Total synthesis of carbazomycin G by a thermal ring expansion/self-redox reaction cascade

Article abstract of DOI:10.1002/ejoc.201402065

The total synthesis of carbazomycin G (7) has been accomplished in six steps and 26% overall yield starting from commercially available materials. As an efficient access to the tricyclic skeleton of carbazomycins A-H, an interesting thermal ring expansion/self-redox reaction cascade of intermediate 11 has been developed in our study. The self-redox reaction of intermediate 10 can be readily accelerated in the presence of triethylamine, and a plausible reaction mechanism for this process has been proposed. Finally, the synthesis of carbazomycin G was completed by the widely applied regioselective methylation reaction. Copyright

Full text of DOI:10.1002/ejoc.201402065

FULL PAPER
DOI: 10.1002/ejoc.201402065
Total Synthesis of Carbazomycin G by a Thermal Ring Expansion/Self-Redox
Reaction Cascade
Yong An,[a] Yunxia Wang,[a] and Xiangdong Hu*[a]
Keywords: Total synthesis / Alkaloids / Ring expansion / Redox chemistry
The total synthesis of carbazomycin G (7) has been ac-
complished in six steps and 26% overall yield starting from
commercially available materials. As an efficient access to
the tricyclic skeleton of carbazomycins A–H, an interesting
thermal ring expansion/self-redox reaction cascade of inter-
mediate 11 has been developed in our study. The self-redox
reaction of intermediate 10 can be readily accelerated in the
presence of triethylamine, and a plausible reaction mecha-
nism for this process has been proposed. Finally, the synthe-
sis of carbazomycin G was completed by the widely applied
regioselective methylation reaction.
Introduction
Carbazomycins A–H (1–8 in Figure 1) are homologous
natural products isolated from Streptoverticillium ehimense
H 1051-MY 10 by Nakamura and co-workers.[1] Biological
testing disclosed that all eight carbazomycins possess prom-
ising antibacterial or antifungal activity,[1,2] with carbazo-
mycin G (7) showing antifungal activity against the Tricho-
phyton species.[1g] Structurally, these compounds are tricy-
clic carbazole alkaloids containing a fully substituted C
ring (Figure 1). In contrast to other carbazomycins,
carbazomycin G and H (7 and 8) have unique structural
characters with a quinol ring and a stereogenic center.
Because of their promising biological activity and com-
plex substitution patterns, these alkaloids have attracted the
attention of several organic synthetic groups.[3] Knölker and
co-workers developed an iron-mediated successive C–C and
C–N bond-formation protocol and reported the first total
synthesis of 7 and 8.[4] The second generation of successful
synthetic pathways to 7 and 8 developed by the same group
employed a palladium-catalyzed cyclization of N,N-di-
arylamines as a convergent approach to the tricyclic core of
these carbazole alkaloids.[5] Hibino and co-workers dis-
closed an allene-mediated electrocyclization strategy for the
total synthesis of 7.[6] Very recently, Chakraboty and Saha
accomplished the synthesis of 7 by using a single-step
oxidation of keto-tetrahydrocarbazoles with cerium(IV)
ammonium nitrate as a novel approach to carbazolequin-
Figure 1. Structures of carbazomycins A–H.
ones.[7] And now we report herein a new synthetic route
to 7 characterized by a thermal ring expansion/self-redox
reaction cascade.
Retrosynthetic Plan
Our retrosynthetic analysis for
7 is presented in
Scheme 1. Carbazolequinone 7 is finally reached by the
widely applied regioselective methylation of quinone 9,[4–7]
which exhibits significant anti-TB activity.[8] For the prepa-
ration of 9, our original plan was the oxidation and depro-
tection of hydroquinone 10, which can be obtained by the
thermal ring expansion of intermediate 11 through the
methodology initially developed by Moore and Liebeskind
and their co-workers.[9] Fortunately, we have developed an
interesting thermal ring expansion/self-redox reaction cas-
[a] Department of Chemistry & Material Science, Key Laboratory
of Synthetic and Natural, Functional Molecule Chemistry of
the Ministry of Education of China, Northwest University,
229 N. Taibai Road, Xi’an 710069, China
E-mail: xiangdonghu@nwu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402065.
Eur. J. Org. Chem. 2014, 3715–3718
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y. An, Y. Wang, X. Hu
FULL PAPER
cade of intermediate 11 as an efficient access to 9, with 11
being obtained by the addition of organolithium reagent 12
to cyclobutenedione 13.
Scheme 1. Retrosynthetic pathway to carbazomycins G (7).
Results and Discussion
Our synthesis started with the preparation of 11. Cyclo-
butenedione 13 was prepared in 66% yield from commer-
cially available 16 according to the one-pot procedure of
Moore and co-workers (Scheme 2).[10] Compound 15 was
obtained in 99% overall yield by the bromination of indole
14 and subsequent tosyl protection. The indole 12, formed
in situ by the treatment of 15 with n-butyllithium, readily
reacted with 13 to afford intermediate 11. Owing to its
ready decomposition, freshly prepared 11 was submitted to
the next step directly without further purification. Heating
a solution of 11 at reflux in toluene for 3 h led to 10 in 63%
yield. This process occurs by a four-electron electrocyclic
ring-opening/six-electron electrocyclic ring closure/aromati-
zation reaction cascade[11] to form the tricyclic core of the
target. To our surprise, the key intermediate 9 was obtained
as a minor product in 5% yield. Subsequently, it was ob-
served that 10 can readily be transformed into 9 in DMF
at room temperature, the presence of triethylamine being
essential for this process.
Scheme 2. Synthesis of 10. Reagents and conditions: a) Br2, DMF;
b) TsCl, BTEAC, NaOH, CH2Cl2, 99% from 14; c) MeLi, –110 °C,
then TFAA, 66%; d) nBuLi, THF; e) reflux, toluene, 3 h; 10: 63%,
9: 5%, from 13; f) DMF, Et3N, room temp., 95%.
A plausible mechanism for this process is presented in
Scheme 3. The first step is an intramolecular proton ex-
change of 10, which leads to the formation of intermediate
10a. Notably, both the reductive ability of the hydroquinone
motif and the oxidative ability of the Ts motif in 10a are
increased. The following self-redox reaction furnishes inter-
Scheme 3. Plausible mechanism for the self-redox reaction of 10.
Therefore the formation of 9 from 11 basically occurs
mediate 10b. Intermediate 10c is then generated by the re- by an interesting thermal ring expansion/self-redox reaction
lease of a proton and the subsequent isomerization of 10b. cascade. However, the yield was low. Fortunately, heating a
The decomposition of 10c leads to anion 9a and 4-methyl- solution of 11 in DMF at reflux afforded 9 in 66% yield
benzenesulfinic acid 17. Finally, 9 is obtained by the pro- (Scheme 4), which significantly increases the efficiency of
tonation of 9a. Taking into account the acceleration of this our synthetic route to 7. With 9 in hand, the synthesis of 7
process in the presence of triethylamine, the decomposition is straightforward. By employing the widely used regioselec-
of 10c could be the rate-determining step of this self-redox tive methylation reaction,[4–7] carbazomycin G was synthe-
reduction.
sized in 60% yield.
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Total Synthesis of Carbazomycin G
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 21.5, 99.5, 113.5, 120.0,
123.8, 124.7, 125.7,126.9, 129.7, 130.0, 134.2, 134.8, 145.3 ppm.
HRMS (ESI+): calcd. for C15H12BrNNaO2S+ 371.9664 [M +
Na]+; found 371.9660.
Carbazole-hydroquinone (10): n-Butyllithium (0.22 mL, 2.4 m in
hexane, 0.53 mmol) was added dropwise to a solution of 15
(186 mg, 0.53 mmol) in dry THF (5 mL) under Ar. The system was
stirred for 5 min at –110 °C and a solution of 13 (55 mg,
0.44 mmol) in dry THF (1 mL) was added dropwise. The mixture
was stirred at –110 °C for another 10 min, then quenched with
water, and extracted with ethyl acetate. The organic layer was
washed with brine, dried with Na2SO4, and concentrated. The
crude intermediate 11 was dissolved in toluene and heated at reflux
for 3 h. Removal of the solvent and flash chromatography of the
residue on silica gel (ethyl acetate/petroleum ether = 1:8) afforded
10 (108 mg, 63%) and 9 (5 mg, 5%).
Scheme 4. Synthesis of carbazomycins G (7). Reagents and codi-
tions: g) DMF, reflux, 2 h, 66%; h) MeLi, THF, 60%.
Conclusions
A concise synthetic route to carbazomycin G has been
developed. The thermal ring expansion/self-redox reaction
cascade is a very interesting transformation discovered dur-
ing our study that offers a novel and efficient strategy for
the construction of the tricyclic skeleton of carbazomy-
cins A–H.[12] As a result, carbazomycin G has been synthe-
sized in six steps in a total yield of 26% starting from com-
mercially available materials.
10: Rf = 0.2 (ethyl acetate/petroleum ether = 1:8). 1H NMR
(CDCl3, 400 MHz): δ = 2.20 (s, 3 H), 2.37 (s, 3 H), 3.80 (s, 3 H),
5.81 (s, 1 H), 6.95–6.97 (d, 2 H), 7.29–7.39 (m, 4 H), 8.02 (d, J =
8 Hz, 1 H), 8.20 (d, J = 8 Hz, 1 H), 9.03 (br. s, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 10.4, 21.5, 61.1, 115.6, 117.2, 119.0,
122.7, 122.8, 125.5, 126.3, 126.8, 128.2, 129.3, 131.6, 137.0, 138.5,
139.2, 143.4, 145.1 ppm.
Experimental Section
9: R = 0.25 (ethyl acetate/petroleum ether = 1:8). IR (neat): ν =
˜
f
General: All reactions were executed in flame-dried round-bot-
tomed flasks under an inert atmosphere of argon in dry solvents
unless stated otherwise. All reagents were obtained from commer-
cial suppliers unless stated otherwise. Flash chromatography: silica
gel (300–400 mesh). 1H and 13C NMR spectra: Varian INOVA-400
spectrometer; internal standard: TMS or the signal of the deuter-
iated solvent; δ in ppm, coupling constants (J) in Hz. MS: Bruker
micrOTOF-QII spectrometer. IR: Bruker EQUINOX-55 spectrom-
eter.
3259, 2952, 1641, 1531, 1153, 741 cm–1. 1H NMR ([D6]DMSO,
400 MHz): δ = 1.87 (s, 3 H), 4.01 (s, 3 H), 7.28–7.36 (m, 2 H), 7.50
(d, J = 8 Hz, 1 H), 7.97 (d, J = 8 Hz, 1 H), 12.82 (br. s, 1 H) ppm.
13C NMR ([D6]DMSO, 100 MHz): δ = 8.5, 61.1, 113.7, 113.9,
121.5, 123.5, 123.9, 126.0, 126.3, 136.1, 137.6, 157.7, 178.4,
180.6 ppm. HRMS (ESI+): calcd. for C14H11NNaO3+ 264.0631 [M
+ Na]+; found 264.0630.
Preparation of Quinone
9 from 10: Compound 10 (20 mg,
0.05 mmol) was dissolved in DMF (5 mL) and then triethylamine
(5.1 mg, 0.05 mmol) was added. The mixture was stirred at room
temperature for 3 h, then quenched with saturated NH4Cl, and ex-
tracted with ethyl acetate. The organic layer was washed with brine,
dried with Na2SO4, and concentrated. Then the residue was puri-
fied by column chromatography (ethyl acetate/petroleum ether =
1:8) to afford 9 (11.5 mg, 95%). Rf = 0.45 (ethyl acetate/petroleum
ether = 1:4).
3-Methoxy-4-methylcyclobutene-1,2-dione (13): Compound 13 was
prepared according to procedure reported in the literature.[10] Rf =
0.5 (ethyl acetate/petroleum ether = 1:1). IR (neat): ν = 2964, 1816,
˜
1790, 1755, 1600, 1455, 1380, 1343, 1080, 980 cm–1. 1H NMR
(CDCl3, 400 MHz): δ = 2.24 (s, 3 H), 4.43 (s, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 9.5, 60.8, 180.1, 193.7, 195.5, 199.0 ppm.
+
HRMS (ESI+): calcd. for C6H6NaO3 149.0209 [M + Na]+; found
149.0201.
Preparation of Quinone 9 from Intermediate 11: n-Butyllithium
(0.16 mL, 2.4 m in hexane, 0.38 mmol) was added dropwise to a
solution of 15 (133.2 mg, 0.38 mmol) in dry THF (5 mL) under Ar.
The system was stirred for 5 min at –110 °C and a solution of 13
(40 mg, 0.32 mmol) in dry THF (1 mL) was added dropwise. The
mixture was stirred at –110 °C for another 10 min, then quenched
with water, and extracted with ethyl acetate. The organic layer was
washed with brine, dried with Na2SO4, and concentrated. The resi-
due was dissolved in DMF (5 mL) and heated at reflux for 2 h.
Removal of the solvent and flash chromatography of the residue
on silica gel (ethyl acetate/petroleum ether = 1:8) afforded 9
(50.9 mg, 66%). Rf = 0.45 (ethyl acetate/petroleum ether = 1:4).
3-Bromo-1-tosylindole (15):
A solution of bromine (0.46 mL,
8.94 mmol) in DMF (5 mL) was added dropwise to a solution of
indole (14, 1 g, 8.51 mmol) in DMF (10 mL) at 0 °C. After stirring
at this temperature for 30 min, the reaction mixture was poured
into a solution of NaHCO3 (0.73 g, 8.94 mmol) and NaHSO3
(0.93 g, 8.94 mmol) at 0 °C. After 24 h the precipitate was isolated
by filtration, washed with H2O, and dried in vacuo to afford 3-
bromoindole as a white solid. The solid was then dissolved in
CH2Cl2 (20 mL) and p-toluenesulfonyl chloride (1.95 g, 10.2 mmol),
benzyl(triethyl)ammonium chloride (0.38 g, 1.70 mmol), and so-
dium hydroxide (0.58 g, 14.5 mmol) were added sequentially at
0 °C. The reaction was stirred at room temperature for 4 h,
quenched with a saturated solution of NH4Cl, and extracted with
CH2Cl2. The organic layer was dried with Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography to afford the desired product 15 (2.95 g,
Carbazomycin G (7): A solution of methyllithium (1.6 m in Et2O,
0.42 mL, 0.66 mmol) was added dropwise to a solution of 9 (14 mg,
0.06 mmol) in THF (5 mL) at –78 °C. The reaction mixture was
warmed to room temperature in 20 min. The reaction was then
quenched by the addition of saturated NH4Cl. The aqueous layer
was extracted with ethyl acetate (10 mL) three times, and the com-
bined organic layers were dried with Na2SO4. Removal of the sol-
vent and column chromatography (ethyl acetate/petroleum ether =
99%). R = 0.5 (ethyl acetate/petroleum ether = 1:15). IR (neat): ν
˜
f
= 1594, 1442, 1370, 1262, 1170, 1120, 1088, 1023, 928, 811, 752,
702, 658, 577 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 2.32 (s, 3 H),
7.21 (d, J = 8 Hz, 2 H), 7.28–7.39 (m, 2 H), 7.48 (d, J = 8 Hz, 1
H), 7.62 (s, 1 H), 7.76 (d, J = 8 Hz, 2 H), 7.99 (d, J = 8 Hz, 1 1:2) on silica gel provided 7 (7.2 mg, 60%). Rf = 0.15 (ethyl acetate/
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Y. An, Y. Wang, X. Hu
FULL PAPER
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petroleum ether = 1:2). IR (neat): ν = 3423, 3234, 2925, 1616, 1477,
˜
1091, 748 cm–1. 1H NMR ([D6]DMSO, 400 MHz): δ = 1.57 (s, 3
H), 1.98 (s, 3 H), 3.68 (s, 3 H), 5.96 (s, 1 H), 7.17–7.22 (m, 2 H),
7.45 (d, J = 8 Hz, 1 H), 8.01 (d, J = 8 Hz, 1 H), 12.23 (br. s, 1
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67.3, 108.4, 112.1, 120.5, 121.6, 123.0, 123.8, 136.5, 140.9, 147.6,
+
154.4, 177.6 ppm. HRMS (ESI+): calcd. for C15H15NNaO3
280.0944 [M + Na]+; found 280.0958.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all key intermediates and final
products.
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The authors are grateful for financial support from the National
Natural Science Foundation of China (NSFC) (grant numbers
21002078 and 21372184), the Education Department of Shaanxi
Province (grant number 2010JK873), the Science and Technology
Department of Shaanxi Province (grant number 2011JQ2011), and
the Science and Technology Program Foundation of Xi’an City
[grant number SF1028(5)].
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intermediate 11 discovered in our laboratory is the subject of
an application for a Chinese Patent: Northwest University,
China, Chin. Pat. Appl. 201410056142.X, 2014.
Received: February 12, 2014
Published Online: April 24, 2014
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Eur. J. Org. Chem. 2014, 3715–3718