Synthesis of (±)-cephalanthrin a using baeyer-villiger oxidation

Article abstract of DOI:10.3987/COM-16-S(S)5

Indoloquinazoline alkaloid (±)-cephalanthrin A was synthesized through the Baeyer-Villiger oxidation of the phenyl ketone derived from aldol reaction of tryptanthrin and acetophenone.

Full text of DOI:10.3987/COM-16-S(S)5

HETEROCYCLES, Vol. 95, No. 1, 2017, pp. -. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 11th May, 2016, Accepted, 7th June, 2016, Published online, 22nd June, 2016
DOI: 10.3987/COM-16-S(S)5
SYNTHESIS OF (±)-CEPHALANTHRIN A USING BAEYER-VILLIGER
OXIDATION
Tomoki Itoh,a Takumi Abe,a Tominari Choshi,b Takashi Nishiyama,b and
Minoru Ishikuraa*
aSchool of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan. E-mail; ishikura@hoku-iryo-u.ac.jp
bFaculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University,
Fukuyama, Hiroshima 729-0292, Japan
Abstract – Indoloquinazoline alkaloid (±)-cephalanthrin A was synthesized
through the Baeyer-Villiger oxidation of the phenyl ketone derived from aldol
reaction of tryptanthrin and acetophenone.
Alkaloids, characterized by an indolo[2,1-b]quinazoline core, exhibit a wide range of potential biological
activities (Figure 1).1 The diverse biological activities and structural intricacy elicited intense synthetic
interest.2 (+)-Cephalanthrins A (3a) and B (4) were first isolated from Cephalantheropsis gracilis in
2015.3 The first enantioselective total synthesis of (+)-3a was achieved by the Ni-catalyzed
enantioselective aldol-decarboxylation reaction of malonic acid and tryptanthrin (1a). The absolute
configuration of (+)-3a was determined as (S) based on the asymmetric synthesis and X-ray analysis.4
O
O
O
O
CO2Me
Me
OH
HO
OH
H
N
N
N
N
N
N
N
N
N
N
MeO
O
CO2Me
O
O
O
tryptanthrin (1a)
phaitanthrin E (2)
phaitanthrin A (5)
cephalanthrin A (3a)
cephalanthrin B (4)
Figure 1. Indoloquinazoline alkaloids
We previously reported the one-pot synthesis of tryptanthrin (1a) by the oxidative dimerization of
indole-3-carbaldehyde,5a and skatole.5b In this paper, we describe the synthesis of (±)-cephalanthrin A
(3a) starting from tryptanthrin (1a) and acetophenone 8a through Baeyer-Villiger oxidation of phenyl

ketone 7a.
Baeyer-Villiger oxidation is a valuable process by which ketones are converted into esters or lactones.6 In
2013, Baeyer-Villiger oxidation of phaitanthrin A (5) with m-CPBA in CH2Cl2 was reported. Because the
Me group is a poor migrator, the methyl ketone in 5 was converted to acetate ester though migration of
the methylene unit.7 Therefore, we were interested in whether phenyl migration would be dominant
during the oxidation of ketone 7a, leading to ester 6a. Tryptanthrin (1a) can be obtained on the gram scale
from indole-3-carbaldehyde,5a and ketone 7a can be obtained by aldol reaction of 1a with acetophenone
8a. Hydrolysis of 6a could produce (±)-cephalanthrin A (3a) (Scheme 1).
O
O
O
HO
Ph
OH
Ph
7a
O
OH
OH
Baeyer-Villiger
oxidation
hydrolysis
N
N
N
N
N
N
O
O
O
6a
cephalanthrin A (3a)
O
oxidative
dimerization
N
aldol reaction
CHO
N
PhCOMe
8a
+
N
O
H
tryptanthrin (1a)
Scheme 1
Aldol reaction of 1 and acetophenone 8 (4 equiv) was performed in diethylamine at room temperature for
16 h, smoothly affording 7 (Scheme 2).
O
O
R
OH
Me
8
N
X
X
7
N
+
N
O
R
Et2NH, rt
N
O
1
X
a: R = H
O
a: X = H
b: X = Me
c: X = Br
X
b: R = 4-methoxy
c: R = 3-methoxy
d: R = 2-methoxy
e: R = 4-bromo
f : R = 3-bromo
g: R = 2-bromo
a: R = X = H
80%
84%
82%
70%
71%
f : R = 3-bromo, X = H
g: R = 2-bromo, X = H
h: R = H, X = methyl
i : R = H, X = Br
66%
65%
73%
76%
b: R = 4-methoxy, X = H
c: R = 3-methoxy, X = H
d: R = 2-methoxy, X = H
e: R = 4-bromo, X = H
Scheme 2

Baeyer-Villiger oxidation of ketone 7a was investigated (Table 1). Initially, 7a was treated with m-CPBA,
but no reaction occurred (Entry 1). Treating 7a with urea hydrogen peroxide (UHP) produced 1a in 10%
yield without 6a (Entry 2). Because Baeyer-Villiger oxidation is assisted by an acid or base,6,8 the
reaction was examined in the presence of NaHCO3, although only 1a was obtained in 20% yield (Entry 3).
In addition, the oxidation was examined in the presence of a catalytic amount of acid. Although treating
7a with concentrated H2SO4 in CH2Cl2 afforded trace amounts of 6a and 1a (Entry 4), replacing CH2Cl2
with MeCN increased the yield to 58% (Entry 5). Moreover, the reaction in DMF produced 6a in 72%
yield (Entry 6). TFA and AcOH were less effective than concentrated H2SO4 (Entries 7 and 8). In
addition, UHP was used for the oxidation instead of m-CPBA. The oxidation in DMF produced trace
amounts of 6a (Entry 9). The reaction was greatly accelerated in MeCN, affording 6a in 80% yield (Entry
10). Only trace amounts of 1a were produced with AcOH (Entry 11), and 6a was obtained in 53% yield
in the presence of TFA (Entry 12).
Table 1. Baeyer-Villiger oxidation of ketone 7a
O
O
O
N
Ph
Ph
7a
O
OH
OH
Conditions
N
N
N
+
N
N
O
1a
O
6a
O
Yield (%)a
Entry
Conditions
6a
1a
---
10
20
5
1
2
m-CPBA (5 equiv), CH2Cl2, rt, 72 h
---b
---c
---d
6
UHP (5 equiv), CH2Cl2, rt, 16 h
3
m-CPBA (5 equiv), NaHCO3 (5 equiv), CH2Cl2, rt, 72 h
m-CPBA (5 equiv), concd H2SO4 (cat), CH2Cl2, rt, 16 h
m-CPBA (5 equiv), concd H2SO4 (cat), MeCN, rt, 16 h
m-CPBA (5 equiv), concd H2SO4 (cat), DMF, rt, 16 h
m-CPBA (5 equiv), TFA (cat), DMF, rt, 16 h
4
5
58
72
68
34
5
---
---
---
---
---
---
10
---
6
7
8
m-CPBA (5 equiv), AcOH (cat), DMF, rt, 16 h
UHP (5 equiv), concd H2SO4 (cat), DMF, rt, 16 h
UHP (5 equiv), concd H2SO4 (cat), MeCN, rt, 16 h
UHP (5 equiv), AcOH (cat), MeCN, rt, 16 h
9
10
11
12
80
---
53
UHP (5 equiv), TFA (cat), MeCN, rt, 16 h
aIsolated yield. bRecovery of 7a in 75%. cRecovery of 7a in 50%. dRecovery of 7a in 40%.

In addition, the oxidation of aryl ketones 7b–7i was examined under the optimized conditions (UHP,
concentrated H2SO4, MeCN). Initially, methoxyphenyl ketones 7b–7d were oxidized. The reaction of 7b
and 7c reached completion within 16 h to produce 6b and 6c in 75% and 79% yields, respectively (Table
2, Entries 1 and 2), and 6d was obtained in 45% yield from 7d, although the reaction took 24 h (Entry 3).
Moreover, bromophenyl ketones 7e–7g were oxidized under the same conditions to give 6e–6g but in
decreased yields (40% to 60%) (Entries 4–6) and required a long reaction time (96 h). The reactions of 7h
and 7i, which had a Me or Br substituent on the quinazoline system, respectively, produced 6h in 70%
yield and 6i in 65% yield (Entries 7 and 8).
Table 2. Baeyer-Villiger oxidation of ketones 7b–7i
O
O
R
R
OH
UHP (5 equiv)
concd H2SO4 (cat)
O
OH
N
N
X
X
N
N
MeCN, rt
O
7
O
6
X
X
Entry
X
Reaction time
16 h
Yield (%)a
75 (6b)
79 (6c)
45 (6d)
52 (6e)
60 (6f)
7
1
2
3
4
5
6
7
8
7b (R = 4-methoxyphenyl)
7c (R = 3-methoxyphenyl)
7d (R = 2-methoxyphenyl)
7e (R = 4-bromophenyl)
7f (R = 3-bromophenyl)
7g (R = 2-bromophenyl)
7h (R = phenyl)
H
H
16 h
H
24 h
H
96 h
H
96 h
H
96 h
40 (6g)
70 (6h)
65 (6i)
Me
Br
96 h
7i (R = phenyl)
96 h
aIsolated yield.
Finally, 6a was subjected to hydrolytic cleavage. Ester 6a was not appreciably hydrolyzed by 10% aq.
KOH in 1,4-dioxane, and (±)-cephalanthrin A (3a) was obtained in 25% yield by treating 6a with 10% aq.
NaOH. Hydrolysis of 6a with Cs2CO3 in THF/MeOH produced (±)-3a in 60% yield, whereas hydrolysis
of 6a with LiOH in THF/H2O afforded (±)-3a in 87% yield (Scheme 3). The NMR data of (±)-3a were
good agreement with those reported in the literature.3
In conclusion, (±)-cephalanthrin A (3a) was synthesized starting from tryptanthrin (1a) and acetophenone
(8a) through Baeyer-Villiger oxidation of ketone 7a.

O
O
Ph
HO
OH
O
OH
N
N
N
N
O
(±)-3a
6a
O
10% aq. KOH, 1,4-dioxane, rt, 16 h
10% aq. NaOH, 1,4-dioxane, rt, 16 h
Cs2CO3 (3 equiv), THF/H2O, rt, 16 h
LiOH (3 equiv), THF/H2O, rt, 3 h
---
25%
60%
87%
Scheme 3
EXPERIMENTAL
Melting points were recorded with a Yamato MP21 and were uncorrected. High-resolution MS spectra
were recorded with a JEOL JMS-T100LP mass spectrometer. IR spectra were measured with a Shimadzu
IRAffinity-1 spectrometer. The NMR experiments were performed with a JEOL JNM-ECA500 (500
MHz) spectrometer, and chemical shifts are expressed in ppm (G).
General procedure for aldol reaction between 1a and 8: Acetophenone 8 (40 mmol) was added to a
solution of tryptanthrin (1) (10 mmol) in diethylamine (80 mL), and the mixture was stirred at room
temperature for 16 h. The mixture was added to 10% HCl aqueous solution (100 mL). The mixture was
extracted with AcOEt (500 mL), and the extract was washed with brine and dried over MgSO4. The
solvent was removed, and the residue was purified by silica gel column chromatography with
hexane/AcOEt (1:2) to give 7.
6-Hydroxy-6-(2-oxo-2-phenylethyl)indolo[2,1-b]quinazolin-12(6H)-one (7a): A colorless solid. Mp
1
224-225 °C. IR (CHCl3): 3447, 3013, 2976, 1681, 1670 cm-1. H-NMR (DMSO-d6) G: 4.12 (d, J = 18.3
Hz, 1H), 4.51 (d, J = 18.3 Hz, 1H), 6.56 (br s, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.42-7.48 (m, 3H), 7.57-7.61
(m, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.81-7.84 (m, 3H), 8.30 (dd, J = 1.2, 8.1 Hz,
1H), 8.43 (d, J = 8.0 Hz, 1H). 13C-NMR (DMSO-d6) G: 48.3, 75.6, 116.5, 121.9, 124.3, 127.0, 127.1,
127.9, 128.0, 128.5, 129.3, 130.2, 134.3, 134.7, 135.3, 136.1, 139.9, 147.7, 159.5, 162.0, 197.3. HRMS
(ESI) m/z: Calcd for C23H16N2NaO3 [(M + Na)+] 391.1059. Found 391.1062.
6-Hydroxy-6-[2-(4-methoxyphenyl)-2-oxoethyl]indolo[2,1-b]quinazolin-12(6H)-one (7b): A colorless
solid. Mp 213-214 °C. IR (CHCl3): 3447, 3012, 2976, 1680, 1672, 1647, 1602 cm-1. 1H-NMR (DMSO-d6)
G: 3.77 (s, 3H), 4.05 (dd, J = 2.3, 18.4 Hz, 1H), 4.44 (d, J = 18.4 Hz, 1H), 6.53 (br s, 1H), 6.94 (d, J = 8.6
Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 7.5 Hz,
1H), 7.70 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.83 (t, J = 8.0 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H),
8.42 (d, J = 8.1 Hz, 1H). 13C-NMR (DMSO-d6) G: 47.9, 56.1, 75.7, 114.4, 116.5, 121.9, 124.2, 126.9,
127.8, 127.9, 129.1, 130.1, 130.9, 134.8, 135.3, 140.0, 147.7, 159.5, 162.2, 164.0, 195.5. HRMS (ESI)
m/z: Calcd for C24H18N2NaO4 [(M + Na)+] 421.1164. Found 421.1161.

6-Hydroxy-6-[2-(3-methoxyphenyl)-2-oxoethyl]indolo[2,1-b]quinazolin-12(6H)-one (7c): A colorless
solid. Mp 170-172 °C. IR (CHCl3): 3385, 3365, 3014, 2976, 1683, 1647, 1605 cm-1. 1H-NMR (DMSO-d6)
G: 3.71 (s, 3H), 4.11 (d, J = 18.9 Hz, 1H), 4.51 (d, J = 18.9 Hz, 1H), 6.55 (br s, 1H), 7.14 (dd, J = 2.9, 8.0
Hz, 1H), 7.26 (s, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.49 (t, J
= 7.5 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.83 (t, J = 8.6
13
Hz, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H). C-NMR (DMSO-d6) G: 48.4, 55.8, 75.6,
112.4, 116.5, 120.8, 121.2, 121.9, 124.3, 126.9, 127.1, 127.9, 128.0, 130.2, 130.5, 134.7, 135.3, 137.4,
140.0, 147.6, 159.5, 159.9, 162.0, 197.1. HRMS (ESI) m/z: Calcd for C24H18N2NaO4 [(M + Na)+]
421.1164. Found 421.1168.
6-Hydroxy-6-[2-(2-methoxyphenyl)-2-oxoethyl]indolo[2,1-b]quinazolin-12(6H)-one (7d): A colorless
1
solid. Mp 206-208 °C. IR (CHCl3): 3447, 3010, 2976, 1684, 1647, 1605 cm-1. H-NMR (DMSO-d6) G:
3.94 (s, 3H), 4.11 (dd, J = 18.9 Hz, 1H), 4.26 (d, J = 18.4 Hz, 1H), 6.50 (br s, 1H), 6.84 (t, J = 7.5 Hz,
1H), 7.12 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 1.7, 8.0 Hz, 1H), 7.28 (dt, J = 1.2, 7.5 Hz, 1H), 7.44-7.49 (m,
2H), 7.57-7.60 (m, 2H), 7.71 (d, J = 7.5 Hz, 1H), 7.84 (dt, J = 1.8, 8.6 Hz, 1H), 8.29 (dd, J = 1.2, 8.0 Hz,
1H), 8.41 (d, J = 8.1 Hz, 1H). 13C-NMR (DMSO-d6) G: 53.6, 56.5, 75.5, 113.1, 116.5, 120.9, 121.9, 124.2,
126.4, 126.9, 127.8, 128.0, 130.0, 130.1, 134.6, 135.2, 135.3, 139.9, 147.7, 159.4, 159.5, 162.1, 197.7.
HRMS (ESI) m/z: Calcd for C24H18N2NaO4 [(M + Na)+] 421.1164. Found 421.1162.
6-Hydroxy-6-[2-(4-bromophenyl)-2-oxoethyl]indolo[2,1-b]quinazolin-12(6H)-one (7e): A colorless
solid. Mp 201-202 °C. IR (CHCl3): 3447, 3016, 2976, 1728, 1684 cm-1. 1H-NMR (DMSO-d6) G: 4.09 (d,
J = 18.3 Hz, 1H), 4.49 (d, J = 18.4 Hz, 1H), 6.57 (br s, 1H), 7.29 (dt, J = 1.2, 6.9 Hz, 1H), 7.47 (dt, J =
1.2, 8.0 Hz, 1H), 7.59 (dt, J = 1.2, 8.6 Hz, 1H), 7.63-7.66 (m, 3H), 7.70 (d, J = 7.5 Hz, 1H), 7.77 (d, J =
13
6.9 Hz, 2H), 7.83 (dt, J = 1.2, 7.5 Hz, 1H), 8.30 (dd, J = 1.2, 8.1 Hz, 1H), 8.42 (d, J = 8.1 Hz, 1H). C
NMR (DMSO-d6) G: 48.2, 75.6, 116.5, 121.9, 124.3, 127.0, 127.1, 127.9, 128.0, 128.5, 130.3, 130.6,
132.3, 134.5, 135.1, 135.3, 139.9, 147.6, 159.5, 161.9, 196.6. HRMS (ESI) m/z: Calcd for
C23H15BrN2NaO3 [(M + Na)+] 469.0164, 471.0143. Found 469.0159, 471.0148.
6-Hydroxy-6-[2-(3-bromophenyl)-2-oxoethyl]indolo[2,1-b]quinazolin-12(6H)-one (7f): A colorless
1
solid. Mp 203-204 °C. IR (CHCl3): 3458, 3014, 2976, 1684, 1651, 1605 cm-1. H-NMR (DMSO-d6) G:
4.11 (d, J = 18.3 Hz, 1H), 4.54 (d, J = 18.3 Hz, 1H), 6.57 (br s, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.40 (t, J =
8.0 Hz, 1H), 7.47 (dt, J = 1.1, 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.70 (d, J =
8.1 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1H), 7.82-7.85 (m, 2H), 8.30 (d, J = 6.9 Hz, 1H), 8.42 (d, J = 8.1 Hz,
13
1H). C-NMR (DMSO-d6) G: 48.3, 75.6, 116.5, 121.9, 122.7, 124.4, 127.0, 127.1, 127.6, 127.9, 128.0,
130.3, 131.2, 131.5, 134.5, 135.3, 136.9, 138.0, 139.9, 147.6, 159.5, 161.9, 196.4. HRMS (ESI) m/z:
Calcd for C23H15BrN2NaO3 [(M + Na)+] 469.0164, 471.0143. Found 469.0163, 471.0156.
6-Hydroxy-6-[2-(2-bromophenyl)-2-oxoethyl]indolo[2,1-b]quinazolin-12(6H)-one (7g): A colorless
1
solid. Mp 198-199 °C. IR (CHCl3): 3447, 3419, 3014, 2976, 1683, 1649 cm-1. H-NMR (DMSO-d6) G:
4.05 (d, J = 17.8 Hz, 1H), 4.27 (d, J = 17.8 Hz, 1H), 6.62 (br s, 1H), 7.32-7.35 (m, 2H), 7.38 (dt, J = 1.2,

7.5 Hz, 1H), 7.49 (dt, J = 1.2, 8.0 Hz, 2H), 7.56 (dd, J = 1.2, 8.0 Hz, 1H), 7.60 (dt, J = 1.2, 7.4 Hz, 1H),
7.70 (d, J = 6.9 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1 H), 7.86 (dt, J = 1.8, 7.9 Hz, 1H), 8.29 (dd, J = 1.2, 8.1 Hz,
1H), 8.41 (d, J = 8.0 Hz, 1H). 13C-NMR (DMSO-d6) G: 51.5, 75.5, 116.6, 118.5, 121.9, 124.7, 126.9,
127.1, 127.9, 128.1, 128.3, 129.8, 130.4, 133.1, 133.9, 134.2, 135.4, 139.7, 139.8, 147.6, 159.4, 161.4,
200.1. HRMS (ESI) m/z: Calcd for C23H15BrN2NaO3 [(M + Na)+] 469.0164, 471.0143. Found 469.0158,
471.0151.
6-Hydroxy-2,8-dimethyl-6-(2-oxo-2-phenylethyl)indolo[2,1-b]quinazolin-12(6H)-one
(7h):
A
1
colorless solid. Mp 214-216 °C. IR (CHCl3): 3447, 3014, 2976, 1716, 1680, 1645 cm-1. H-NMR
(DMSO-d6) G: 2.29 (s, 3H), 2.46 (s, 3H), 4.10 (d, J = 18.3 Hz, 1H), 4.45 (d, J = 18.3 Hz, 1H), 6.49 (br s,
1H), 7.25 (dd, J = 1.2, 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.5 Hz, 1H), 7.56-7.59 (m, 2H),
7.62 (dd, J = 1.2, 8.6 Hz, 1H), 7.82 (d, J = 6.9 Hz, 2H), 8.08 (s, 1H), 8.29 (d, J = 8.6 Hz, 1H). 13C-NMR
(DMSO-d6) G: 21.3, 21.4, 48.3, 75.5, 116.3, 121.7, 124.7, 126.3, 127.8, 128.5, 129.3, 130.4, 134.2, 134.7,
136.1, 136.3, 136.4, 137.5, 137.8, 145.7, 161.3, 197.2. HRMS (ESI) m/z: Calcd for C25H20N2NaO3 [(M +
Na)+] 419.1372. Found 419.1375.
6-Hydroxy-2,8-dibromo-6-(2-oxo-2-phenylethyl)indolo[2,1-b]quinazolin-12(6H)-one (7i): A colorless
1
solid. Mp 258-260 °C (decomp.). IR (CHCl3): 3447, 3017, 2976, 1716, 1688 cm-1. H-NMR (DMSO-d6)
G: 4.13 (d, J = 18.4 Hz, 1H), 4.63 (d, J = 18.9 Hz, 1H), 6.70 (br s, 1H), 7.45 (t, J = 8.1 Hz, 2H), 7.59 (t, J
= 7.5 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.69 (dd, J = 1.7, 8.6 Hz, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.94 (d, J
= 1.7 Hz, 1H), 7.99 (dd, J = 2.3, 8.6 Hz, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 2.3 Hz, 1H). 13C-NMR
(DMSO-d6) G: 48.2, 75.6, 118.4, 119.7, 120.7, 123.4, 127.6, 128.6, 129.2, 129.3, 130.4, 133.1, 134.4,
135.9, 137.3, 138.4, 138.9, 146.6, 158.2, 162.1, 197.5. HRMS (ESI) m/z: Calcd for C23H14Br2N2NaO3
[(M + Na)+] 546.9269, 548.9248, 550.9228. Found 546.9262, 548.9246, 550.9241.
General procedure for Baeyer-Villiger oxidation: UHP (941 mg, 10 mmol) was added to a solution of
ketone 7 (2 mmol) in MeCN (30 mL), followed by the addition of concentrated H2SO4 (10 PL) at 0 °C.
The mixture was stirred at room temperature. After specific time, the resulting mixture was added to
saturated NaHCO3 solution, extracted with AcOEt (100 mL), washed with brine, and dried over MgSO4.
The solvent was removed, and the residue was purified by silica gel column chromatography with
hexane/AcOEt (1:2) to give ester 6.
Phenyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)acetate (6a): A colorless solid.
Mp 197-198 °C. IR (CHCl3): 3393, 1703, 1620 cm-1. 1H-NMR (CDCl3) G: 3.52 (d, J = 16.0 Hz, 1H), 3.69
(d, J = 16.1 Hz, 1H), 4.96 (br s, 1H), 6.78 (d, J = 8.1 Hz, 2H), 7.11-7.24 (m, 5H), 7.46 (td, J = 1.7, 7.0 Hz,
1H), 7.62 (d, J = 6.9 Hz, 1H), 7.71-7.77 (m, 2H), 8.16 (d, J = 7.5 Hz, 1H), 8.26 (d, J = 8.1 Hz, 1H).
13C-NMR (CDCl3) G: 43.3, 75.5, 116.9, 121.3, 121.7, 123.7, 126.2, 127.1, 127.2, 127.6, 127.8, 129.5,
130.8, 131.3, 134.6, 139.0, 147.2, 149.9, 159.4, 159.8, 168.3. HRMS (ESI) m/z: Calcd for C23H16N2NaO4
[(M + Na)+] 407.1008. Found 407.1005.
4-Methoxyphenyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)acetate (6b): A

colorless solid. Mp 169-170 °C. IR (CHCl3): 3446, 1749, 1681, 1649, 1604 cm-1. 1H-NMR (DMSO-d6) G:
3.60 (s, 3H), 3.61 (d, J = 15.5 Hz, 1H), 3.66 (d, J = 15.5 Hz, 1H), 6.48 (d, J = 8.6 Hz, 2H), 6.73 (d, J =
9.2 Hz, 2H), 6.77 (br s, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H),
7.78 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.88 (t, J = 7.5 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H), 8.39
13
(d, J = 8.0 Hz, 1H). C-NMR (DMSO-d6) G: 43.8, 55.9, 75.5, 114.9, 116.6, 121.8, 122.4, 124.9, 127.0,
127.3, 128.2, 130.8, 133.4, 135.5, 139.6, 143.5, 147.5, 157.4, 159.3, 161.1, 168.4. HRMS (ESI) m/z:
Calcd for C24H18N2NaO5 [(M + Na)+] 437.1113. Found 437.1116.
3-Methoxyphenyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)acetate (6c): A
1
colorless solid. Mp 145-146 °C. IR (CHCl3): 3361, 3336, 1759, 1683, 1666, 1649, 1606 cm-1. H-NMR
(DMSO-d6) G: 3.56 (s, 3H), 3.62 (d, J = 15.5 Hz, 1H), 3.67 (d, J = 15.5 Hz, 1H), 6.06 (t, J = 2.3 Hz, 1H),
6.15 (dd, J = 1.7, 8.0 Hz, 1H), 6.66 (dd, J = 2.3, 8.6 Hz, 1H), 6.81 (br s, 1H), 7.10 (t, J = 8.6 Hz, 1H),
7.43 (td, J = 1.2, 6.9 Hz, 1H), 7.55 (td, J = 1.2, 8.1 Hz, 1H), 7.60 (td, J = 1.2, 7.5 Hz, 1H), 7.79 (d, J = 6.9
Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.88 (td, J = 1.1, 7.5 Hz, 1H), 8.26 (dd, J = 1.2, 8.0 Hz, 1H), 8.41 (d, J
= 8.0 Hz, 1H). 13C-NMR (DMSO-d6) G: 43.9, 55.8, 75.5, 107.4, 112.3, 113.8, 116.6, 121.8, 125.1, 127.0,
127.4, 128.1, 128.2, 130.5, 130.9, 133.3, 135.5, 139.5, 147.5, 151.1, 159.3, 160.5, 160.9, 167.9. HRMS
(ESI) m/z: Calcd for C24H18N2NaO5 [(M + Na)+] 437.1113. Found 437.1112.
2-Methoxyphenyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)acetate (6d): A
colorless solid. Mp 170-172 °C. IR (CHCl3): 3462, 3446, 1681, 1668, 1656 cm-1. 1H-NMR (DMSO-d6) G:
3.35 (s, 3H), 3.65 (d, J = 16.6 Hz, 1H), 3.69 (d, J = 15.5 Hz, 1H), 6.60 (dd, J = 1.7, 8.0 Hz, 1H),
6.72-6.75 (m, 2H), 6.88 (dd, J = 1.7, 8.0 Hz, 1H), 7.06 (dt, J = 1.7, 8.3 Hz, 1H), 7.42 (dt, J = 1.1. 8.0 Hz,
1H), 7.52 (dt, J = 1.2, 7.5 Hz, 1H), 7.59 (dt, J = 1.2, 7.6 Hz, 1H), 7.78 (dd, J = 1.1, 8.0 Hz, 1H), 7.83 (d, J
= 7.5 Hz, 1H), 7.87 (dt, J = 1.2, 8.0 Hz, 1H), 8.26 (dd, J = 1.2, 8.1 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H).
13C-NMR (DMSO-d6) G: 43.2, 55.9, 75.3, 113.3, 116.5, 120.9, 121.9, 122.6, 124.9, 126.9, 127.2, 127.5,
128.1, 130.7, 133.5, 135.4, 139.1, 139.7, 147.6, 150.9, 159.3, 161.0, 167.5. HRMS (ESI) m/z: Calcd for
C24H18N2NaO5 [(M + Na)+] 437.1113. Found 437.1115.
4-Bromophenyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)acetate (6e):
A
1
colorless solid. Mp 223-224 °C. IR (CHCl3): 3462, 3446, 1749, 1684 cm-1. H-NMR (DMSO-d6) G: 3.67
(s, 2H), 6.61 (d, J = 8.6 Hz, 2H), 6.79 (br s, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.54 (t,
J = 7.5 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.88 (t, J =
6.9 Hz, 1H), 8.26 (d, J = 8.1 Hz, 1H), 8.39 (d, J = 8.1 Hz, 1H). 13C-NMR (DMSO-d6) G: 43.7, 75.4, 116.6,
118.8, 121.9, 124.1, 125.0, 127.0, 127.3, 128.1, 128.2, 130.9, 132.9, 133.3, 135.5, 139.5, 147.5, 149.4,
159.3, 160.9, 168.0. HRMS (ESI) m/z: Calcd for C23H15BrN2NaO4 [(M + Na)+] 485.0113, 487.0092.
Found 485.0109, 487.0085.
3-Bromophenyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)acetate (6f):
A
colorless solid. Mp 184-185 °C. IR (CHCl3): 3447, 1749, 1684 cm-1. 1H-NMR (DMSO-d6) G: 3.64 (d, J =
16.1 Hz, 1H), 3.68 (d, J = 16.1 Hz, 1H), 6.65 (dd, J = 1.8, 7.5 Hz, 1H), 6.81 (br s, 1H), 6.84 (t, J = 2.3 Hz,

1H), 7.20 (t, J = 8.1 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H),
7.60 (t, J = 8.1 Hz, 1H), 7.80 (t, J = 8.0 Hz, 2H), 7.88 (t, J = 7.5 Hz, 1H), 8.26 (dd, J = 1.2, 8.0 Hz, 1H),
13
8.39 (d, J = 8.0 Hz, 1H). C-NMR (DMSO-d6) G: 43.7, 75.4, 116.6, 121.1, 121.8, 121.9, 124.9, 125.1,
127.0, 127.4, 128.1, 128.2, 129.6, 130.9, 131.8, 133.3, 135.5, 139.5, 147.5, 150.8, 159.3, 160.9, 168.0.
HRMS (ESI) m/z: Calcd for C23H15BrN2NaO4 [(M + Na)+] 485.0113, 487.0092. Found 485.0110,
487.0092.
2-Bromophenyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)acetate (6g):
A
1
colorless solid. Mp 213-215 °C. IR (CHCl3): 3523, 3446, 1762, 1683 cm-1. H-NMR (DMSO-d6) G: 3.74
(d, J = 16.6 Hz, 1H), 3.79 (d, J = 16.6 Hz, 1H), 6.81 (br s, 1H), 6.85 (dd, J = 1.8, 8.6 Hz, 1H), 7.08 (dt, J
= 1.2, 7.5 Hz, 1H), 7.25 (dt, J = 1.2, 8.0 Hz, 1H), 7.40 (dt, J = 1.1, 7.5 Hz, 1H), 7.49 (dd, J = 1.2, 8.0 Hz,
1H), 7.51 (dt, J = 1.2, 7.5 Hz, 1H), 7.59 (dt, J = 1.2, 7.5 Hz, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.87 (dt, J =
13
1.2, 6.9 Hz, 1H), 8.25 (dd, J = 1.2, 8.0 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H). C-NMR (DMSO-d6) G: 43.2,
75.2, 115.7, 116.6, 121.9, 124.2, 125.1, 127.0, 127.3, 128.1, 128.2, 128.6, 129.6, 130.8, 133.3, 133.5,
135.4, 139.7, 147.5, 147.7, 159.3, 160.8, 167.5. HRMS (ESI) m/z: Calcd for C23H15BrN2NaO4 [(M +
Na)+] 485.0113, 487.0092. Found 485.0111, 487.0085.
Phenyl 2-(6-hydroxy-2,8-dimethyl-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)acetate (6h): A
1
colorless solid. Mp 218-220 °C. IR (CHCl3): 3446, 1749, 1680, 1647 cm-1. H-NMR (DMSO-d6) G: 2.38
(s, 3H), 2.45 (s, 3H), 3.59 (d, J = 15.5 Hz, 1H), 3.66 (d, J = 15.5 Hz, 1H), 6.59 (d, J = 8.0 Hz, 2H), 6.72
(br s, 1H), 7.09 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 8.0 Hz, 2H), 7.33 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.68 (t,
J = 8.0 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 8.03 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H). 13C-NMR (DMSO-d6) G:
21.3, 21.4, 43.8, 75.3, 116.3, 121.6, 125.3, 126.3, 126.5, 127.9, 129.9, 131.0, 133.5, 136.5, 136.8, 137.4,
137.9, 145.5, 150.2, 159.1, 160.3, 168.1. HRMS (ESI) m/z: Calcd for C25H20N2NaO4 [(M + Na)+]
435.1321. Found 435.1325.
Phenyl 2-(2,8-dibromo-6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)acetate (6i): A
1
colorless solid. Mp 222-224 °C. IR (CHCl3): 3446, 1738, 1684 cm-1. H-NMR (CDCl3) G: 3.54 (d, J =
16.6 Hz, 1H), 3.71 (d, J = 16.6 Hz, 1H), 6.81 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 7.22-7.28 (m,
4H), 7.65 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 2.3, 8.6 Hz, 1H), 8.01 (d, J = 8.6 Hz,
13
1H), 8.19 (d, J = 1.7 Hz, 1H). C-NMR (CDCl3) G: 43.1, 75.3, 118.2, 120.9, 121.2, 122.0, 122.8, 126.4,
127.1, 129.5, 129.6, 133.5, 133.9, 137.6, 138.2, 145.9, 149.8, 158.4, 159.2, 168.1. HRMS (ESI) m/z:
Calcd for C23H14Br2N2NaO4 [(M + Na)+] 562.9218, 564.9198, 566.9177. Found 562.9225, 564.9203,
566.9173.
Synthesis of (±)-cephalanthrin A (3a): LiOH•H2O (420 mg, 10 mmol) was added to a solution of
phenyl ester 7a (1.47 g, 4 mmol) in THF (80 mL) and H2O (20 mL) and the mixture was stirred at room
temperature. After 3 h, the resulting mixture was added to 10% HCl aq. solution, extracted with AcOEt
(300 mL), washed with brine, and dried over MgSO4. The solvent was removed, and the residue was
purified by silica gel column chromatography with hexane/AcOEt (1:1) to give (±)-3a (1.08 g, 87%). A

pale purple amorphous powder. Mp 218-220 °C (lit.1 Mp 212-214 °C). IR (CHCl3): 3444, 1710, 1683,
1605 cm-1. 1H-NMR (acetone-d6) G: 3.46 (d, J = 16.6 Hz, 1H), 3.57 (d, J = 16.6 Hz, 1H), 5.56 (br s, 1H),
7.37 (dt, J = 1.1, 7.4 Hz, 1H), 7.57 (dt, J = 1.2, 8.0 Hz, 1H), 7.59 (dt, J = 1.2, 7.5 Hz, 1H), 7.72 (d, J = 7.5
Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.85 (dt, J = 1.7, 8.6 Hz, 1H), 8.33 (dd, J = 1.7, 8.0 Hz, 1H), 8.48 (d, J
13
= 8.0 Hz, 1H), 10.91 (br s, 1H). C-NMR (acetone-d6) G: 42.7, 75.2, 116.5, 122.2, 123.9, 126.5, 126.6,
127.3, 127.8, 130.1, 133.3, 134.5, 140.1, 147.7, 159.2, 161.1, 169.9. HRMS (ESI) m/z: Calcd for
C17H12N2NaO4 [(M + Na)+] 331.0695. Found 331.0699.
ACKNOWLEDGEMENTS
This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology
of Japan through a Grant-in Aid for Scientific Research (No. 26460012), the Akiyama Foundation, and
the Hoyu Science Foundation.
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