Divergent Syntheses of Carbazole Alkaloids Clausenapin, Indizoline, Claulansine M, and Clausenaline D

Article abstract of DOI:10.1021/acs.joc.6b00729

We described the first total syntheses of clausenapin, indizoline, claulansine M, and a novel synthetic route to clausenaline D via divergent method. Key steps involved TFAA-mediated intramolecular acylation to construct the carbazole core and subsequent Claisen rearrangement to generate key intermediates for further elaboration to target molecules.

Full text of DOI:10.1021/acs.joc.6b00729

Article
pubs.acs.org/joc
Divergent Syntheses of Carbazole Alkaloids Clausenapin, Indizoline,
Claulansine M, and Clausenaline D
Yizhen Liu, Yanqin Guo, Feixiang Ji, Dong Gao, Chuanjun Song,* and Junbiao Chang*
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, People’s Republic of China
S
* Supporting Information
ABSTRACT: We described the first total syntheses of clausenapin, indizoline, claulansine M, and a novel synthetic route to
clausenaline D via divergent method. Key steps involved TFAA-mediated intramolecular acylation to construct the carbazole core
and subsequent Claisen rearrangement to generate key intermediates for further elaboration to target molecules.
steps. Dihydroxylation of 13 followed by sodium periodate
oxidation furnished aldehyde 14 in 70% yield. Treatment of 14
with boron tribromide resulted in the formation of
furocarbazole 15 in 51% isolated yield via demethylation and
concomitant furan ring formation. Transformation of the
methyl ester functional group of 15 into aldehyde by lithium
aluminum hydride reduction and Dess-Martin oxidation gave
clausenaline D19,20 (4) in 40% isolated yield over the two steps.
On the other hand, treatment of 13 with lithium aluminum
hydride in refluxing 1,4-dioxane21 afforded 16 in 94% isolated
yield. Olefin metathesis of 16 with 2,3-dimethyl-2-butene 17
gave access to clausenapin (1) in excellent yield.
The successful synthesis of clausenapin (1) inspired us to
tackle our next target, indizoline (2). Thus, ester 13 was first
converted into aldehyde 18 in 81% isolated yield following a
two-step procedure (Scheme 2). The olefin metathesis reaction
of 18 with 2,3-dimethyl-2-butene 17 was then carried out in the
hope to obtain the desired indizoline (2). Unfortunately,
compound 19 resulting from self-metathesis of 18 was actually
obtained as it readily precipitated out of the reaction media. We
then attempted the olefin metathesis of 13 with 17. However,
the reaction was difficult to be driven to completion under a
variety of conditions. At best, the desired product 20 was
isolated in 44% yield together with substantial amount of the
unreacted starting material 13 recovered.
INTRODUCTION
■
The carbazole alkaloids are mainly isolated from plants.1 For
example, clausenapin (1)2 and indizoline (2)3 were isolated
from Clausena heptaphylla and Clausena indica, respectively,
while claulansine I (3),4 clausenaline D (4), claulamine E (7),5
claulansine M (5),6 claulamine A (6),7 and mafaicheenaine A
(8)8 were isolated from Clausena lansium (Figure 1).
Furthermore, microbes9 and algae10 are also reported to be
sources of natural cabazoles. Because of their promising
biological activities, numerous methods have been developed
for the synthesis of carbazole alkaloids. These methods could
be further divided into two categories based on the way to
construct the carbazole core. One way is to form the pyrrolyl
ring, including Fischer-Borsche synthesis,11 Graebe-Ullmann
synthesis,12 palladium-catalyzed cyclization,13 iron-mediated
synthesis,14 etc. The other way starts from an indole derivative
to construct the benzene ring, such as electrocyclic reaction,15
cycloaddition reaction,16 and so on. Herein, we report the first
total syntheses of clausenapin, indizoline, and claulansine M,
and a facile synthetic route to clausenaline D via divergent
method.
RESULTS AND DISSCUTION
■
Our synthesis commenced with Stobbe condensation of indole-
3-carbaldehyde 9 with dimethyl succinate in the presence of
sodium hydride, which produced succinic monoester 10 in 97%
isolated yield (Scheme 1). It should be indicated that
compound 10 could be obtained only in low yield if methoxide
was used as the base.17 TFAA-mediated intramolecular
acylation18 of 10 provided carbazole 11, allylation of which
followed by Claisen rearrangement and methylation gave the
key intermediate 13 in good combined yield over the three
Since there is low conversion rate of 13 to 20 and it is hard
to separate the two, we next explored an alternative strategy to
introduce the requisite prenyl group of indizoline (2). As
shown in Scheme 3, propargylation of 11 with 1,1-
Received: April 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00729
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Figure 1. Representative carbazole alkaloids.
a
Scheme 1
a
Reagents and conditions: (a) dimethyl succinate, NaH, THF, reflux, 97%; (b) TFAA, DCM, reflux, 70%; (c) allyl bromide, K2CO3, acetone, 77%;
(d) (i) DMF, reflux; (ii) K2CO3, MeI, 71% over the two steps; (e) OsO4, NaIO4, THF-H2O, 70%; (f) BBr3, DCM, 51%; (g) (i) LiAlH4, THF, 0 °C;
(ii) DMP, DCM, 40% over the two steps; (h) LiAlH4, 1,4-dioxane, reflux, 94%; (i) 2,3-dimethyl-2-butene (17), Grubbs 2nd generation catalyst,
DCM, reflux, 84%.
a
pyranocarbazole 23 in almost quantitative yield. Finally, two-
step transformation of the ester group into aldehyde completed
the total synthesis of claulansine M (5).
Scheme 2
CONCLUSION
■
In summary, we have accomplished the first total syntheses of
clausenapin, indizoline, and claulansine M, as well as the
synthesis of clausenaline D via divergent method. Studies
toward the total synthesis of other carbazole alkaloids using the
valuable precursor 20 are currently underway in our laboratory.
EXPERIMENTAL SECTION
■
Melting points were determined on a hot-stage apparatus and were
uncorrected. Infrared spectra were obtained using an FT-IR
spectrometer. 1H and 13C NMR spectra were obtained on a 400
MHz spectrometer. High-resolution mass spectra were recorded on a
Q-TOF mass spectrometer. Flash column chromatography was
performed over silica gel 200−300 mesh.
a
Reagents and conditions: (a) (i) LiAlH4, THF, 0 °C; (ii) DMP,
DCM; (b) 17, Grubbs 2nd generation catalyst, DCM, reflux.
dimethylpropargyl trifluoroacetate provided 21 in 60% isolated
yield.22 Hydrogenation of the triple bond in 21 in the presence
of Lindlar’s catalyst followed by Claisen rearrangement of the
resulting allyl ether provided 22 in 71% isolated yield over the
two steps. Methylation of phenol 22 gave 20, ester group
manipulation of which as described for the synthesis of
clausenaline D (4) furnished indizoline (2) in good yield. On
the other hand, [3,3]-sigmatropic rearrangement of propargyl
ether 21 followed by rearomatization and cyclization gave
(E)-4-(1′H-Indol-3′-yl)-3-(methoxycarbonyl)but-3-enoic Acid
(10). Sodium hydride (60% dispersion in mineral oil, 6.4 g, 160 mmol)
was added slowly at 0 °C to a solution of indole-3-carbaldehyde 9 (5.8
g, 40 mmol) and dimethyl succinate (11.7 g, 10 mL, 80 mmol) in dry
THF (200 mL). The resulting mixture was heated at reflux under
nitrogen atmosphere for 20 h. The mixture was cooled to −20 °C, and
water (100 mL) was added to quench the reaction. The mixture was
acidified with concentrated HCl until a pH of 1 was reached, and then
B
DOI: 10.1021/acs.joc.6b00729
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a
Scheme 3
a
Reagents and conditions: (a) 1,1-dimethylpropargyl trifluoroacetate, CuCl2, DBU, MeCN, 0 °C; (b) (i) Lindlar’s catalyst, quinoline, H2, EtOAc;
(ii) silica gel, EtOAc, 50 °C; (c) MeI, K2CO3, acetone; (d) (i) LiAlH4, THF, 0 °C; (ii) DMP, DCM; (e) p-xylene, reflux.
extracted with ethyl acetate (100 mL × 4). The combined organic
extracts were dried over sodium sulfate. The solvent was evaporated in
vacuo. The residue was purified by column chromatography on silica
gel (13% ethyl acetate in petroleum ether, then ethyl acetate) to give
acid 10 (10.1 g, 97%) as a pale-yellow solid: mp 180−183 °C [lit.17b
with 30 mL of ethyl acetate and washed with brine (20 mL × 2). The
separated aqueous layer was extracted with ethyl acetate (30 mL × 3).
The combined organic extracts were dried over sodium sulfate. The
solvent was removed in vacuo. The residue was purified by column
chromatography on silica gel (6% ethyl acetate in petroleum ether) to
give 13 (2.3 g, 71%) as a colorless solid: mp 112−115 °C. IR (KBr,
1
mp 166−168 °C]. H NMR (DMSO-d6, 400 MHz): δ = 12.44 (s,
1
cm−1): νmax 3345, 1684, 1607, 1346, 1262. H NMR (CDCl3, 400
1H), 11.83 (s, 1H), 8.07 (s, 1H), 7.73 (m, 2H), 7.50 (d, J = 7.6 Hz,
1H), 7.22 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 3.77 (s, 3H),
3.60 (s, 2H) ppm. 13C NMR (DMSO-d6, 100 MHz): δ = 172.3, 168.0,
135.8, 132.5, 127.4, 127.3, 122.5, 120.5, 119.4, 118.0, 112.1, 110.2,
51.8, 34.4 ppm. HRMS (ESI): m/z [M + Na]+ calcd for
C14H13NO4Na 282.0737; found 282.0737.
MHz): δ = 8.51 (s, 1H), 8.42 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.47−
7.41 (m, 2H), 7.26 (t, J = 6.4 Hz, 1H), 6.11 (ddt, J = 16.8, 10.0, 5.6
Hz, 1H), 5.02−4.93 (m, 2H), 4.03 (dt, J = 5.6, 1.6 Hz, 2H), 3.94 (s,
3H), 3.93 (s, 3H) ppm. 13C NMR(CDCl3, 100 MHz): δ = 168.5,
143.5, 140.0, 138.4, 135.6, 131.3, 126.6, 124.0, 123.0, 122.4, 120.7,
120.5, 120.4, 114.7, 111.3, 61.5, 52.0, 30.8 ppm. HRMS (ESI): m/z [M
+ Na]+ calcd for C18H17NO3Na 318.1101; found 318.1095.
Methyl 1-Hydroxy-9H-carbazole-3-carboxylate (11). To a
solution of acid 10 (10.1 g, 39 mmol) in DCM (150 mL) was added
trifluoroacetic anhydride (24.6 g, 16.5 mL, 117 mmol). The mixture
was stirred under reflux for 5 h before being cooled to −20 °C and
neutralized with saturated aqueous sodium bicarbonate. The separated
aqueous layer was extracted with ethyl acetate (100 mL × 3). The
combined organic extracts were dried over sodium sulfate. The solvent
was evaporated in vacuo. The residue was purified by column
chromatography on silica gel (30% ethyl acetate in petroleum ether) to
provide carbazolecarboxylate 11 (6.6 g, 70%) as a colorless solid: mp
Methyl 1-Methoxy-2-(2′-oxoethyl)-9H-carbazole-3-carboxy-
late (14). Sodium periodate (1.3 g, 6 mmol) and osmium tetroxide
(40 mg/mL in t-BuOH, 1.6 mL, 0.25 mmol) were added to a solution
of ester 13 (0.3 g, 1 mmol) in THF-H2O (3:1, 20 mL). The mixture
was stirred at ambient temperature for 13 h before being quenched
with 2 M sodium dithionite solution (15 mL). The mixture was stirred
for 0.5 h, and then filtered through a pad of Celite. The filter cake was
washed with ethyl acetate (10 mL × 3). The filtrate was separated. The
aqueous layer was extracted with ethyl acetate (20 mL × 4). The
combined organic extracts were dried over sodium sulfate. The solvent
was removed in vacuo. The residue was purified by column
chromatography on silica gel (30% ethyl acetate in petroleum ether)
to provide 14 (0.2 g, 70%) as a colorless solid: mp 171−174 °C. IR
121−123 °C, [lit.17a mp 203−205 °C]. H NMR (DMSO-d6, 400
1
MHz): δ = 11.57 (s, 1H), 10.23 (s, 1H), 8.33 (d, J = 3.6 Hz, 1H), 8.18
(d, J = 8.0 Hz, 1H), 7.55−7.49 (m, 2H), 7.42 (t, J = 7.2 Hz, 1H), 7.20
(t, J = 7.2 Hz, 1H), 3.88 (s, 3H) ppm. 13C NMR (DMSO-d6, 100
MHz): δ = 167.1, 142.9, 140.2, 132.7, 126.0, 123.4, 123.0, 120.6, 120.5,
119.3, 114.1, 111.7, 110.1, 51.7 ppm. HRMS (ESI): m/z [M + Na]+
calcd for C14H11NO3 Na 264.0631; found 264.0633.
1
(KBr, cm−1): νmax 3336, 1703, 1240, 1058, 756. H NMR (DMSO-d6,
400 MHz): δ = 11.81 (s, 1H), 9.80 (s, 1H), 8.64 (s, 1H), 8.22 (d, J =
7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.48 (m, 1H), 7.24 (m, 1H),
4.25 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H) ppm. 13C NMR (DMSO-d6,
100 MHz): δ = 200.1, 167.2, 144.0, 140.5, 135.2, 126.5, 124.5, 122.9,
122.8, 120.6, 120.0, 119.8, 111.7, 61.1, 51.8, 41.3 ppm. HRMS (ESI):
m/z [M + Na]+ calcd for C17H15NO4Na 320.0893; found 320.0893.
Methyl 10H-Furo[2,3-a]carbazole-4-carboxylate (15).19
Boron tribromide (1 M solution in DCM, 2 mL, 2.0 mmol) was
added to a solution of 14 (144 mg, 0.5 mmol) in dry DCM (5 mL) at
−78 °C under nitrogen. The mixture was stirred at −78 °C for 10 min
before being allowed to warm to ambient temperature and stirred for a
further 3 h. The reaction was quenched by the addition of methanol (1
mL) and the mixture was stirred for 1 h. The solvent was removed in
vacuo and the residue was purified by column chromatography on
silica gel (13% ethyl acetate in petroleum ether) to provide 15 (67 mg,
Methyl 1-Allyloxy-9H-carbazole-3-carboxylate (12). Potassi-
um carbonate (5.7 g, 41 mmol) and allyl bromide (5.0 g, 3.5 mL, 41
mmol) were added to a solution of 11 (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 column chromatography on silica gel (6% then 12% ethyl
acetate in petroleum ether) to give 12 (3.4 g, 73%) as a pale-yellow
solid: mp 179−180 °C. IR (KBr, cm−1): νmax 3368, 1686, 1248, 1215.
1H NMR (CDCl3, 400 MHz): δ = 8.54 (s, 1H), 8.47 (s, 1H), 8.09 (d, J
= 8.0 Hz, 1H), 7.59 (s, 1H), 7.49−7.42 (m, 2H), 7.28 (t, J = 7.2 Hz,
1H), 6.15 (ddt, J = 17.2, 10.4, 5.2 Hz, 1H), 5.49 (d, J = 17.2 Hz, 1H),
5.35 (d, J = 10.4 Hz, 1H), 4.77 (d, J = 5.2 Hz, 2H), 3.97 (s, 3H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 168.1, 144.1, 139.6, 133.2, 133.0,
126.5, 123.9, 122.0, 120.9, 120.4, 118.5, 116.5, 111.4, 108.0, 69.5, 52.2
ppm. HRMS (ESI): m/z [M + Na]+ calcd for C17H15NO3Na
304.0944; found 304.0956.
1
51%) as a yellow oil. H NMR (CDCl3, 400 MHz): δ = 8.75 (s, 1H),
8.70 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.57
(d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H),
7.32 (t, J = 7.6 Hz, 1H), 4.04 (s, 3H) ppm. 13C NMR (CDCl3, 100
MHz): δ = 167.8, 145.2, 140.6, 139.5, 127.9, 126.2, 126.1, 124.2, 121.0,
120.8, 120.5, 119.9, 114.7, 111.4, 109.4, 52.0 ppm. HRMS (ESI): m/z
[M + Na]+ calcd for C16H11NO3Na 288.0637; Found 288.0631.
Methyl 2-Allyl-1-methoxy-9H-carbazole-3-carboxylate (13).
Ester 12 (3.1 g, 11 mmol) was dissolved in DMF (15 mL) and the
solution was heated to reflux for 5 h. The mixture was cooled to
ambient temperature. Potassium carbonate (1.5 g, 11 mmol) and
iodomethane (1.6 g, 0.7 mL, 11 mmol) were added, and the mixture
was stirred at ambient temperature for 15 h. The mixture was diluted
C
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Clausenaline D (4).19 Lithium aluminum hydride (14 mg, 0.4
mmol) was added to a solution of 15 (50 mg, 0.2 mmol) in dry THF
(5 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 15
h before being quenched with saturated aqueous ammonium chloride
(10 mL). The mixture was filtered through a pad of Celite. The filter
cake was washed with ethyl acetate (10 mL × 3). The filtrate was
separated. The aqueous phase was extracted with ethyl acetate (10 mL
× 3). The combined organic extracts were dried over sodium sulfate.
The bulk of solvent was evaporated in vacuo. The residue was purified
by column chromatography on silica gel (13% ethyl acetate in
petroleum ether) to provide (10H-furo[2,3-a]carbazol-4-yl)-
solution of ester 13 (90 mg, 0.3 mmol) in dry THF (10 mL). After
addition, the mixture was stirred at 0 °C for 15 h before being
quenched with saturated aqueous ammonium chloride (10 mL). The
mixture was filtered through a pad of Celite. The filter cake was
washed with ethyl acetate (10 mL × 3). The separated aqueous layer
of the filtrate was extracted with ethyl acetate (10 mL × 3). The
combined organic extracts were dried over sodium sulfate, and then
filtered. The solvent was evaporated in vacuo. The residue was purified
by column chromatography on silica gel (13% ethyl acetate in
petroleum ether) to give (2-allyl-1-methoxy-9H-carbazol-3-yl)-
methanol (73 mg, 86%) as a pale-yellow solid: mp 137−140 °C. IR
1
1
(KBr, cm−1): νmax 3425, 1450, 1348, 1117. H NMR (CDCl3, 400
methanol (27 mg, 61%) as a colorless oil. H NMR (CD3OD, 400
MHz): δ = 8.04 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.82 (m, 1H), 7.51
(d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H),
7.12 (m, 1H), 4.96 (s, 2H) ppm. 13C NMR (CD3COCD3, 100 MHz):
δ = 145.1, 141.9, 140.8, 126.1, 125.9, 125.8, 124.8, 123.6, 121.5, 120.6,
120.3, 116.3, 112.3, 107.9, 71.3 ppm. HRMS (ESI): m/z [M + Na]+
calcd for C15H11NO2Na 260.0687; found 260.0688.
Dess-Martin periodinane (48 mg, 0.1 mmol) was added to a
solution of (10H-furo[2,3-a]carbazol-4-yl)methanol (27 mg, 0.1
mmol) in DCM (2 mL). The resulting mixture was stirred for 3 h
at ambient temperature and filtered. The filter cake was washed with
ethyl acetate (10 mL × 3). The filtrate was concentrated and the
residue was purified by column chromatography on silica gel (6% ethyl
acetate in petroleum ether) to give clausenaline D 4 (18 mg, 65%) as a
colorless solid. 1H NMR (CD3COCD3, 400 MHz): δ = 11.46 (s, 1H),
10.26 (s, 1H), 8.65 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 1.6
Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.50 (t, J =
7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H) ppm. HRMS (ESI): m/z [M +
Na]+ calcd for C15H9NO2Na 258.0531; Found 258.0525.
MHz): δ = 8.15 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.88 (s, 1H), 7.46
(d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.23 (m, 1H), 6.13 (ddt, J
= 17.2, 10.4, 5.2 Hz, 1H), 5.06 (dq, J = 10.4, 1.6 Hz, 1H), 4.93 (dq, J =
17.2, 1.6 Hz, 1H), 4.83 (s, 2H), 3.96 (s, 3H), 3.73 (dt, J = 5.2, 1.6 Hz,
2H), 1.69 (s, 1H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 143.6,
139.8, 138.4, 132.9, 132.1, 127.6, 126.0, 124.0, 123.8, 120.5, 119.9,
116.9, 115.3, 111.1, 64.3, 61.4, 30.1 ppm. HRMS (ESI): m/z [M +
Na]+ calcd for C17H17NO2Na 290.1151; Found 290.1155.
Dess-Martin periodinane (68 mg, 0.2 mmol) was added to a
solution of (2-allyl-1-methoxy-9H-carbazol-3-yl)methanol (43 mg, 0.2
mmol) in DCM (5 mL). The resulting mixture was stirred for 10 h at
ambient temperature, and then filtered. The filter cake was washed
with ethyl acetate (10 mL × 3). The filtrate was concentrated and the
residue was purified by column chromatography on silica gel (13%
ethyl acetate in petroleum ether) to give aldehyde 18 (39 mg, 94%) as
an orange oil. IR (KBr, cm−1): νmax 3279, 1662, 1595, 1232, 1106. 1H
NMR (CDCl3, 400 MHz): δ = 10.26 (s, 1H), 8.63 (s, 1H), 8.44 (s,
1H), 8.08 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.47 (td, J =
8.0, 0.8 Hz, 1H), 7.30 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 6.16 (ddt, J =
17.2, 10.4, 5.6 Hz, 1H), 5.08 (dq, J = 10.4, 1.6 Hz, 1H), 4.93 (dq, J =
17.2, 1.6 Hz, 1H), 4.04 (dt, J = 5.6, 1.6 Hz, 2H), 3.98 (s, 3H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 192.0, 143.3, 140.0, 138.0, 137.0, 131.3,
127.8, 126.9, 124.0, 123.7, 121.9, 120.9, 120.8, 115.8, 111.5, 61.7, 29.0
ppm. HRMS (ESI): m/z [M + Na]+ calcd for C17H15NO2Na
288.0995; found 288.1001.
2-Allyl-1-methoxy-3-methyl-9H-carbazole (16). Lithium alu-
minum hydride (190 mg, 5.0 mmol) was added to a solution of 13
(738 mg, 2.5 mmol) in dry 1,4-dioxane (15 mL). The mixture was
heated at reflux under nitrogen for 4 h before being cooled to 0 °C and
quenched with saturated aqueous ammonium chloride (20 mL). The
mixture was filtered through a pad of Celite. The filter cake was
washed with ethyl acetate (15 mL × 3). The filtrate was separated. The
aqueous layer was extracted with ethyl acetate (20 mL × 3). The
combined organic extracts were dried over sodium sulfate. The solvent
was removed in vacuo. The residue was purified by column
chromatography on silica gel (3% ethyl acetate in petroleum ether)
to provide carbazole 16 (590 mg, 94%) as a colorless solid: mp 92−95
2,2′-(But-2″-ene-1″,4″-diyl)bis(1-methoxy-9H-carbazole-3-
carbaldehyde) (19). Under nitrogen atmosphere, Grubbs second
generation catalyst (18 mg, 0.02 mmol) and 2,3-dimethyl-2-butene 17
(698 mg, 1.0 mL, 8.3 mmol) were added to a solution of carbazole 18
(110 mg, 0.4 mmol) in dry DCM (20 mL). The resulting mixture was
heated at reflux for 12 h and cooled. The formed precipitate was
filtered and washed with DCM (5 mL × 3) to provide 19 (58 mg,
56%) as a colorless solid: mp 271 °C, decomposition. IR (KBr, cm−1):
1
°C. IR (KBr, cm−1): νmax 3350, 1310, 1276. H NMR (CDCl3, 400
MHz): δ = 8.08 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.45
(d, J = 8.0 Hz, 1H), 7.40 (m, 1H), 7.23 (m, 1H), 6.06 (ddt, J = 17.2,
10.0, 5.2 Hz, 1H), 5.06 (dq, J = 10.0, 1.0 Hz, 1H), 4.95 (dq, J = 17.2,
1.8 Hz, 1H), 3.97 (s, 3H), 3.64 (dt, J = 5.2, 1.8 Hz, 2H), 2.47 (s, 3H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 143.4, 139.8, 136.9, 131.6,
129.6, 128.0, 125.7, 124.0, 123.7, 120.3, 119.5, 117.2, 115.1, 110.9,
61.4, 30.9, 19.9 ppm. HRMS (ESI): m/z [M + Na]+ calcd for
C17H17NONa 274.1202; found 274.1188.
1
νmax 3266, 1665, 1595, 1232. H NMR (DMSO-d6, 400 MHz): δ =
11.81 (s, 2H), 10.13 (s, 2H), 8.45 (s, 2H), 8.18 (d, J = 7.6 Hz, 2H),
7.55 (d, J = 8.0 Hz, 2H), 7.46 (m, 2H), 7.24 (t, J = 7.6 Hz, 2H), 5.64
(t, J = 2.0 Hz, 2H), 3.91 (d, J = 2.0 Hz, 4H), 3.85 (s, 6H) ppm. 13C
NMR (DMSO-d6, 400 MHz): δ = 191.7, 142.9, 140.5, 136.4, 130.9,
130.4, 126.6, 126.5, 123.0, 122.6, 121.8, 120.6, 120.0, 111.8, 61.0, 27.2
ppm. HRMS (ESI): m/z [M + Na]+ calcd for C32H26N2O4Na
525.1785; found 525.1782.
Clausenapin (1).2 Under nitrogen atmosphere, Grubbs second
generation catalyst (13 mg, 0.015 mmol) and 2,3-dimethyl-2-butene
17 (498 mg, 0.7 mL, 6.0 mmol) were added to a solution of carbazole
16 (77 mg, 0.3 mmol) in dry DCM (10 mL). The resulting mixture
was heated at reflux for 24 h and cooled. The mixture was filtered
through a pad of silica gel. The filter cake was washed with DCM (10
mL × 3). The filtrate was concentrated and the residue was purified by
column chromatography on silica gel (3% ethyl acetate in petroleum
ether) to give clausenapin 1 (72 mg, 84%) as a pale-yellow solid: mp
81−83 °C. 1H NMR (CDCl3, 400 MHz): δ = 8.10 (s, 1H), 8.00 (d, J =
8.0 Hz, 1H), 7.65 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.6 Hz,
1H), 7.21 (t, J = 7.6 Hz, 1H), 5.16 (m, 1H), 3.96 (s, 3H), 3.56 (d, J =
6.4 Hz, 2H), 2.47 (s, 3H), 1.85 (s, 3H), 1.73 (s, 3H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 143.1, 139.7, 131.8, 131.7, 130.4, 129.3,
125.5, 124.0, 123.3, 123.2, 120.3, 119.4, 117.2, 110.9, 61.2, 26.0, 25.9,
20.1, 18.2 ppm. HRMS (ESI): m/z [M + H]+ calcd for C19H22NO
280.1696; found 280.1689.
Methyl 1-[(2′-Methylbut-3′-yn-2′-yl)oxy]-9H-carbazole-3-
carboxylate (21). At 0 °C, DBU (1.1 g, 1.1 mL, 8 mmol) was
added to a solution of 2-methyl-3-butyn-2-ol (0.5 g, 0.6 mL, 6 mmol)
in acetonitrile (10 mL). TFAA (1.1 g, 0.7 mL, 5 mmol) was then
added dropwise. The solution was stirred at 0 °C for 0.5 h before
being poured into a mixture of ester 11 (1.2 g, 5 mmol), DBU (1.1 g,
1.1 mL, 8 mmol) and CuCl2 (1 mg, 0.005 mmol) in acetonitrile (30
mL). The resulting mixture was stirred at 0 °C for 4 h. The solvent
was evaporated in vacuo. The residue was dissolved in ethyl acetate (30
mL) and washed successively with 2 M hydrochloric acid (30 mL), 2
M sodium hydroxide (30 mL), saturated aqueous sodium bicarbonate
(30 mL) and brine (30 mL). The organic layer was dried over sodium
sulfate, and then filtered and evaporated in vacuo. The residue was
purified by column chromatography on silica gel (6% ethyl acetate in
petroleum ether) to provide 21 (1.4 g, 60%) as a yellow solid: mp
1
2-Allyl-1-methoxy-9H-carbazole-3-carbaldehyde (18). At 0
°C, lithium aluminum hydride (58 mg, 1.5 mmol) was added to a
120−123 °C. IR (KBr, cm−1): νmax 3319, 1687, 1343, 1261, 1218. H
NMR (CDCl3, 400 MHz): δ = 8.60 (s, 1H), 8.56 (s, 1H), 8.15 (d, J =
D
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1.2 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.48−7.42 (m, 2H), 7.27 (ddd, J
= 8.0, 6.8, 1.6 Hz, 1H), 3.97 (s, 3H), 2.61 (s, 1H), 1.79 (s, 6H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 168.0, 140.4, 139.7, 136.4, 126.6,
124.5, 123.9, 121.7, 120.9, 120.4, 118.0, 117.4, 111.2, 85.9, 74.6, 73.8,
52.2, 29.8 ppm. HRMS (ESI): m/z [M + Na]+ calcd for
C19H17NO3Na 330.1101; found 330.1104.
mixture was stirred for 5 h at ambient temperature, and then filtered
through a pad of Celite. The filter cake was washed with ethyl acetate
(15 mL × 3). The filtrate was concentrated and the residue was
purified by column chromatography on silica gel (6% ethyl acetate in
petroleum ether) to provide indizoline 2 (135 mg, 92%) as a colorless
solid: mp 168−171 °C [lit23 mp =169−170 °C]. H NMR (CDCl3,
1
400 MHz): δ = 10.29 (s, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 8.07 (d, J =
7.6 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.45 (td, J = 8.0, 1.2 Hz, 1H),
7.28 (ddd, J = 8.0, 6.8, 1.6 Hz, 1H), 5.24 (m, 1H), 3.96−3.94 (m, 5H),
1.84 (s, 3H), 1.69 (d, J = 0.8 Hz, 3H) ppm. 13C NMR (CDCl3, 100
MHz): δ = 192.1, 142.9, 140.0, 137.1, 134.1, 132.2, 127.9, 126.8, 124.2,
124.0, 123.4, 121.3, 120.9, 120.8, 111.4, 61.6, 25.8, 24.2, 18.3. HRMS
(ESI): m/z [M + Na]+ calcd for C19H19NO2Na 316.1308; found
316.1299.
Methyl 1-Hydroxy-2-(3′-methylbut-2′-en-1′-yl)-9H-carba-
zole-3-carboxylate (22). Palladium (5% on calcium carbonate,
poisoned with lead, 149 mg, 0.07 mmol) and quinoline (3.9 g, 3.6 mL,
30.5 mmol) were added to a solution of acetylene 21 (1.1 g, 3.5
mmol) in ethyl acetate (20 mL). The resulting mixture was
hydrogenated (3 atm) for 4 h. Silica gel (200−300 mesh, 1.0 g) was
added. The mixture was heated at 50 °C for 12 h, and then cooled.
The mixture was filtered through a pad of Celite. The filter cake was
washed with ethyl acetate (20 mL × 3). The filtrate was concentrated
in vacuo. The residue was purified by column chromatography on
aluminum oxide (13% ethyl acetate in petroleum ether) to provide
alkene 22 (0.8 g, 71%) as a yellow solid: mp 146−149 °C. IR (KBr,
cm−1): νmax 3427, 1656, 1429, 1301. 1H NMR (CDCl3, 400 MHz): δ =
8.42 (s, 1H), 8.29 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.43−7.38 (m,
2H), 7.24 (m, 1H), 5.84 (s, 1H), 5.35 (t, J = 6.8 Hz, 1H), 3.96−3.94
(m, 5H), 1.88 (s, 3H), 1.77 (s, 3H) ppm. 13C NMR (CDCl3, 100
MHz): δ = 169.3, 140.8, 139.9, 135.2, 132.2, 126.3, 123.9, 123.8, 122.6,
122.4, 122.0, 120.7, 120.2, 116.9, 111.2, 52.2, 26.8, 25.9, 18.1 ppm.
HRMS (ESI): m/z [M + Na]+ calcd for C19H19NO3Na 332.1257;
found 332.1254.
Methyl 2,2-Dimethyl-2,11-dihydropyrano[2,3-a]carbazole-
5-carboxylate (23). A solution of acetylene 21 (98 mg, 0.3 mmol)
in p-xylene was refluxed for 1 h and cooled. The solvent was removed
in vacuo. The residue was purified by column chromatography on silica
gel (6% ethyl acetate in petroleum ether) to provide 23 (97 mg, 99%)
as a colorless solid: mp 152−155 °C. IR (KBr, cm−1): νmax 3378, 1689,
1
1340, 1248, 1049. H NMR (CDCl3, 400 MHz): δ = 8.47 (s, 1H),
8.35 (s, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.51 (d, J = 10.0 Hz, 1H), 7.44−
7.39 (m, 2H), 7.23 (ddd, J = 8.0, 6.4, 2.0 Hz, 1H), 5.73 (d, J = 10.0 Hz,
1H), 3.95 (s, 3H), 1.51 (s, 6H) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 168.3, 140.2, 138.6, 132.0, 130.1, 126.6, 124.0, 123.3, 121.6, 120.7,
120.3, 118.2, 118.1, 116.8, 111.2, 76.1, 52.0, 27.8 ppm. HRMS (ESI):
m/z [M + Na]+ calcd for C19H17NO3Na 330.1101; found 330.1107.
Claulansine M (5).6 Lithium aluminum hydride (61 mg, 1.6
mmol) was add to a solution of 23 (97 mg, 0.3 mmol) in dry THF (10
mL) at 0 °C. The reaction was stirred at 0 °C for 15 h before being
quenched with saturated aqueous ammonium chloride (15 mL). The
mixture was filtered through a pad of Celite. The filter cake was
washed with ethyl acetate (15 mL × 3). The separated aqueous layer
of the filtrate was extracted with ethyl acetate (15 mL × 3). The
combined organic extracts were dried over sodium sulfate, and then
filtered. The solvent was removed in vacuo. The residue was purified
by column chromatography on silica gel (13% ethyl acetate in
petroleum ether) to provide (2,2-dimethyl-2,11-dihydropyrano[2,3-
a]carbazol-5-yl)methanol (82 mg, 93%) as a yellow solid: mp 142−
145 °C. IR (KBr, cm−1): νmax 3246, 1250, 1128. 1H NMR (CDCl3, 400
MHz): δ = 8.33 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.39−
7.34 (m, 2H), 7.18 (ddd, J = 8.0, 6.4, 2.4 Hz, 1H), 6.78 (d, J = 10.0 Hz,
1H), 5.64 (d, J = 10.0 Hz, 1H), 4.81 (s, 2H), 1.83 (s, 1H), 1.49 (s, 6H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 140.0, 138.6, 129.4, 129.2,
128.1, 126.0, 124.1, 123.8, 120.4, 119.9, 119.6, 116.1, 112.8, 111.1,
76.4, 64.0, 28.0 ppm. HRMS (ESI): m/z [M + Na]+ calcd for
C18H17NO2Na 302.1151; found 302.1149.
Methyl 1-Methoxy-2-(3′-methylbut-2′-en-1′-yl)-9H-carba-
zole-3-carboxylate (20). Potassium carbonate (191 mg, 1.4 mmol)
and methyl iodide (196 mg, 1.4 mmol) were added to a solution of
phenol 22 (285 mg, 0.9 mmol) in acetone (5 mL). The resulting
mixture was stirred at ambient temperature for 15 h. The solvent was
evaporated in vacuo. The residue was partitioned between ethyl acetate
(10 mL) and water (10 mL). The separated aqueous layer was
extracted with ethyl acetate (10 mL × 3). The combined organic
extracts were dried over sodium sulfate, and then filtered. The solvent
was evaporated in vacuo. The residue was purified by column
chromatography on silica gel (6% ethyl acetate in petroleum ether) to
provide ether 20 (256 mg, 86%) as a colorless solid: mp 139−142 °C.
1
IR (KBr, cm−1): νmax 3341, 1687, 1608, 1260. H NMR (CDCl3, 400
MHz): δ = 8.47 (s, 1H), 8.34 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.48−
7.41 (m, 2H), 7.27 (ddd, J = 8.0, 6.8, 1.6 Hz, 1H), 5.25 (m, 1H), 3.95
(s, 3H), 3.94−3.92 (m, 5H), 1.83 (s, 3H), 1.70 (d, J = 0.8 Hz, 3H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 168.8, 143.3, 140.0, 135.6,
133.4, 131.5, 126.4, 124.3, 124.1, 122.8, 122.6, 120.6, 120.4, 120.3,
111.2, 61.3, 52.1, 26.1, 25.9, 18.2 ppm. HRMS (ESI): m/z [M + Na]+
calcd for C20H21NO3Na 346.1414; found 346.1414.
Indizoline (2). Lithium aluminum hydride (80 mg, 2.1 mmol) was
added to a solution of ester 20 (226 mg, 0.7 mmol) in dry THF (10
mL) 0 °C. The reaction was stirred at 0 °C for 15 h before being
quenched with saturated aqueous ammonium chloride (15 mL). The
mixture was filtered through a pad of Celite. The filter cake was
washed with ethyl acetate (15 mL × 3). The separated aqueous layer
of the filtrate was extracted with ethyl acetate (15 mL × 3). The
combined organic extracts were dried over sodium sulfate, and then
filtered. The solvent was removed in vacuo. The residue was purified
by column chromatography on silica gel (13% ethyl acetate in
petroleum ether) to provide [1-methoxy-2-(3′-methylbut-2′-en-1′-
yl)-9H-carbazol-3-yl]-methanol (148 mg, 72%) as a colorless solid:
mp 141−144 °C. IR (KBr, cm−1): νmax 3417, 3239, 1451, 1341, 1250.
1H NMR (CDCl3, 400 MHz): δ = 8.17 (s, 1H), 8.00 (d, J = 8.0 Hz,
1H), 7.85 (s, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.39 (t, J = 8.6 Hz, 1H),
7.22 (t, J = 8.6 Hz, 1H), 5.20 (t, J = 6.4 Hz, 1H), 4.81 (s, 2H), 3.95 (s,
3H), 3.65 (d, J = 6.4 Hz, 2H), 1.85 (s, 3H), 1.78 (s, 1H), 1.71 (s, 3H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 143.4, 139.8, 132.9, 132.3,
132.1, 130.1, 125.9, 124.2, 124.1, 123.5, 120.4, 119.8, 116.9, 111.0,
64.4, 61.3, 25.9, 25.2, 18.2 ppm. HRMS (ESI): m/z [M + Na]+ calcd
for C19H21NO2Na 318.1465; found 318.1448.
Dess-Martin periodinane (127 mg, 0.3 mmol) was added to a
solution of (2,2-dimethyl-2,11-dihydropyrano[2,3-a]carbazol-5-yl)-
methanol (82 mg, 0.3 mmol) in DCM (5 mL). The resulting mixture
was stirred for 5 h at ambient temperature, and then filtered through a
pad of Celite. The filter cake was washed with ethyl acetate (10 mL ×
3). The filtrate was concentrated in vacuo. The residue was purified by
column chromatography on silica gel (6% ethyl acetate in petroleum
ether) to provide claulansine M 5 (60 mg, 74%) as a pale yellow solid:
1
mp 124−127 °C. H NMR (CDCl3, 400 MHz): δ = 10.18 (s, 1H),
8.54 (s, 1H), 8.07−8.05 (m, 2H), 7.64 (d, J = 10.0 Hz, 1H), 7.49−7.43
(m, 2H), 7.29 (ddd, J = 8.0, 6.8, 2.0 Hz, 1H), 5.78 (d, J = 10.0 Hz,
1H), 1.53 (s, 6H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 193.0,
140.1, 138.7, 132.7, 131.1, 126.9, 124.6, 123.9, 123.7, 121.8, 120.8,
120.7, 120.0, 117.2, 111.5, 76.6, 27.9 ppm. HRMS (ESI): m/z [M +
Na]+ calcd for C18H15NO2Na 300.0995; found 300.1006.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00729.
■
S
Dess-Martin periodinane (212 mg, 0.5 mmol) was added to a
solution of [1-methoxy-2-(3′-methylbut-2′-en-1′-yl)-9H-carbazol-3-
yl]methanol (148 mg, 0.5 mmol) in DCM (15 mL). The resulting
1H and 13C NMR spectra for compounds 1, 2, 5, 10−16 ,
1
and 18−23. H NMR spectra for compound 4 (PDF)
E
DOI: 10.1021/acs.joc.6b00729
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The Journal of Organic Chemistry
Article
(d) Mal, D.; Senapati, B.; Pahari, P. Tetrahedron Lett. 2006, 47, 1071−
1075.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: changjunbiao@zzu.edu.cn.
*E-mail: chjsong@zzu.edu.cn.
Notes
■
(17) (a) Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron 1998, 54,
1585−1588. (b) del Corral, J. M. M.; Gordaliza, M.; Castro, M. A.;
Salinero, M. A.; Dorado, J. M.; Feliciano, A. S. Synthesis 2000, 2000,
154−164. (c) Gordaliza, M.; del Corral, J. M. M.; Castro, M. A.;
Feliciano, A. S.; Valle, F. Synlett 1996, 1996, 1201−1202.
(18) (a) Song, C.; Knight, D. W.; Whatton, M. A. Tetrahedron Lett.
2004, 45, 9573−9576. (b) Song, C.; Zhao, P.; Liu, Y.; Liu, H.; Li, W.;
Shi, S.; Chang, J. Tetrahedron 2010, 66, 5378−5383. (c) Song, C.; Liu,
Y.; Zhao, P.; Sun, X.; Li, W.; Liu, H.; Chang, J. Synthesis 2011, 2011,
45−50. (d) Chang, J.; Sun, L.; Dong, J.; Shen, Z.; Zhang, Y.; Wu, J.;
Wang, R.; Wang, J.; Song, C. Synlett 2012, 23, 2704−2706.
(19) For a similar strategy for the synthesis of this compound, see:
Markad, S. B.; Argade, N. P. Org. Lett. 2014, 16, 5470−5473.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NSFC (#81330075; #21172202;
#21201152) and Zhengzhou University (#1421316040) for
financial support.
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DOI: 10.1021/acs.joc.6b00729
J. Org. Chem. XXXX, XXX, XXX−XXX