A novel total synthesis of antibiotic carbazole alkaloid carbazomycin G

Article abstract of DOI:10.1016/S0040-4020(00)00543-3

A total synthesis of carbazomycin G (1) has been newly completed in seven steps. The 1,3-dioxygenated carbazole (4) via the 3-methoxy-1-methoxymethyloxycarbazole (11) as a synthetic precursor was synthesized by using the allene-mediated electrocyclic reaction of a 6π electron system generating from the 2-propargylindole derivative (10), which was derived from the 3-vinylindole (8) in three steps. Finally, the oxidation of the phenol (4) followed by the addition of methyl lithium to the carbazole-1,4-quinone (3) provided carbazomycin G (1). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00543-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5807±5811
A Novel Total Synthesis of Antibiotic Carbazole Alkaloid
Carbazomycin G
*
Hitomi Hagiwara, Tominari Choshi, Hiroyuki Fujimoto, Eiichi Sugino and Satoshi Hibino
Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University,
Fukuyama, Hiroshima 729-0292, Japan
Received 11 May 2000; accepted 12 June 2000
AbstractÐA total synthesis of carbazomycin G (1) has been newly completed in seven steps. The 1,3-dioxygenated carbazole (4) via the
3-methoxy-1-methoxymethyloxycarbazole (11) as a synthetic precursor was synthesized by using the allene-mediated electrocyclic reaction
of a 6p electron system generating from the 2-propargylindole derivative (10), which was derived from the 3-vinylindole (8) in three steps.
Finally, the oxidation of the phenol (4) followed by the addition of methyl lithium to the carbazole-1,4-quinone (3) provided carbazomycin G
(1). q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
provide a 1,3-dioxygenated carbazole (4) as a synthetic
precursor based on a retrosynthetic analysis (Scheme 1).
Carbazomycin G (1) and H (2) were isolated from Strepto-
verticillium ehimense as a racemate by Nakamura and
co-workers1 together with carbazomycins
A
to F.2
Results and Discussion
Carbazomycin G (1) possesses moderate antifungal activity
against Trichophyton species.1 Their structures, which have
a unique quinol moiety, have been determined by spectro-
scopic and X-ray crystallographic analyses.1 Total syntheses
The required 3-(2-methoxyethenyl)indole-2-carbaldehyde
(7) was initially prepared from the 3-(2-methoxyethenyl)-
N-(phenylsulfonyl)indole (8).7 Namely, treatment of a
mixture of E and Z-isomer (8) (1:0.7) with LDA at 278
to 08C for 3 h followed by addition of N,N-dimethylform-
amide (DMF) at 278 to 08C for 3 h gave the 3-(2-methoxy-
ethenyl)indole-2-carbaldehyde (7) (41%) having the
E-stereochemistry along with unreactive Z-isomer (8)
(14%). Based on the fact that no 3-[(Z)-methoxyethenyl]-
of both alkaloids have recently been developed by the
È
3
Knolker group. Two synthetic methodologies have been
ef®ciently employed, one based on the iron-mediated C±C
and C±N bond formation,3a and the other on palladium-
catalyzed oxidative cyclization3b to carbazole-1,4-quinone
as synthetic precursor. In the course of our study, we are
developing the synthesis of biologically interesting
condensed-heteroaromatic compounds, including natural
products by the thermal electrocyclic reaction4 of either
conjugated hexatriene5 or azahexatriene6 systems incorpor-
ating the double bond of the principal aromatic or hetero-
aromatic ring. We recently reported the total synthesis of
highly substituted carbazole alkaloids by the construction of
the appropriate carbazole framework based on the allene-
mediated electrocyclic reaction of the hexatriene system
involving the indole 2,3-bond.5 In the present paper, we
describe the novel total synthesis of carbazomycin G (1)
by application of this methodology. We envisaged that an
electrocyclic reaction of a 2-allenylindole intermediate (5)
derived from a 2-propargylindole derivative (6) would
indole-2-carbaldehyde, selective lithiation of
E and
Z-isomer (8) followed by formylation might have occurred.
Further, based on the low recovery yield of unreactive
Z-isomer (8), it would appear that the reactivity of the
lithiated Z-isomer (8) with DMF was more weak than that
of the E-isomer (8) with DMF due to the formation of a
more stable 6-membered ring in the former. Although the
yield of this reaction was moderate, the stereochemistry was
extremely covenient for our key-step. Subsequently,
Grignard reaction of 7 with ethynylmagnesium bromide at
08C afforded the propargyl alcohol (9) (87%), which was
treated with chloromethyl methyl ether (MOMCl) in the
presence of ethyl diisopropylamine to yield the MOM-
ether (10) (98%). The acetylene derivative (10) was
subjected to an allene-mediated electrocyclic reaction
using potassium t-butoxide in t-butanol and THF at 908C
to produce the desired 1,3-dioxygenated carbazole (11)
(85%). Cleavage of MOM-ether of 11 with chlorotrimethyl-
silane and sodium iodide8 at 2208C gave the phenol (4)
(69%) as the synthetic precursor (Scheme 2).
Keywords: allenes; electrocyclic reactions; polycyclic heterocyclic
compounds; quinonoid compounds.
* Corresponding author. Tel.: 181-849-36-2111; fax: 181-849-36-2024;
e-mail: hibino@fupharm.fukuyama-u.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00543-3

5808
H. Hagiwara et al. / Tetrahedron 56 (2000) 5807±5811
Scheme 1.
Temporally, we examined an oxidation step and a ®nal step
using the previously reported 1-hydroxy-3-ethoxy-2-
methylcarbazole (12)5c instead of 4. Oxidations by Fremy's
salt,9 cerium ammonium nitrate,10 and salcomine-molecular
oxygen11 did not work well in this case. Among them,
the carbazole-1,4-quinone (13) was only obtained by a
system of salcomine-molecular oxygen in DMF at room
temperature in low yield (20%). However, we found that
the oxidation to carbazole-1,4-quinone (13) from the
phenol (12) proceeded in a good yield (73%) by using
Scheme 2.

H. Hagiwara et al. / Tetrahedron 56 (2000) 5807±5811
5809
[bis(tri¯uoroacetoxy)iodo]benzene12 in an aqueous aceto-
nitrile. Furthermore, the nucleophilic addition of the
carbazole-1,4-quinone (13) with methyl lithium according
È
to the Knolker's procedure provided the carbazomycin G
ethyl-congenor (14) in an excellent yield (98%).
magnesium bromide (0.5 M in THF, 2.3 ml, 1.64 mmol)
was added to the solution of the 2-formylindole (7)
(372 mg, 1.09 mmol) in THF (15 ml) under cooling with
ice. After stirring at the same temperature for 3 h, the
reaction mixture was quenched with an aqueous NH4Cl
(saturated) solution and the mixture was extracted with
EtOAc. The EtOAc layer was washed with brine, dried
over Na2SO4, and concentrated. The residue was puri®ed
by column chromatography (silica gel, 15 g) using
EtOAc±hexane (1:4 v/v) as an eluent to give the oily
propargyl alcohol (9) (348 mg, 87%). IR (neat) n: 3290,
2131, 1362 cm21; H NMR (CDCl3) d: 2.67 (1H, d,
Jˆ2.5 Hz), 3.77 (3H, s), 4.49 (1H, d, Jˆ11 Hz), 5.83 (1H,
d, Jˆ13 Hz), 6.01 (1H, dd, Jˆ2.5, 11 Hz), 6.99 (1H, d,
Jˆ13 Hz), 7.20±7.38 (4H, m), 7.47 (2H, t, Jˆ7 Hz),
7.85(2H, d, Jˆ7 Hz), 7.98 (1H, d, Jˆ8 Hz); MS m/z: 367
(M1). HRMS calcd for C20H17NO4S: 367.0878; observed:
367.0891.
3
Therefore, the oxidation of the true precursor, 1-hydroxy-
3-methoxy-2-methylcarbazole (4), with [bis(tri¯uoro-
acetoxy)iodobenzene was carried out in a similar way to
obtain the expected carbazole-1,4-quinone (3) in an
excellent yield (98%). Finally, treatment of 3 with methyl
lithium in the same manner gave carbazomycin G (1) regio-
selectively (87%) (Scheme 2). The spectral and physical
data of synthetic carbazomycin G (1) were identical to the
data reported for the natural product.1 Thus a new total
synthesis of carbazomycin G (1) was established in a
seven-step sequence (17.5% overall yield) by the construc-
tion of the 1,3-dioxygenated carbazole nucleus (12) based
on the allene-mediated electrocyclic reaction of the hexa-
triene system involving the indole 2,3-bond, together with
the synthesis of carbazomycin G ethyl-congenor (14).
3-[(E)-2-Methoxyethenyl]-2-[(1-methoxymethyloxy)prop-
2-yn-1-yl]-N-(phenylsulfonyl)indole (10). A stirred solu-
tion of MOMCl (0.27 ml, 3.6 mmol) was added to a solution
of the propargyl alcohol (9) (163 mg, 0.44 mmol) and ethyl
diisopropylamine (0.6 ml, 3.60 mmol) in CH2Cl2 (15 ml) at
an ambient temperature, and the mixture was heated at 508C
for 12 h. After cooling to rt, the reaction mixture was
quenched with water. The mixture was extracted with
CH2Cl2. The CH2Cl2 layer was washed with brine, dried
over Na2SO4 and concentrated. The residue was puri®ed
by column chromatography (silica gel, 10 g) using
EtOAc±hexane (1:9 v/v) as an eluent to give the oily
MOM-ether (10) (183 mg, 98%). IR (neat) n: 2123,
Experimental
All air-sensitive reactions were conducted in ¯ame-dried
glassware under an argon atmosphere unless otherwise
stated. THF was freshly distilled from benzophenone
ketyl. DMF, diisopropylamine and ethyl diisopropylamine
were freshly distilled after drying over CaH2. Silica gel
(100 mesh, Merck Art 7734) was used for column chroma-
tography. Melting points were measured by a Yanagimoto
MP-500D micro melting points apparatus and were uncor-
rected. IR spectra were recorded on a Shimadzu FTIR-8500
1
1373 cm21; H NMR (CDCl3) d: 2.64 (1H, d, Jˆ2.5 Hz),
3.44 (3H, s), 3.74 (3H, s), 4.70 (1H, d, Jˆ7 Hz), 4.99 (1H, d,
Jˆ7 Hz), 6.23 (1H, d, Jˆ13 Hz), 6.61 (1H, d, Jˆ2.5 Hz),
7.15±7.38 (5H, m), 7.47 (1H, t, Jˆ6 Hz), 7.60 (1H, d,
Jˆ7 Hz), 7.81 (2H, d, Jˆ6 Hz), 8.19 (1H, d, Jˆ8 Hz);
MS m/z: 411 (M1). HRMS calcd for C22H21NO5S:
411.1140; observed: 411.1157.
1
spectrophotometer. H and 13C NMR spectra were taken
with a JEOL-AL 300 using tetramethylsilane as an internal
standard. All mass spectra were obtained by using Shimadzu
9020DF and QP5050 spectrometers equipped with an
electrospray ionization source at 70 eV.
3-Methoxy-1-(methoxymethyloxy)-2-methylcarbazole (11).
A stirred solution of the MOM-ether (10) (182 mg,
0.442 mmol) in THF (2 ml) was added to a solution of
t-BuOK (149 mg, 1.33 mmol) in t-BuOH (6 ml) at an ambi-
ent temperature. The mixture was re¯uxed at 908C for 12 h
and cooled to rt. The mixture was quenched with an aqueous
NH4Cl (saturated) solution, which was extracted with
EtOAc. The EtOAc layer was washed with brine, dried
over Na2SO4 and concentrated. The residue was puri®ed
by column chromatography (silica gel, 10 g) using
EtOAc±hexane (1:19 v/v) as an eluent to give the oily car-
bazole (11) (102 mg, 85%). 1H NMR (CDCl3) d: 2.31 (3H,
s), 3.76 (3H, s), 3.95 (3H, s), 5.24 (2H, s), 7.17 (1H, t,
Jˆ7.9 Hz), 7.30 (1H, s), 7.37 (1H, t, Jˆ7.9 Hz), 7.43 (1H,
d, Jˆ7.9 Hz), 7.99 (1H, d, Jˆ7.9 Hz), 9.15(1H, br s); MS m/
z: 271(M1). HRMS calcd for C16H17NO3: 271.1208;
observed: 271.1196.
3-[(E)-2-Methoxyethenyl]-N-(phenylsulfonyl)indole-2-
carbaldehyde (7). A stirred solution of 3-(2-methoxy-
ethenyl)indole (8)7 [a mixture of E/Z (1:0.7), 1.5 g,
4.79 mmol)] in THF (10 ml) was treated with a solution of
LDA [prepared from diisopropylamine (1.4 ml, 10.5 mmol)
and n-BuLi (2.52 mol/L in hexane, 4.2 ml, 10.5 mmol) in
THF (10 ml)] at 2788C. The reaction temperature was
gradually raised to 08C during stirring for 3 h. A solution
of DMF (0.9 ml, 12 mmol) in THF (2 ml) was added to the
cooled mixture at 2788C. After stirring at 08C for 2 h, the
mixture was quenched with water. The EtOAc layer was
washed with brine, dried over Na2SO4 and concentrated.
The residue was puri®ed by column chromatography (silica
gel, 50 g) using EtOAc±hexane (3:17 v/v) as an eluent to
give the E-2-formylindole (7) (670 mg, 41%), mp 120±
1
1238C (from EtOAc). IR (KBr) n: 1641, 1356 cm21; H
NMR (CDCl3) d: 3.79 (3H, s), 6.54 (1H, d, Jˆ13 Hz),
7.26±7.71 (9H, m), 8.24 (1H, d, Jˆ8 Hz), 10.57 (1H, s):
MS m/z: 341 (M1). Anal. calcd for C18H15NO4S: C, 63.33;
H, 4.43; N, 4.10. Found: C, 63.45; H, 4.51; N, 4.13.
1-Hydroxy-3-methoxy-2-methylcarbazole (4). A stirred
solution of TMSCl (0.19 ml, 1.52 mmol) was added to a
suspension of the carbazole (11) (275 mg, 1.01 mmol) and
NaI (228 mg, 1.52 mmol) in CH3CN (10 ml) at 2208C. The
mixture was stirred at 2208C for 10 min, and then
2-(1-Hydroxyprop-2-yl)-3-[(E)-2-methoxyethenyl]-N-
(phenylsulfonyl)indole (9). A stirred solution of ethynyl-

5810
H. Hagiwara et al. / Tetrahedron 56 (2000) 5807±5811
1
1.01 equiv. of NaI (151 mg) and TMSCl (0.13 ml) were
added twice every 5 min to the mixture at 2208C, respec-
tively, under monitoring with TLC. After the starting
material disappeared, the reaction mixture was quenched
with water and EtOAc at the same temperature, and then
the mixture was extracted with EtOAc. The EtOAc layer
was washed with 10% aqueous Na2SO3 solution and brine,
dried over Na2SO4, and then concentrated. The residue was
puri®ed by column chromatography (silica gel, 20 g)
using EtOAc±hexane (3:17 v/v) as an eluent to give the
1-hydroxycarbazole (4) (159 mg, 69%), mp 165±1678C
(KBr) n: 3200, 2930, 1690 cm21; H NMR (CDCl3) d:
1.25 (3H, t, Jˆ7 Hz), 1.56 (3H, s), 1.98 (3H, s), 3.94 (2H,
q, Jˆ7 Hz), 5.91 (1H, s), 7.13±7.23 (2H, m), 7.43 (1H, d,
Jˆ7 Hz), 7.99 (1H, d, Jˆ7 Hz), 12.2 (1H, s); 13C NMR
(CDCl3) d: 177.8, 154.3, 146.5, 141.0, 136.4, 123.8,
122.9, 121.5, 120.5, 112.0, 108.4, 67.3, 67.0, 28.0, 15.5,
10.5; MS m/z: 271 (M1). Anal. calcd for C16H17NO3:
C, 70.83; H, 6.32; N, 5.16. Found: C, 70.86; H, 6.39; N,
4.97.
Carbazomycin G (1). The above procedure was then
carried out using the carbazole-1,4-quinone (3) (27 mg,
0.11 mmol) and methyllithium (1.09 mol/L, 1 ml,
1.12 mmol) to give carbazomycin G (1) (25 mg, 87%), mp
266±2688C (from EtOAc) (lit.,1 mp 241±2438C and lit.,3a
1
(from Et2O±hexane). IR (KBr) n: 3398 cm21; H NMR
(CDCl3) d: 2.34 (3H, br s), 2.99 (3H, s), 3.94 (3H, br s),
7.15 (1H, br s), 7.18 (1H, t, Jˆ8 Hz), 7.37 (1H, t, Jˆ8 Hz),
7.43 (1H, d, Jˆ8 Hz), 7.99 (1H, d, Jˆ8 Hz), 8.08 (1H, br s);
MS m/z: 227 (M1). Anal. Calcd for C14H13NO2: C, 73.99; H,
5.77; N, 6.16. Found: C, 74.06; H, 5.84; N, 6.07.
mp 266±2688C). IR (KBr) n: 3204, 2926, 1611 cm21; H
1
NMR (DMSO-d6) d: 1.58 (3H, s), 1.99 (3H, s), 3.77 (3H, s),
5.95 (1H, s), 7.15±7.24 (2H, m), 7.44 (1H, d, Jˆ7 Hz),
8.01(1H, d, Jˆ7 Hz), 12.22 (1H, br s); 13C NMR (CDCl3)
d: 177.4, 154.2, 147.5, 140.7, 136.3, 123.7, 122.9, 121.4,
120.4, 112.0, 108.3, 67.2, 59.1, 27.8, 10.1; MS m/z: 257
(M1).
3-Ethoxy-2-methylcarbazole-1,4-dione (13). [Bis(tri¯uoro-
acetoxy)iodo]benzene (283 mg, 0.66 mmol) was added to a
stirred solution of the 1-hydroxycarbazole (12)5c (72 mg,
0.30 mmol) in CH3CN (7 ml) and H2O (3.5 ml) under cool-
ing with ice and an N2 atmosphere. After stirring at the same
temperature for 1 h, the reaction mixture was quenched with
an aqueous NaHCO3 (saturated) solution and the mixture
was extracted with 10% MeOH±CHCl3. The CHCl3 layer
was washed with brine, dried over Na2SO4 and concen-
trated. The residue was puri®ed by column chromatography
(silica gel, 40 g) using EtOAc±hexane as an eluent to give
the carbazole-1,4-quinone (13) (56 mg, 73%), mp 209±
2118C (from EtOAc±hexane). IR (KBr) n: 3260,
Acknowledgements
This work was supported in part by a Grant-in-Aid for
Scienti®c Research from the Ministry of Education,
Science, Sports and Culture in Japan.
1
1641 cm21; H NMR (DMSO-d6) d:1.32 (3H, t, Jˆ7 Hz),
References
1.91 (3H, s), 4.33 (2H, q, Jˆ7 Hz), 7.30 (1H, t, Jˆ7.9 Hz),
7.36 (1H, t, Jˆ7.5 Hz), 7.52 (1H, d, Jˆ7.9 Hz), 7.99 (1H, d,
Jˆ7.5 Hz), 12.85 (1H, br s); 13C NMR (CDCl3) d: 181.3,
179.2, 158.0, 137.0, 135.7, 127.3, 126.6, 124.3, 124.2,
122.7, 114.9, 112.9, 70.0, 16.2, 9.68; MS m/z: 255(M1).
Anal. calcd for C15H13NO3: C, 70.58; H, 5.13; N, 5.49.
Found: C, 70.70; H, 5.11; N, 5.62.
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(4) (25 mg, 0.11 mmol) and [bis(tri¯uoroacetoxy)iodo]-
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1
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È
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