Exploiting an intramolecular Diels-Alder cyclization/dehydro-aromatization sequence for the total syntheses of ellipticines and calothrixin B

Article abstract of DOI:10.1039/d0ob02527e

The tetracyclic and pentacyclic skeletons of pyrido and quinolinocarbazole alkaloids have been synthesizedviaa unified strategy. The prominent key step involved a Diels-Alder intramolecular cyclization/dehydro-aromatization sequence. From these carbazole-lactam cores, linear syntheses have been developed for ellipticines and calothrixin B.

Full text of DOI:10.1039/d0ob02527e

Organic &
Biomolecular Chemistry
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Exploiting an intramolecular Diels–Alder
cyclization/dehydro-aromatization sequence for
the total syntheses of ellipticines and calothrixin
Cite this: Org. Biomol. Chem., 2021,
9, 1395
1
B†
a,b
a,b
b
b
a,b
Chengdan Deng,‡ Yuancui Liu,‡ Mei Xu, Kaiqiang Xie* and Sheng Liu
*
Received 18th December 2020,
Accepted 18th January 2021
The tetracyclic and pentacyclic skeletons of pyrido and quinolinocarbazole alkaloids have been syn-
thesized via a unified strategy. The prominent key step involved a Diels–Alder intramolecular cyclization/
dehydro-aromatization sequence. From these carbazole-lactam cores, linear syntheses have been devel-
oped for ellipticines and calothrixin B.
DOI: 10.1039/d0ob02527e
rsc.li/obc
domino process to deliver the basic framework of natural
Introduction
quino[4,3-b]carbazoles (Scheme 1a), thus achieving a novel
1
1
Pyrido and quinolinocarbazole alkaloids (Fig. 1) are well- total synthesis of calothrixin B. Very recently, we further dis-
1
known for their wide range of potent biological activities.
covered a DBU-catalyzed intermolecular cyclization to con-
Ellipticine (1a) was isolated from the leaves of Ochrosia elliptica struct the pentacyclic skeleton of calothrixin alkaloids
Labill by Goodwin et al. and Ochrosia sandwicensis A.DC. of the (Scheme 1b), permitting us to accomplish a total synthesis of
2
12
Apocynaceae family in 1959. In the following years, a group of calothrixin B with atom and step economy. The intra-
related metabolites of ellipticine such as 3,4-dehydroellipticine molecular Diels–Alder reaction is a powerful strategy for the
1
3
(
1b) and 1,2,3,4-tetrahydroellipticine (1c) were also isolated construction of multicyclic natural products. Due to our con-
3
from different plants. The biological activity of ellipticine was tinued interest in the synthesis of biologically active carba-
considered to be based mainly on DNA intercalation and topoi- zoles, we seek to develop a unified synthetic strategy involving
4
somerase II inhibition. Calothrixin A (2) and B (3) are two cya-
a
tandem Diels–Alder cyclization/dehydro-aromatization
nobacterial metabolites with quino[4,3-b]carbazole frameworks sequence (Scheme 1c) for construction of the tetracyclic and
that were first isolated from cell extracts of Calothrix cyanobac- pentacyclic cores of pyrido and quinolino carbazoles.
5
terium in 1999. They possess a unique framework with an
The retrosynthetic strategy is shown in Scheme 2. We envi-
assembly of quinoline, quinone, and indole pharmacophores. saged that both ellipticines and calothrixin B could be derived
Calothrixin A is known to be an N-oxide analog of calothrixin from carbazole-lactam precursors 4, then the most salient
B. They act as human DNA topoisomerase I poisons exhibiting feature of this strategy is the creation of the C and D rings of
lethal effects on human cancer cell lines at low nano-molar intermediates 4 using an intramolecular Diels–Alder cycliza-
concentrations, and inhibit in vitro growth of a chloroquine- tion/dehydro-aromatization tandem transformation from
6
resistant strain of the human parasite Plasmodium falciparum.
To date, numerous efforts have also been invested in devel-
amides 5. In turn, the amides 5 could be readily produced
7
,8
oping efficient synthetic avenues to ellipticines
calothrixins,
and
9
,10
which are well documented. In 2018, we
reported that an oxidative Heck reaction could trigger a
a
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou
Medical University, Guiyang 550014, China. E-mail: lsheng@126.com
b
Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese
Academy of Sciences, Guiyang 550014, China. E-mail: 982169912@qq.com
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob02527e
These authors contributed equally to this work.
‡
Fig. 1 Ellipticines (1a–c) and calothrixins A–B (2,3).
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a
Table 1 Conditions screening for cascade ring closure
b
Temp.
(°C)
Yield (%):
Entry
Solvent/oxidant
4a/4b
1
2
3
4
5
6
7
8
9
DMSO : DMF(9 : 1)/O
2
90
90
85
0/0
0/0
DMSO : DMF(9 : 1)/2 eq. Cu(OAc)
i-PrOH/O
Glycol/O
Glycerine/O
Pivalic acid/O
2
2
0/38
64/50
15/29
5/35
23/81
10/71
15/20
0/64
0/96
0/95
56/92
49/0
2
120
120
120
120
120
200
100
100
100
200
180
2
2
PEG200/O
PEG400/O
2
2
1,2-Dichlorobenzene/O
DMSO/0.2 eq. CuCl
2
1
0
2
11
DMSO/0.1 eq. I
2
Scheme 1 Key domino processes in our previous work and the present 12
study.
DMSO/0.2 eq. I
2
13
1,2-Dichlorobenzene/2 eq. Cu(OAc)
1,2-Dichlorobenzene/2 eq. DDQ
2
14
a
Reactions were performed using amide 5a/5b (0.6 mmol) in 3.0 mL of
b
solvent. Isolated yield.
terminal oxidant, and more solvents such as isopropanol,
glycol, glycerine, pivalic acid, PEG200, PEG400 and 1,2-dichlor-
obenzene were examined as the reaction medium (Table 1,
entries 3–9). Among these screenings, the two substrates 5a
and 5b demonstrated different reactivity: designed conversion
of 5a to 4a could take place in 64% yield when glycol was
adopted as the solvent, also it was interesting to discover that
the PEG200/O
Moreover, to increase the yields of the cyclic products, other
oxidants [CuCl , Cu(OAc) , I and DDQ] were also investigated
Table 1, entries 10–14); no improvement was observed in the
yield of 4a with these conditions, however, it was gratifyingly
from the coupling of 3-(1H-indol-3-yl) acrylic acids 6 and found that 0.1 equiv. I in hot DMSO was the most effective
2
system could furnish 4b in 81% yield.
Scheme 2 Retrosynthetic plan.
2
2
2
(
2
amines 7.
system to furnish 4b which significantly raised the reaction
yield up to 96% (Table 1, entry 11), and there was no obvious
change in the yield on a higher loading of I
2). Notably, general routes that convert 2- or 3-alkenyl indoles
to carbazole derivatives involving a Diels–Alder reaction and
2
(Table 1, entry
1
Results and discussion
We started the above proposed synthetic route by conducting a dehydro-aromatization process have been developed through
DCC coupling of acid 6 and methyl (E)-5-aminopent-2-enoate two-step procedures, also stoichiometric DDQ was required for
1
4,15
18
or butyl (E)-3-(2-aminophenyl) acrylate 7,
two type of amides: 5a and 5b in 58 and 65% yield respectively. toxic, the adoption of O
thus to produce the transformation. Since DDQ was relatively expensive and
2
or a catalytic amount of I as the
2
Next step was to realize the designed cascade and generate oxidant in the above optimized conditions was economical
cyclic products 4a–b. Attempts focused on heating the precur- and eco-friendly.
sors in different solvents to initiate the domino sequence, and
With a view to briefly understand the generality of this pro-
a wide range of oxidants used in dehydro-aromatic processes tocol, we have prepared a number of amide substrates (5c–r).
1
6
17
18
including O , Cu(OAc) , CuCl , I , and DDQ were identi- These functionalized precursors were then respectively sub-
2
2
2
2
fied for this specific transformation (Table 1). Initial investi- jected to one of the above two optimized conditions
gation was performed with O or Cu(OAc)
as the oxidant in (Scheme 3). Substrates bearing electron-donating groups
DMF/DMSO (9 : 1) at 90 °C (Table 1, entries 1 and 2); these (OMe, Me group) or mild electron-withdrawing substituents (F,
2
2
1
1
conditions, related to our previous work, did not catalyze the Cl and Br) on the A ring gave the desired products 4d–h in
cyclization at all. In further screenings, to maximize technical moderate yields (36–40%), however, a precursor bearing a
simplicity and eco-friendliness, we tried to employ O as the strong electron-withdrawing group such as an ester group on
2
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Scheme 3 Substrate scope for tandem process. 5c–5o (0.6 mmol) in
2.0 mL glycol under O
2 2
at 120 °C, 5p–5r (0.6 mmol) with I (15 mg,
0
.06 mmol) in 2.0 mL DMSO at 100 °C. Yields refer to the isolated yield.
Scheme 4 Completion of the syntheses of ellipticines (1a–c) and calo-
thrixin B (3).
the A ring significantly reduced the efficiency, as the resulting
derivative 4i was obtained in lower yield (15%). Functional
group substitution of the N–H atom (Me, Bn) of the indole
fragment apparently affected the reactivity, although the Me
substituted substrate gave the corresponding product 4j in a
normal yield, the substrate with the larger steric Bn substi-
tution only produced 4k in 10% yield under the favourable
conditions. Moreover, four D ring modified substrates also
formed the expected products 4l–o uneventfully. In a parallel
investigation, three 4b-type compounds 4p–r with a Me substi-
21c
O
2
system, thus delivering the ellipticine (1c) in 30% yield,
and 3,4-dehydroellipticine (1b) was also in accompaniment
22%). In a parallel synthesis (Scheme 4b), for establishment
(
of the approach to calothrixin B, complete reduction of 4b
using LiAlH4 led to alcohol 10 in moderate yield (50%).
Further regioselective oxidation of compound 10 using I2/
DMSO afforded phenanthridine product 11 in 72% yield. With
the critical intermediate 11 in hand, although no similar trans-
formation has been achieved, we planned to realize the one-
step conversion of 11 to calothrixin B. After a series of oxidants
were examined (IBX, Dess–Martin periodinane, TBHP), we
found that IBX in hot DMSO could promote the demanding
transformation to provide the requisite product in 35% yield,
also an aldehyde derivative 12 was concurrently formed.
Product 12 was nonreactive when subjected to the IBX oxi-
dative conditions again, however, it could be directly converted
to calothrixin B in 40% yield through a Baeyer–Villiger proce-
tuent or different ester group (–CO tBu and –CO Bn) on the C
2
2
ring could be generated in 80–89% yields.
Notably, carbazolelactams 4a–b provided by the above
tandem approach possess the basic skeleton of natural pyrido
and quinolinocarbazoles. Reduction of compound 4a by
3 2
BH ·Me S afforded alcohol 8 in 64% yield (Scheme 4a). An
attempt for the direct conversion of 8 to 1c by catalytic hydro-
genation with Pd/C failed, which reveals that the presence of
the free piperidyl NH would be problematic. Further, to
conquer this problem, compound 9 bearing a Boc group was
prepared, then it was successfully converted into compound 1c
10k
dure. Further attempt to enhance the selectivity of the IBX-
through hydrogenation and deprotection.
A
previously
mediated oxidative transformation using base or acid as addi-
tives was not successful; the adoption of pyridine decreased
the yield of calothrixin B, and aldehyde 12 was even formed as
the sole product in 80% yield when catalytic benzenesulfonic
acid (BSA) was used.
reported effort using MnO as the oxidant to directly transform
2
1
9
1
c to ellipticine was not successful. We turned to examine
other dehydrogenative reagents. Treatment of 1c with 2 equiva-
2
0
lents of V O in pivalic acid under an O atmosphere only
2
5
2
afforded 3,4-dehydroellipticine 1b in 72% yield. Notably, 1b
was a known intermediate to generate ellipticine through Pd/C
8
n
16,21a–b
catalyzed aromatization. Although several oxidants
2
such as CuCl ·2H O, I , and IBX have been reported for
Conclusions
2
2
directly oxidative didehydrogenation to generate isoquinoline In summary, we have developed a unified strategy to construct
fragments, we found 1c could only be provided by a CoTPP/ the basic frameworks of ellipticines and calothrixins.
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1
3
Additionally, highlighting the advantages of the protocol, Hz, 1H), 4.01 (s, 3H), 3.40–3.37 (m, 4H); C NMR (150 MHz,
further syntheses provide expedient entries to these biologi- DMSO-d ) δ 166.6, 164.9, 140.6, 140.4, 139.0, 126.6, 124.0,
6
cally active alkaloids in short reaction sequences. Although the 122.3, 122.0, 121.5, 120.4, 120.0, 112.0, 110.5, 52.2, 38.9, 27.1.
+
synthesis of ellipticines and calothrixins are intensively HRMS (ESI) m/z calcd for C17
H
15
N
2
O
3
[M + H] : 295.1083,
studied, the synthetic sequence used for conversion of amides found: 295.1088.
5
into ellipticines and calothrixin B has its own characteristics,
Methyl 8-methoxy-1-oxo-2,3,4,6-tetrahydro-1H-pyrido[4,3-b]
for example, the conversion of 1c to ellipticine and intermedi- carbazole-5-carboxylate (4d). 75 mg, yield 39%, brown solid, IR
ate 11 or 12 to calothrixin B has been achieved as directly as (KBr) 3321, 3012, 1714, 1654, 1504, 1078, 1007 cm− . H NMR
possible. Moreover, this synthetic method is also having the (600 MHz, DMSO-d ) δ 11.26 (s, 1H), 8.76 (s, 1H), 8.10 (d, J =
8.4 Hz, 1H), 7.93 (s, 1H), 7.20 (d, J = 2.4 Hz, 1H), 6.86 (dd, J =
1 1
6
advantage of using simple reagents for the transformations.
1
3
8.4 Hz, 1H), 4.00 (s, 3H), 3.85 (s, 3H), 3.38–3.34 (m, 4H);
C
6
NMR (150 MHz, DMSO-d ) δ 166.4, 166.1, 156.0, 147.2, 138.3,
1
5
33.1, 129.3, 121.9, 120.5, 119.0, 115.8, 112.2, 110.2, 95.3, 55.2,
1.2, 37.2, 32.0. HRMS (ESI) m/z calcd for C H N O [M +
Experimental
1
8
17 2 4
+
The solvents were dried and distilled prior to use according to
the literature methods. Column chromatographic purifications
were performed on SDZF silica gel 160. H and C NMR
spectra were obtained on a Bruker NMR spectrometer at
H] : 325.1188, found: 325.1187.
Methyl 8-methyl-1-oxo-2,3,4,6-tetrahydro-1H-pyrido[4,3-b]
carbazole-5-carboxylate (4e). 66 mg, yield 36%, light pink
solid, IR (KBr) 3342, 3020, 1665, 1493, 1210, 1081 cm
NMR (600 MHz, DMSO-d ) δ 11.25 (s, 1H), 8.83 (s, 1H), 8.11 (d,
J = 7.8 Hz, 1H), 7.96 (s, 1H), 7.47 (s, 1H), 7.07 (d, J = 7.8 Hz,
1
13
−
1 1
. H
6
00 MHz and 150 MHz, respectively, and referenced internally
6
based on the residual solvent signal. The data reported for the
1
1
3
H NMR spectra are as follows: chemical shift (δ, ppm), multi-
1
(
1
2
3
H), 4.00 (s, 3H), 3.39–3.36 (m, 4H), 2.48 (s, 3H); C NMR
150 MHz, DMSO-d ) δ 166.7, 165.0, 140.9, 140.7, 138.4, 136.2,
23.5, 122.4, 121.6, 121.4, 120.1, 119.8, 112.0, 110.4, 52.2, 38.9,
plicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multi-
plet), coupling constant in hertz, and number of protons. The
6
13
+
data reported for the C spectra are given as chemical shift (δ,
ppm). High-resolution mass spectra (HRMS) were obtained on
an Agilent mass spectrometer by electrospray ionization-time
of flight (ESI-TOF) analysis. Melting points were measured
with a melting point instrument without correction. All the
chemical reagents were purchased from commercial sources
and used as received unless otherwise indicated.
17 2 3
7.1, 21.8. HRMS (ESI) m/z calcd for C18H N O [M + H] :
09.1239, found: 309.1234.
Methyl 8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-pyrido[4,3-b]car-
bazole-5-carboxylate (4f). 73 mg, yield 39%, off-white solid, IR
KBr) 3350, 3010, 1662, 1507, 1402, 1081 cm−
600 MHz, DMSO-d ) δ 11.47 (s, 1H), 8.90 (s, 1H), 8.30–8.28 (m,
1
.
1
H NMR
(
(
6
1
1
H), 8.00 (s, 1H), 7.43 (dd, J = 9.6, 2.4 Hz, 1H), 7.10–7.06 (m,
H), 4.01 (s, 3H), 3.39–3.36 (m, 4H); C NMR (150 MHz,
1
3
General procedure for the synthesis of carbazolelactams (4a,
DMSO-d ) δ 166.5, 164.8, 162.3, 160.7, 141.2, 141.1, 138.7,
1
6
4
c–o)
23.9, 122.1, 122.0, 121.9, 118.8, 110.6, 108.1, 108.0, 98.6, 98.4,
1
9
Synthesis of 4a. Compound 5a (0.6 mmol) was dissolved in 52.3, 38.9, 27.1. F NMR (564 MHz, DMSO-d
ethylene glycol (2.0 mL). The mixture was heated to 120 °C and HRMS (ESI) m/z calcd for C H N O F [M + H] : 313.0988,
6
) δ −114.24.
+
1
7
14 2 3
stirred under O
room temperature and diluted with ethyl acetate. The organic
phase washed with H O, brine, and dried over anhydrous bazole-5-carboxylate (4g). 79 mg, yield 40%, yellow solid, IR
2
for 24 h. The reaction solution was cooled to found: 313.0989.
Methyl 8-chloro-1-oxo-2,3,4,6-tetrahydro-1H-pyrido[4,3-b]car-
2
. After evaporation, the crude product was purified by (KBr) 3371, 3016, 1705, 1664, 1520, 1076, 980 cm− . H NMR
1 1
Na
flash column chromatography (DCM/EA = 6 : 1–3 : 1) to obtain (600 MHz, DMSO-d
product 4a. 8.4 Hz, 1H), 8.02 (s, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.26 (dd, J =
Methyl 11-methyl-1-oxo-2,3,4,6-tetrahydro-1H-pyrido[4,3-b] 8.4, 2.4 Hz, 1H), 4.01 (s, 3H), 3.38 (s, 4H); C NMR (150 MHz,
carbazole-5-carboxylate (4a). 118 mg, yield 64%, white solid, IR DMSO-d ) δ 166.5, 164.7, 141.0, 141.0, 139.4, 130.9, 124.3,
H NMR 122.2, 122.0, 121.7, 121.0, 120.2, 111.7, 110.8, 52.3, 38.8, 27.2.
2 4
SO
6
) δ 11.48 (s, 1H), 8.93 (s, 1H), 8.29 (d, J =
1
3
6
−
1
1
(
(
KBr) 3450, 3016, 1729, 1650, 1198, 1094 cm
600 MHz, DMSO-d ) δ 11.35 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), HRMS (ESI) m/z calcd for C17
.02 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), found: 329.0697.
.26 (t, J = 7.2 Hz, 1H), 4.00 (s, 3H), 3.26 (s, 4H), 3.17 (s, 3H); Methyl 10-bromo-1-oxo-2,3,4,6-tetrahydro-1H-pyrido[4,3-b]
) δ 166.8, 165.7, 140.3, 140.1, carbazole-5-carboxylate (4h). 89 mg, yield 40%, light brown
.
+
6
14 2 3
H N O Cl [M + H] : 329.0693,
8
7
1
3
C NMR (150 MHz, DMSO-d
39.0, 125.8, 122.7, 122.6, 122.0, 121.3, 119.9, 111.9, 108.8, solid, IR (KBr) 3354, 3020, 1654, 1489, 1082, 1014 cm
6
−
1 1
1
5
+
. H
2.2, 38.6, 29.1, 18.7. HRMS (ESI) m/z calcd for C H N O [M NMR (600 MHz, DMSO-d ) δ 11.68 (s, 1H), 9.40 (s, 1H), 8.07 (s,
H] : 309.1239, found: 309.1245.
Methyl 1-oxo-2,3,4,6-tetrahydro-1H-pyrido[4,3-b]carbazole-5- 7.8 Hz, 1H), 4.02 (s, 3H), 3.39 (s, 4H); C NMR (150 MHz,
carboxylate (4c). 97 mg, yield 58%, yellow solid, IR (KBr) 3350, DMSO-d ) δ 166.9, 165.2, 142.2, 141.2, 140.1, 128.1, 125.7,
6
016, 1664, 1344, 1082 cm . H NMR (600 MHz, DMSO-d ) δ 124.4, 122.2, 122.0, 120.8, 115.7, 112.1, 111.3, 63.3, 52.9, 27.6.
1
8
17
2
3
6
+
1H), 7.76 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.41 (t, J =
1
3
6
−
1 1
3
1
7
+
1.37 (s, 1H), 8.91 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.99 (s, 1H), HRMS (ESI) m/z calcd for C17
.69 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 7.2 found: 373.0187.
14 2 3
H N O Br [M + H] : 373.0188,
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Dimethyl 1-oxo-2,3,4,6-tetrahydro-1H-pyrido[4,3-b]carbazole- NMR (600 MHz, DMSO-d
6
) δ 11.37 (s, 1H), 8.91 (s, 1H), 8.25 (d,
5
3
,8-dicarboxylate (4i). 31 mg, yield 15%, white solid, IR (KBr) J = 7.8 Hz, 1H), 7.98 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.46 (t, J =
−
1 1
346, 3018, 1733, 1661, 1473, 1078 cm . H NMR (600 MHz, 7.2 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 4.02 (s, 3H), 3.69–3.68 (m,
) δ 11.62 (s, 1H), 8.99 (s, 1H), 8.38–8.36 (m, 2H), 8.04 1H), 3.58 (dd, J = 16.8, 4.2 Hz, 1H), 2.99–2.95 (m, 1H), 1.25 (d, J
DMSO-d
6
1
3
(s, 1H), 7.85 (dd, J = 8.4, 1.2 Hz, 1H), 4.02 (s, 3H), 3.91 (s, 3H), = 6.6 Hz, 3H); C NMR (150 MHz, DMSO-d ) δ 167.0, 165.4,
6
1
3
3
.40 (s, 4H); C NMR (150 MHz, DMSO-d
6
) δ 167.2, 166.8, 141.1, 140.9, 138.5, 127.1, 124.3, 122.8, 122.5, 121.5, 120.9,
1
1
65.1, 142.2, 141.1, 140.3, 127.8, 126.3, 125.6, 122.7, 122.0, 120.5, 112.5, 111.2, 52.7, 46.2, 35.2, 21.5. HRMS (ESI) m/z calcd
+
21.1, 121.0, 114.0, 111.3, 52.8, 52.7, 39.3, 27.7. HRMS (ESI) for C H N O [M + H] : 309.1239, found: 309.1242.
1
8
17 2 3
+
m/z calcd for C19
H
17
N
2
O
5
[M + H] : 353.1137, found: 353.1132.
Methyl 13-oxo-5,7,7a,8,9,10,11,13-octahydroquinolizino[2,3-
Methyl
6-methyl-1-oxo-2,3,4,6-tetrahydro-1H-pyrido[4,3-b] b]carbazole-6-carboxylate (4o). 117 mg, yield 56%, white solid,
carbazole-5-carboxylate (4j). 83 mg, yield 45%, white solid, IR IR (KBr) 3332, 3024, 1712, 1617, 1458, 1105 cm−
(
1 1
.
H NMR
−
1 1
KBr) 3327, 2929, 2860, 1718, 1666, 1471, 1084 cm . H NMR (600 MHz, DMSO-d
6
) δ 11.38 (s, 1H), 8.96 (s, 1H), 8.25 (d, J =
(
600 MHz, DMSO-d ) δ 8.81 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H),
6
7
7
2
1
1
.98 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 12.6 Hz, 1H), 4.01 (s, 3H),
.30 (t, J = 7.8 Hz, 1H), 4.02 (s, 3H), 3.76 (s, 3H), 3.44–3.41 (m, 3.75–3.70 (m, 2H), 3.54 (s, 1H), 2.69 (t, J = 10.2 Hz, 1H), 1.86
1
3
13
6
H), 2.99 (t, J = 6.0 Hz, 2H); C NMR (150 MHz, DMSO-d ) δ (d, J = 11.4 Hz, 1H), 1.76 (s, 2H), 1.42 (s, 2H); C NMR
68.2, 164.7, 141.7, 138.1, 134.3, 126.8, 122.2, 121.7, 121.6, (150 MHz, DMSO-d ) δ 166.4, 164.6, 140.7, 140.4, 137.1, 126.7,
6
20.8, 120.5, 120.3, 114.3, 109.9, 52.7, 39.0, 30.8, 26.3. HRMS 124.6, 122.5, 122.1, 120.4, 120.4, 120.1, 112.0, 109.9, 53.8, 52.3,
+
(ESI) m/z calcd for C18
H
17
N
2
O
3
[M + H] : 309.1239, found: 43.0, 33.1, 32.6, 24.4, 23.1. HRMS (ESI) m/z calcd for
+
3
09.1235.
C H N O [M + H] : 349.1547, found: 349.1542.
2
1
21 2 3
Methyl
6-benzyl-11-methyl-1-oxo-2,3,4,6-tetrahydro-1H-
pyrido[4,3-b]carbazole-5-carboxylate (4k). 24 mg, yield 10%,
yellow solid, IR (KBr) 3420, 3211, 2948, 1725, 1665, 1454, 1340,
General procedure for the synthesis of carbazolelactams (4b,
4p–r)
42 cm− . H NMR (600 MHz, CDCl
.45 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.31–7.28 (m,
1
1
7
7
3
3
2
1
1
3
) δ 8.40 (d, J = 7.8 Hz, 1H),
2
Synthesis of 4b. Compound 5b (0.6 mmol) and I (15 mg,
H), 7.26–7.23 (m, 2H), 7.04 (d, J = 7.2 Hz, 2H), 5.52 (s, 2H), 0.06 mmol) were dissolved in DMSO (2.0 mL) and stirred at
.49–3.47 (m, 2H), 3.44 (s, 3H), 3.35 (s, 3H), 2.98 (t, J = 6.0 Hz, 100 °C in air for 24 h. The reaction was cooled to room temp-
1
3
H); C NMR (150 MHz, CDCl
3 2
) δ 169.0, 166.9, 141.7, 139.6, erature, extracted with ethyl acetate and washed with H O, the
37.2, 136.3, 135.5, 128.4, 127.1, 126.0, 125.4, 123.4, 123.3, organic phase was dried over anhydrous Na SO and concen-
20.5, 119.9, 112.7, 109.3, 51.9, 47.5, 39.3, 28.5, 18.6. HRMS trated under reduced pressure to obtain a crude product. The
2
4
+
(
ESI) m/z calcd for C25
H
23
N
2
O
3
2
[M + H] : 399.1709, found: crude product was purified by trituration with Et O to obtain
3
99.1706.
Methyl 1-oxo-1,2,3,5-tetrahydropyrrolo[3,4-b]carbazole-4-car-
boxylate (4l). 75 mg, yield 45%, brown solid, IR (KBr) 3340, carboxylate (4b). 220 mg, yield 96%, IR (KBr) 3016, 2873, 1687,
product 4b.
Butyl 6-oxo-6,12-dihydro-5H-indolo[3,2-j]phenanthridine-13-
−1
1
−1 1
3
1
7
026, 1653, 1456, 1076 cm . H NMR (600 MHz, DMSO-d ) δ 1660, 1595 cm . H NMR (600 MHz, DMSO-d ) δ 11.71 (s, 1H),
6 6
1.62 (s, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 8.34 (d, J = 7.2 Hz 1H), 11.70 (s, 1H), 9.28 (s, 1H), 8.37 (d, J = 7.2 Hz, 1H), 7.83 (d, J =
.77 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.27 (t, J = 7.8 8.4 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H),
1
3
Hz, 1H), 4.69 (s, 2H), 4.03 (s, 3H); C NMR (150 MHz, DMSO- 7.49 (t, J = 8.4 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 7.8
d
6
) δ 169.7, 165.9, 144.2, 141.3, 140.8, 126.8, 125.0, 124.4, Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 4.52 (t, J = 6.6 Hz, 2H),
1
21.8, 120.8, 120.1, 120.1, 112.3, 106.7, 52.1, 46.6. HRMS (ESI) 1.70–1.66 (m, 2H), 1.31–1.27 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H);
+
13
m/z calcd for C H N O [M + H] : 281.0926, found: 281.0924.
C NMR (150 MHz, DMSO-d ) δ 169.0, 161.1, 141.8, 140.7,
6
1
6
13
2
3
Methyl 5-oxo-1,2,3,5,11,12b-hexahydropyrrolizino[1,2-b]car- 136.8, 129.4, 129.0, 127.7, 125.8, 123.8, 122.0, 121.8, 121.5,
bazole-12-carboxylate (4m). 111 mg, yield 58%, white solid, IR 121.2, 120.3, 118.6, 116.9, 116.4, 112.0, 110.8, 65.8, 29.7, 18.7,
−
1
1
+
(
KBr) 3342, 3010, 1653, 1401, 1076 cm . H NMR (600 MHz, 13.5. HRMS (ESI) m/z calcd for C H N O [M + H] : 385.1547,
24 20 2 3
DMSO-d
6
) δ 11.64 (s, 1H), 8.71 (s, 1H), 8.33 (d, J = 7.8 Hz, 1H), found: 385.1539.
Butyl 7-methyl-6-oxo-6,12-dihydro-5H-indolo[3,2-j]phenan-
Hz, 1H), 5.10–5.08 (m, 1H), 4.04 (s, 3H), 3.67–3.62 (m, 1H), thridine-13-carboxylate (4p). 206 mg, yield 86%, yellow solid,
7
.77 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.26 (t, J = 7.8
1
1
3
.31–3.27 (m, 1H), 2.59–2.55 (m, 1H), 2.27–2.22 (m, 2H), 1.20 IR (KBr) 3566, 2359, 1716, 1653, 1558, 1458 cm−
.
H NMR
) δ 11.54 (s, 1H), 11.37 (s, 1H), 8.37 (d, J =
65.5, 146.3, 141.4, 140.8, 126.9, 125.3, 124.5, 121.8, 120.8, 7.8 Hz, 1H), 7.74–7.70 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.45 (t, J
20.4, 120.2, 112.4, 106.9, 65.4, 52.0, 41.9, 29.7, 28.1. HRMS = 6.6 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H),
1
3
6 6
(d, J = 9.6 Hz, 1H); C NMR (150 MHz, DMSO-d ) δ 170.6, (600 MHz, DMSO-d
1
1
+
(ESI) m/z calcd for C19
H
17
N
2
O
3
[M + H] : 321.1239, found: 7.16 (t, J = 8.4 Hz, 1H), 4.40 (t, J = 6.6 Hz, 2H), 3.51 (s, 3H),
1.61–1.56 (m, 2H), 1.21–1.17 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H);
3
21.1236.
Methyl
1
3
3-methyl-1-oxo-2,3,4,6-tetrahydro-1H-pyrido[4,3-b]
6
C NMR (150 MHz, DMSO-d ) δ 169.1, 162.5, 141.6, 140.6,
carbazole-5-carboxylate (4n). 77 mg, yield 42%, light brown 139.7, 136.6, 131.9, 129.3, 127.0, 126.8, 123.4, 123.4, 122.5,
solid, IR (KBr) 3340, 3018, 1682, 1603, 1456, 1071 cm−
1
.
1
H
121.0, 120.3, 117.2, 116.7, 115.3, 112.0, 108.4, 65.4, 29.6, 19.4,
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+
1
3
8.6, 13.5. HRMS (ESI) m/z calcd for C25
99.1703, found: 399.1692.
H
23
N
2
O
3
[M + H] : (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.2 Hz,
1H), 7.13 (t, J = 6.6 Hz, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.85 (d, J =
Tert-butyl
6-oxo-6,12-dihydro-5H-indolo[3,2-j]phenanthri- 4.8 Hz, 2H), 4.64 (s, 2H), 3.58 (s, 2H), 3.04 (t, J = 6.0 Hz, 2H),
1
3
dine-13-carboxylate (4q). 205 mg, yield 89%, white solid, IR 2.69 (s, 3H), 1.45 (s, 9H); C NMR (150 MHz, DMSO-d
6
) δ
KBr) 3311, 3286, 2978, 1660, 1597, 1456, 1150 cm . H NMR 154.1, 140.2, 137.9, 131.2, 124.7, 122.9, 122.1, 119.6, 119.0,
600 MHz, DMSO-d ) δ 11.66 (s, 1H), 11.33 (s, 1H), 9.26 (s, 1H), 118.3, 110.8, 78.8, 56.3, 40.0, 28.1, 15.1. HRMS (ESI) m/z calcd
.37 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 8.4 for C22
Hz, 1H), 7.55–7.49 (m, 2H), 7.42 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 5,11-Dimethyl-2,3,4,6-tetrahydro-1H-pyrido[4,3-b]carbazole
.8 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 1.59 (s, 9H); C NMR (1c). The product 9 (450 mg, 1.2 mmol) was dissolved in absol-
150 MHz, DMSO-d ) δ 168.4, 161.6, 142.3, 141.4, 137.1, 129.9, ute ethanol (20.0 mL), and 10% Pd/C (90 mg) was added. The
−
1 1
(
(
8
6
+
27 2 3
H N O [M + H] : 367.2022, found: 367.2017.
13
7
(
6
1
1
C
28.0, 127.7, 124.5, 122.4, 122.2, 121.5, 121.3, 120.8, 119.2, reaction was stirred at 50 °C for 5 days in a hydrogen atmo-
17.5, 116.6, 112.8, 112.3, 83.5, 28.0. HRMS (ESI) m/z calcd for sphere, the resulting mixture was filtered through Celite®, and
+
24
H
21
N
2
O
3
[M + H] : 385.1547, found: 385.1537.
the filtrate was concentrated under reduced pressure to obtain
Benzyl 6-oxo-6,12-dihydro-5H-indolo[3,2-j]phenanthridine- a crude product (410 mg). The crude product was dissolved in
3-carboxylate (4r). 201 mg, yield 80%, white solid, IR (KBr) dichloromethane (12.0 mL), 1,4-dimethoxybenzene (553 mg,
1
3
586, 2359, 1670, 1507, 1418, 1184 cm− . H NMR (600 MHz, 4.0 mmol) and TFA (1.0 mL, 14.0 mmol) were added, and the
1
1
DMSO-d ) δ 11.75 (s, 1H), 11.63 (s, 1H), 9.28 (s, 1H), 8.39 (d, J = reaction mixture was stirred at room temperature for 6 h. The
6
7
7
7
.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), solvent and excess TFA were removed, then saturated Na
.56 (t, J = 7.2 Hz, 1H), 7.48–7.47 (m, 2H), 7.43–7.38 (m, 5H), solution and ethyl acetate were added. The organic phase was
2 3
CO
1
3
.32 (t, J = 7.2 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 5.59 (s, 2H);
) δ 168.6, 161.0, 141.7, 140.7, 136.8, crude product. The crude product was purified by trituration
34.8, 129.3, 129.3, 129.0, 128.6, 127.7, 125.9, 123.8, 122.1, with Et O, then filtered to obtain product 1c. 235 mg, yield
21.8, 121.4, 121.2, 120.3, 118.6, 116.7, 116.3, 111.8, 110.4, 56% (2 steps), yellow solid, IR (KBr) 3315, 3012, 2817, 1682,
C
dried over anhydrous Na SO , and concentrated to obtain a
2 4
NMR (150 MHz, DMSO-d
6
1
1
6
2
+
−1 1
7.9. HRMS (ESI) m/z calcd for C27
H
19
N
2
O
3
[M + H] : 419.1390, 1508, 1076 cm . H NMR (600 MHz, DMSO-d
8.13 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.2
11-Methyl-2,3,4,6-tetrahydro-1H-pyrido[4,3-b]carbazol-5-yl) Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 3.99 (s, 2H), 3.16 (s, 1H), 3.00
6
) δ 10.89 (s, 1H),
found: 419.1375.
(
1
3
methanol (8). Compound 4a (3.00 g, 9.7 mmol) was dissolved (s, 2H), 2.75 (s, 2H), 2.60 (s, 3H), 2.37 (s, 3H); C NMR
in dry THF (50 mL), borane dimethyl sulfide complex (10 mol (150 MHz, DMSO-d ) δ 140.1, 137.8, 130.8, 125.4, 124.8, 124.2,
in DMS, 97.3 mmol) was slowly added at 0 °C, and the 123.5, 122.0, 118.7, 118.1, 114.8, 110.6, 46.5, 43.3, 27.4, 14.7,
6
−
1
L
+
19 2
reaction was refluxed for 5 h. The reaction was cooled to room 12.6. HRMS (ESI) m/z calcd for C17H N [M + H] : 251.1548,
temperature, and methanol was added dropwise at 0 °C. The found: 251.1557.
solution was evaporated under reduced pressure. The crude
product was purified by flash column chromatography (DCM/ dehydroellipticine, 1b). The product 1c (50 mg, 0.2 mmol),
MeOH = 30 : 1) to obtain product 8. 1.63 g, yield 64%, light pivalic acid (3.0 g) and V (145 mg, 0.8 mmol) were heated
brown solid, IR (KBr) 3383, 3012, 1652, 1163, 1078 cm− . H at 120 °C for 10 h under O . Then the reaction was cooled, and
5,11-Dimethyl-4,6-dihydro-3H-pyrido[4,3-b]carbazole (3,4-
2 5
O
1
1
2
NMR (600 MHz, DMSO-d
6
2 3
) δ 11.05 (s, 1H), 8.16 (d, J = 7.8 Hz, saturated Na CO solution was slowly added. The resulting
1
7
4
H), 7.53 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.13 (t, J = mixture was extracted with ethyl acetate. The organic phase
.8 Hz, 1H), 6.43 (s, 1H), 5.01 (s, 1H), 4.84 (d, J = 6.0 Hz, 2H), was concentrated under reduced pressure to obtain a crude
.19 (d, J = 13.8 Hz, 1H), 3.75–3.70 (m, 1H), 3.32 (d, J = 13.2 product. The crude product was purified by flash column
13
Hz, 2H), 3.14 (d, J = 4.2 Hz, 2H), 2.65 (s, 3H); C NMR chromatography (DCM/MeOH = 10 : 1) to obtain 1b. 36 mg,
(
1
1
150 MHz, DMSO-d ) δ 140.3, 138.0, 129.0, 127.9, 124.8, 122.8, yield 72%, yellow solid, IR (KBr) 3421, 3032, 2924, 2850, 1923,
6
22.1, 120.6, 119.9, 118.6, 118.3, 110.9, 56.3, 52.1, 48.8, 24.5, 1653, 1558, 1082 cm− . H NMR (600 MHz, DMSO-d
1 1
) δ 11.50
6
+
5.0. HRMS (ESI) m/z calcd for C17
H
19
N
2
O [M + H] : 267.1497, (s, 1H), 8.89 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz,
found: 267.1502.
1H), 7.41 (t, J = 7.2 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 3.62 (t, J =
Tert-butyl
5-(hydroxymethyl)-11-methyl-1,3,4,6-tetrahydro- 6.6 Hz, 2H), 2.93 (s, 3H), 2.81 (t, J = 7.2 Hz, 2H), 2.44 (s, 3H);
1
3
2
H-pyrido[4,3-b]carbazole-2-carboxylate (9). The product 8
6
C NMR (150 MHz, DMSO-d ) δ 158.5, 141.4, 140.1, 132.7,
(
(
107 mg, 0.4 mmol) was dissolved in THF, 10% NaHCO3 130.9, 125.1, 123.6, 122.4, 119.4, 119.2, 118.2, 114.4, 111.2,
1.0 mL) and di-tert-butyl dicarbonate (131 mg, 0.6 mmol) was 45.4, 23.0, 14.7, 12.4. HRMS (ESI) m/z calcd for C17 [M +
17 2
H N
+
added. The reaction was stirred at room temperature for 6 h. H] : 249.1392, found: 249.1398.
After the reaction was completed, H O and ethyl acetate were 5,11-Dimethyl-6H-pyrido[4,3-b]carbazole (ellipticine, 1a). To
O, dried with the product 1c (50 mg, 0.2 mmol) in N,N-dimethylformamide
, and concentrated under reduced pressure. (2.0 mL) was added Co(II)TPP (25 mg, 0.1 mmol), and the reac-
The crude product was purified by silica gel chromatography tion mixture was reacted at 120 °C for 36 h under O . The solu-
2
added, the organic layer was washed with H
anhydrous Na SO
2
2
4
2
(
PE/EA = 2 : 1) to obtain the product 9. 147 mg, yield 70%, tion was filtered through Celite®, and ethyl acetate was added
white solid, IR (KBr) 3381, 3018, 1667, 1471, 1167, 1003, to the filtrate. The organic phase was washed with H O, and
76 cm− . H NMR (600 MHz, DMSO-d ) δ 11.07 (s, 1H), 8.16 dried with anhydrous Na SO . After evaporation, the crude
2
1
1
9
6
2
4
1400 | Org. Biomol. Chem., 2021, 19, 1395–1403
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product is purified by flash column chromatography (DCM/ organic layer was washed with 10% NaHCO
3
, dried over anhy-
MeOH = 50 : 1–10 : 1) to obtain ellipticine 1a and product 1b drous Na SO and concentrated under reduced pressure. The
2
4
(
(
11 mg, 22%). Ellipticine: 15 mg, yield 30%, yellow solid, IR crude product was purified by flash column chromatography
KBr) 3434, 3145, 3091, 2958, 2922, 2851, 2869, 1653 cm− . H (DCM/EA = 10 : 1) to obtain product 12. 79 mg, isolated yield
1
1
−
1
NMR (600 MHz, DMSO-d ) δ 11.40 (s, 1H), 9.70 (s, 1H), 8.43 (d, 80%, yellow solid, IR (KBr) 3567, 1654, 1560, 1458, 1122 cm
J = 6.0 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 6.0 Hz, 1H),
.
6
1
6
H NMR (600 MHz, DMSO-d ) δ 12.36 (s, 1H), 10.82 (s, 1H),
7
.58 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.26 (t, J = 7.2 9.54 (s, 1H), 9.37 (s, 1H), 8.41 (d, J = 7.2 Hz, 1H), 8.37 (d, J =
1
3
Hz, 1H), 3.26 (s, 3H), 2.79 (s, 3H); C NMR (150 MHz, DMSO- 8.4 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.91 (t, J = 8.4 Hz, 2H),
d
6
) δ 149.6, 142.7, 140.6, 140.4, 132.5, 128.1, 127.1, 123.8, 7.81 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 7.8
1
3
1
6
23.4, 123.1, 122.0, 119.2, 115.9, 110.7, 108.0, 14.3, 11.9. Hz, 1H); C NMR (150 MHz, DMSO-d ) δ 191.1, 153.9, 145.5,
+
HRMS (ESI) m/z calcd for C H N [M + H] : 247.1230, found: 142.5, 141.1, 131.8, 129.8, 129.3, 129.2, 128.0, 127.0, 126.6,
1
7
15 2
2
47.1227.
,12-dihydro-5H-indolo[3,2-j]phenanthridin-13-yl)methanol (10). (ESI) m/z calcd for C20
To compound 4b (500 mg, 1.3 mmol) in dry THF (10 mL), 297.1018.
LiAlH (148 mg, 3.9 mmol) was added at 0 °C. The reaction 7H-Indolo[3,2-j]phenanthridine-7,13(12H)-dione (calothrixin
125.7, 122.4, 121.3, 121.1, 120.1, 120.0, 112.9, 112.6. HRMS
+
6
13 2
H N O [M + H] : 297.1022, found:
4
mixture was heated to 60 °C and stirred for 24 h. The reaction B, 3). Compound 11 (100 mg, 0.34 mmol) and IBX (476 mg,
mixture was cooled to 0 °C, and Na SO ·10H O was added 1.70 mmol) in DMSO (4.0 mL) was heated at 110 °C to react
2
4
2
until the reaction was completely quenched. The reaction solu- for 4 h. The reaction mixture was cooled to room temperature,
tion was filtered, and the filtrate was evaporated under and ethyl acetate and H O were added. The organic layer was
reduced pressure. The crude product was purified by flash washed with 10% NaHCO , dried over anhydrous Na SO and
2
3
2
4
column chromatography (DCM/MeOH = 50 : 1–10 : 1) to obtain concentrated under reduced pressure. The crude product was
product 10. 195 mg, yield 50%, white solid, IR (KBr) 3413, purified by flash column chromatography (DCM/EA = 30 : 1) to
−
1 1
3
1
(
6
5
018, 1654, 1560, 1457 cm . H NMR (600 MHz, DMSO-d ) δ obtain products 12 (35 mg, 36%) and 3 (35 mg, 35%).
6
1.09 (s, 1H), 8.05 (dd, J = 7.8, 2.4 Hz, 2H), 7.91 (s, 1H), 7.56 Calothrixin B (3): brick red solid, IR (KBr) 3399, 1654, 1529,
d, J = 8.4 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.15–7.10 (m, 2H), 1457, 1078 cm− . H NMR (600 MHz, DMSO-d
1
1
) δ 13.14 (s, 1H),
.88 (d, J = 7.8 Hz, 1H), 6.81 (t, J = 7.8 Hz, 1H), 5.88 (s, 1H), 9.60 (s, 1H), 9.56 (d, J = 7.2 Hz, 1H), 8.16 (d, J = 4.2 Hz, 1H),
6
1
3
.43 (s, 1H), 4.93 (d, J = 3.6 Hz, 2H), 4.24 (s, 2H); C NMR 8.15 (d, J = 4.2 Hz, 1H), 7.94 (t, J = 7.2 Hz, 1H), 7.87 (t, J = 7.8
) δ 149.5, 140.4, 140.3, 129.8, 128.7, 128.3, Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.38 (t,
27.9, 125.3, 122.7, 122.4, 119.9, 119.0, 118.5, 117.7, 116.3, J = 7.8 Hz, 1H); C NMR (150 MHz, DMSO-d ) δ 180.8, 180.4,
6
15.1, 111.1, 58.2, 47.5. HRMS (ESI) m/z calcd for C20
M + H] : 301.1335, found: 301.1332.
(150 MHz, DMSO-d
6
1
3
1
1
[
H
17
N
2
O
151.2, 147.5, 138.4, 138.0, 132.6, 131.6, 130.3, 129.8, 127.2
+
(127.19), 127.2 (127.17), 124.9, 124.3, 123.3, 122.6, 122.3,
+
(
12H-Indolo[3,2-j]phenanthridin-13-yl)methanol (11). The 115.5, 113.5. HRMS (ESI) m/z calcd for C H N O [M + H] :
1
9
11 2 2
product 10 (195 mg, 0.65 mmol) and I
was dissolved in DMSO (2.0 mL), and the reaction mixture was
heated at 100 °C under O for 2 h. After cooling to room temp- (PhSe) (63 mg, 0.20 mmol) in DCM (10.0 mL), 30% hydrogen
2
(16 mg, 0.065 mmol) 299.0821, found: 299.0831.
To the solution of compound 12 (200 mg, 0.67 mmol) and
2
2
2
erature, H O was added. The resulting mixture was extracted peroxide (2.0 mL, 20.10 mmol) was added. The mixture was
with ethyl acetate. The organic layer was dried over anhydrous reacted at room temperature for 48 h, then 10% sodium hypo-
Na SO and concentrated under reduced pressure. The crude sulfite solution was added to quench the reaction. The result-
2
4
product was purified by flash column chromatography (DCM/ ing mixture was extracted by ethyl acetate. The organic layer
EA = 2 : 1) to obtain product 11. 137 mg, yield 72%, white was washed with H O, dried over anhydrous Na SO and con-
H NMR centrated under reduced pressure. The crude product was puri-
) δ 11.80 (s, 1H), 9.38 (s, 1H), 9.21 (d, J = fied by flash column chromatography (DCM/EA = 30 : 1) to
.4 Hz, 1H), 8.99 (s, 1H), 8.36 (d, J = 7.2 Hz, 1H), 8.10 (dd, J = obtain product 3 (80 mg, 40%).
.4, 1.2 Hz, 1H), 7.77 (t, J = 7.2 Hz, 1H), 7.71–7.67 (m, 2H), 7.56
2
2
4
−
1 1
solid, IR (KBr) 3411, 1654, 1617, 1558, 1072 cm
600 MHz, DMSO-d
;
(
6
8
8
(
t, J = 7.2 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 5.79 (t, J = 4.8 Hz,
H), 5.41 (d, J = 4.2 Hz, 2H); C NMR (150 MHz, DMSO-d ) δ
6
54.8, 144.9, 143.2, 141.9, 129.2, 128.0, 127.9, 127.5, 125.8,
1
3
1
1
1
Conflicts of interest
24.5, 123.9, 121.5, 121.3, 121.1, 119.6, 117.2, 111.4, 58.0.
There are no conflicts to declare.
−
HRMS (ESI) m/z calcd for C20
H
13
N
2
O [M − H] : 297.1022,
found: 297.1030.
1
2H-Indolo[3,2-j]phenanthridine-13-carbaldehyde (12). To
the solution of compound 11 (100 mg, 0.34 mmol) and benze-
nesulfonic acid (11 mg, 0.07 mmol) in DMSO (4.0 mL), IBX
Acknowledgements
(476 mg, 1.70 mmol) was added, and the mixture was heated The work was financially supported by NSFC (No. 21762014)
at 110 °C to react for 4 h. The reaction mixture was cooled to and Guizhou Provincial Science and Technology Foundation
room temperature, and ethyl acetate and H O were added. The QKH [2020]1Y033.
2
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Drugs, 2016, 14, 17; (c) T. Choshi and S. Hibino,
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