Iron-mediated synthesis of carbazomycin G and carbazomycin H, the first carbazole-1,4-quinol alkaloids from Streptoverticillium ehimense

Article abstract of DOI:10.1002/ejoc.200390116

The total synthesis of the carbazole-1,4-quinol alkaloids carbazomycin G (7) and carbazomycin H (8) was achieved by a highly convergent iron-mediated construction of the carbazole framework. Electrophilic substitution of the arylamine 15 using the iron co

Full text of DOI:10.1002/ejoc.200390116

FULL PAPER
Iron-Mediated Synthesis of Carbazomycin G and Carbazomycin H, the First
Carbazole-1,4-quinol Alkaloids from Streptoverticillium ehimense[‡]
Hans-Joachim Knölker,*[a] Wolfgang Fröhner,[a] and Kethiri R. Reddy[a]
Keywords: Iron / Electrophilic substitution / Oxidation / Cyclization / Quinones / Alkaloids
The total synthesis of the carbazole-1,4-quinol alkaloids car-
were transformed to the corresponding carbazole-1,4-
bazomycin G (7) and carbazomycin H (8) was achieved by a quinones 9 and 10 by oxidation with cerium(IV) ammonium
highly convergent iron-mediated construction of the carba- nitrate. Finally, regioselective addition of methyllithium at
zole framework. Electrophilic substitution of the arylamine
15 using the iron complex salts 13 and 14, followed by oxidat-
ive iron-mediated arylamine cyclization, afforded the carba-
C−1 provided carbazomycin G (7) and carbazomycin H (8).
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
zole derivatives 11 and 12, respectively. These carbazoles Germany, 2003)
Introduction
Streptoverticillium species KCC U-0166.[2e] The same alkal-
oids were obtained by Nakamura from Streptoverticillium
ehimense, along with carbazomycin C (3) and carbazomycin
D (4).[2f] Carbazomycin A (1) and carbazomycin B (2) in-
hibit the growth of phytopathogenic fungi and show anti-
bacterial and antiyeast activities.[2a] Compounds 2 and 3
have been found to inhibit 5-lipoxygenase.[3] Carbazomycin
G (7) exhibits antifungal activity against Trichophyton spe-
cies.[2g] The unique structural feature of 7 and 8 is the
quinol of ring A. Although 7 has a stereogenic center at C-
1, it shows no optical rotation and crystallizes in the space
group P21/a. Both observations led to the conclusion that
7 exists as a racemate in nature.[2g] The same can be as-
sumed for natural 8.
The carbazomycin alkaloids 1؊8 were first isolated by
Nakamura and his group from Streptoverticillium ehimense
H 1051-MY 10 (Scheme 1).[2] They described the structural
elucidation and biogenesis of these alkaloids, which repres-
ent an unprecedented class of antibiotics with a carbazole
framework.[2] The biogenesis of the carbazomycins, which
are derived from tryptophan, was found to be quite differ-
ent from that of previous carbazole alkaloids, mainly
isolated from terrestrial plants.[2d] Marumo reported the
isolation of carbazomycin E (carbazomycinal; 5) and
carbazomycin F (6-methoxycarbazomycinal; 6) from the
The carbazomycins exhibit an unusually congested sub-
stitution pattern, which initiated the development of novel
synthetic routes to carbazoles.[4] The challenging structures
of the carbazomycins and their promising biological activit-
ies, have prompted several groups to investigate strategies
for the total synthesis of these compounds.[5Ϫ10] Our
approach is based on an iron-mediated construction of the
carbazole ring system via consecutive CϪC and CϪN bond
formation. This methodology has been applied to the total
synthesis of the carbazomycins A, B,[5aϪ5d] C, D,[6] E,[7] G,
H[8] and a broad variety of further carbazole alkaloids.[11]
In addition to the iron-mediated synthesis,[8] we have de-
veloped a palladium-catalyzed approach for the total syn-
thesis of the carbazomycins G and H.[9] A third total syn-
thesis of carbazomycin G was reported more recently by
Hibino.[10] In the present paper we describe full details of
the iron-mediated synthesis of carbazomycins G and H.
Scheme 1
[‡]
Transition Metal Complexes in Organic Synthesis, Part 66.
Part 65: Ref.[1]
[a]
Institut für Organische Chemie,
Synthetic Plan
Technische Universität Dresden,
Bergstraße 66, 01069 Dresden, Germany
Fax: (internat.) ϩ49-351-463-37030
Retrosynthetic analysis of 7 and 8, based on the iron-
mediated construction of the carbazole nucleus, led us to
E-mail: hans-joachim.knoelker@chemie.tu-dresden.de
740
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0204Ϫ0740 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 740Ϫ746

Carbazole-1,4-quinol Alkaloids from Streptoverticillium ehimense
FULL PAPER
acetic anhydride and glacial acetic acid afforded the desired
nitro derivative 19 in 92% yield. Our earlier studies demon-
strated that 5-hydroxyanilines provide high yields in elec-
trophilic aromatic substitutions with tricarbonyliron-com-
plexed cyclohexadienyl cations.[5aϪ5c,6] Therefore, we first
cleaved the acetate of compound 19 with potassium hydrox-
ide in aqueous ethanol to give the nitrophenol 20. Sub-
sequent hydrogenation with palladium on activated carbon
led to the arylamine 15.[15] The present sequence provides
15 on a multigram scale in five steps. The overall yield is
70%, based on 16.
Synthesis of Carbazomycin G (7)
Reaction of the iron complex 13 with two equivalents of
15 in acetonitrile at room temperature provided the iron
complex 21 in 96% yield (Scheme 4). From previous results
we knew that the free hydroxy group of compound 21 had
to be protected prior to the iron-mediated arylamine cyc-
lization.[5b,5c] This was achieved by chemoselective O-
acetylation to the corresponding acetate 22. The iron-medi-
ated arylamine cyclization of 22 with very active manganese
dioxide[16] in dichloromethane at room temperature af-
forded the carbazole 11 in 72% yield.
Scheme 2
the carbazole-1,4-quinones 9 and 10 as key intermediates
(Scheme 2). Compounds 9 and 10 are accessible by oxida-
tion of the carbazoles 11 and 12, which can be prepared by
coupling of the arylamine 15 with the iron complexes 13
and 14, respectively.[8] Alternatively, 9 and 10 can be pro-
vided by a palladium-catalyzed oxidative cyclization of the
corresponding arylaminobenzo-1,4-quinones.[9]
The iron complex 13 can be prepared quantitatively on
a large scale by 1-azabutadiene-catalyzed complexation of
cyclohexa-1,3-diene with pentacarbonyliron[12] and sub-
sequent hydride abstraction using triphenylcarbenium tetra-
fluoroborate.[13] Complex 14 was prepared in three steps
from 1,3-dimethoxybenzene, following the procedure de-
scribed by Birch.[14]
Synthesis of the Arylamine Precursor
The synthesis of the arylamine 15 starts from commer-
cially available 2,6-dimethoxytoluene 16 (Scheme 3).
FriedelϪCrafts acylation of 16, promoted by titanium
tetrachloride, provided the acetophenone 17. This com-
pound was transformed into the aryl acetate 18 by a pro-
ton-catalyzed BaeyerϪVilliger oxidation. Regioselective ni-
tration of 18 with fuming nitric acid in a 3:1 mixture of
Scheme 4
Oxidation of 11 with ceric() ammonium nitrate gave
the carbazole-1,4-quinone 9 in 95% yield (Scheme 5). The
important final step for the synthesis of 7 was the regiose-
lective introduction of the methyl group at C-1. In the total
synthesis of carbazoquinocin C the introduction of a heptyl
side chain to 9 led, depending on the reaction conditions,
Scheme 3
Scheme 5
Eur. J. Org. Chem. 2003, 740Ϫ746
741

H.-J. Knölker, W. Fröhner, K. R. Reddy
FULL PAPER
Table 1. Addition of methylmetal reagents to the carbazole-1,4-quinone 9
Methyl-[M] (equiv.)
Reaction conditions
7, yield (%)
23, yield (%)
MeMgCl (7.5)
MeMgCl (12.5)
MeMgCl (10.0)
MeLi (5.0)
Ϫ78 °C, 4.5 h
18
30
36
50
54
59
69
71
5
Ϫ78 °C, 2.5 h
25
17
27
19
27
17
12
Ϫ78 °C, 4.5 h
Ϫ78 °C, 6 h
MeLi (7.5)
Ϫ78 °C, 3 h
MeLi (10.0)
MeLi (10.0)
MeLi (4.6)
Ϫ78 °C, 2.5 h
Ϫ78 °C, 5 h; room temp., 12 h
Ϫ78 °C, 15 min; room temp., 30 min
to all three possible regioisomeric products, by 1,2-addition has a 3-methoxycyclohexadiene ligand, had to be cyclized
at C-1, 1,4-addition at C-3 followed by elimination of the regioselectively. Previous studies with deuterium-labelled
methoxy group, or 1,2-addition at C-4.[17] Addition of 7.5 cyclohexadiene ligands have shown that cyclizations by two-
equivalents of methylmagnesium chloride to 9 in tetrahy- electron oxidants (such as manganese dioxide) initially lead
drofuran at Ϫ78 °C provided 7 (the product of 1,2-addition to the product resulting exclusively from attack at C-4 of
at C-1) along with 2,3-dimethylcarbazole-1,4-quinone (23; the cyclohexadiene ligand.[18] In the present example, this
the product of 1,4-addition at C-3 followed by elimination regioselectivity would provide the undesired 8-methoxycar-
of the methoxy group) as a by-product. The regioisomeric bazole 26. However, a proton-catalyzed rearrangement to a
carbazolequinol resulting from 1,2-addition at C-4 was not 6-methoxycarbazole can occur at the stage of the tri-
detected. Increasing the equivalents of the Grignard reagent carbonyl(η4-4a,9a-dihydrocarbazole)iron complex.[6,18] The
led to an increase in the yields of both products, with a driving force behind this isomerization is the well-estab-
maximum yield of 36% of 7 (Table 1). However, use of lished regiodirecting effect of the 2-methoxy substituent of
methyllithium afforded significantly higher yields of 7. Us- the intermediate tricarbonyl(η5-2-methoxycyclohexadienyl)-
ing optimized reaction conditions, 7 was obtained in 71% iron cation.[19] The regiodirecting effect causes a preferen-
yield along with 12% of 23 (Table 1). This route leads to 7 tial attack of the incoming amino group at the 5-position
in five steps with an overall yield of 46%, based on the iron of the ligand (para to the methoxy group). Dehydrogenation
complex 13.
of the thermodynamic product by manganese dioxide pro-
vides the desired 6-methoxycarbazole 12.[20] This regiocon-
trol has been efficiently utilized for our syntheses of 4-de-
oxycarbazomycin C, carbazomycin C (3), and carbazomy-
cin D (4).[6] In the present case, however, the dehydrogena-
tion to the 8-methoxycarbazole 26 at the kinetic product
stage can obviously compete with the proton-catalyzed re-
arrangement, thus leading to a 2:1 ratio of the 6-methoxy-
carbazole 12 and 8-methoxycarbazole 26.
Synthesis of Carbazomycin H (8)
Electrophilic substitution of the arylamine 15, by reac-
tion with the iron complex 14 in acetonitrile at room tem-
perature, afforded the iron complex 24 (Scheme 6). Sub-
sequent O-acetylation provided the corresponding acetate
25. For the total synthesis of 8, the iron complex 25, which
Oxidation of 12 with ceric() ammonium nitrate af-
forded the carbazole-1,4-quinone 10, which is the direct
synthetic precursor of 8 (Scheme 7). The final step for
transformation of 10 to 8 was, again, the regioselective in-
troduction of the methyl group at C-1. Addition of an ex-
cess of methyllithium to 10 in tetrahydrofuran at Ϫ78 °C
provided, after some optimization, a best yield of 42% for
Scheme 6
742
Scheme 7
Eur. J. Org. Chem. 2003, 740Ϫ746

Carbazole-1,4-quinol Alkaloids from Streptoverticillium ehimense
Table 2. Addition of methyllithium to the carbazole-1,4-quinone 10
FULL PAPER
MeLi (equiv.)
Reaction conditions
8, yield (%)
27, yield (%)
10.0
10.0
7.5
Ϫ78 °C, 2.5 h
20
42
35
42
22
5
32
14
Ϫ78 °C, 5 h; room temp., 16 h
Ϫ78 °C, 2 h
5.0
Ϫ78 °C, 6 h
2,4-Dimethoxy-3-methyl-5-nitrophenol (20): A solution of KOH
(4.10 g, 89 mmol) in H2O (5 mL) was added at room temperature
to a stirred solution of 19 (5.65 g, 22.1 mmol) in EtOH (50 mL).
On moderate warming, a dark red solution was formed. This solu-
tion was stirred at room temperature for 2 h. The EtOH was evap-
orated in vacuo and H2O (100 mL) was added. The aqueous layer
was washed with Et2O (2 ϫ 20 mL). The solution of the phenolate
was acidified with conc. HCl (5 mL) and extracted with Et2O (2 ϫ
50 mL). The combined organic layers were washed with H2O
(100 mL) and dried over sodium sulfate. Removal of the solvent
gave an orange oil, which crystallized on addition of pentane.
Recrystallization from CCl4 gave 20 as yellow crystals. Yield: 4.40 g
(93%), m.p. 64 °C (CCl4). UV (MeOH): λ ϭ 195, 213 (sh), 245,
285, 342 nm. IR (drift): ν˜ ϭ 3419 (br), 2937, 1586, 1507, 1347,
1333, 1265, 1237, 1116, 1045, 991, 772 cmϪ1. 1H NMR (400 MHz,
CDCl3): δ ϭ 2.30 (s, 3 H), 3.859 (s, 3 H), 3.863 (s, 3 H), 6.09 (br.
s, 1 H), 7.35 (s, 1 H) ppm. 13C NMR and DEPT (100 MHz,
CDCl3): δ ϭ 10.00 (CH3), 61.03 (CH3), 62.15 (CH3), 109.47 (CH),
127.53 (C), 139.94 (C), 145.10 (C), 146.34 (C), 150.25 (C) ppm. MS
(55 °C): m/z (%) ϭ 213 (100) [Mϩ], 166 (12), 152 (12), 137 (14),
125 (11), 122 (9), 109 (7). HRMS (C9H11NO5): calcd. 213.0637;
found 213.0627. C9H11NO5 (213.20): calcd. C 50.70, H 5.20, N
6.57; found C 50.70, H 5.11, N 6.62.
8 (the product of 1,2-addition at C-1), along with 14% of
6-methoxy-2,3-dimethylcarbazole-1,4-quinone (27; the
product of 1,4-addition at C-3 followed by elimination;
Table 2). The regioisomeric carbazolequinol formed by 1,2-
addition at C-4 could not be isolated. The present synthesis
provides 8 in five steps with an overall yield of 7%, based
on the iron complex 14.
Experimental Section
General: All reactions were carried out using dry solvents and un-
der an argon atmosphere, unless otherwise stated. Flash chromato-
graphy: Merck silica gel (0.03Ϫ0.06 mm). M.p.: Büchi 535. UV
spectra: PerkinϪElmer Lambda 2 (UV/Vis spectrometer). IR spec-
tra: Bruker IFS 88 (FT-IR). 1H NMR and 13C NMR spectra:
Bruker AM-400 and Bruker DRX-500; internal standard: TMS or
the signal of the deuterated solvent; δ in ppm; coupling constants
(J) in Hz. MS: Finnigan MAT-90; ionization potential: 70 eV. Ele-
mental analyses: Heraeus CHN-Rapid.
1-(2,4-Dimethoxy-3-methylphenyl)ethanone (17): For synthesis and
5-Amino-2,4-dimethoxy-3-methylphenol (15): Palladium on carbon
(10%, 250 mg) was added to a solution of 20 (2.51 g, 11.8 mmol)
in MeOH (25 mL). This mixture was vigorously stirred under a
hydrogen atmosphere (800Ϫ900 Torr) at room temperature until no
further hydrogen uptake was detected (2.5 h). Evaporation of the
solvent in vacuo and flash chromatography (hexane/EtOAc, 2:1)
of the residue on silica gel afforded a light red solid, which was
recrystallized from hexane/EtOAc (5:1) to give 15 as light red crys-
tals. Yield: 2.04 g (95%), m.p. 102Ϫ103 °C (hexane/EtOAc, dec.).
UV (MeOH): λ ϭ 203, 232 (sh), 292 nm. IR (drift): ν˜ ϭ 3388, 3304,
2934 (br), 1593, 1517, 1464, 1430, 1364, 1271, 1240, 1219, 1123,
spectroscopic data, see ref.[17b]
2,4-Dimethoxy-3-methylphenyl Acetate (18): For synthesis and
spectroscopic data, see ref.[17b]
2,4-Dimethoxy-3-methyl-5-nitrophenyl Acetate (19): A solution of
HNO3 (100%, 0.87 mL, 21 mmol) in HOAc/Ac2O (1:3, 4 mL) was
added to a solution of 18 (2.20 g, 10.5 mmol) in HOAc/Ac2O (1:3,
12 mL) at 0 °C, with vigorous stirring, over a period of 45 min.
After the addition was complete, the reaction mixture was
quenched with ice-water (20 mL). On cooling, a concentrated aque-
ous solution of NH3 (20 mL) was added portionwise. The aqueous
layer was extracted with Et2O (2 ϫ 20 mL). The combined organic
layers were washed with a saturated aqueous solution of NaHCO3
(2 ϫ 20 mL), then washed with H2O (20 mL) and dried over so-
dium sulfate. Evaporation of the solvent and flash chromatography
(hexane/EtOAc, 4:1) of the residue on silica gel gave an orange oil,
which crystallized on addition of pentane. Recrystallization from
MeOH provided 19 as light yellow crystals. Yield: 2.44 g (92%),
m.p. 44 °C (MeOH). UV (MeOH): λ ϭ 194, 212 (sh), 275 nm. IR
1
1059, 990, 834 cmϪ1. H NMR (400 MHz, [D6]DMSO): δ ϭ 2.04
(s, 3 H), 3.52 (s, 3 H), 3.55 (s, 3 H), 4.45 (br. s, 2 H), 6.08 (s, 1 H),
8.51 (s, 1 H) ppm. 13C NMR and DEPT (100 MHz, [D6]DMSO):
δ ϭ 9.18 (CH3), 58.67 (CH3), 59.56 (CH3), 100.31 (CH), 123.38
(C), 136.20 (C), 136.92 (C), 136.96 (C), 146.10 (C) ppm. MS (30
°C): m/z (%) ϭ 183 (54) [Mϩ], 168 (100), 153 (21), 140 (9), 125 (14).
HRMS (C9H13NO3): calcd. 183.0895; found 183.0880. C9H13NO3
(183.21): calcd. C 59.00, H 7.15, N 7.65; found C 59.00, H 7.16,
N 7.73.
(drift): ν˜ ϭ 3109, 2950, 1762, 1583, 1530, 1476, 1418, 1349, 1306,
1
1245, 1207, 1113, 1046, 991, 893, 787 cmϪ1. H NMR (400 MHz, [(1-4-η)-5-(2-Amino-6-hydroxy-3,5-dimethoxy-4-methylphenyl)-
CDCl3): δ ϭ 2.28 (s, 3 H), 2.36 (s, 3 H), 3.85 (s, 3 H), 3.90 (s, 3
cyclohexa-1,3-diene]tricarbonyliron (21): A solution of 15 (445 mg,
H), 7.56 (s, 1 H) ppm. 13C NMR and DEPT (100 MHz, CDCl3):
2.43 mmol) and tricarbonyl(η5-cyclohexadienylium)iron tetra-
δ ϭ 9.93 (CH3), 20.58 (CH3), 60.87 (CH3), 61.99 (CH3), 117.97 fluoroborate (13; 370 mg, 1.21 mmol) in degassed acetonitrile
(CH), 128.91 (C), 138.76 (C), 138.98 (C), 151.18 (C), 155.13 (C), (20 mL) was stirred for 2 days at room temperature in the absence
168.61 (CϭO) ppm. MS (36 °C): m/z (%) ϭ 255 (10) [Mϩ], 213 of light. Removal of the solvent and flash chromatography (hexane/
(100), 166 (7), 43 (18). HRMS (C11H13NO6): calcd. 255.0743; EtOAc, 2:1) of the residue on silica gel gave 21 as a light yellow
found 255.0752. C11H13NO6 (255.23): calcd. C 51.76, H 5.13, N solid. Yield: 468 mg (96%), m.p. 168Ϫ170 °C (dec.). UV (MeOH):
5.49; found C 51.65, H 5.07, N 5.69.
λ ϭ 205, 225 (sh), 292 nm. IR (drift): ν˜ ϭ 3443, 3345, 2040, 1967,
Eur. J. Org. Chem. 2003, 740Ϫ746
743

H.-J. Knölker, W. Fröhner, K. R. Reddy
FULL PAPER
1459, 1420, 1060, 981, 857, 622 cmϪ1
.
1H NMR (400 MHz, 134.47 (C), 139.59 (C), 140.83 (C), 143.52 (C), 169.18 (CϭO) ppm.
[D6]DMSO): δ ϭ 1.92 (m, 2 H), 2.05 (s, 3 H), 3.05 (dd, J ϭ 5.4, MS (100 °C): m/z (%) ϭ 299 (29) [Mϩ], 257 (52), 256 (14), 242
2.5 Hz, 1 H), 3.33 (m, 1 H), 3.51 (s, 3 H), 3.52 (s, 3 H), 3.87 (m, 1
H), 4.07 (br. s, 2 H), 5.61 (m, 1 H), 5.75 (m, 1 H), 8.15 (s, 1 H)
ppm. 13C NMR and DEPT (100 MHz, [D6]DMSO): δ ϭ 9.14
(CH3), 25.65 (CH2), 34.01 (CH), 58.96 (CH3), 60.12 (CH3), 61.82
(CH), 66.43 (CH), 84.84 (CH), 85.81 (CH), 112.83 (C), 120.99 (C),
134.66 (C), 137.05 (C), 137.80 (C), 143.99 (C), 212.74 (3 CO) ppm.
MS (100 °C): m/z (%) ϭ 401 (22) [Mϩ], 373 (12), 345 (26), 317 (88),
315 (100), 302 (17), 285 (19), 284 (19), 261 (12), 259 (11), 246 (10),
244 (21), 224 (29), 223 (37), 208 (45), 168 (10). HRMS
(C18H19FeNO6): calcd. 401.0562; found 401.0544. C18H19FeNO6
(401.21): calcd. C 53.89, H 4.77, N 3.49; found C 54.04, H 4.73,
N 3.53.
(100), 226 (10), 213 (13), 198 (11), 170 (13). HRMS (C17H17NO4):
calcd. 299.1158; found 299.1167. C17H17NO4 (299.33): calcd. C
68.22, H 5.72, N 4.68; found C 68.03, H 5.85, N 4.55.
3-Methoxy-2-methyl-9H-carbazole-1,4-quinone (9): A solution of
ceric() ammonium nitrate (650 mg, 1.19 mmol) in H2O (5 mL)
was added dropwise over a period of 1 h to a vigorously stirred
solution of 11 (118 mg, 394 µmol) in acetonitrile (5 mL) at 0 °C. A
dark green precipitate was formed. Ice-water (10 mL) was added
and stirring was continued for 1 h at 0 °C. The precipitate was
isolated by filtration, washed with a large volume of H2O, and
dried in vacuo to give the product 9 as a dark green solid. Recrys-
tallization from EtOAc gave 9 as dark green crystals. Yield: 90 mg
(95%), m.p. 248Ϫ256 °C (EtOAc, dec.). For spectral data, see
ref.[17b]
[(1-4-η)-5-(2-Acetoxy-6-amino-3,5-dimethoxy-4-methylphenyl)-
cyclohexa-1,3-diene]tricarbonyliron (22): A solution of acetic anhyd-
ride (180 mg, 1.73 mmol) and triethylamine (180 mg, 1.79 mmol) in
degassed dichloromethane (15 mL) was added to a mixture of 21
(650 mg, 1.62 mmol) and DMAP (20 mg). The orange solution was
stirred at room temperature for 4 h, then heated at reflux for a
short period. Evaporation of the solvent in vacuo and flash chro-
matography (hexane/EtOAc, 2:1) of the residue on silica gel af-
forded a light yellow oil. This oil became solid in Et2O to give 22
as a light yellow solid. Yield: 707 mg (98%), m.p. 50Ϫ60 °C. UV
(MeOH): λ ϭ 204, 224 (sh), 297 nm. IR (drift): ν˜ ϭ 3464, 3378,
2940, 2044, 1968, 1760, 1462, 1417, 1370, 1343, 1264, 1203, 1118,
Carbazomycin G (1,4-Dihydro-1-hydroxy-3-methoxy-1,2-dimethyl-
9H-carbazol-4-one; 7) and 2,3-Dimethyl-9H-carbazole-1,4-quinone
(23): A solution of methyllithium in Et2O (1.6 , 0.25 mL,
0.4 mmol) was added dropwise to a solution of 9 (21 mg, 87 µmol)
in degassed THF (10 mL) at Ϫ78 °C. The reaction mixture was
warmed to room temperature over a period of 30 min, then
quenched with a 10% aqueous solution of ammonium chloride
(10 mL). The aqueous layer was extracted with ethyl acetate
(10 mL) and the combined organic layers were dried over sodium
sulfate. The solvent was removed in vacuo. Flash chromatography
(hexane/EtOAc, 1:2) of the residue on silica gel provided 23 as the
less polar fraction and 7 as the more polar fraction. Compound 7
was recrystallized from ethanol.
1058, 1011, 622 cmϪ1
. δ ϭ
1H NMR (400 MHz, CDCl3):
1.87Ϫ1.91 (m, 1 H), 1.98Ϫ2.05 (m, 1 H), 2.18 (s, 3 H), 2.38 (s, 3
H), 2.99 (m, 1 H), 3.24 (m, 1 H), 3.60Ϫ3.63 (m, 1 H), 3.64 (s, 3
H), 3.70 (s, 3 H), 3.87 (br. s, 2 H), 5.46 (m, 1 H), 5.54 (m, 1 H)
ppm. 13C NMR and DEPT (100 MHz, CDCl3): δ ϭ 9.49 (CH3),
20.66 (CH3), 25.07 (CH2), 35.99 (CH), 59.34 (CH3), 60.47 (CH),
60.80 (CH3), 64.14 (CH), 83.96 (CH), 85.81 (CH), 118.31 (C),
123.58 (C), 134.45 (C), 139.04 (C), 141.96 (C), 143.75 (C), 169.63
(CϭO), 211.67 (3 CO) ppm. MS (90 °C): m/z (%) ϭ 443 (23) [Mϩ],
415 (14), 387 (33), 359 (100), 357 (19), 344 (87), 331 (11), 329 (12),
316 (16), 314 (13), 284 (36), 281 (41), 266 (30), 251 (13), 244 (10),
238 (22), 208 (23), 150 (23). HRMS (C20H21FeNO7): calcd.
443.0667; found 443.0687. C20H21FeNO7 (443.25): calcd. C 54.20,
H 4.78, N 3.16; found C 54.36, H 4.86, N 3.24.
7: Light yellow crystals. Yield: 16 mg (71%), m.p. 266Ϫ268 °C
(EtOH, dec.) (ref.[2g] 241Ϫ243 °C; ref.[10] 266Ϫ268 °C from EtOAc).
UV (MeOH): λ (ε) ϭ 212 (39600), 251 (20200), 270 (sh, 8500), 277
(7300), 340 (5800) nm. IR (drift): ν˜ ϭ 3209 br, 1643, 1620, 1611,
1482, 1453, 1401, 1377, 1317, 1292, 1189, 1150, 1093, 1012, 962,
925, 879, 807, 750 cmϪ1 1H NMR (500 MHz, [D6]DMSO): δ ϭ
.
1.57 (s, 3 H), 1.98 (s, 3 H), 3.68 (s, 3 H), 5.93 (s, 1 H), 7.15Ϫ7.23
(m, 2 H), 7.44 (dd, J ϭ 7.8, 0.8 Hz, 1 H), 8.01 (d, J ϭ 7.8 Hz,
1 H), 12.21 (br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz,
[D6]DMSO): δ ϭ 10.19 (CH3), 27.89 (CH3), 59.26 (CH3), 67.30
(C), 108.42 (C), 112.05 (CH), 120.47 (CH), 121.51 (CH), 122.98
(CH), 123.79 (C), 136.46 (C), 140.82 (C), 147.61 (C), 154.32 (C),
177.51 (CϭO) ppm. MS (160 °C): m/z (%) ϭ 257 (100) [Mϩ], 242
(77), 241 (17), 240 (46), 239 (28), 238 (12), 226 (25), 225 (21), 224
(13), 214 (28), 210 (14), 199 (36), 198 (20), 197 (24), 196 (16).
HRMS (C15H15NO3): calcd. 257.1052; found 257.1062. C15H15NO3
(257.30): calcd. C 70.02, H 5.88, N 5.45; found C 70.27, H 6.06,
N 5.27.
4-Acetoxy-1,3-dimethoxy-2-methyl-9H-carbazole (11): Alox B ‘‘Su-
per 1’’ (ICN, 1.75 g) and very active manganese dioxide (3.50 g)
were added to a solution of 22 (387 mg, 873 µmol) in degassed
dichloromethane (25 mL). The heterogeneous reaction mixture was
vigorously stirred for 2 h at room temperature. The mixture was
filtered through a short length of Celite. The Celite was sub-
sequently washed, first with CH2Cl2 (150 mL) and then with
CH2Cl2/Et2O (10:1, 150 mL). The solvent was removed from the
combined filtrates and the residue was subjected to flash chromato-
graphy (hexane/EtOAc, 2:1) on silica gel to provide 11 as a colorless
oil. Crystallization from hexane/EtOAc (4:1) at Ϫ30 °C provided
11 as colorless crystals. Yield: 188 mg (72%), m.p. 133Ϫ135 °C
(hexane/EtOAc). UV (MeOH): λ ϭ 223 (sh), 239, 247 (sh), 258
(sh), 282 (sh), 290, 325, 338 nm. IR (drift): ν˜ ϭ 3399, 2991, 2961,
2936, 1753, 1612, 1504, 1455, 1412, 1385, 1370, 1320, 1291, 1216,
23: Red crystals. Yield: 2.4 mg (12%), m.p. 276Ϫ278 °C (hexane/
EtOAc). UV (MeOH): λ ϭ 224, 256, 264 (sh), 293, 382 nm. IR
(drift): ν˜ ϭ 3212, 1658, 1632, 1603, 1541, 1471, 1405, 1385, 1328,
1237, 1053, 756, 747, 687 cmϪ1
.
1H NMR (500 MHz,
[D6]DMSO) ϭ 1.99 (s, 3 H), 2.01 (s, 3 H), 7.28 (br. t, J ϭ 7.5 Hz,
1 H), 7.35 (br. t, J ϭ 7.5 Hz, 1 H), 7.50 (d, J ϭ 8.2 Hz, 1 H), 8.0
(d, J ϭ 8.0 Hz, 1 H), 12.75 (br. s, 1 H) ppm. 13C NMR and DEPT
(125 MHz, [D6]DMSO): 11.78 (CH3), 12.24 (CH3), 113.74 (CH),
115.10 (C), 121.71 (CH), 123.58 (C), 123.63 (CH), 126.09 (CH),
135.63 (C), 137.54 (C), 138.52 (C), 142.00 (C), 179.90 (CϭO),
182.76 (CϭO) ppm. MS (130 °C): m/z (%) ϭ 225 (100) [Mϩ], 197
(28), 196 (18), 168 (12), 143 (12), 115 (20). HRMS (C14H11NO2):
calcd. 225.0790; found 225.0773.
1167, 1125, 1110, 1073, 1022, 1010, 922, 888, 754, 740 cmϪ1 1H
.
NMR (400 MHz, CDCl3): δ ϭ 2.37 (s, 3 H), 2.53 (s, 3 H), 3.815
(s, 3 H), 3.822 (s, 3 H), 7.16 (dt, J ϭ 1.3, 7.3 Hz, 1 H), 7.29Ϫ7.36
(m, 2 H), 7.86 (d, J ϭ 7.8 Hz, 1 H), 8.29 (br. s, 1 H) ppm. 13C
NMR and DEPT (100 MHz, CDCl3): δ ϭ 9.86 (CH3), 20.85 (CH3),
60.58 (CH3), 61.21 (CH3), 110.90 (CH), 115.44 (C), 119.55 (CH), [(1-4-η)-6-(2-Amino-6-hydroxy-3,5-dimethoxy-4-methylphenyl)-2-
121.43 (CH), 121.90 (C), 122.47 (C), 125.82 (CH), 130.49 (C), methoxycyclohexa-1,3-diene]tricarbonyliron (24): A solution of 15
744
Eur. J. Org. Chem. 2003, 740Ϫ746

Carbazole-1,4-quinol Alkaloids from Streptoverticillium ehimense
(1.143 g, 6.24 mmol) and tricarbonyl(η5-3-methoxycyclohexadieny-
FULL PAPER
288 (sh), 298, 339, 353 nm. IR (drift): ν˜ ϭ 3378, 3004, 2939, 2835,
lium)iron hexafluorophosphate 14 (1.23 g, 3.12 mmol) in degassed 1750, 1576, 1507, 1488, 1467, 1435, 1409, 1376, 1308, 1269, 1217,
acetonitrile (40 mL) was stirred at room temperature for 3.5 h, then
1178, 1127, 1112, 1014, 908, 801, 775, 603 cmϪ1 1H NMR
heated at reflux for a short time. The acetonitrile was evaporated (400 MHz, CDCl3): δ ϭ 2.35 (s, 3 H), 2.51 (s, 3 H), 3.77 (s, 3 H),
.
and the residue was subjected to flash chromatography (hexane/
EtOAc, 2:1) on silica gel. After removal of the solvent, the solid
3.81 (s, 3 H), 3.86 (s, 3 H), 6.96 (dd, J ϭ 8.8, 2.5 Hz, 1 H), 7.14 (d,
J ϭ 8.8 Hz, 1 H), 7.36 (d, J ϭ 2.5 Hz, 1 H), 8.31 (br. s, 1 H) ppm.
was washed twice with boiling Et2O (5 mL) to afford 24 as a light 13C NMR and DEPT (100 MHz, CDCl3): δ ϭ 9.82 (CH3), 20.78
yellow solid. Yield: 1.29 g (96%), m.p. 194Ϫ195 °C (dec.). UV
(MeOH): λ ϭ 204, 225 (sh), 293 nm. IR (drift): ν˜ ϭ 3475, 3388, (CH), 114.46 (CH), 115.32 (C), 122.30 (C), 122.38 (C), 131.38 (C),
2933, 2046, 1955, 1628, 1605, 1490, 1463, 1426, 1415, 1347, 1316, 134.32 (C), 134.69 (C), 140.90 (C), 143.12 (C), 153.54 (C), 169.22
1259, 1224, 1065, 1000, 629 cmϪ1 1H NMR (400 MHz, (CϭO) ppm. MS (95 °C): m/z (%) ϭ 329 (52) [Mϩ], 287 (66), 272
[D6]DMSO): δ ϭ 1.78Ϫ1.82 (m, 2 H), 2.04 (s, 3 H), 2.88 (m, 1 H), (100), 257 (6). HRMS (C18H19NO5): calcd. 329.1263; found
(CH3), 55.93 (CH3), 60.42 (CH3), 61.20 (CH3), 104.76 (CH), 111.54
.
3.21 (m, 1 H), 3.50 (s, 3 H), 3.52 (s, 3 H), 3.56 (s, 3 H), 3.67 (m, 1 329.1273. C18H19NO5 (329.36): C 65.64, H 5.81, N 4.25; found C
H), 4.09 (br. s, 2 H), 5.63 (m, 1 H), 8.13 (s, 1 H) ppm. 13C NMR 65.59, H 5.84, N 4.46.
and DEPT (100 MHz, [D6]DMSO): δ ϭ 9.19 (CH3), 26.61 (CH2), 26: Light brown crystals. Yield: 28 mg (17%), m.p. 172Ϫ173 °C
35.90 (CH), 50.50 (CH), 54.56 (CH3), 58.17 (CH), 59.06 (CH3), (hexane/EtOAc). UV (MeOH): λ ϭ 228 (sh), 243, 251 (sh), 276,
60.17 (CH3), 67.98 (CH), 113.50 (C), 121.02 (C), 134.84 (C), 137.18 286, 323, 337 nm. IR (drift): ν˜ ϭ 3376, 2947, 2842, 1757, 1578,
(C), 137.98 (C), 140.35 (C), 144.27 (C), 212.29 (3 CO) ppm. MS 1499, 1434, 1410, 1303, 1268, 1250, 1214, 1127, 1073, 1016, 788,
1
(115 °C): m/z (%) ϭ 431 (4) [Mϩ], 403 (3), 375 (64), 347 (100), 345 736 cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 2.39 (s, 3 H), 2.52 (s,
(74), 332 (26), 315 (10), 300 (15), 224 (21), 223 (28), 208 (31).
HRMS (C19H21FeNO7): calcd. 431.0667; found 431.0654.
3 H), 3.81 (s, 3 H), 3.90 (s, 3 H), 3.98 (s, 3 H), 6.87 (d, J ϭ 7.9 Hz,
1 H), 7.11 (t, J ϭ 7.9 Hz, 1 H), 7.47 (d, J ϭ 7.9 Hz, 1 H), 8.44 (br.
C19H21FeNO7 (431.23): calcd. C 52.92, H 4.91, N 3.25; found C s, 1 H) ppm. 13C NMR and DEPT (100 MHz, CDCl3): δ ϭ 9.86
52.93, H 4.96, N 3.41.
(CH3), 20.83 (CH3), 55.49 (CH3), 60.69 (CH3), 61.19 (CH3), 105.99
(CH), 113.99 (CH), 115.92 (C), 120.08 (CH), 122.42 (C), 122.91
(C), 129.89 (C), 130.30 (C), 134.42 (C), 141.17 (C), 143.62 (C),
145.68 (C), 169.02 (CϭO) ppm. MS (95 °C): m/z (%) ϭ 329 (54)
[Mϩ], 287 (63), 286 (10), 272 (100). HRMS (C18H19NO5): calcd.
329.1263; found 329.1257. C18H19NO5 (329.36): calcd. C 65.64, H
5.81, N 4.25; found C 65.46, H 5.79, N 3.93.
[(1-4-η)-6-(2-Acetoxy-6-amino-3,5-dimethoxy-4-methylphenyl)-2-
methoxycyclohexa-1,3-diene]tricarbonyliron (25):
A solution of
acetic anhydride (122 mg, 1.2 mmol) and triethylamine (121 mg,
1.2 mmol) in degassed dichloromethane (30 mL) was added to a
mixture of the iron complex 24 (435 mg, 1.01 mmol) and DMAP
(30 mg). The orange solution was stirred at room temperature for
24 h, then the solvent was removed in vacuo. Flash chromato-
graphy (hexane/EtOAc, 2:1) of the residue on silica gel gave a light
yellow oil. This oil became solid in Et2O to give 25 as a light yellow
solid. Yield: 460 mg (96%), m.p. 53Ϫ63 °C (dec.). UV (MeOH):
λ ϭ 202, 225 (sh), 297 nm. IR (drift): ν˜ ϭ 3480, 3381, 2939, 2042,
3,6-Dimethoxy-2-methyl-9H-carbazole-1,4-quinone (10): A solution
of ceric() ammonium nitrate (449 mg, 0.82 mmol) in H2O (5 mL)
was added dropwise over 20 min to a vigorously stirred solution of
12 (90 mg, 0.273 mmol) in acetonitrile (5 mL) at 0 °C. A black
precipitate formed during the addition. The reaction mixture was
stirred for 40 min at 0 °C. Ice-water (15 mL) was added and stirring
was continued for 30 min at 0 °C. The precipitate was isolated by
filtration, washed with a large volume of H2O, and dried in vacuo.
The residual solid was dissolved in acetone (50 mL). Silica gel (3 g)
was added and the solvent was removed in vacuo. The residue was
subjected to flash chromatography (EtOAc/MeOH, 10:1) on silica
gel. Evaporation of the solvent and recrystallization from THF at
Ϫ30 °C provided 10 as black-green crystals. Yield: 40 mg (54%),
m.p. 270Ϫ275 °C (THF, dec.). UV (MeOH): λ ϭ 224, 260, 297,
309, 441 nm. IR (drift): ν˜ ϭ 3244, 2955, 1637, 1601, 1529, 1489,
1962, 1760, 1619, 1484, 1462, 1424, 1206, 1014, 623 cmϪ1 1H
.
NMR (400 MHz, CDCl3): δ ϭ 1.70 (br. d, J ϭ 15.1 Hz, 1 H), 1.88
(ddd, J ϭ 15.1, 11.0, 4.1 Hz, 1 H), 2.17 (s, 3 H), 2.37 (s, 3 H), 2.80
(ddd, J ϭ 6.3, 4.1, 2.0 Hz, 1 H), 3.31 (t, J ϭ 2.5 Hz, 1 H),
3.54Ϫ3.58 (m, 1 H), 3.59 (s, 3 H), 3.64 (s, 3 H), 3.69 (s, 3 H), 3.81
(br. s, 2 H), 5.35 (dd, J ϭ 6.6, 2.0 Hz, 1 H) ppm. 13C NMR and
DEPT (100 MHz, CDCl3): δ ϭ 9.50 (CH3), 20.61 (CH3), 25.81
(CH2), 37.49 (CH), 48.72 (CH), 54.67 (CH3), 56.63 (CH), 59.36
(CH3), 60.77 (CH3), 67.33 (CH), 118.85 (C), 123.56 (C), 134.44 (C),
139.04 (C), 140.48 (C), 141.99 (C), 143.90 (C), 169.54 (CϭO),
211.11 (3 CO) ppm. MS (105 °C): m/z (%) ϭ 473 (6) [Mϩ], 445 (4),
417 (73), 389 (88), 387 (10), 374 (100), 359 (15), 346 (18), 314 (23),
281 (44), 266 (22), 228 (19). HRMS (C21H23FeNO8): calcd.
473.0773; found 473.0762. C21H23FeNO8 (473.27): calcd. C 53.30,
H 4.90, N 2.96; found C 53.30, H 4.90, N 2.95.
1
1296, 1263, 1219, 1106, 1029, 835, 810, 753, 643 cmϪ1. H NMR
(500 MHz, [D6]DMSO): δ ϭ 1.88 (s, 3 H), 3.80 (s, 3 H), 4.01 (s, 3
H), 6.97 (dd, J ϭ 8.9, 2.6 Hz, 1 H), 7.38Ϫ7.41 (m, 2 H), 12.76 (br.
s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]DMSO): δ ϭ
8.50 (CH3), 55.33 (CH3), 61.03 (CH3), 101.47 (CH), 113.41 (C),
114.99 (CH), 117.18 (CH), 124.46 (C), 126.46 (C), 132.71 (C),
135.96 (C), 156.92 (C), 157.75 (C), 178.32 (CϭO), 180.22 (CϭO)
ppm. MS (125 °C): m/z (%) ϭ 271 (100) [Mϩ], 257 (56), 256 (40),
242 (14), 228 (16), 200 (12). HRMS (C15H13NO4): calcd. 271.0845;
found 271.0828. C15H13NO4 (271.28): calcd. C 66.41, H 4.83, N
5.16; found C 65.97, H 5.00, N 4.77.
4-Acetoxy-1,3,6-trimethoxy-2-methyl-9H-carbazole (12) and 4-Ace-
toxy-1,3,8-trimethoxy-2-methyl-9H-carbazole (26): Alox B ‘‘Super
1’’ (ICN, 470 mg) and very active manganese dioxide (3.53 g) were
added to a solution of 25 (235 mg, 0.497 mmol) in degassed dichlo-
romethane (30 mL). The heterogeneous reaction mixture was
stirred vigorously for 45 min at room temperature. The mixture was
filtered through a short length of Celite, which was subsequently
washed with CH2Cl2 (300 mL). The solvent was evaporated from Carbazomycin
H
(1,4-Dihydro-1-hydroxy-3,6-dimethoxy-1,2-di-
the combined organic filtrates. Flash chromatography (CH2Cl2/ methyl-9H-carbazol-4-one; 8) and 6-Methoxy-2,3-dimethyl-9H-car-
Et2O, 10:1) of the residue on silica gel gave 26 as the less polar bazole-1,4-quinone (27): A solution of methyllithium in cumene/
fraction and 12 as the more polar fraction. Both carbazoles were THF (9:1; 1 , 1.85 mL, 1.85 mmol) was added dropwise to a solu-
recrystallized at Ϫ30 °C from hexane/EtOAc (4:1).
tion of 10 (100 mg, 0.37 mmol) in degassed THF (100 mL) at
12: Light yellow crystals. Yield: 57 mg (35%), m.p. 113Ϫ114 °C Ϫ78 °C. Stirring was continued for a further 6 h at Ϫ78 °C. The
(hexane/EtOAc). UV (MeOH): λ ϭ 230, 243, 253 (sh), 263 (sh), reaction mixture was quenched at Ϫ78 °C by addition of an aque-
Eur. J. Org. Chem. 2003, 740Ϫ746
745

H.-J. Knölker, W. Fröhner, K. R. Reddy
FULL PAPER
[3]
D. J. Hook, J. J. Yacobucci, S. OЈConnor, M. Lee, E. Kerns, B.
Krishnan, J. Matson, G. Hesler, J. Antibiot. 1990, 43,
1347Ϫ1348.
ous solution of ammonium chloride (50 mL). The aqueous layer
was extracted with EtOAc (4 ϫ 50 mL). The combined organic
layers were washed with H2O (3 ϫ 50 mL) and dried over sodium
sulfate. Evaporation of the solvent and flash chromatography
(hexane/EtOAc, 1:2) of the residue on silica gel provided 27 as the
less polar fraction and 8 as the more polar fraction.
[4] [4a]
D. P. Chakraborty, S. Roy in Prog. Chem. Org. Nat. Prod.,
vol. 57 (Eds.: W. Herz, H. Grisebach, G. W. Kirby, C. Tamm),
Springer, Wien, 1991, pp. 71Ϫ152. [4b]H.-J. Knölker, Synlett
1992, 371Ϫ387. [4c] D. P. Chakraborty in The Alkaloids, vol. 44
(Ed.: G. A. Cordell), Academic, 1993, pp. 257Ϫ364. [4d]C. J.
Moody, Synlett 1994, 681Ϫ688. [4e] H.-J. Knölker, K. R. Reddy,
8: Light yellow crystals. Yield: 44.2 mg (42%), m.p. 208Ϫ209 °C
(EtOAc, dec.) (ref.[2g] 228Ϫ230 °C). UV (MeOH): λ (ε) ϭ 210
(33600), 253 (19400), 259 (sh, 17700), 293 (6600), 342 (6400) nm.
IR (drift): ν˜ ϭ 3360 (sh), 3170, 2987, 2938, 1637, 1630, 1615, 1604
(sh), 1482, 1463, 1288, 1261, 1218, 1166, 1129, 1103, 1069, 1003,
Chem. Rev. 2002, 102, 4303Ϫ4427.
For the total syntheses of carbazomycin A and B, see:
[5]
[5a]
H.-
J. Knölker, M. Bauermeister, D. Bläser, R. Boese, J.-B. Pannek,
Angew. Chem. 1989, 101, 225Ϫ227; Angew. Chem. Int. Ed.
980, 926, 909, 887, 848, 806, 769, 676 cmϪ1. H NMR (500 MHz,
1
[5b]
Engl. 1989, 28, 223Ϫ225.
H.-J. Knölker, M. Bauermeister,
[D6]DMSO): δ ϭ 1.54 (s, 3 H), 1.96 (s, 3 H), 3.67 (s, 3 H), 3.78 (s,
3 H), 5.91 (s, 1 H), 6.83 (dd, J ϭ 8.8, 2.5 Hz, 1 H), 7.32 (d, J ϭ
[5c]
J. Chem. Soc., Chem. Commun. 1989, 1468Ϫ1470.
H.-J.
Knölker, M. Bauermeister, Helv. Chim. Acta 1993, 76,
8.8 Hz, 1 H), 7.50 (d, J ϭ 2.5 Hz, 1 H), 12.08 (br. s, 1 H) ppm. 13
C
[5d]
2500Ϫ2514.
H.-J. Knölker, W. Fröhner, Tetrahedron Lett.
[5e]
NMR and DEPT (125 MHz, [D6]DMSO): δ ϭ 10.18 (CH3), 28.00
(CH3), 55.28 (CH3), 59.25 (CH3), 67.32 (C), 102.39 (CH), 108.40
(C), 112.58 (CH), 112.80 (CH), 124.49 (C), 131.22 (C), 140.65 (C),
147.59 (C), 154 41 (C), 155.16 (C), 177.47 (CϭO) ppm. MS (155
°C): m/z (%) ϭ 287 (100) [Mϩ], 272 (74), 271 (18), 270 (21), 256
(28), 255 (14), 254 (11), 244 (20), 229 (27), 228 (19), 227 (17), 226
(13). HRMS (C16H17NO4): calcd. 287.1158; found 287.1172.
C16H17NO4 (287.32): calcd. C 66.89, H 5.96, N 4.87; found C
66.40, H 6.15, N 4.22.
1999, 40, 6915Ϫ6918.
C. J. Moody, P. Shah, J. Chem. Soc.,
[5f]
Perkin Trans. 1 1989, 376Ϫ377.
C. J. Moody, P. Shah, J.
Chem. Soc., Perkin Trans. 1 1989, 2463Ϫ2471. [5g] D. L. J. Clive,
N. Etkin, T. Joseph, J. W. Lown, J. Org. Chem. 1993, 58,
[5h]
2442Ϫ2445.
E. M. Beccalli, A. Marchesini, Tetrahedron
1996, 52, 3029Ϫ3036.
[6]
For the total synthesis of carbazomycin C and D, see: H.-J.
Knölker, G. Schlechtingen, J. Chem. Soc., Perkin Trans. 1
1997, 349Ϫ350.
For the total synthesis of carbazomycin E, see: H.-J. Knölker,
M. Bauermeister, Heterocycles 1991, 32, 2443Ϫ2450.
For a preliminary communication of this work, see: H.-J.
Knölker, W. Fröhner, Tetrahedron Lett. 1997, 38, 4051Ϫ4054.
For the palladium-catalyzed total synthesis of carbazomycin G
and H, see: H.-J. Knölker, W. Fröhner, J. Chem. Soc., Perkin
Trans. 1 1998, 173Ϫ175.
[7]
[8]
[9]
27: Red crystals. Yield: 13.5 mg (14%), m.p. 259Ϫ261 °C (hexane/
EtOAc). UV (MeOH): λ ϭ 224, 259, 282 (sh), 444 nm. IR (drift):
ν˜ ϭ 3225, 2956, 2836, 1651, 1631, 1606, 1532, 1482, 1382, 1261,
1235, 1218, 1094, 828, 715, 684 cmϪ1 1H NMR (500 MHz,
.
[D6]DMSO) ϭ 1.99 (s, 3 H), 2.01 (s, 3 H), 3.80 (s, 3 H), 6.99 (dd,
J ϭ 9.0, 2.5 Hz, 1 H), 7.40 (d, J ϭ 9.0 Hz, 1 H), 7.42 (d, J ϭ 2.5 Hz,
1 H), 12.67 (br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz,
[D6]DMSO): 11.77 (CH3), 12.19 (CH3), 55.30 (CH3), 101.65 (CH),
114.80 (C), 114.86 (CH), 117.32 (CH), 124.51 (C), 132.80 (C),
135.63 (C), 138.59 (C), 141.98 (C), 156.72 (C), 179.56 (CϭO),
182.58 (CϭO) ppm. MS (135 °C): m/z (%) ϭ 255 (100) [Mϩ], 240
(14), 227 (15), 212 (12), 184 (7). HRMS (C15H13NO3): calcd.
255.0895; found 255.0891.
[10]
[11]
For an alternative total synthesis of carbazomycin G, see: H.
Hagiwara, T. Choshi, H. Fujimoto, E. Sugino, S. Hibino, Tetra-
hedron 2000, 56, 5807Ϫ5811.
For recent reviews, see: [11a] H.-J. Knölker, in Transition Metals
for Organic Synthesis, vol. 1 (Eds.: M. Beller, C. Bolm), Wiley-
VCH, Weinheim, 1998, chap. 3.13. [11b]H.-J. Knölker, Chem.
[11c]
Soc. Rev. 1999, 28, 151Ϫ157.
H.-J. Knölker, A. Braier, D.
J. Bröcher, S. Cämmerer, W. Fröhner, P. Gonser, H. Hermann,
D. Herzberg, K. R. Reddy, G. Rohde, Pure Appl. Chem. 2001,
73, 1075Ϫ1086.
[12] [12a]
H.-J. Knölker, E. Baum, P. Gonser, G. Rohde, H. Röttele,
[12b]
Acknowledgments
Organometallics 1998, 17, 3916Ϫ3925.
Chem. Rev. 2000, 100, 2941Ϫ2961.
H.-J. Knölker,
This work was supported by the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie, and the Alexander
von Humboldt Stiftung. We thank BASF AG, Ludwigshafen, for
a generous gift of iron pentacarbonyl.
[13]
[14]
E. O. Fischer, R. D. Fischer, Angew. Chem. 1960, 72, 919.
A. J. Birch, L. F. Kelly, D. J. Thompson, J. Chem. Soc., Perkin
Trans. 1 1981, 1006Ϫ1012.
[15]
[16]
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