Indoloquinones, part 7. Total synthesis of the potent lipid peroxidation inhibitor carbazoquinocin C by an intramolecular palladium-catalyzed oxidative coupling of an anilino-1,4-benzoquinone

Article abstract of DOI:10.1055/s-2002-20953

A highly efficient total synthesis of the potent lipid peroxidation inhibitor carbazoquinocin C is presented. The key-step is a palladium(II)-catalyzed oxidative cyclization of an anilino-1,4-benzoquinone to a carbazole-1,4-quinone which proceeds in up to 91% yield. Using this approach the natural product is obtained in four steps and 39% overall yield starting from aniline.

Full text of DOI:10.1055/s-2002-20953

FEATURE ARTICLE
557
Indoloquinones, Part 7.1 Total Synthesis of the Potent Lipid Peroxidation
Inhibitor Carbazoquinocin C by an Intramolecular Palladium-Catalyzed
Oxidative Coupling of an Anilino-1,4-benzoquinone
Total
S
ynthesis of
athe Potent
L
n
ipid Peroxid
s
ation Inh
-
ibitor Ca
J
r
bazoquin
o
ocin C achim Knölker,* Wolfgang Fröhner, Kethiri R. Reddy
Institut für Organische Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax +49(351)46337030; E-mail: hans-joachim.knoelker@chemie.tu-dresden.de
Received 17 December 2001
Dedicated to Professor Ekkehard Winterfeldt on the occasion of his 70th birthday
Abstract: A highly efficient total synthesis of the potent lipid per-
oxidation inhibitor carbazoquinocin C is presented. The key-step is
a palladium(II)-catalyzed oxidative cyclization of an anilino-1,4-
benzoquinone to a carbazole-1,4-quinone which proceeds in up to
91% yield. Using this approach the natural product is obtained in
four steps and 39% overall yield starting from aniline.
Key words: quinones, palladium catalysis, oxidative cyclization,
total synthesis, carbazole alkaloids
Introduction
Oxygen-derived free radicals play a key role in the initia-
tion of a variety of diseases, like myocardial and cerebral
ischemia, arteriosclerosis, inflammation, rheumatism, se-
nility, autoimmune diseases, and cancer.2 Therefore, free
radical scavengers are believed to provide lead com-
pounds for the development of potential novel drugs
against these diseases. During their screening program for
antioxidative substances Seto and co-workers isolated
structurally unprecedented carbazole-3,4-quinone alka-
loids from different Streptomyces species (Figure1).
Carquinostatin A (1), isolated from Streptomyces exfolia-
tus 2419-SVT23 and lavanduquinocin (2), isolated from
Streptomyces viridochromogenes 2942-SVS3,4 represent
potent neuronal cell protecting compounds due to their an-
tioxidative activity. The carbazoquinocins A–F (3a–f)
were isolated from Streptomyces violaceus 2448-SVT2
and exhibit a strong inhibitory activity against lipid perox-
idation induced by free radicals.5 In view of the large
number of biologically active carbazole alkaloids which
were isolated from natural sources,6,7 several groups be-
came interested in their synthesis.8–12 We have an ongoing
research project directed towards the development of nov-
el transition metal-mediated and -catalyzed methodolo-
gies for the total synthesis of carbazole alkaloids.12 Using
the iron-mediated construction of the carbazole frame-
work by oxidative coupling of a fully functionalized ary-
lamine and cyclohexa-1,3-diene we described the first
total syntheses of carquinostatin A (1) and lavanduquino-
cin (2).13,14 A more direct synthesis of carquinostatin A (1)
Figure 1 Carbazole-3,4-quinone alkaloids
was achieved by oxidative coupling of 4-prenylaniline
with an appropriately substituted 1,2-benzoquinone.15 In
1996 Ogasawara et al. reported the total synthesis of the
first members of the carbazoquinocin family, carbazo-
quinocin A (3a) and carbazoquinocin D (3d).16 We antic-
ipated that the application of our transition metal-
mediated and/or -catalyzed processes furnishing the car-
Synthesis 2002, No. 4, 15 03 2002. Article Identifier:
1437-210X,E;2002,0,04,0557,0564,ftx,en;E08501SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

558
H.-J. Knölker et al.
FEATURE ARTICLE
bazole nucleus should provide convergent and therefore
more simple routes to the carbazoquinocin family.
Retrosynthetic Considerations
The iron-mediated oxidative coupling of cyclohexa-1,3-
diene (4) and 2-heptyl-4,5-dimethoxy-3-methylaniline (5)
via a consecutive C–C and C–N bond formation led to the
first total synthesis of carbazoquinocin
C
(3c)
(Scheme 1).17
Our second approach utilized the palladium-catalyzed ox-
idative coupling of aniline (6) and 2-methoxy-3-methyl-
1,4-benzoquinone (7) followed by regioselective alkyla-
tion for the total synthesis of carbazoquinocin C (3c).18
In a third total synthesis of carbazoquinocin C (3c) we
applied the palladium-mediated oxidative coupling of
aniline (6) and 4-heptyl-3-methyl-1,2-benzoquinone (8).15
Further total syntheses of carbazoquinocin C were subse-
quently reported by the groups of Hibino and Pindur.19,20
Scheme 1 Retrosynthetic analyses of carbazoquinocin C (3c)
Biographical Sketches
Hans-Joachim
Knölker organometallic chemistry fessor of Organic Chemistry
was born in 1958 in Rehren, during his postdoctoral in 1991 at the University of
Germany. He studied chem- studies in the research group Karlsruhe. In 1998 he re-
istry at the universities of of Professor K. P. C. Voll- ceived a fellowship of the
Göttingen and Hannover, hardt at the University of Japan Society for the Pro-
where he received his diplo- California in Berkeley. In motion of Science. In 2001
ma degree in 1983 and his 1987 he returned to the Uni- he moved to the Institute of
Ph.D. in 1985 with Profes- versity of Hannover and fin- Organic Chemistry at the
sor E. Winterfeldt. He be- ished his habilitation in Technical University of
came
interested
in 1990. He became Full Pro- Dresden.
Wolfgang Fröhner was his diploma degree in the Rauxel he returned to the
born in 1963 in Heidelberg, group of Professor G. Ege in group of Professor H.-J.
Germany. His professional 1994. Subsequently, he Knölker in Karlsruhe as a
training started at Teroson joined the research group of postdoctoral fellow (1999–
GmbH in Heidelberg where Professor H.-J. Knölker at 2000). Since November
he graduated as a technician the University of Karlsruhe 2000 he is a research scien-
in chemistry. He studied and received his Ph.D. in tist at the Nucleotide Ana-
chemistry at the University 1998. After six months at logue Design (NAD) AG in
of Heidelberg and received Rütgers VFT in Castrop München.
Kethiri Raghava Reddy the group of Professor H. Ila group of Professor H.-J.
was born in 1963 in Ga- at the North-Eastern Hill Knölker at the University of
rimilla
Pally,
Andhra University in Shillong for a Karlsruhe, Germany. He
Pradesh, India. He studied PhD, which he completed in continued as a post-doctoral
chemistry at Kakatiya Uni- 1995. He continued in the fellow in the same group un-
versity in Warangal, where same group as research as- til 2001, when he followed
he received his BSc in 1984 sociate (CSIR) until 1996, the Knölker research group
and MSc in 1987. After when he moved as an Alex- to the Technical University
qualifying for the National ander von Humboldt fellow of Dresden as a staff scien-
Educational Test, he joined (1997–1999) to the research tist.
Synthesis 2002, No. 4, 557–564 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of the Potent Lipid Peroxidation Inhibitor Carbazoquinocin C
559
In the present article we describe full details of an opti- The addition of aniline (6) to two equivalents of 2-meth-
mized total synthesis of carbazoquinocin C (3c) based on oxy-3-methyl-1,4-benzoquinone (7) in methanol at room
the palladium-catalyzed oxidative coupling of aniline (6) temperature provided 5-anilino-2-methoxy-3-methyl-1,4-
and 2-methoxy-3-methyl-1,4-benzoquinone (7).18 Al- benzoquinone (13) (Scheme 3). The observed regioselec-
though being not as convergent as the two alternative syn- tivity resulted from vinylogous addition of the amine to
theses depicted in Scheme 1,15,17 this approach to the the more reactive carbonyl group. In this reaction the sec-
natural product is currently the only one which is catalytic ond equivalent of 2-methoxy-3-methyl-1,4-benzoquinone
with respect to the transition metal. Moreover, the optimi- (7) was used for the oxidation of the initially formed anili-
zation of the second route is of more general importance nohydroquinone to the anilinobenzoquinone 13. There-
for the total synthesis of biologically active carbazole al- fore, one equivalent of 2-methoxy-3-methylhydroquinone
kaloids, since the same strategy has been applied previ- was generated during this process along with the desired
ously to the palladium-catalyzed total synthesis of product 13 (78% yield). After separation of the anili-
carbazomycin G,21 an antifungal carbazolequinol alkaloid nobenzoquinone 13 by crystallization, the 2-methoxy-3-
isolated by Nakamura and co-workers from Streptoverti- methylhydroquinone remaining in the mother-liquor was
cillium ehimense.22
reoxidized to 2-methoxy-3-methyl-1,4-benzoquinone (7)
with commercial 1,4-benzoquinone. The recycled 2-
methoxy-3-methyl-1,4-benzoquinone (7) was reacted
once again with aniline (6) to afford additional anili-
nobenzoquinone 13. Thus, the anilinobenzoquinone 13,
Total Synthesis
Our procedure for the preparation of 2-methoxy-3-meth- which represents the precursor for the intramolecular pal-
yl-1,4-benzoquinone (7)23 starts from commercial 2,6- ladium(II)-catalyzed oxidative coupling, could be ob-
dimethoxytoluene (9) (Scheme 2). It follows the first two tained in a total yield of 84%.
steps for the preparation of the precursor for the iron-me-
diated synthesis of carbazomycin G, in which a 2,3,6-tri-
oxygenated toluene has already been described.24
Scheme 3 Palladium(II)-catalyzed oxidative cyclization
The palladium-mediated oxidative cyclization of N,N-di-
arylamines described by Åkermark represents a highly ef-
ficient procedure for the synthesis of substituted
carbazoles.27 The application of this method to the oxida-
tive cyclization of 2-anilino-1,4-benzoquinones provided
carbazole-1,4-quinones and was reported first by Furuka-
wa and co-workers.28 However, the drawback of these in-
tramolecular palladium(II)-mediated oxidative couplings
is that stoichiometric amounts of palladium(II) were re-
quired because the final step is a reductive elimination
Scheme 2 Synthesis of 2-methoxy-3-methyl-1,4-benzoquinone (7)
which generates one equivalent of palladium(0). For the
development of an oxidative cyclization which is catalytic
The titanium tetrachloride promoted Friedel-Crafts acyla-
tion of 2,6-dimethoxytoluene (9) provided the acetophe-
none 10.25 Compound 10 was transformed to the aryl
acetate 11 by a proton-catalyzed Baeyer–Villiger oxida-
tion. Cleavage of the ester led to the phenol 12.26 Oxida-
tion of the phenol 12 with ceric ammonium nitrate (CAN)
in a mixture of acetonitrile and water at 0 °C afforded 2-
methoxy-3-methyl-1,4-benzoquinone (7).
with respect to the transition metal an in situ reoxidation
of palladium(0) to palladium(II) was required. In the well-
known Wacker process the reoxidation of palladium(0) is
achieved with copper(II).29 The feasibility to achieve a
palladium(II)-catalyzed oxidative cyclization by reoxida-
tion of palladium(0) with copper(II) was demonstrated
first in our earlier study describing the synthesis of ben-
zo[b]carbazole-6,11-diones.30,31 Åkermark and co-work-
Synthesis 2002, No. 4, 557–564 ISSN 0039-7881 © Thieme Stuttgart · New York

560
H.-J. Knölker et al.
FEATURE ARTICLE
ers subsequently reported the use of tert-butyl heptyl side chain at C-1. We expected the 1,2-addition at
hydroperoxide for the reoxidation of palladium(0).32
C-4 to be disfavored due to the more deactivating effect of
the vinylogous amide resonance contribution as compared
to the vinylogous ester resonance of the C-1 carbonyl
group. However, the addition of heptyllithium in tetrahy-
drofuran at –78 °C provided almost quantitatively a mix-
ture of the desired carbazolequinol 15 and 3-heptyl-2-
methylcarbazole-1,4-quinone 16 in a ratio of 1:2 along
with a trace of the regioisomeric carbazolequinol 17
(Scheme 4, Table 2). Surprisingly, the major product was
compound 16, resulting from a vinylogous addition of the
metal reagent followed by elimination of methoxide. By
changing to the corresponding Grignard reagent the car-
bazolequinol 15 became the major product with the best
result (55% yield) being obtained at –78 °C. The structur-
al assignment for the carbazolquinol 15 was based on
The oxidative cyclization of the anilinobenzoquinone 13
using stoichiometric amounts of palladium(II) acetate in
glacial acetic acid at reflux for 5 h under argon atmos-
phere provided the carbazole-1,4-quinone 14 in 83% yield
(Scheme 3, Table 1). When the reaction was performed
with 10 mol% of palladium(II) acetate in the presence of
an excess of copper(II) acetate (2.5 equiv) in the air, the
carbazole-1,4-quinone 14 was obtained in 71% yield after
a reaction time of 17 h. However, the reaction did not be-
come catalytic in copper(II). Decreasing the amount of
copper(II) acetate led at the same time to a decrease of the
yield of 14 down to a yield of only 24% with 25 mol% of
copper(II). These results show that in contrast to the
Wacker process mentioned above our oxidative cycliza-
tion under the reaction conditions applied in this study did
not become catalytic in copper(II). We then investigated
the variation of the amount of the palladium catalyst. Us-
ing 5 mol% of palladium(II) acetate provided the carba-
zole-1,4-quinone 14 in 56% yield. An increase of the
amount of palladium catalyst to 20 mol% led only to an in-
significant increase of the yield of 14 (73%), when the re-
action time was about the same as in the 10 mol%
experiment. However, we found that with 10 mol% of pal-
ladium(II) acetate the yield of the carbazole-1,4-quinone
14 could be increased to 78% by an extension of the reac-
tion time to 4 days. Finally, using 30 mol% of palladi-
um(II) acetate the oxidative cyclization of the
anilinobenzoquinone 13 provided the carbazole-1,4-
quinone 14 in 91% yield after a reaction time of 3 days.
1
comparison of its characteristic UV, H NMR, and 13C
NMR spectral data with those of synthetic21,24 as well as
natural22 carbazomycin G.
Table 1 Optimization of the Oxidative Cyclization to the Carba-
zole-1,4-quinone 14
Scheme 4 Regioselective introduction of the heptyl side chain
Pd(OAc)2 Cu(OAc)2 Time
Reaction
14, Yield
(equiv)
(equiv)
(h)
Conditions
(%)
1.0
–
5
HOAc, 117 °C, Ar
HOAc, 117 °C, air
HOAc, 117 °C, air
HOAc, 117 °C, air
HOAc, 117 °C, air
HOAc, 117 °C, air
HOAc, 117 °C, air
HOAc, 117 °C, air
HOAc, 117 °C, air
HOAc, 117 °C, air
83
71
69
54
24
56
56
73
78
91
Table 2 Results of the Nucleophilic Addition of the Heptylmetal
Reagents to the Carbazole-1,4-quinone 14
0.1
2.5
2.2
1.0
0.25
2.5
2.5
2.5
2.5
2.5
17
17
17
18
19
40
22
96
72
0.1
C7H15–met (equiv)
Reaction Conditions
Yield (%)
15
16
17
0.1
C7H15Li (7.5)
THF, –78 °C, 2 h
THF, –78 °C, 0.5 h;
then 25 °C, 17 h
THF, –78 °C, 3 h
33
66
trace
0.1
C7H15MgCl (10.5)
0.05
0.05
0.2
43
55
23
8
31
C7H15MgCl (15)
trace
0.1
Cleavage of the methyl ether along with elimination of
water was achieved by treatment of the carbazolequinol
15 with concentrated hydrogen bromide in methanol
(1:2.5) and provided carbazoquinocin C (3c) in 92% yield
(Scheme 5).
0.3
The next important step for the total synthesis of carbazo-
quinocin C (3c) was the regioselective introduction of the
Synthesis 2002, No. 4, 557–564 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of the Potent Lipid Peroxidation Inhibitor Carbazoquinocin C
561
zene (50 mL) was added within 10 min under vigorous stirring. Dur-
ing this addition the temperature was kept below 8 °C. After the
addition was completed, the orange solution was stirred for 30 min
at 0 °C. The reaction mixture was subsequently poured into cold
HCl (5%, 450 mL) and extracted with Et2O (3 100 mL). The com-
bined organic layers were washed with HCl (5%, 2 100 mL), a sat.
aq solution of NaHCO3 (2 100 mL), H2O (100 mL) and dried
(Na2SO4). After removal of the solvent the residue was distilled in
vacuo to provide the acetophenone 10 as a pale yellow oil (bp:
87 °C/0.02 Torr), which crystallized in the refrigerator overnight,
colorless crystals, yield: 18.9 g (95%), mp 35–36 °C (hexane)
(Lit.25 31–32 °C).
Scheme 5 Carbazole-1,4-quinol to carbazole-3,4-quinone conver-
sion
All spectral data described by Seto and co-workers for the
natural product (UV, IR, 1H NMR, and 13C NMR) are in
full agreement with those of our synthetic carbazoquino-
cin C (3c). The melting point for the carbazoquinocin C
(3c) from the present synthesis (mp: 227–228 °C from
MeOH/H2O) is in good agreement with the value obtained
by Hibino for his synthetic 3c (mp: 227–229 °C from
EtOAc).19 Whereas Seto reported a lower value for the
natural product (mp: 210–212 °C from MeOH/H2O),5
which was confirmed by the synthetic 3c from our iron-
mediated synthesis (mp: 211–212 °C from pyridine)17 and
by the synthetic 3c described by Pindur (mp: 212–213 °C
from MeOH).20 This difference may be explained by poly-
morphism.
IR (DRIFT): 2965, 1660, 1588, 1358, 1273, 1110, 1002, 822 cm–1.
1H NMR (400 MHz, CDCl3): = 2.16 (s, 3 H), 2.62 (s, 3 H), 3.75
(s, 3 H), 3.87 (s, 3 H), 6.68 (d, 1 H, J = 8.8 Hz), 7.62 (d, 1 H, J = 8.8
Hz).
13C NMR and DEPT (100 MHz, CDCl3): = 8.90 (CH3), 30.28
(CH3), 55.76 (CH3), 61.85 (CH3), 105.89 (CH), 120.20 (C), 125.53
(C), 128.98 (CH), 159.34 (C), 162.15 (C), 198.89 (C=O).
2,4-Dimethoxy-3-methylphenyl Acetate (11)
A solution of anhyd 3-chloroperbenzoic acid (70–75%, 49.2 g, 200
mmol) in CH2Cl2 (240 mL) was added over a period of 30 min to a
vigorously stirred solution of the acetophenone 10 (25.9 g, 133.3
mmol) and TsOH (200 mg) in CH2Cl2 (30 mL) at 0 °C. The result-
ing suspension was stirred for 30 min at 0 °C and for 4 h at r.t. Sub-
sequently, an aq solution of Na2SO3 (1 M, 100 mL) was added at
0 °C and the suspension stirred for 15 min at r.t. to destroy excess
peracid. After the addition of an aq solution of Na2CO3 (2 M, 100
mL) the suspension stirred for additional 15 min at r.t. The organic
layer was separated and the aq layer was extracted with CH2Cl2 (50
mL). The combined organic layers were washed with an aq solution
of Na2CO3 (10%, 100 mL), H2O (100 mL), and dried (Na2SO4).
Evaporation of the solvent and distillation of the residue in vacuo
afforded a yellow oil (bp: 84 °C/0.02 Torr), which became a yellow
solid (mp: 37–38 °C) in the refrigerator. A crystallization from hex-
ane–Et2O (5:1) at low temperature (–30 °C) provided the aryl ace-
tate 11 as colorless crystals, yield: 25.6 g (91%), mp 40–41 °C
(hexane–Et2O, 5:1).
Conclusion
The synthesis reported above provides carbazoquinocin C
(3c) in four steps and 39% overall yield based on aniline
(6). The crucial step of our approach is the intramolecular
palladium(II)-catalyzed oxidative coupling of the ani-
linobenzoquinone 13 to the carbazole-1,4-quinone 14
which was achieved in up to 91% yield. However, the best
result could be obtained only when using 30 mol% of the
palladium(II) catalyst and, in contrast to the Wacker oxi-
dation copper(II) could not be used in catalytic amounts.
These two facts emphasize that optimization is still re-
quired. The impact of the present work for the total syn-
thesis of biologically active carbazole alkaloids is even
broader than described, since the carbazole-1,4-quinone
14 could be applied to the synthesis of the other members
of the carbazoquinocin family and, it represents also a pre-
cursor for carbazomycin B and G.21
IR (DRIFT): 2965, 1758, 1486, 1228, 1210, 1108 cm–1.
1H NMR (250 MHz, CDCl3): = 2.15 (s, 3 H), 2.32 (s, 3 H), 3.74
(s, 3 H), 3.81 (s, 3 H), 6.60 (d, 1 H, J = 8.9 Hz), 6.86 (d, 1 H, J = 8.9
Hz).
13C NMR and DEPT (100 MHz, CDCl3): = 9.18 (CH3), 20.77
(CH3), 55.73 (CH3), 60.78 (CH3), 105.53 (CH), 119.68 (CH),
121.16 (C), 137.52 (C), 150.40 (C), 156.34 (C), 169.76 (C=O).
2,4-Dimethoxy-3-methylphenol (12)
A solution of KOH (16.6 g, 296 mmol) in H2O (20 mL) was added
at r.t. over a period of 10 min to a stirred solution of the aryl acetate
11 (15.6 g, 74.2 mmol) in EtOH (200 mL). With moderate warming
an orange-brown solution was formed, which was stirred at r.t. for
1 h. Then, H2O (80 mL) was added and the EtOH was evaporated in
vacuo. The aq layer was washed with Et2O (100 mL). The solution
of the phenolate was acidified with HCl (concd, about 21 mL) to pH
< 1 and extracted with Et2O (2 75 mL). The combined organic lay-
ers were washed with H2O (100 mL) and dried (Na2SO4). Removal
of the solvent and distillation of the residue in vacuo provided a red
oil (bp: 83–84 °C/0.35 Torr), which became a light orange solid in
the refrigerator, yield: 11.25 g (90%), mp 33–34 °C (Lit.26 32.5–
34 °C from pentane).
All reactions were carried out using dry solvents and under argon at-
mosphere unless otherwise stated. Flash chromatography: Merck
silica gel (0.03–0.06 mm). Mps: Büchi 535. UV spectra: Perkin–
Elmer Lambda 2 (UV/VIS spectrometer). IR spectra: Bruker IFS 88
1
(FT-IR). H NMR and 13C NMR spectra: Bruker AC-250, Bruker
AM-400, and Bruker DRX-500; internal standard: TMS or the sig-
nal of the deuterated solvent; in ppm; coupling constants (J) in Hz.
MS: Finnigan MAT-90; ionization potential: 70 eV. Elemental
analyses: Heraeus CHN-Rapid.
1-(2,4-Dimethoxy-3-methylphenyl)ethanone (10)
Acetyl chloride (14.5 mL, 16.0 g, 204 mmol) was added to TiCl4
(22.6 mL, 39.1 g, 206 mmol) at –10 °C (on moderate warming a yel-
low solution was formed). After the temperature had dropped again,
a solution of 2,6-dimethoxytoluene (9) (15.6 g, 102.5 mmol) in ben-
1H NMR (250 MHz, CDCl3): = 2.17 (s, 3 H), 3.77 (s, 6 H), 5.40
(br s, 1 H), 6.53 (d, 1 H, J = 8.8 Hz), 6.75 (d, 1 H, J = 8.8 Hz).
Synthesis 2002, No. 4, 557–564 ISSN 0039-7881 © Thieme Stuttgart · New York

562
H.-J. Knölker et al.
FEATURE ARTICLE
2-Methoxy-3-methyl-1,4-benzoquinone (7)
zole-1,4-quinone (14) as dark green crystals, yield: 751 mg (91%),
A solution of CAN (8.22 g, 15.0 mmol) in H2O (10 mL) was added
via a syringe pump over a period of 20 min to a stirred solution of
the phenol 12 (1.01 g, 6.01 mmol) in MeCN (10 mL) at 0 °C. After
stirring for additional 10 min at 0 °C, H2O (50 mL) was added and
the aq layer was extracted with Et2O (3 20 mL). The combined or-
mp 248–256 °C (dec.).
UV (MeOH): max = 193, 225, 257, 307, 384 nm.
IR (DRIFT): 3261 (br), 1640, 1619, 1534, 1300, 1104, 746, 740
cm–1.
1H NMR (400 MHz, DMSO-d6): = 1.90 (s, 3 H), 4.03 (s, 3 H),
7.28–7.38 (m, 2 H), 7.52 (d, 1 H, J = 7.8 Hz), 8.00 (d, 1 H, J = 7.5
Hz), 12.84 (br s, 1 H).
13C NMR and DEPT (100 MHz, DMSO-d6): = 8.40 (CH3), 60.97
(CH3), 113.56 (C), 113.78 (CH), 121.36 (CH), 123.39 (C), 123.73
(CH), 125.83 (CH), 126.24 (C), 135.98 (C), 137.47 (C), 157.59 (C),
178.32 (C=O), 180.45 (C=O).
ganic layers were washed with H2O (2
20 mL) and dried
(Na2SO4). Evaporation of the solvent afforded a yellow oil which by
a cycle of freeze in liquid nitrogen and thaw in vacuum (30 min)
provided 2-methoxy-3-methyl-1,4-benzoquinone (7) as a yellow
solid, yield: 820 mg (90%), mp 31–33 °C (Lit.23 29–30 °C).
1H NMR (250 MHz, CDCl3): = 1.96 (s, 3 H), 4.03 (s, 3 H), 6.61
(d, 1 H, J = 10.0 Hz), 6.70 (d, 1 H, J = 10.0 Hz).
MS (85 °C): m/z (%) = 241 (M+, 100), 240 (19), 226 (9), 212 (12),
198 (10), 170 (12).
HRMS: m/z [M+] calcd for C14H11NO3: 241.0739; found: 241.0727.
5-Anilino-2-methoxy-3-methyl-1,4-benzoquinone (13)
A solution of aniline (6) (1.33 g, 14.3 mmol) in MeOH (4 mL) was
added dropwise over a period of 5 min to a solution of 2-methoxy-
3-methyl-1,4-benzoquinone (7) (4.36 g, 28.7 mmol) in MeOH (14
mL). The resulting red-brown solution was stirred for 1 h at r.t. and
a brown-violet precipitate was formed. Subsequently, the reaction
mixture was diluted with MeOH (22 mL), heated at reflux to dis-
solve the solid then cooled to –30 °C. The precipitate was isolated
by filtration, washed with dry ice-cooled MeOH (5 10 mL) and
dried in vacuo to provide 5-anilino-2-methoxy-3-methyl-1,4-ben-
zoquinone (13) as brown-violet crystals, yield: 2.71 g (78%).
Anal. Calcd for C14H11NO3: C, 69.70; H, 4.60; N, 5.81. Found: C,
69.42; H, 4.76; N, 6.11.
1,4-Dihydro-1-heptyl-1-hydroxy-3-methoxy-2-methyl-9H-
carbazol-4-one (15)
3-Heptyl-2-methyl-9H-carbazole-1,4-quinone (16)
1,4-Dihydro-4-heptyl-4-hydroxy-3-methoxy-2-methyl-9H-
carbazol-1-one (17)
a) A solution of heptylmagnesium chloride in Et2O (1.6 M, 1.35
mL, 2.16 mmol) was added dropwise to a stirred solution of the car-
bazolequinone 14 (50 mg, 0.205 mmol) in THF (10 mL) at –78 °C.
After stirring for 30 min at –78 °C the resulting black colored reac-
tion mixture was allowed to warm up to r.t. and the stirring was con-
tinued for 17 h. The mixture was poured into a sat. aq solution of
NH4Cl (25 mL) and extracted with Et2O (3 25 mL). The combined
organic layers were washed with H2O (25 mL) and dried (Na2SO4).
Evaporation of the solvent in vacuo and flash chromatography of
the residue on silica gel (hexane–EtOAc, 1.5:1) afforded in the se-
quence of increasing polarity the compounds 16 as red crystals,
yield: 15 mg (23%), 17 as a light yellow powder, yield: 22.3 mg
(31%), and 15 as light yellow crystals, yield: 30.4 mg (43%).
1,4-Benzoquinone (1.40 g, 13.0 mmol) was added to the filtrate and
after 15 min of stirring at r.t. aniline (6) (0.61 g, 6.5 mmol) was add-
ed dropwise. The solution was stirred for 1 h at r.t. On concentration
in vacuo to a volume of about 50 mL, a brown-violet precipitate was
formed. The mixture was cooled to –30 °C, the precipitate was iso-
lated by filtration, washed with dry ice-cooled MeOH (4 10 mL),
recrystallized from MeOH, and dried in vacuo to afford additional
5-anilino-2-methoxy-3-methyl-1,4-benzoquinone (13) as brown-vi-
olet crystals, yield: 1.54 g (97%).
Total yield of 13: 4.25 g [84%, based on 20.8 mmol of aniline (6)],
mp: 151–152 °C (MeOH).
UV (MeOH): max = 192, 203, 259, 277 (sh), 321, 510 nm.
IR (DRIFT): 313, 2951, 1653, 1635, 1595, 1528, 1449, 1352, 1283,
1223, 1164, 1001, 985, 837, 816, 785, 749, 725, 687, 644 cm–1.
1H NMR (500 MHz, CDCl3): = 1.96 (s, 3 H), 4.14 (s, 3 H), 5.97
(s, 1 H), 7.17–7.21 (m, 3 H), 7.39 (m, 2 H), 7.51 (br s, 1 H).
13C NMR and DEPT (125 MHz, CDCl3): = 8.49 (CH3), 61.51
(CH3), 98.70 (CH), 122.22 (2 CH), 123.02 (C), 125.43 (CH),
129.63 (2 CH), 137.58 (C), 143.07 (C), 157.81 (C), 182.57 (C=O),
184.37 (C=O).
b) A solution of heptylmagnesium chloride in Et2O (1.6 M, 1.92
mL, 3.07 mmol) was added at once to a stirred solution of the car-
bazolequinone 14 (50 mg, 0.205 mmol) in THF (10 mL) at –78 °C.
After stirring at –78 °C for 3 h, the mixture was poured into a sat.
aq solution of NH4Cl (25 mL) and extracted with Et2O (3 25 mL).
The combined organic layers were washed with H2O (25 mL) and
dried (Na2SO4). Removal of the solvent and flash chromatography
of the residue on silica gel (hexane–EtOAc, 1.5:1) afforded in the
sequence of increasing polarity the compounds 16 as red crystals,
yield: 4.9 mg (8%), 17 as a trace, and 15 as light yellow crystals,
yield: 38.4 mg (55%).
MS (65 °C): m/z (%) = 243 (M+, 100), 242 (17), 214 (12), 184 (11),
144 (29), 83 (12), 77 (13).
HRMS: m/z [M+] calcd for C14H13NO3 : 243.0895; found: 243.0908.
1,4-Dihydro-1-heptyl-1-hydroxy-3-methoxy-2-methyl-9H-
carbazol-4-one (15)
Light yellow crystals, mp 174–176 °C (hexane–EtOAc).
Anal. Calcd for C14H13NO3: C, 69.12; H, 5.39; N, 5.76. Found: C,
69.15; H, 5.57; N, 5.40.
UV (MeOH): max = 212, 253, 271, 277, 342 nm.
3-Methoxy-2-methyl-9H-carbazole-1,4-quinone (14)
A
mixture of 5-anilino-2-methoxy-3-methyl-1,4-benzoquinone
IR (DRIFT): 3186, 2928, 2857, 1640, 1619, 1499, 1475, 1454,
1403, 1377, 1322, 1298, 1186, 1152, 1137, 1122, 1103, 1051, 1012,
880, 806, 744 cm–1.
1H NMR (500 MHz, CDCl3): = 0.59 (m, 1 H), 0.76 (t, 3 H, J = 7.2
Hz), 0.86 (m, 1 H), 1.05–1.16 (m, 8 H), 2.02 (s, 3 H), 2.04 (dt, 1 H,
J = 4.7, 12.6 Hz), 2.13 (dt, 1 H, J = 4.7, 12.6 Hz), 3.71 (s, 3 H), 4.25
(br s, 1 H), 7.08 (br t, 1 H, J = 7.5 Hz), 7.13 (dt, 1 H, J = 1.1, 7.5
Hz), 7.30 (d, 1 H, J = 7.5 Hz), 7.93 (d, 1 H, J = 7.5 Hz), 9.80 (br s,
1 H).
(13) (836 mg, 3.44 mmol), Pd(OAc)2 (250 mg, 1.11 mmol), and
Cu(OAc)2 (1.56 g, 8.56 mmol) in glacial HOAc (40 mL) was heated
at reflux in the air for 3 d. Then silica gel (2 g) was added to the re-
action mixture and the HOAc was removed in vacuo. The residue
was subjected to chromatography (CH2Cl2–EtOAc, 6:1) on silica
gel. After removal of the eluent, the residue was dissolved in CHCl3
(20 mL) by heating at reflux. Crystallization at –30 °C afforded a
green solid, which was washed with a small portion of CHCl3 and
dried in vacuo. Recrystallization from EtOAc provided the carba-
13C NMR and DEPT (125 MHz, CDCl3): = 10.05 (CH3), 13.97
(CH3), 22.47 (CH2), 23.46 (CH2), 28.88 (CH2), 29.24 (CH2), 31.61
Synthesis 2002, No. 4, 557–564 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of the Potent Lipid Peroxidation Inhibitor Carbazoquinocin C
563
(CH2), 40.22 (CH2), 60.14 (CH3), 71.90 (C), 111.46 (C), 111.60
(CH), 121.18 (CH), 122.33 (CH), 123.75 (CH, C), 136.31 (C),
139.57 (C), 149.91 (C), 152.13 (C), 179.04 (C=O).
(92%), mp 227–228 °C (MeOH–H2O) (Lit.6 210–212 °C from
MeOH–H2O; Lit.17 mp 211–212 °C from pyridine; Lit.19 227–
229 °C from EtOAc; Lit.20 212–213 °C from MeOH).
MS (125 °C): m/z (%) = 341 (M+, 14), 325 (4), 310 (4), 242 (100),
UV (MeOH): max = 228, 265, 401 nm.
199 (6).
IR (DRIFT): 3216, 2927, 2856, 1640, 1627, 1467, 1249, 752 cm–1.
HRMS: m/z [M+] calcd for C21H27NO3: 341.1991; found: 341.1973.
1H NMR (500 MHz, DMSO-d6): = 0.85 (t, 3 H, J = 6.8 Hz), 1.24–
1.34 (m, 6H), 1.44 (m, 2 H), 1.54 (m, 2 H), 1.89 (s, 3 H), 2.64 (t, 2
H, J = 7.8 Hz), 7.23 (m, 2 H), 7.49–7.51 (m, 1 H), 7.84–7.86 (m, 1
H), 12.32 (br s, 1 H).
Anal. Calcd for C21H27NO3: C, 73.87; H, 7.97; N, 4.10. Found: C,
73.53; H, 7.90; N, 4.06.
3-Heptyl-2-methyl-9H-carbazole-1,4-quinone (16)
Red crystals, mp 161–163 °C (hexane–EtOAc).
13C NMR and DEPT (125 MHz, DMSO-d6): = 11.45 (CH3), 13.94
(CH3), 22.06 (CH2), 28.06 (CH2), 28.52 (CH2), 28.62 (CH2), 29.00
(CH2), 31.25 (CH2), 111.04 (C), 113.37 (CH), 120.26 (CH), 123.95
(CH), 124.17 (CH), 125.66 (C), 133.10 (C), 137.06 (C), 142.12 (C),
145.62 (C), 172.71 (C=O), 183.46 (C=O).
MS (180 °C): m/z (%) = 311 (M+ + 2, 85), 310 (M+ + 1, 18), 309
(M+, 31), 281 (67), 238 (9), 226 (100), 225 (23), 197 (23), 196 (21),
168 (9), 167 (11).
UV (MeOH): max = 191, 193, 224, 256, 298, 388 nm.
IR (DRIFT): 3275, 3062, 2924, 2857, 1638, 1509, 1432, 1330,
1238, 1154, 1079, 885, 822, 748, 735, 685 cm–1.
1H NMR (500 MHz, CDCl3): = 0.88 (t, 3 H, J = 7.0 Hz), 1.26–
1.50 (m, 10 H), 2.12 (s, 3 H), 2.59 (m, 2 H), 7.32 (br t, 1 H, J = 8.0
Hz), 7.39 (dt, 1 H, J = 7.1, 1.0 Hz), 7.50 (br d, 1 H, J = 8.3 Hz), 8.22
(d, 1 H, J = 8.0 Hz), 9.83 (br s, 1 H).
HRMS: m/z [M+] calcd for C20H23NO2: 309.1729; found: 309.1698.
13C NMR and DEPT (125 MHz, CDCl3): = 11.66 (CH3), 14.11
(CH3), 22.66 (CH2), 26.87 (CH2), 29.16 (2 CH2), 30.04 (CH2), 31.81
(CH2), 112.84 (CH), 116.75 (C), 123.03 (CH), 124.08 (CH), 124.36
(C), 126.86 (CH), 135.17 (C), 137.24 (C), 138.39 (C), 145.63 (C),
181.23 (C=O), 183.25 (C=O).
Acknowledgement
We are grateful to the Fonds der Chemischen Industrie and the
Alexander von Humboldt Stiftung for the financial support of our
project.
MS (105 °C): m/z (%) = 309 (M+, 45), 294 (3), 266 (5), 225 (100),
196 (9).
HRMS: m/z [M+] calcd for C20H23NO2: 309.1729; found: 309.1719.
References
Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C,
77.35; H, 7.20; N, 4.53.
(1) Part 6: Knölker, H.-J.; Reddy, K. R. Synlett 1999, 596.
(2) (a) Hammond, B.; Kantos, H. A.; Hess, M. L. Can. J.
Physiol. Pharmacol. 1985, 63, 173. (b) Cerutti, P. A.
Science 1985, 227, 375. (c) Halliwell, B.; Gutteridge, J. M.
C. Method in Enzymology 1990, 186, 1.
1,4-Dihydro-4-heptyl-4-hydroxy-3-methoxy-2-methyl-9H-
carbazol-1-one (17)
Light yellow powder, mp 156–158 °C (hexane–EtOAc).
(3) Shin-ya, K.; Tanaka, M.; Furihata, K.; Hayakawa, Y.; Seto,
H. Tetrahedron Lett. 1993, 34, 4943.
UV (MeOH): max = 218, 249, 334 nm.
(4) Shin-ya, K.; Shimizu, S.; Kunigami, T.; Furihata, K.;
Furihata, K.; Seto, H. J. Antibiot. 1995, 48, 574.
(5) Tanaka, M.; Shin-ya, K.; Furihata, K.; Seto, H. J. Antibiot.
1995, 48, 326.
IR (DRIFT): 3270, 3080, 2925, 1636, 1619, 1556, 1390, 1334,
1297, 1133, 1008, 744, 683 cm–1.
1H NMR (500 MHz, CDCl3): = 0.60 (m, 1 H), 0.77 (t, 3 H, J = 7.2
Hz), 0.90 (m, 1 H), 1.04–1.17 (m, 8 H), 2.03 (s, 3 H), 2.25 (dt, 1 H,
J = 4.9, 12.3 Hz), 2.32 (dt, 1 H, J = 4.9, 12.3 Hz), 2.68 (br s, 1 H),
4.07 (s, 3 H), 7.18 (dd, 1 H, J = 7.1, 0.9 Hz), 7.36 (dd, 1 H, J = 7.1,
1.0 Hz), 7.48 (br d, 1 H, J = 8.4 Hz), 7.91 (br d, 1 H, J = 8.1 Hz),
9.46 (br s, 1 H).
13C NMR and DEPT (125 MHz, CDCl3): = 9.14 (CH3), 13.99
(CH3), 22.51 (CH2), 24.31 (CH2), 28.92 (CH2), 29.34 (CH2), 31.64
(CH2), 39.81 (CH2), 61.91 (CH3), 74.75 (C), 112.79 (CH), 119.93
(C), 120.82 (CH), 122.03 (CH), 124.03 (C), 124.58 (C), 125.92
(CH), 130.09 (C), 137.93 (C), 172.94 (C), 180.92 (C=O).
(6) (a) Chakraborty, D. P. In Prog. Chem. Org. Nat. Prod., Vol.
34; Herz, W.; Grisebach, H.; Kirby, G. W., Eds.; Springer:
Wien, 1977, 299. (b) Bhattacharyya, P.; Chakraborty, D. P.
In Progress in the Chemistry of Organic Natural Products,
Vol. 52; Herz, W.; Grisebach, H.; Kirby, G. W., Eds.;
Springer: Wien, 1987, 159. (c) Chakraborty, D. P.; Roy, S.
In Progress in the Chemistry of Organic Natural Products,
Vol. 57; Herz, W.; Grisebach, H.; Kirby, G. W.; Tamm, C.,
Eds.; Springer: Wien, 1991, 71. (d) Chakraborty, D. P. In
The Alkaloids, Vol. 44; Cordell, G. A., Ed.; Academic Press:
New York, 1993, 257.
(7) Furukawa, H. J. Indian Chem. Soc. 1994, 71, 303.
(8) (a) Pindur, U. Heterocycles 1988, 27, 1253. (b) Pindur, U.
Chimia 1990, 44, 406. (c) Pindur, U.; Rogge, M. Chimia
1992, 46, 441. (d) Pindur, U. In Advances in Nitrogen
Heterocycles, Vol. 1; Moody, C. J., Ed.; JAI Press:
Greenwich (CT), 1995, 121.
MS (115 °C): m/z (%) = 341 (M+, 9), 243 (12), 242 (100), 227 (6).
HRMS: m/z [M+] calcd for C21H27NO3: 341.1991. Found: 341.1976.
Anal. Calcd for C21H27NO3: C, 73.87; H, 7.97; N, 4.10. Found: C,
73.48; H,7.37; N, 4.32.
Carbazoquinocin C (1-Heptyl-2-methyl-9H-carbazole-3,4-
quinone) (3c)
(9) Bergman, J.; Pelcman, B. Pure Appl. Chem. 1990, 62, 1967.
(10) Moody, C. J. Synlett 1994, 681.
(11) (a) Kawasaki, T.; Sakamoto, M. J. Indian Chem. Soc. 1994,
71, 443. (b) Hibino, S.; Sugino, E. In Advances in Nitrogen
Heterocycles, Vol. 1; Moody, C. J., Ed.; JAI Press:
Greenwich (CT), 1995, 205.
HBr (48%, 0.4 mL) was added dropwise to a stirred solution of the
carbazolequinol 15 (25 mg, 0.073 mmol) in MeOH (1 mL) at r.t.
During the addition a greenish black precipitate was formed. The
mixture was stirred at r.t. for 45 min. The precipitate was isolated
by filtration, washed with H2O, and dried in vacuum to afford car-
bazoquinocin C (3c) as a greenish black powder, yield: 20.8 mg
Synthesis 2002, No. 4, 557–564 ISSN 0039-7881 © Thieme Stuttgart · New York

564
H.-J. Knölker et al.
FEATURE ARTICLE
(12) (a) Knölker, H.-J. In 40 Jahre Fonds der Chemischen
Industrie 1950-1990; Verband der Chemischen Industrie,
Ed: Frankfurt, 1990, 219. (b) Knölker, H.-J. In Organic
Synthesis via Organometallics; Dötz, K. H.; Hoffmann, R.
W., Eds.; Vieweg: Braunschweig, 1991, 119. (c) Knölker,
H.-J. Synlett 1992, 371. (d) Knölker, H.-J. In Advances in
Nitrogen Heterocycles, Vol. 1; Moody, C. J., Ed.; JAI Press:
Greenwich (CT), 1995, 173. (e) Knölker, H.-J. In
Transition Metals for Organic Synthesis, Vol. 1; Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998, 534.
(f) Knölker, H.-J. Chem. Soc. Rev. 1999, 28, 151.
(g) Knölker, H.-J.; Braier, A.; Bröcher, D. J.; Cämmerer, S.;
Fröhner, W.; Gonser, P.; Hermann, H.; Herzberg, D.; Reddy,
K. R.; Rohde, G. Pure Appl. Chem. 2001, 73, 1075.
(13) (a) Knölker, H.-J.; Fröhner, W. Synlett 1997, 1108.
(b) Knölker, H.-J.; Baum, E.; Reddy, K. R. Tetrahedron Lett.
2000, 41, 1171.
(14) (a) Knölker, H.-J.; Fröhner, W. Tetrahedron Lett. 1998, 39,
2537. (b) Knölker, H.-J.; Baum, E.; Reddy, K. R. Chirality
2000, 12, 526.
(15) Knölker, H.-J.; Reddy, K. R. Synlett 1999, 596.
(16) Shin, K.; Ogasawara, K. Synlett 1996, 922.
(17) Knölker, H.-J.; Fröhner, W. Tetrahedron Lett. 1997, 38,
1535.
(24) Knölker, H.-J.; Fröhner, W. Tetrahedron Lett. 1997, 38,
4051.
(25) Crump, D. R.; Franck, R. W.; Gruska, R.; Ozorio, A. A.;
Pagnotta, M.; Siuta, G. J.; White, J. G. J. Org. Chem. 1977,
42, 105.
(26) Godfrey, I. M.; Sargent, M. V.; Elix, J. A. J. Chem. Soc.,
Perkin Trans. 1 1974, 1353.
(27) (a) Åkermark, B.; Eberson, L.; Jonsson, E.; Petersson, E. J.
Org. Chem. 1975, 40, 1365. (b) Miller, R. B.; Moock, T.
Tetrahedron Lett. 1980, 21, 3319. (c) Ames, D. E.; Opalko,
A. Tetrahedron 1984, 40, 1919. (d) Furukawa, H.; Ito, C.;
Yogo, M.; Wu, T.-S. Chem. Pharm. Bull. 1986, 34, 2672.
(e) Hall, R. J.; Marchant, J.; Olivaira-Campos, A. M. F.;
Queiroz, M.-J. R. P.; Shannon, P. V. R. J. Chem. Soc.,
Perkin Trans. 1 1992, 3439.
(28) (a) Furukawa, H.; Yogo, M.; Ito, C.; Wu, T.-S.; Kuoh, C.-S.
Chem. Pharm. Bull. 1985, 33, 1320. (b) Yogo, M.; Ito, C.;
Furukawa, H. Chem. Pharm. Bull. 1991, 39, 328.
(c) Bittner, S.; Krief, P.; Massil, T. Synthesis 1991, 215.
(29) (a) Tsuji, J. Palladium Reagents and Catalysts – Innovations
in Organic Synthesis, Chap. 3; Wiley: Chichester, 1995.
(b) Omae, I. Applications of Organometallic Compounds,
Chap. 20.6; Wiley: Chichester, 1998.
(30) (a) Knölker, H.-J.; O’Sullivan, N. Tetrahedron Lett. 1994,
35, 1695. (b) Knölker, H.-J.; O’Sullivan, N. Tetrahedron
1994, 50, 10893.
(18) Knölker, H.-J.; Reddy, K. R.; Wagner, A. Tetrahedron Lett.
1998, 39, 8267.
(19) Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama, C.; Sugino,
E.; Hibino, S. J. Org. Chem. 1997, 62, 2535.
(20) Aygün, A.; Pindur, U. Synlett 2000, 1757.
(21) Knölker, H.-J.; Fröhner, W. J. Chem. Soc., Perkin Trans. 1
1998, 173.
(22) Kaneda, M.; Naid, T.; Kitahara, T.; Nakamura, S.; Hirata, T.;
Suga, T. J. Antibiot. 1988, 41, 602.
(23) Luly, J. R.; Rapoport, H. J. Org. Chem. 1981, 46, 2745.
(31) (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry – A Guide for the Synthetic Chemist, Chap. 1.1;
Pergamon: Oxford, 2000. (b) Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry – A Guide for the
Synthetic Chemist, Chap. 3.2; Pergamon: Oxford, 2000.
(32) (a) Åkermark, B.; Oslob, J. D.; Heuschert, U. Tetrahedron
Lett. 1995, 36, 1325. (b) Hagelin, H.; Oslob, J. D.;
Åkermark, B. Chem.– Eur. J. 1999, 5, 2413.
Synthesis 2002, No. 4, 557–564 ISSN 0039-7881 © Thieme Stuttgart · New York