4
Q. Liu et al. / Tetrahedron xxx (xxxx) xxx
ethyl acetate was added to extract the product. The extract was
separated and concentrated in vacuo to afford a yellow oil. The
crude product was purified by column chromatography on silica gel
(ethyl acetate-ether petroleum, 1:5) to afford a light yellow oil
calcd. for C20H40N2NaO7[MþNa]þ: 563.2728; found: 563.2721.
Note: Compound 6 is a mixture of diastereoisomers, so its 13C
NMR spectrum is complex.
(7.1 g, 80%). 1H NMR (400 MHz, CDCl3)
d
9.72 (s, 1H), 7.93 (d,
4.6. (7S)-7-((2S,4S)-2-tert-butyl-4-ethyl-5-oxo-1,3-dioxolan-4-yl)-
J ¼ 8.5 Hz, 1H), 7.82 (d, J ¼ 4.3 Hz, 1H), 7.67 (d, J ¼ 8.1 Hz, 1H), 7.56 (t,
J ¼ 7.6 Hz,1H), 7.41 (t, J ¼ 7.3 Hz,1H), 5.31 (s,1H), 4.89e4.53 (m, 2H),
3.27 (dd, J ¼ 70.3, 15.6 Hz, 1H), 3.01 (t, J ¼ 16.6 Hz, 1H), 1.46 (s, 9H).
5b,6,7,8-tetrahydroindolizino[1,2-b]quinolin-9(11H)-one (14)
To a solution of compound 6 (5.4 g, 10.0 mmol) in DCM (60 mL)
was added 2,6-lutidine (2.1 g, 20.0 mmol, 2.0 equiv.). The solution
was cooled to 0 ꢁC and then TMSOTf (4.4 g, 20.0 mmol, 2.0 equiv.)
was added. The mixture was stirred at 0 ꢁC for 8 h to complete the
cleavage of the Boc group. Saturated NaHCO3 solution (100 mL) was
added to the solution, which was then stirred for 30 min. The DCM
layer was separated and concentrated in vacuo. The residue was
dissolved in CHCl3 (50 mL) and heated to reflux for 8 h to complete
the cyclization. The CHCl3 was removed in vacuo, and the residue
purified by column chromatography on silica gel (ethyl acetate-
ether petroleum, 5:1 to 1:1) to afford a white solid (3.1 g, 75%). 1H
13C NMR (100 MHz, CDCl3)
d 199.56, 161.40, 161.11, 154.23, 153.94,
147.90, 129.65, 129.42, 129.22, 128.72, 128.20, 127.70, 127.42, 126.41,
126.35,81.13, 80.36, 58.54, 58.40,50.01, 49.73, 48.80, 47.71, 28.31.
HRMS (ESI) calcd. for C18H20N2NaO3[MþNa]þ: 335.1366; found:
335.1353.
4.4. (E/Z)-tert-butyl-3-(3-(methoxycarbonyl)allyl)-1H-pyrrolo[3,4-
b]quinoline-2(3H)-carboxylate (7)
To a solution of compound 12 (7.0 g, 22.4 mmol) in DCM
(100 mL) was added methyl (triphenylphosphoranylidene)acetate
(11.2 g, 33.6 mmol, 1.5 equiv.). The solution was stirred at room
temperature for 5 h. The solvent was removed in vacuo and the
residue was purified by column chromatography on silica gel (ethyl
acetate-ether petroleum, 1:6) to afford a light yellow solid (7.5 g,
NMR (400 MHz, CDCl3)
d
8.06 (dd, J ¼ 13.7, 5.9 Hz, 2H), 7.81 (d,
J ¼ 7.9 Hz, 1H), 7.71 (t, J ¼ 7.5 Hz, 1H), 7.54 (t, J ¼ 7.4 Hz, 1H),
5.37e5.00 (m, 2H), 5.00e4.79 (m, 1H), 4.67 (dd, J ¼ 44.1, 16.2 Hz,
1H), 2.89e2.54 (m, 3H), 2.54e2.34 (m, 1H), 2.11e1.95 (m, 1H),
1.93e1.64 (m, 2H), 1.03 (t, J ¼ 7.3 Hz, 3H), 0.97 (d, J ¼ 8.0 Hz, 9H). 13
C
91%).1H NMR (400 MHz, CDCl3)
d
8.06 (d, J ¼ 7.1 Hz, 1H), 7.97 (d,
NMR (100 MHz, CDCl3) d 173.82, 170.02, 168.01, 161.84, 161.24,
J ¼ 27.3 Hz, 1H), 7.80 (d, J ¼ 7.4 Hz, 1H), 7.70 (t, J ¼ 7.6 Hz, 1H), 7.53 (t,
J ¼ 7.3 Hz, 1H), 6.66 (m, 1H), 5.79 (d, 1H), 5.27 (d, J ¼ 28.3 Hz, 1H),
4.89 (dd, J ¼ 49.4, 15.7 Hz, 1H), 4.65 (d, J ¼ 15.7 Hz, 1H), 3.61 (d, 3H),
3.20 (m, 1H), 2.97 (m, 1H), 1.55 (s, 9H). 13C NMR (100 MHz, CDCl3)
148.14, 130.65, 130.28, 129.79, 129.13, 129.07,128.18, 128.06, 128.01,
127.91, 127.86, 127.75, 126.96, 126.94, 109.59, 109.16, 84.44, 84.21,
62.05, 59.91, 48.53, 48.10, 38.04, 35.11, 35.05 34.63, 33.67, 32.24,
29.77, 29.30, 27.05, 26.58, 23.75, 8.28, 8.08. HRMS (ESI) calcd. for
d
166.60, 166.39, 161.80, 161.38, 154.47, 154.19, 148.33, 143.86,
C
24H28N2NaO4[MþNa]þ:431.1941; found: 431.1944.
143.77,129.99, 129.75, 129.49, 129.12, 128.91, 128.56, 127.95, 127.89,
127.64, 126.64, 124.41, 124.19, 80.78, 80.38, 62.19, 51.42, 50.47,
Note: Compound 14 is a mixture of diastereoisomers (because of
the chiral centers in the C-ring and D-ring), so its 13C NMR spec-
trum is complex.
49.88,
C
37.61,
35.87,
28.54.
HRMS
(ESI)
calcd.
for
21H24N2NaO4[MþNa]þ: 391.1628; found: 391.1624.
4.7. 7-((2R,4S)-2-tert-butyl-4-ethyl-5-oxo-1,3-dioxolan-4-yl)
4.5. Tert-butyl 3-((R)-3-(methoxycarbonyl)-2-((2R,4S)-2-tert-
butyl-4-ethyl-5-oxo- 1, 3-dioxolan-4-yl)propyl)-1H-pyrrolo[3,4-b]
quinoline-2(3H)-carboxylate (6)
indolizino[1,2-b]quinolin-9(11H)-one (15)
To a solution of compound 14 (0.82 g, 2.0 mmol) in THF (15 mL)
was added DDQ (1.0 g, 4.4 mol, 2.2 equiv.). The solution was stirred
at room temperature for 5 h. The THF was removed in vacuo and the
residue purified by column chromatography on silica gel (DCM-
MeOH, 50:1) to afford a light yellow solid which was pulped in DCM
(4 mL) to remove the undesired epimer. The mixture was filtrated
A solution of diisopropylamine (4.02 g, 40.0 mmol, 4.0 equiv.) in
THF (50 mL) in a N2 atmosphere was cooled to ꢀ40 ꢁC. BuLi (2.5 M
in hexanes, 16 mL, 40.0 mmol, 4.0 equiv.) was added to the solution,
which was then stirred for 1 h. Compound 3 (6.90 g, 40.0 mmol)
was added to the solution and the temperature was maintained
below ꢀ30 ꢁC. The mixture was stirred for another 1 h and then
cooled to ꢀ60 ꢁC. A solution of 7 (3.68 g in 20 mL of THF, 10 mmol)
was added to the mixture drop-wise keeping the temperature
below ꢀ50 ꢁC; the mixture was stirred for another 5 h. Saturated
NH4Cl solution (60 mL) was added into the solution and then the
solvent was removed in vacuo and 100 mL of ethyl acetate was
added to extract the product. The extract was separated and
concentrated in vacuo and the residue was purified by column
chromatography on silica gel (ethyl acetate-ether petroleum, 1:6)
to afford a light yellow oil (4.90 g, 90%). 1H NMR (400 MHz, CDCl3)
through a funnel to obtain a light yellow solid (0.75 g, 92%). Mp:
D
185 ꢁCe187 ꢁC.
(400 MHz, CDCl3)
[
a
d
]
¼ ꢀ15.7ꢁ (c ¼ 0.66, CHCl3). 1H NMR
20
8.32 (s, 1H), 8.18 (d, J ¼ 8.5 Hz, 1H), 7.87 (d,
J ¼ 8.1 Hz, 1H), 7.78 (t, J ¼ 7.6 Hz, 1H), 7.61 (t, J ¼ 7.4 Hz, 1H), 7.47 (s,
1H), 6.88 (s, 1H), 5.21 (s, 2H), 5.19 (s, 1H), 2.14 (dd, J ¼ 14.5, 7.2 Hz,
2H), 1.04 (s, 9H), 0.95 (t, 3H). 13C NMR (100 MHz, CDCl3)
d 171.93,
161.10, 152.49, 150.48, 148.93, 146.87, 131.05, 130.54, 129.85, 128.73,
128.17, 128.13, 127.96, 116.30, 108.13, 98.22, 83.21, 49.94, 34.57,
31.84, 23.64, 8.15. HRMS (ESI) calcd. for C24H24N2NaO4 [MþNa]þ:
427.1628; found: 427.1625.
d
8.06 (dd, J ¼ 22.2, 8.4 Hz, 1H), 8.01e7.90 (m, 1H), 7.78 (d, J ¼ 7.7 Hz,
4.8. 20(S)-camptothecin (1)
1H), 7.72e7.60 (m, 1H), 7.50 (t, J ¼ 7.1 Hz, 1H), 5.46e4.51 (m, 4H),
3.69e3.23 (m, 3H), 2.94e1.86 (m, 5H), 1.85e1.60 (m, 2H), 1.53 (s,
9H), 0.86 (t, J ¼ 16.7 Hz, 9H), 0.59 (d, 3H).13C NMR (100 MHz, CDCl3)
Compound 15 (100 mg, 0.25 mmol) was charged into a 10 mL
tube. Then to this tube was added 36% HCl (0.4 mL), AcOH (0.4 mL),
40% formaldehyde (0.92 g, 1.25 mmol, 5.0 equiv.) and 1,4-dioxane
(3.0 mL). The solution was heated to 90 ꢁC and then stirred for 19 h.
The solution was neutralized by saturated NaHCO3 solution (20 mL)
and then was extracted with CHCl3 (15 mL). The CHCl3 was
removed under reduced pressure and the residue was purified by
column chromatography on silica gel (DCM-MeOH, 25:1 to 10:1) to
afford a yellow solid (68 mg, 80%). Mp: 260 ꢁCe262 ꢁC (dec.);
d
174.27,174.14, 172.95, 172.80, 172.75, 172.28, 162.43, 154.52, 147.91,
129.81, 129.63, 129.55,129.48,129.35,129.30, 129.22, 129.16,128.81,
128.37, 127.89, 127.80, 127.50, 127.46, 126.62, 126.53, 111.53, 106.96,
106.80, 106.38, 106.27, 87.07, 85.06, 85.01, 84.51, 84.39, 83.38, 80.77,
80.73, 80.27, 80.24, 69.15, 61.35, 60.87, 60.25, 59.91, 51.84, 51.59,
51.49, 50.04, 49.16, 47.78, 46.30, 35.93, 35.06, 34.35, 34.25, 34.04,
33.79, 31.76, 28.65, 28.06, 23.89, 23.80, 23.70, 23.43, 23.26, 23.04,
21.28, 20.95, 20.64, 20.28, 10.39, 8.87, 8.26, 8.04, 7.47. HRMS (ESI)
D
D
[a
]
¼ þ29.1ꢁ (c ¼ 0.5, CHCl3-MeOH, 4:1) [Lit [19]. [
a
]
¼ 31.3ꢁ
20
20
Please cite this article as: Q. Liu et al., Asymmetric total synthesis of (20S)-Camptothecin using a chiral auxiliary strategy, Tetrahedron, https://
doi.org/10.1016/j.tet.2019.03.028