Divergent Syntheses of Carbazole Alkaloids

Article abstract of DOI:10.1055/s-0037-1610185

Starting from common intermediate methyl 1-hydroxy-9 H -carbazole-3-carboxylate, synthetic routes toward murrayaquinone A, olivacine, and N -methylcalothrixin B were developed.

Full text of DOI:10.1055/s-0037-1610185

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
paper
A
de
F. Ji et al.
Paper
Synthesis
Divergent Syntheses of Carbazole Alkaloids
Feixiang Jia
CO2Me
He Huanga
Mengyang Lia
Yanqin Guoa
Chuanjun Song*a
N
H
OH
Junbiao Chang*a,b
2 steps, 89%
7 steps 29%
7 steps, 28%
O
O
a College of Chemistry and Molecular Engineering, Zhengzhou
N
N
University, Zhengzhou 450001, P. R. of China
chjsong@zzu.edu.cn
b Collaborative Innovation Center of New Drug Research and
Safety Evaluation, Henan Province, Zhengzhou 450001,
P. R. of China
N
N
N
H
Me
H
O
O
murrayaquinone A
olivacine
N-methylcalothrixin B
changjunbiao@zzu.edu.cn
Received: 23.04.2018
Accepted after revision: 18.05.2018
Published online: 05.07.2018
O
O
N
N
DOI: 10.1055/s-0037-1610185; Art ID: ss-2018-h0279-op
N
N
H
N
H
H
O
O
Abstract Starting from common intermediate methyl 1-hydroxy-9H-
carbazole-3-carboxylate, synthetic routes toward murrayaquinone A,
olivacine, and N-methylcalothrixin B were developed.
murrayaquinone A (1)
olivacine (2)
calothrixin B (3)
Figure 1 Representative examples of carbazole alkaloids
Key words carbazole alkaloids, murrayaquinone A, olivacine, N-meth-
ylcalothrixin B, total synthesis
Generally, construction of the carbazole core can be di-
vided into two categories: (a) central pyrrolyl B ring forma-
tion by cyclization of ortho-nitrogen-substituted biphenyls
or diarylamines and (b) A ring formation from substituted
indole derivatives. An example of the latter strategy fea-
tures condensation of indole-3-carbaldehyde with dimeth-
yl succinate followed by intramolecular acylation for the as-
sembly of the carbazole moiety 4 with concomitant instal-
lation of two functional groups onto the A ring for further
elaboration. Despite its potentially broad applicability, this
intermediate has only rarely been utilized in the total syn-
thesis of carbazole natural products.11f,g,12 Herein, we report
three examples that illustrate this potential.
Our synthesis of murrayaquinone A (1) and olivacine
(2), depicted in Scheme 1, started from the known building
block methyl 1-hydroxy-9H-carbazole-3-carboxylate (4),
which could be obtained in 68% isolated yield in a two-step
reaction.11f,12a Thus, treatment of 4 with lithium aluminum
hydride in refluxing 1,4-dioxane converted the ester func-
tionality directly into a methyl group, furnishing carbazolol
5, which was oxidized with chromium trioxide to provide
murrayaquinone A (1) in excellent yield. On the other hand,
allylation of phenol 4, followed by Claisen rearrangement
gave carbazolol 6 in 68% isolated yield over two steps. Con-
version of 6 into triflate 7, followed by palladium-catalyzed
cross coupling with trimethylaluminum13 yielded methyl-
carbazole 8 in excellent yield. Dihydroxylation of the dou-
ble bond in 8 with in situ sodium periodate oxidation of the
Carbazole alkaloids are well-known for their structural
variability and wide range of biological activities, and
therefore there has been many efforts toward the syntheses
of these natural products and their analogues over the past
decades.1 Murrayaquinone A (1) (Figure 1) is the first carba-
zoloquinone isolated from a natural source2 and displays
moderate cardiotonic activity.3 It has received considerable
synthetic attention4 as a testing ground for approaches to-
ward more complex members of this family. Olivacine (2)5
is a representative member of the pyrido[4,3-b]carbazole
alkaloids, while the more complex analogue calothrixin B
(3)6 possesses a unique indolo[3,2-j]phenanthridine frame-
work with a striking assembly of quinoline, quinone, and
indole pharmacophores. Due to their broad range of biolog-
ical activities such as antitumor and antimalarial activity,
as well as structural complexity, many strategies have been
developed for the syntheses of olivacine (2)7,8 and calo-
thrixin B (3).9,10 However, despite the remarkable achieve-
ments toward the synthesis of individual compounds, gen-
eral and efficient synthetic methodologies are desirable. In
continuation of our interest in natural products synthesis,11
we herein report our progress toward the divergent synthe-
sis of murrayaquinone A (1), olivacine (2), and N-methyl-
calothrixin B.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
F. Ji et al.
Paper
Synthesis
O
CO2Me
a
b
97%
92%
N
H
N
N
H
H
OH
O
OH
4
5
murrayaquinone A (1)
c
68%
CO2Me
CO2Me
CO2Me
d
e
100%
98%
N
H
N
H
N
H
OH
OTf
8
6
7
O
CO2Me
N
NH
f
g
h
O
69%
82%
76%
N
N
N
H
H
H
9
10
olivacine (2)
Scheme 1 Reagents and conditions: (a) LiAlH4, 1,4-dioxane, reflux; (b) CrO3, 3,5-dimethylpyrazole, DCM, –15 °C; (c) 1. allyl bromide, K2CO3, acetone;
2. DMF, reflux; (d) Tf2O, Et3N, DCM, –20 °C; (e) AlMe3, Pd(PPh3)4, THF, reflux; (f) OsO4, NaIO4, t-BuOH/THF/H2O, r.t.; (g) NH4OAc, AcOH, 80 °C;
(h) 1. Tf2O, Et3N, DCM, –20 °C; 2. AlMe3, Pd(PPh3)4, THF, reflux.
resulting vicinal diol furnished aldehyde 9 in 69% isolated
yield; 9 then underwent smooth ring closure upon reaction
with ammonium acetate in the presence of acetic acid to
give pyrido[4,3-b]carbazol-1-one 10 in good yield. Treat-
ment of 10 with triflic anhydride yielded an unstable tri-
flate (structure not shown), which was coupled directly
with trimethylaluminum to give olivacine (2) in 76% isolat-
ed yield over two steps.
The versatile intermediate carbazole carboxylate 4 was
also used as the precursor to N-methylcalothrixin B 16
(Scheme 2). For that, we applied a palladium-catalyzed cas-
cade C–C and C–N bond formation14 between bromocarba-
zole-3-carbaldehyde 14 and 2-aminophenylboronic acid to
construct the D-ring of N-methylcalothrixin B. To access
compound 14, a regioselective 2-bromination was required
and this proved problematic. Bromination of a variety of
substrates under different conditions was investigated, and
only reactions of the N,O-diprotected carbazole 12 resulted
in formation of the desired bromide 13, in a respectable
73% yield following a modified procedure developed by
Bringmann.15 Oxidation of 13 with Dess–Martin perio-
dinane gave the key intermediate 14 in excellent yield. The
palladium-catalyzed one-pot C–C and C–N bond formation
of 14 was then explored, and the pentacyclic compound 15
was obtained in an optimized 72% isolated yield. Oxidation
of 15 with chromium trioxide proceeded without incident
to give N-methylcalothrixin B 1616 in 67% yield. Unfortu-
nately, all attempts at N-demethylation (BBr3, concd HCl,
EtSNa, 1-chloroethyl chloroformate) to form calothrixin B
(3) failed. However, this was the first time that this strategy
CO2Me
CO2Me
OH
b
c
a
93%
73%
90%
N
H
N
N
Me
Me
OH
OMOM
CHO
OMOM
4
11
12
N
OH
Br
OMOM
f
d
e
Br
67%
94%
72%
N
N
N
Me
OMOM
Me
Me
OMOM
13
14
15
O
O
N
N
N
N
H
Me
O
O
calothrixin B (3)
16
Scheme 2 Reagents and conditions: (a) 1. MOMCl, K2CO3, acetone, r.t.; 2. NaH, MeI, DMF, r.t.; (b) LiAlH4, THF, 0 °C; (c) n-BuLi, benzene, –20 °C, then
(CBrCl2)2, –20 °C to r.t.; (d) DMP, DCM, 0 °C to r.t.; (e) 2-aminophenylboronic acid, Pd(PPh3)4, K2CO3, DME/H2O, 90 °C; (f) CrO3, 3,5-dimethylpyrazole,
DCM, –15 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

C
F. Ji et al.
Paper
Synthesis
has been used to synthesize this alkaloid skeleton. Many al-
ternative N-protection strategies should solve this draw-
back and, in any event, the present route could readily be
adapted to analogue synthesis.
In summary, we have developed novel and high yielding
synthetic routes toward the total synthesis of murrayaqui-
none A, olivacine, and N-methylcalothrixin B. These brief
syntheses amply illustrate the potential of precursor 4 in
this and related areas of alkaloid synthesis, both of natural
structures and many non-natural analogues, which will be
of interest in drug discovery.
Methyl 2-Allyl-1-hydroxy-9H-carbazole-3-carboxylate (6)
K2CO3 (5.7 g, 41 mmol) and allyl bromide (5.0 g, 3.5 mL, 41 mmol)
were added to a solution of 4 (4.0 g, 16 mmol) in acetone (20 mL). The
mixture was stirred at ambient temperature for 15 h and filtered. The
filtrate was concentrated in vacuo. The residue was purified by col-
umn chromatography (silica gel, EtOAc–PE, 6% then 12%) to give a
pale-yellow solid which was dissolved in DMF (60 mL); the resulting
mixture was heated at reflux for 15 h and cooled. H2O (120 mL) was
added. The resulting mixture was extracted with EtOAc (3 × 120 mL).
The combined organic extracts were washed with brine (2 × 60 mL),
then dried (Na2SO4), filtered, and evaporated in vacuo. The residue
was purified by column chromatography (silica gel, EtOAc–PE, 20%) to
give 6.
Yield: 3.0 g (68%); brown solid; mp 121–123 °C.
IR (neat): 3338, 1708, 1234, 1052, 997 cm–1
.
Melting points were determined on an XT4A hot-stage apparatus and
are uncorrected. IR spectra were obtained by using an IFS25 FT-IR
spectrometer. 1H and 13C NMR spectra were obtained on a Bruker
AV400 instrument. High-resolution mass spectra were recorded on a
Micromass Q-TOF mass spectrometer. Flash column chromatography
was performed over silica gel (200–300 mesh).
1H NMR (400 MHz, DMSO-d6): δ = 11.07 (s, 1 H), 9.16 (s, 1 H), 8.24 (s,
1 H), 8.12 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.40 (t, J = 8.0 Hz,
1 H), 7.18 (t, J = 7.6 Hz, 1 H), 6.01 (m, 1 H), 4.95–4.90 (m, 2 H), 3.93 (d,
J = 6.0 Hz, 2 H), 3.83 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.2, 140.3, 140.0, 137.7, 132.9,
125.8, 123.5, 122.9, 121.4, 121.1, 120.3, 119.3, 115.6, 114.3, 111.6,
51.6, 29.9.
3-Methyl-9H-carbazol-1-ol (5)17
LiAlH4 (303 mg, 8 mmol) was added to a solution of ester 4 (241 mg, 1
mmol) in anhyd 1,4-dioxane (10 mL) at 0 °C. The resulting mixture
was heated at reflux for 4 h and then cooled. The reaction was
quenched with H2O (2 mL). The mixture was filtered through a pad of
Celite. The filtrate was extracted with EtOAc (3 × 20 mL). The com-
bined organic extracts were dried (Na2SO4), then filtered, and evapo-
rated in vacuo. The residue was purified by column chromatography
(silica gel, EtOAc–PE, 20%) to give carbazolol 5.
Yield: 185 mg (97%); light brown solid; mp 152–154 °C (Lit.17 153–
156 °C).
1H NMR (400 MHz, methanol-d4): δ = 7.95 (d, J = 7.6 Hz, 1 H), 7.44 (d,
J = 8.4 Hz, 1 H), 7.35 (m, 1 H), 7.32 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.10
(ddd, J = 8.0, 7.2, 1.2 Hz, 1 H), 6.70 (s, J = 0.8 Hz, 1 H), 2.45 (s, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C17H15NO3Na: 304.0944; found:
304.0941.
Methyl 2-Allyl-1-trifluoromethylsulfonyloxy-9H-carbazole-
3-carboxylate (7)
Et3N (288 mg, 0.39 mL, 2.85 mmol) and Tf2O (803 mg, 0.48 mL, 2.85
mmol) were added to a solution of 6 (700 mg, 2.37 mmol) in anhyd
DCM (15 mL) at –20 °C under N2. The resulting mixture was stirred for
12 h, before being diluted with DCM (30 mL) and washed successively
with H2O (10 mL) and brine (10 mL). The separated organic layer was
dried (Na2SO4), filtered, and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, EtOAc–PE, 13%) to give 7.
Yield: 975 mg (100%); colorless solid; mp 119 °C.
13C NMR (100 MHz, methanol-d4): δ = 142.5, 140.1, 128.5, 127.8,
124.7, 124.5, 123.2, 119.5, 117.9, 111.1, 110.7, 110.5, 20.3.
HRMS (ESI): m/z [M + H]+ calcd for C13H12NO: 198.0919; found:
198.0932.
IR (neat): 3422, 1718, 1144, 1130 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.69 (s, 1 H), 8.61 (br s, 1 H), 8.07 (d,
J = 8.0 Hz, 1 H), 7.53–7.49 (m, 2 H), 7.33 (m, 1 H), 5.99 (ddt, J = 17.2,
10.4, 6.0 Hz, 1 H), 5.03 (dq, J = 10.4, 1.6 Hz, 1 H), 4.96 (dq, J = 17.2, 1.6
Hz, 1 H), 4.04 (dt, J = 6.0, 1.6 Hz, 2 H), 3.96 (s, 3 H).
Murrayaquinone A (1)4a
13C NMR (100 MHz, CDCl3): δ = 167.4, 140.1, 135.7, 134.1, 132.3,
CrO3 (540 mg, 5.4 mmol) was added to a solution of 3,5-dimethylpyr-
azole (520 mg, 5.4 mmol) in anhyd DCM (10 mL) at 0 °C. The mixture
was stirred for 10 min before being cooled to –15 °C. A solution of
carbazolol 5 (60 mg ,0.3 mmol) in DCM (10 mL) was added via a sy-
ringe. The resulting mixture was stirred at –15 °C for 1.5 h. Silica gel
was added and the mixture was evaporated in vacuo. The residue was
purified by column chromatography (silica gel, EtOAc–PE, 20%) to give 1.
131.3, 127.7, 124.7, 124.1, 123.0, 122.8, 121.5, 120.8, 118.7 (q, JF-C
318.0 Hz), 115.9, 111.8, 52.4, 30.9.
HRMS (ESI): m/z [M + Na]+ calcd for C18H14F3NO5SNa: 436.0437;
found: 436.0437.
=
Methyl 2-Allyl-1-methyl-9H-carbazole-3-carboxylate (8)
A 2 M solution of AlMe3 in toluene (2.4 mL, 4.8 mmol) was added
dropwise over 10 min to a mixture of 7 (975 mg, 2.37 mmol) and
Pd(PPh3)4 (409 mg, 0.35 mmol) in anhyd THF (20 mL) at 0 °C under N2.
The resulting mixture was heated at reflux for 9 h. The cooled mix-
ture was quenched with H2O (20 mL), and then extracted with EtOAc
(4 × 12 mL). The organic extracts were dried (Na2SO4), then filtered,
and concentrated in vacuo. The residue was purified by column chro-
matography (silica gel, EtOAc–PE, 12%) to give 8.
Yield: 59 mg (92%); red solid; mp 242–243 °C (Lit.4a 237–239 °C).
1H NMR (400 MHz, DMSO-d6): δ = 12.82 (s, 1 H), 8.05 (d, J = 8.0 Hz,
1 H), 7.54 (d, J = 8.2 Hz, 1 H), 7.39 (td, J = 7.2, 1.2 Hz, 1 H), 7.32 (m,
1 H), 6.62 (q, J = 1.6 Hz, 1 H), 2.07 (d, J = 1.6 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 183.5, 180.5, 148.4, 137.9, 136.3,
132.1, 126.7, 124.3, 124.0, 122.1, 115.9, 114.3, 16.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H10NO2: 212.0712; found:
212.0718.
Yield: 679 mg (98%); colorless solid; mp 123–124 °C.
IR (neat): 3375, 1692, 990 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

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F. Ji et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.54 (s, 1 H), 8.16 (br s, 1 H), 8.04 (d,
J = 7.6 Hz, 1 H), 7.44–7.38 (m, 2 H), 7.24 (m, 1 H), 6.06 (ddt, J = 17.2,
10.4, 2.0 Hz, 1 H), 5.01 (dq, J = 10.4, 2.0 Hz, 1 H), 4.89 (dq, J = 17.2, 2.0
Hz, 1 H), 3.97–3.90 (m, 5 H), 2.46 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.3, 141.7, 139.9, 137.3, 136.5,
126.2, 124.0, 122.3, 121.7, 120.6, 120.5 120.2, 119.4, 114.8, 111.0,
52.0, 34.3, 13.4.
0 °C and quenched by slow addition of H2O (5 mL). The mixture was
acidified with 4 M aq HCl (1 mL), and then extracted with EtOAc (2 ×
6 mL). The separated aqueous phase was neutralized with 10% aq
NaOH (1.5 mL), and then extracted with EtOAc (2 × 6 mL). The com-
bined organic extracts were dried (Na2SO4), filtered, and concentrated
in vacuo. The residue was purified by column chromatography (silica
gel, MeOH–DCM, 3%) to provide 2.
Yield: 37 mg (76%); yellow solid: mp 293–294 °C (Lit.7c >300 °C).
HRMS (ESI): m/z [M + H]+ calcd for C18H18NO2: 280.1332; found:
280.1343.
1H NMR (400 MHz, CDCl3 + CD3OD): δ = 9.08 (s, 1 H), 8.34 (d, J = 8.0
Hz, 1 H), 8.28 (d, J = 6.8 Hz, 1 H), 8.09 (d, J = 7.2 Hz, 1 H), 7.65–7.58 (m,
2 H), 7.37 (m, 1 H), 3.29 (s, 3 H), 2.89 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H15N2: 247.1230; found:
247.1235.
Methyl 1-Methyl-2-(2-oxoethyl)-9H-carbazole-3-carboxylate (9)
OsO4 (53 mg, 0.21 mmol) in t-BuOH (1.1 mL) and NaIO4 (1.342 g, 6.27
mmol) were added to a solution of 8 (292 mg, 1.05 mmol) in H2O–
THF (1:3, 15 mL). The resulting mixture was stirred at r.t. for 15 h be-
fore being quenched with 20% sodium dithionate (15 mL). The mix-
ture was extracted with EtOAc (4 × 12 mL). The combined organic ex-
tracts were dried (Na2SO4), filtered, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, EtOAc–PE,
17%) to provide 9.
Methyl 1-(Methoxymethoxy)-9-methyl-9H-carbazole-3-carboxyl-
ate (11)
Methyl 1-(Methoxymethoxy)-9H-carbazole-3-carboxylate
K2CO3 (6.1 g, 44 mmol) and MOMCl (2.4 g, 30 mmol) were added to a
solution of 4 (4.8 g, 20 mmol) in acetone (80 mL). The resulting mix-
ture was stirred at ambient temperature for 5 h. Sat. aq NH4Cl (100
mL) was added. The mixture was extracted with EtOAc (5 × 50 mL).
The combined organic extracts were dried (Na2SO4) and then filtered
and evaporated in vacuo. The residue was purified by column chro-
matography (silica gel, EtOAc–PE, 17%) to give methyl 1-(methoxyme-
thoxy)-9H-carbazole-3-carboxylate.
Yield: 204 mg (69%); colorless solid; mp 164 °C.
IR (neat): 3347, 1714, 1698 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.56 (s, 1 H), 9.77 (s, 1 H), 8.64 (s,
1 H), 8.19 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.45 (m, 1 H),
7.22 (m, 1 H), 4.27 (s, 2 H), 3.84 (s, 3 H), 2.49 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 200.0, 168.0, 141.8, 140.5, 130.3,
126.2, 122.8, 121.2, 120.9, 120.6, 120.5, 120.3, 119.6, 111.4, 51.8, 44.7,
13.9.
Yield: 5.4 g (96%); pink solid; mp 89–91 °C.
IR (neat): 3265, 1683, 1585, 1500, 1003 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C17H15NO3Na: 304.0944; found:
304.0930.
1H NMR (400 MHz, CDCl3): δ = 8.76 (s, 1 H), 8.53 (s, 1 H), 8.09 (d,
J = 7.8 Hz, 1 H), 7.80 (s, 1 H), 7.50–7.42 (m, 2 H), 7.28 (m, 1 H), 5.38 (s,
2 H), 3.96 (s, 3 H), 3.58 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.7, 142.4, 139.6, 133.4, 126.5,
124.3, 123.7, 121.9, 120.7, 120.3, 117.3, 111.4, 111.2, 95.4, 56.5, 52.1.
5-Methyl-2,6-dihydro-1H-pyrido[4,3-b]carbazol-1-one (10)
Substrate 9 (140 mg, 0.5 mmol) and NH4OAc (578 mg, 7.5 mmol)
were added to AcOH (14 mL). The resulting mixture was stirred for 3
h at 80 °C. H2O (14 mL) was added. The mixture was extracted with
EtOAc (2 × 10 mL). The combined organic extracts were washed with
brine (8 mL), then dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was purified by column chromatography (silica gel, EtO-
Ac–PE, 28%, then 50%) to provide 10.
HRMS (ESI): m/z [M + Na]+ calcd for C16H15NO4Na: 308.0899; found:
308.0903.
11
NaH (0.9 g, 21.6 mmol) and MeI (5.1 g, 2.2 mL, 36.0 mmol) were add-
ed to a solution of methyl 1-(methoxymethoxy)-9H-carbazole-3-car-
boxylate (5.2 g, 18.1 mmol) in anhyd DMF (60 mL) at 0 °C. After addi-
tion, the mixture was allowed to warm to ambient temperature and
stirred for 4 h before being partitioned between EtOAc (60 mL) and
brine (100 mL). The separated aqueous phase was extracted with
EtOAc (2 × 60 mL). The combined organic extracts were washed with
brine (2 × 20 mL), and then dried (Na2SO4), filtered, and evaporated in
vacuo. The residue was purified by column chromatography (silica
gel, EtOAc–PE, 10%) to give carbazole 11.
Yield: 101 mg (82%); off-white solid; mp 226 °C.
IR (neat): 3347, 1698, 1236 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.44 (s, 1 H), 11.00 (d, J = 5.6 Hz,
1 H), 8.90 (s, 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.46
(t, J = 7.6 Hz, 1 H), 7.22 (t, J = 7.6 Hz, 1 H), 7.15 (dd, J = 7.6, 5.6 Hz, 1 H),
6.74 (d, J = 7.6 Hz, 1 H), 2.69 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.9, 142.0, 141.4, 133.7, 127.0,
126.7, 122.9, 122.2, 120.8, 119.3, 117.0, 112.4, 111.0, 101.5, 12.8.
Yield: 5.1 g (94%); colorless solid; mp 92–94 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C16H12N2ONa: 271.0842; found:
271.0828.
IR (neat): 1706, 1593, 1554 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.51 (d, J = 1.6 Hz, 1 H), 8.10 (d, J = 7.6
Hz, 1 H), 7.78 (d, J = 1.6 Hz, 1 H), 7.51 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H),
7.41 (d, J = 8.4 Hz, 1 H), 7.28 (t, J = 7.2 Hz, 1 H), 5.41 (s, 2 H), 4.19 (s, 3
H), 3.96 (s, 3 H), 3.58 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.6, 143.4, 141.9, 133.5, 126.3,
124.4, 123.0, 121.20, 120.4, 119.9, 117.0, 111.3, 109.0, 95.2, 56.6, 52.0,
32.0.
Olivacine (2)7c
Et3N (24 mg, 0.24 mmol) and Tf2O (68 mg, 0.04 mL, 0.24 mmol) were
added to a suspension of 10 (50 mg, 0.20 mmol) in anhyd DCM (10
mL) under N2. The mixture was stirred at –20 °C for 16 h, and then
filtered through a pad of silica gel. The filtrate was evaporated in vac-
uo. The residue was dissolved in anhyd THF (6 mL) at 0 °C under N2.
Pd(PPh3)4 (46 mg, 0.08 mmol) was added, followed by the dropwise
addition of 2 M AlMe3 in toluene (0.2 mL, 0.4 mmol) over a period of 5
min. The mixture was heated at reflux for 20 h, before being cooled to
HRMS (ESI): m/z [M + Na]+ calcd for C16H15NO4Na: 322.1055; found:
322.1064.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

E
F. Ji et al.
Paper
Synthesis
[1-(Methoxymethoxy)-9-methyl-9H-carbazol-3-yl]methanol (12)15
13-(Methoxymethoxy)-12-methyl-12H-indolo[3,2-j]phenanthri-
dine (15)
LiAlH4 (1.9 g, 49 mmol) was added to a solution of 11 (4.9 g, 16 mmol)
in anhyd THF (80 mL) at 0 °C. The mixture was stirred at 0 °C for 4 h
before being quenched with sat. aq NH4Cl (100 mL). The resulting
mixture was filtered through a pad of Celite. The filtrate was extract-
ed with EtOAc (3 × 50 mL). The combined organic extracts were dried
(Na2SO4) and then filtered and evaporated in vacuo. The residue was pu-
rified by column chromatography (silica gel, EtOAc–PE, 20%) to give 12.
A mixture of 14 (35 mg, 0.1 mmol), 2-aminophenylboric acid (20 mg,
0.15 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and K2CO3, (27 mg, 0.2
mmol) in DME–H2O (3:1, 8 mL) under N2 in a sealed tube was stirred
at 90 °C for 12 h and cooled. H2O (4 mL) was added. The resulting
mixture was extracted with EtOAc (3 × 10 mL). The combined organic
extracts were dried (Na2SO4) and then filtered and evaporated in vac-
uo. The residue was purified by column chromatography (silica gel,
EtOAc–PE, 20%) to give 15.
Yield: 4.2 g (93%); pink solid; mp 105–107 °C (Lit.15 109 °C).
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.0 Hz, 1 H), 7.71 (s, 1 H),
7.46 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H), 7.21 (m,
1 H), 7.13 (s, 1 H), 5.34 (s, 2 H), 4.78 (s, 2 H), 4.13 (s, 3 H), 3.56 (s, 3 H).
Yield: 25 mg (72%); brown solid; mp 28–30 °C.
IR (neat): 1592, 1120, 1126 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 144.2, 141.8, 132.4, 130.3, 125.8,
125.0, 122.8, 120.2, 119.0, 112.9, 110.5, 108.8, 95.3, 66.0, 56.5, 32.0.
HRMS (ESI): m/z [M + Na]+ calcd for C16H17NO3Na: 294.1106; found:
294.1113.
1H NMR (400 MHz, CDCl3): δ = 9.48 (dd, J = 8.0, 1.2 Hz, 1 H), 9.32 (s,
1 H), 8.51 (s, 1 H), 8.23 (d, J = 7.6 Hz, 1 H), 8.19 (dd, J = 8.0, 1.2 Hz, 1 H),
7.72 (m, 1 H), 7.68–7.60 (m, 2 H), 7.49 (d, J = 8.2 Hz, 1 H), 7.36 (t,
J = 7.2 Hz, 1 H), 5.31–5.03 (m, 2 H), 4.31 (s, 3 H), 3.47 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.5, 144.5, 143.8, 138.1, 136.6,
129.8, 128.0, 127.7, 126.6, 126.5, 126.4, 123.8, 123.6, 122.6, 122.3,
120.8, 120.2, 117.3, 109.2, 100.3, 58.9, 32.2.
[2-Bromo-1-(methoxymethoxy)-9-methyl-9H-carbazol-3-
yl]methanol (13)15
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O2: 343.1447; found:
343.1444.
A 2.5 M solution of n-BuLi in hexane (415 μL, 1.0 mmol) was added to
a solution of 12 (108 mg, 0.4 mmol) in anhyd benzene (10 mL ) at –20
°C. The mixture was stirred for 0.5 h. Dibromotetrachloroethane (260
mg, 0.8 mmol) dissolved in Et2O (2 mL) was slowly added via syringe.
After addition, the mixture was allowed to warm to ambient tem-
perature and stirred for a further 20 h. Brine (10 mL) was added, and
the pH of the mixture was adjusted to 6 by addition of 1 M hydrochlo-
ric acid. Benzene was evaporated and the remaining mixture was ex-
tracted with EtOAc (3 × 10 mL). The combined organic extracts were
dried (Na2SO4) and then filtered and evaporated in vacuo. The residue
was purified by column chromatography (silica gel, EtOAc–PE, 10%) to
give 13.
N-Methylcalothrixin B (16)16a
CrO3 (152 mg, 1.52 mmol) was added to a solution of 3,5-dimeth-
ylpyrazole (146 mg, 1.52 mmol) in anhyd DCM (7 mL) at –15 °C. The
mixture was stirred for 10 min. A solution of 15 (29 mg, 0.08 mmol)
in DCM (5 mL) was added via syringe. The resulting mixture was
stirred at –15 °C for 4 h. Silica gel was added and the bulk of the sol-
vent was evaporated in vacuo. The residue was purified by column
chromatography (silica gel, EtOAc–PE, 10%) to give 16.
Yield: 21 mg (67%); red solid; mp 259–260 °C (Lit.16a 268–271 °C).
Yield: 101 mg (73%); colorless solid; mp 78–80 °C (Lit.15 91 °C).
1H NMR (400 MHz, CDCl3): δ = 9.74 (s, 1 H), 9.54 (dd, J = 8.4, 1.2 Hz,
1 H), 8.36 (d, J = 8.0 Hz, 1 H), 8.17 (dd, J = 8.4, 1.2 Hz, 1 H), 7.82 (ddd,
J = 8.0, 6.8, 1.2 Hz, 1 H), 7.75 (ddd, J = 8.4, 6.8, 1.6 Hz, 1 H), 7.45–7.43
(m, 2 H), 7.37 (ddd, J = 8.0, 6.0, 2.0 Hz, 1 H), 4.24 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H13N2O2: 313.0978; found:
313.0899.
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 8.0 Hz, 1 H), 7.97 (s, 1 H),
7.52 (t, J = 7.6 Hz, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 7.26 (t, J = 7.6 Hz, 1 H;
this signal was obscured by the solvent peak), 5.27 (s, 2 H), 4.92 (s, 2
H), 4.15 (s, 3 H), 3.64 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 142.1, 139.9, 133.9, 131.1, 126.5,
124.7, 122.5, 120.2, 119.7, 116.7, 115.1, 109.0, 100.6, 66.1, 58.6, 31.5.
HRMS (ESI): m/z [M + Na]+ calcd for C16H1679BrNO3Na: 372.0211;
found: 372.0202.
Funding Information
We are grateful to the NSFC (#81330075; #21172202) and Zheng-
2-Bromo-1-(methoxymethoxy)-9-methyl-9H-carbazole-3-carbal-
dehyde (14)15
zhou University (#1421316040) for financial support.
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DMP (636 mg, 1.5 mmol) was added to a solution of 13 (350 mg, 1.0
mmol) in anhyd DCM (20 mL) at 0 °C. After addition, the mixture was
allowed to warm to ambient temperature and stirred for 12 h. Silica
gel was added and the bulk of the solvent was evaporated in vacuo.
The residue was purified by column chromatography (silica gel,
EtOAc–PE, 17%) to give 14.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610185.
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Yield: 324 mg (94%); colorless solid; mp 143–145 °C (Lit.15 162 °C).
References
1H NMR (400 MHz, CDCl3): δ = 10.45 (s, 1 H), 8.52 (s, 1 H), 8.10 (d,
J = 7.6 Hz, 1 H), 7.57 (ddd, J = 8.4, 7.2, 1.2 Hz, 2 H), 7.44 (d, J = 8.4 Hz,
1 H), 7.33 (t, J = 7.6 Hz, 2 H), 5.30 (s, 2 H), 4.18 (s, 3 H), 3.65 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.7, 142.5, 139.5, 138.2, 127.4,
125.8, 124.6, 122.9, 121.0, 120.7, 118.9, 118.8, 109.5, 100.9, 58.7, 31.7.
(1) For reviews, see: (a) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002,
102, 4303. (b) Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J. Chem.
Rev. 2012, 112, 3193. (c) Roy, J.; Jana, A. K.; Mal, D. Tetrahedron
2012, 68, 6099. (d) Bauer, I.; Knölker, H.-J. Top. Curr. Chem. 2012,
309, 203.
HRMS (ESI): m/z [M + H]+ calcd for C16H1579BrNO3: 348.0224; found:
(2) Wu, T. S.; Ohta, T.; Furukawa, H.; Kuoh, C. S. Heterocycles 1983,
20, 1267.
348.0157.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
F. Ji et al.
Paper
Synthesis
(3) Takeya, K.; Itoigawa, M.; Furukawa, H. Eur. J. Pharmacol. 1989,
169, 137.
Sainsbury, M. Tetrahedron 1990, 46, 2943. (f) Bäckvall, J.-E.;
Plobeck, N. A. J. Org. Chem. 1990, 55, 4528. (g) Zheng, X.; Lv, L.;
Lu, S.; Wang, W.; Li, Z. Org. Lett. 2014, 16, 5156.
(4) (a) Yogo, M.; Ito, C.; Furukawa, H. Chem. Pharm. Bull. 1991, 39,
328. (b) Knölker, H.-J.; Bauermeister, M. Tetrahedron 1993, 49,
11221. (c) Matsuo, K.; Ishida, S. Chem. Pharm. Bull. 1994, 42,
1325. (d) Hagelin, H.; Oslob, J. D.; Åkermark, B. Chem. Eur. J.
1999, 5, 2413. (e) Knölker, H.-J.; Reddy, H. R. Heterocycles 2003,
60, 1049. (f) Scott, T. L.; Söderberg, B. C. G. Tetrahedron 2003, 59,
6323. (g) Mal, D.; Senapati, B. K.; Pahari, P. Tetrahedron 2007, 63,
3768. (h) Nishiyama, T.; Choshi, T.; Kitano, K.; Hibino, S. Tetra-
hedron Lett. 2011, 52, 3876. (i) Norcott, T.; Spielman, C.;
McErlean, C. S. P. Green Chem. 2012, 14, 605. (j) Bhosale, S. M.;
Momin, A. A.; Kusurkar, R. S. Tetrahedron 2012, 68, 6420.
(k) Bedford, R. B.; Bowen, J. G.; Weeks, A. L. Tetrahedron 2013,
69, 4389. (l) Kaliyaperumal, S. A.; Banerjee, S.; Syam Kumar, U.
K. Org. Biomol. Chem. 2014, 12, 6105. (m) Guo, J.; Kiran, I. N. C.;
Reddy, R. S.; Gao, J.; Tang, M.; Liu, Y.; He, Y. Org. Lett. 2016, 18,
2499. (n) Nishiyama, T.; Hatae, N.; Yoshimura, T.; Takaki, S.;
Abe, T.; Ishikura, M.; Hibino, S.; Choshi, T. Eur. J. Med. Chem.
2016, 121, 561.
(9) For reviews, see: (a) Choshi, T.; Hibino, S. Heterocycles 2009, 77,
85. (b) Xu, S.; Nijampatnam, B.; Dutta, S.; Velu, S. E. Mar. Drugs
2016, 14, 17.
(10) For recent examples, see: (a) Ramkumar, N.; Nagarajan, R. Org.
Biomol. Chem. 2015, 13, 11046. (b) Ramkumar, N.; Nagarajan, R.
RSC Adv. 2015, 5, 87838. (c) Guo, J.; Kiran, I. N. C.; Gao, J.; Reddy,
R. S.; He, Y. Tetrahedron Lett. 2016, 57, 3481.
(11) (a) Hong, M.; Liu, H.; Sun, L.; Jia, F.; Liu, Y.; Jiang, Q.; Song, C.;
Chang, J. Synlett 2011, 2995. (b) Song, C.; Liu, H.; Hong, M.; Liu,
Y.; Jia, F.; Sun, L.; Pan, Z.; Chang, J. J. Org. Chem. 2012, 77, 704.
(c) Fan, F.; Dong, J.; Wang, J.; Song, L.; Song, C.; Chang, J. Adv.
Synth. Catal. 2014, 356, 1337. (d) Wang, J.; Wang, J.; Li, C.; Meng,
Y.; Wu, J.; Song, C.; Chang, J. J. Org. Chem. 2014, 79, 6354.
(e) Meng, Y.; Liu, Y.; Lv, Z.; Wang, J.; Wang, Y.; Song, C.; Chang, J.
Nat. Prod. Commun. 2015, 10, 2031. (f) Liu, Y.; Guo, Y.; Ji, F.; Gao,
D.; Song, C.; Chang, J. J. Org. Chem. 2016, 81, 4310. (g) Guo, Y.;
Huang, H.; Zhang, T.; Qi, S.; Liu, Y.; Li, M.; Wang, P.; Song, C.;
Chang, J. Asian J. Org. Chem. 2016, 5, 1269.
(5) Schmutz, J.; Hunziker, F. Pharm. Acta Helv. 1958, 33, 341.
(6) Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de Chazal, N. M.;
Kirk, J.; Kirk, K.; Saliba, K. J.; Smith, G. D. Tetrahedron 1999, 55,
13513.
(12) (a) Bringmann, G.; Tasler, S.; Endress, H.; Peters, K.; Peters, E.-M.
Synthesis 1998, 1501. (b) Markad, S. B.; Argade, N. P. Org. Lett.
2014, 16, 5470.
(7) For strategies involving phenyl C-ring formation, see:
(a) Bergman, J.; Carlsson, R. Tetrahedron Lett. 1978, 19, 4055.
(b) Miki, Y.; Tsuzaki, Y.; Hibino, H.; Aoki, Y. Synlett 2004, 2206.
(c) Ramkumar, N.; Nagarajan, R. J. Org. Chem. 2014, 79, 736.
(d) Ishikura, M.; Takahashi, N.; Yamada, K.; Abe, T.; Yanada, R.
Helv. Chim. Acta 2008, 91, 1828. (e) Itoh, T.; Abe, T.; Choshi, T.;
Nishiyama, T.; Yanada, R.; Ishikura, M. Eur. J. Org. Chem. 2016,
2290.
(8) For strategies involving pyridinyl D-ring formation, see:
(a) Naito, T.; Iida, N.; Ninomiya, I. J. Chem. Soc., Chem. Commun.
1981, 44. (b) Besselièvre, R.; Husson, H.-P. Tetrahedron 1981, 37,
241. (c) Narasimhan, N. S.; Gokhale, S. M. J. Chem. Soc., Chem.
Commun. 1985, 86. (d) Hogan, I.; Jenkins, P.; Sainsbury, M. Tet-
rahedron Lett. 1988, 29, 6505. (e) Hogan, I.; Jenkins, P. D.;
(13) Hirota, K.; Isobe, Y.; Maki, Y. J. Chem. Soc., Perkin Trans. 1 1989,
2513.
(14) (a) Borah, A.; Gogoi, P. Eur. J. Org. Chem. 2016, 2200. (b) Ge, J.;
Wang, X.; Liu, T.; Shi, Z.; Xiao, Q.; Yin, D. RSC Adv. 2016, 6,
19571.
(15) Tasler, S.; Endress, H.; Bringmann, G. Synthesis 2001, 1993.
(16) (a) Abe, T.; Ikeda, T.; Choshi, T.; Hibino, S.; Hatae, N.; Toyata, E.;
Yanada, R.; Ishikura, M. Eur. J. Org. Chem. 2012, 5018.
(b) Matsumoto, K.; Choshi, T.; Hourai, M.; Zamami, Y.; Sasaki,
K.; Abe, T.; Ishikura, M.; Hatae, N.; Iwamura, T.; Tohyama, S.;
Nobuhiro, J.; Hibino, S. Bioorg. Med. Chem. Lett. 2012, 22, 4762.
(c) Hatae, N.; Satoh, R.; Chiba, H.; Osaki, T.; Nishiyama, T.;
Ishikura, M.; Abe, T.; Hibino, S.; Choshi, T.; Okada, C.; Toyota, E.
Med. Chem. Res. 2014, 23, 4956.
(17) Martin, T.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1988, 235.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F