), the organic layers combined, dried over Na2SO4, con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy (petroleum ether/ethyl acetate 1:1, v/v) to give 9 (2.8 g, 85%),
the ee values of 9 was upgraded from 88% to 94% by recrystallized
from ethyl acetate, determined by HPLC analysis, Daicel AD-H, col-
analysis, Daicel AD-H, column (25 cm ꢂ 4.6 mm ꢂ 5
lm), n-hex-
ane/ i-PrOH = 70:30, 1.0 mL/min, 220 nm, 30 °C, tR(major)
= 26.5 min, tR (minor) = 54.7 min. Mp = 179–181 °C (lit. mp = 176–
21.8
20.0
177 °C), [
a]
= +115.3 (c 0.62, CHCl3) (lit. [
a]
+120.6 (c 0.62,
D
D
CHCl3)). 1H NMR (400 MHz, CDCl3): d 7.23 (s, 1H), 5,63 (d,
J = 16.8 Hz, 1H), 5.22 (d, J = 16.8 Hz, 1H), 4.35 (t, J = 6.8 Hz, 2H),
3.89 (br s, 1H), 2.98 (t, J = 6.0 Hz, 2H), 1.81 (q, J = 2.8, 4.4 Hz, 2H),
0.98 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 196.0, 173.1,
157.6, 149.2, 139.8, 124.4, 100.7, 72.2, 66.1, 42.1, 33.6, 31.6, 7.6.;
HRMS calcd for C13H14NO5 [M+H]+ m/z 264.0872, found m/z
264.0870.
umn (25 cm ꢂ 4.6 mm ꢂ 5
lm), n-hexane/i-PrOH = 80:20, 0.6 mL/
min, 220 nm, 30 °C, tR(minor)=42 min, tR (major) = 66 min. Mp
= 197.7–198.4 °C. IR (neat): mmax (cmꢀ1) 3359, 1739, 1635, 1546,
1450, 1163, 1042, 755, 691. 1H NMR (400 MHz, CDCl3): d 7.35–
7.50 (m, 5H), 7.27 (br s, 1H), 6.93 (s, 1H), 5.62 (d, J = 16.4 Hz,
1H), 5.20 (d, J = 16.4 Hz, 1H), 4.27 (m, 2H), 3.85 (br s, 1H), 3.27
(dt, J = 2.4, 5.6 Hz, 2H), 1.81 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3): d 174.7, 158.6, 150.1, 136.1, 134.3, 129.8,
129.5, 129.3, 127.9, 126.7, 95.2, 73.4, 67.0, 47.6, 32.0, 27.8, 8.4.
HRMS calcd for C20H20NO4 [M+H]+ m/z 338.1392, found m/z
338.1390.
4.9. (20S)-Camptothecin 116
Yield 78%. Mp = 264–265 °C (lit: 265–266 °C). IR (neat): mmax
(cmꢀ1). 3265, 2989, 2938, 1755, 1645, 1578, 1399, 1227, 1157,
20.4
1098, 1039, 997, 766, 723, 659. [
a
]
D
+41.5 (c 0.2, CHCl3/
23
MeOH = 4:1), lit. [
a
]
D
+42.0 (c 0.51, CHCl3/MeOH = 4:1). 1H NMR
(400 MHz, DMSO-d6): d 8.68 (s, 1H), 8.10 (dd, J = 8.4, 11.2 Hz,