From phenylacetylphenylacetic acids to indoles: A simple new divergent synthesis of 6,11-dihydro-5H-benzo[a]carbazol-5,6-diones and 6,11-dihydro-5H-benzo[b]carbazol-6,11-diones

Article abstract of DOI:10.1016/S0040-4020(02)00192-8

The synthesis 6,11-dihydro-5H-benzo[a]carbazole-5,6-diones and 6,11-dihydro-5H-benzo[b]carbazole-6,11-diones from common starting materials, 1-(2′-nitrophenylacetyl)phenylacetic acids is described.

Full text of DOI:10.1016/S0040-4020(02)00192-8

TETRAHEDRON
Pergamon
Tetrahedron 58 .2002) 3015±3019
From phenylacetylphenylacetic acids to indoles: a simple new
divergent synthesis of 6,11-dihydro-5H-benzo[a]carbazol-5,6-
diones and 6,11-dihydro-5H-benzo[b]carbazol-6,11-diones
   Â
Jacobo Cruces, Elena Martõnez, Monica Treus, Luis A. Martõnez, Juan C. Estevez,
p
Ramon J. Estevez and Luis Castedo
Â
Â
 Â
Departamento de Quõmica Organica e Unidade Asociada ꢀC.S.I.C.), Universidade de Santiago de Compostela,
15706 Santiago de Compostela, Spain
Received 17 May 2001; revised 21 January 2002; accepted 21 February 2002
AbstractÐThe synthesis 6,11-dihydro-5H-benzo[a]carbazole-5,6-diones and 6,11-dihydro-5H-benzo[b]carbazole-6,11-diones from
common starting materials, 1-.20-nitrophenylacetyl)phenylacetic acids is described. q 2002 Elsevier Science Ltd. All rights reserved.
Numerous methods have been developed for the synthesis
of indoles due to the importance of compounds that incor-
porate the indole subunit. However, the search for new
methods for the simple and ef®cient construction of the
indole ring system continues to be an important synthetic
goal.1 Of particular interest are methods for the synthesis of
polycyclic indoles, including benzo- or pyrido-fused
carbazoles, because of their potential in the development
of antitumor agents.2 Antineoplastic activity in these
compounds has been attributed3 to their ring systems,
which contain an embedded 2-phenylnaphthalene-like
structure in a planar conformation. Interesting examples
are benzo[a]carbazoles which, besides having industrial
applications as colorants,4 are known carcinogens with anti-
arrhythmic, antimicrobial and antitumoral activity,5 and are
also related to indolo[2,3-a]quinolizine alkaloids.6
Benzo[b]carbazoles7 are closely related to pyrido[b]carba-
zoles,2b which have well documented antitumour properties,
and examples include elliptinium, a compound used for
treatment of thyroid, breast and kidney cancer. Neverthe-
less, oxidized derivatives like benzo[a]carbazolequinones 1
.Scheme 1) have received very little attention to date and, in
the course of our studies on these compounds, only one
recent synthesis has been described.8 In contrast, benzo[b]-
carbazolequinones 2 have been the object of great synthetic
interest in the past decade because they were related to the
kynamicin family of antibiotics.9 The antitumour activity of
these compounds has also been established.10
Scheme 1. Retrosynthetic scheme for the syntheses of benzo[a]carbazolequinones and benzo[b]carbazolequinones.
Keywords: carbazolequinone; indole; phenylacetylphenylacetic acid.
Corresponding author. Tel.: 134-981-563100x14242; fax: 134-981-591014; e-mail: qorjec@usc.es
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020.02)00192-8

3016
J. Cruces et al. / Tetrahedron 58 ꢀ2002) 3015±3019
We describe here a single and ef®cient divergent synthesis
of benzo[a]carbazolequinones and benzo[b]carbazole-
quinones from readily available phenylacetylphenylacetic
acids, a class of compounds previously used by ourselves11
and others12 for the ef®cient syntheses of a variety of
compounds, including isoquinolines and related
compounds, benzo[b]naphtho[2,1-d]furans and benzo[a]-
carbazoles.
atmosphere for 24 h in order to oxidize the hydroquinone
6a to the aminophenylnaphthoquinone 3a. This reaction
gave two new isomeric compounds, 1a and 2a, of molecular
formula C20H17NO6 .as deduced by microanalysis and mass
spectrometry). The two isomers could result from amino-
phenylnaphthoquinone 3a by spontaneous attack of the
amino group on the naphthoquinone system. The direct
amino-carbonyl condensation would led to indolonaphtho-
quinone 1a. The alternative conjugate addition of the amino
group to the quinone system and subsequent dehydration
would furnish indolonaphthoquinone 2a.
Retrosynthetic considerations suggested that benzo[a]- and
benzo[b]carbazolequinones might be obtained from amino-
phenylhydroxynaphthoquinones 3 .by linking the amino to
positions 1 and 3, respectively), and that aminophenyl-
hydroxynaphthoquinones 3 should be readily available
from nitrophenylacetylphenylacetic acids 4.
1
The H NMR spectra of these two compounds are very
similar, with the major component showing three singlets
at 7.28, 7.63 and 7.82 ppm, corresponding to four aromatic
protons, and a singlet at 12.81 ppm, corresponding to the
N±H proton; the minor component shows three singlets at
6.93, 7.50 and 7.52ppm, due to the four aromatic protons,
and a singlet at 12.79 ppm, corresponding to the N±H
proton. Further evidence for the structural assignment was
provided by the IR spectra. The o-quinone 1a presented two
carbonyl bands at 1668 and 1618 cm21, and for the isomeric
p-quinone 2a, a typical stretching band for the p-quinone
system at 1642cm 21 was observed.
Accordingly, we studied the transformation of nitroketo-
acids 4 into benzo[a]carbazolequinone 1a and benzo[b]car-
bazolequinones 2a and 2b .Scheme 2). Nitroketoester 4a
was easily prepared by nitration of the corresponding keto-
acid13 followed by esteri®cation upon treatment with metha-
nol containing a few drops of concentrated sulfuric acid.
Treatment of the nitroketoester 4a with 15% aqueous potas-
sium hydroxide in re¯uxing ethanol for 30 min afforded
nitrophenylhydroxynaphthoquinone 5a in 98% yield, prob-
ably by a mixed intramolecular Claisen condensation
followed by oxidation of the dinaphthol intermediate in
the reaction medium.
The structure proposed for compound 1a was con®rmed by
direct comparison with a sample of this compound obtained
by oxidation of benzo[a]carbazole 7a, previously prepared
by us11f from nitroketoester 4a .Scheme 2). On the other
hand, when indolonaphthoquinone 2a was treated with
NaH and MeI in dry DMF, the N-methylindolonaphtho-
quinone 8a was obtained in 98% yield .Scheme 2). The
availability of the N-methyl indole 8a, which proved to be
more soluble than the indoles 1a and 2a, prompted us to
obtain further con®rmation of the structural assignment by
A solution of 5a in ethyl acetate was subjected to catalytic
hydrogenation at room temperature, using PtO2 as the
catalyst, and reduction of the nitro group to the amino was
achieved along with reduction of the quinone system to give
the aminophenyltrinaphthol 6a, which was not isolated. The
reaction mixture was heated under re¯ux in an air
Scheme 2. .i) KOH, EtOH, re¯ux, 30 min. .ii) .a) H2 .1 atm), PtO2, AcOEt, room temperature, 1 h; .b) air, re¯ux, 23 h. .iii) NaBH4, i-PrOH. .iv) NaOH, O2,
room temperature, 96 h. .v) NaH, MeI, DMF, room temperature, 1 h.

J. Cruces et al. / Tetrahedron 58 ꢀ2002) 3015±3019
3017
synthesis of antitumoral ellipticines.6b,14 In addition, we
believe that it will not prove dif®cult to extend this method
to other classes of biologically interesting compounds such
as indeneindoles, compounds that are inhibitors of patho-
genic radical chain reactions resulting in them possessing
potent antioxidant properties.15
1. Experimental
1.1. General
Figure 1. Important 1H±13C couplings observed in the HMBC experiment.
means of nOe, HMQC and HMBC correlation experiments
.Fig. 1). Irradiation of the N-methyl group of 8a at d 4.18
showed an nOe enhancement at 6.73 ppm for only one
aromatic proton. In addition, the HMBC experiment showed
correlations between d 7.57 .H7) and 177.52.C6), and
between d 7.61 .H10) and 181.14 .C11). These results
allowed us to con®rm the structure proposed for benzo[b]-
carbazole-6,11-dione 2a.
Melting points were determined on a Ko¯er Thermogerate
apparatus and are uncorrected. Infrared spectra were
recorded on a MIDAC FTIR spectrophotometer. Nuclear
magnetic resonance spectra were recorded on a Bruker
WM-250 apparatus, using deuterochloroform solutions
containing tetramethylsilane as an internal standard. Mass
spectra were obtained on a Kratos MS 50 TC mass spectro-
meter. Thin layer chromatography .tlc) was performed
using Merck GF-254 type 60 silica gel and CH2Cl2/MeOH
mixtures as eluents; the tlc spots were visualized with ultra-
violet light or iodine vapour. Column chromatography was
carried out using Merck type 9385 silica gel. Solvents were
puri®ed as per Ref. 16.
The next part of this study involved ®nding the best condi-
tions for the selective transformation of nitrophenyl-
naphthoquinones 5 into benzo[b]carbazolequinones 2 as
the conditions described above allowed the formation of
1a as the major product. In this respect, we found that treat-
ment of nitrophenylnaphthoquinone 5a with NaBH4 in
isopropanol at room temperature for 4 h led exclusively to
the benzo[b]carbazolequinone 2a in 99% yield. It is possible
that these new conditions prevent the reduction of the
quinone system, thus allowing selective reduction of the
nitro group to the amino group and spontaneous regio-
selective conjugate addition of the amino group to the
quinone system.
1.1.1. Methyl 2-[2-+4,5-dimethoxy-2-nitrophenyl)acetyl]-
4,5-dimethoxyphenylacetate +4a). 2-[2-.4,5-Dimethoxy-2-
nitrophenyl)acetyl]-4,5-dimethoxyphenylacetic acid13 .2g,
4.75 mmol) was dissolved in 110 mL of methanol and 1 mL
of concentrated H2SO4 was added. The mixture was heated
under re¯ux for 2.5 h and the methanol was then evaporated
in vacuo. The residue was suspended in water .100 mL) and
extracted with dichloromethane .3£25 mL). The combined
organic layers were dried with anhydrous sodium sulfate,
®ltered and the solvent removed in vacuo to give methyl
2-[2-.4,5-dimethoxy-2-nitrophenyl)acetyl]-4,5-dimethoxy-
phenylacetate .4a) .2.05 g, 99% yield) as a white solid, mp
130±1318C .MeOH). IR .n, cm21, KBr): 1741 .CvO),
1678 .CvO), 1516 .NO2), 1341 .NO2). 1H NMR .d,
To study the scope of this synthetic strategy, we prepared
the benzo[b]carbazolequinone 2b possessing only two
aromatic methyl ethers. The starting nitroketoester 4b was
easily obtained by Friedel±Crafts acylation of ethyl homo-
veratrate with o-nitrophenylacetic acid chloride.11f The
procedure was the same as that for the synthesis of 2a
and, as such, compound 4b was re¯uxed with an ethanolic
solution of KOH to give the expected dimethoxylated nitro-
phenylnaphthoquinone 5b. Finally, nitroquinone 5b was
reacted with NaBH4 in isopropanol at room temperature to
give the benzo[b]carbazolequinone 2b in 97% yield, as
con®rmed by analytical and spectroscopic data. The IR
spectrum of this compound showed a single band at
1653 cm21 due to the p-quinone system and a band at
3280 cm21 corresponding to the N±H group. The 1H
NMR spectrum presented signals at 7.30±7.38, 7.40±7.43
and 8.13 ppm for a total of six aromatic protons and a singlet
at 12.92 ppm due to the N±H proton.
ppm): 3.62.s, 3H, OCH ), 3.86 .s, 2H, CH2), 3.94 .s, 3H,
3
OCH3), 3.95 .s, 9H, 3£OCH3), 4.63 .s, 2H, CH2), 6.73 .s,
1H, Ar-H), 6.74 .s, 1H, Ar-H), 7.48 .s, 1H, Ar-H), 7.75 .s,
1H, Ar-H). 13C NMR .d, ppm): 40.24 .CH2), 46.59 .CH2),
56.26 .OCH3), 56.42.OCH 3), 56.60 .OCH3), 56.75 .OCH3),
56.80 .OCH3), 108.81 .CH), 113.04 .CH), 115.31 .CH),
115.68 .CH), 126.43 .C), 129.30 .C), 129.68 .C), 141.36
.C), 147.87 .C), 148.35 .C), 152.24 .C), 153.65 .C), 172.61
.CvO), 197.50 .CvO). MS .m/z, %): 433 .M1, 1), 237
.34), 209 .100). Anal. Calcd for C19H19NO7: C, 61.12; H,
5.13; N, 3.75. Found: C, 60.99; H, 5.18; N, 3.81.
1.1.2. 6,7-Dimethoxy-2-+3,4-dimethoxy-2-nitrophenyl)-3-
hydroxy-1,4-naphthoquinone +5a). A mixture of nitro-
ketoester 4a .2.4 g, 5.54 mmol), EtOH .180 mL) and 15%
aqueous KOH solution .36 mL) was heated under re¯ux for
30 min. The EtOH was then evaporated in vacuo and the
residue suspended in water .250 mL). The mixture was
acidi®ed with 10% aqueous HCl solution .20 mL) and
extracted with CH2Cl2 .3£50 mL). The combined organic
layers were dried with anhydrous sodium sulfate, ®ltered
and evaporated in vacuo to give quinone 5a .2.26 g, 98%)
as a red solid, mp 258±2608C .MeOH). IR .n, cm21, KBr):
In summary, we have developed a new divergent synthesis
for benzo[a]carbazolequinone 1a and benzo[b]carbazole-
quinones 2a and 2b from key nitrophenylnaphthoquinones
5a and 5b, which can be easily obtained from nitrophenyl-
acetylphenylacetates 4a and b. Conditions were developed
for the synthesis of benzo[a]carbazolequinone 1a as the
major product and for the regiospeci®c synthesis of
benzo[b]carbazolequinone 2b. The convenient new route
to benzo[b]carbazolequinones is now being applied to the

3018
J. Cruces et al. / Tetrahedron 58 ꢀ2002) 3015±3019
1
3382.OH), 1653 .C vO), 1520 .NO2), 1335 .NO2). H
NMR .d, ppm): 3.96 .s, 3H, OCH3), 4.01 .s, 3H, OCH3),
4.03 .s, 3H, OCH3), 4.04 .s, 3H, OCH3), 6.87 .s, 1H, Ar-H),
7.55 .s, 1H, Ar-H), 7.56 .s, 1H, Ar-H), 7.61 .s, 1H, OH),
7.77 .s, 1H, Ar-H). 13C NMR .d, ppm): 56.87 .OCH3), 56.94
.OCH3), 57.01 .OCH3), 57.12.OCH 3), 108.21 .CH), 108.39
.CH), 109.51 .CH), 113.96 .CH), 120.43 .2£C), 123.95 .C),
128.43 .C), 142.16 .C), 149.45 .C), 151.68 .C), 153.37 .C),
153.65 .C), 155.24 .C), 180.91 .CvO), 182.77 .CvO). MS
.m/z, %): 369 .M1, 100), 164 .21), 136 .26), 58 .37). Anal.
Calcd for C20H17NO9: C, 57.83; H, 4.13; N, 3.37. Found: C,
58.01; H, 4.27; N, 3.21.
1.1.5. N-Methyl-2,3,8,9-tetramethoxy-6,11-dihydro-5H-
benzo[b]carbazol-6,11-dione +8a). A solution of 2,3,8,9-
tetramethoxy-6,11-dihydro-5H-benzo[b]carbazol-6,11-
dione .2a) .25 mg, 0.07 mmol) in dry DMF .11 mL) was
added dropwise to a stirred mixture of sodium hydride
.25 mg) in dry THF .6 mL). This suspension was stirred
at room temperature for 1 h. Excess methyl iodide .1 mL)
was added and the mixture stirred at room temperature for a
further 3 h. Water .25 mL) was added and the resulting
mixture extracted with ethyl acetate .3£15 mL). The
combined organic layers were washed with water
.2£15 mL), dried with anhydrous sodium sulfate and
concentrated in vacuo to give N-methyl-2,3,8,9-tetra-
methoxy-6,11-dihydro-5H-benzo[b]carbazol-6,11-dione .8a)
1.1.3. 2,3,8,9-Tetramethoxy-6,11-dihydro-5H-benzo[a]-
carbazol-5,6-dione +1a). Procedure a. PtO2 .440 mg,
0.19 mmol) was added to a deoxygenated solution of 6,7-
dimethoxy-2-.3,4-dimethoxy-2-nitrophenyl)-3-hydroxy-
1,4-naphthoquinone .5a) .0.4 g, 1.05 mmol) in ethyl acetate
.300 mL) and the resulting mixture was stirred under a
hydrogen atmosphere .pˆ1 atm) for 1 h. The catalyst was
®ltered off and the solution was heated under re¯ux in an air
atmosphere for 23 h. The brown precipitate formed was then
®ltered off and identi®ed as 2,3,8,9-tetramethoxy-6,11-
dihydro-5H-benzo[a]carbazol-5,6-dione .1a) .254 mg,
71% yield), mp 268±2708C .MeOH). IR .n, cm21, KBr):
3433 .NH), 1668 .CvO), 1618 .CvO). 1H NMR .d, ppm,
CF3CO2D): 4.21 .s, 3H, OCH3), 4.24 .s, 3H, OCH3), 4.29 .s,
6H, 2£OCH3), 7.28 .s, 1H, Ar-H), 7.63 .s, 2H, 2£Ar-H),
7.82.s, 1H, Ar-H), 12.81 .s, 1H, NH). MS . m/z, %): 367
.M1, 100), 324 .46), 280 .19), 169 .23). Anal. Calcd for
C20H17NO6: C, 65.39; H, 4.66; N, 3.81. Found: C, 65.25; H,
4.49; N, 3.89.
.25 mg, 98% yield), mp 210±2128C .MeOH). IR .n, cm21
,
KBr): 1660 .CvO). 1H NMR .d, ppm): 4.00 .s, 3H, OCH3),
4.02.s, 3H, OCH 3), 4.03 .s, 3H, OCH3), 4.04 .s, 3H, OCH3),
4.18 .s, 3H, NCH3), 6.73 .s, 1H, Ar-H), 7.57 .s, 1H, Ar-H),
7.61 .s, 1H, Ar-H), 7.74 .s, 1H, Ar-H). MS .m/z, %): 381
.M1, 100), 366 .30), 338 .23). Anal. Calcd for C21H19NO6:
C, 66.13; H, 5.02; N, 3.67. Found: C, 66.30; H, 4.91; N,
3.59.
1.1.6. 6,7-Dimethoxy-2-+2-nitrophenyl)-3-hydroxy-1,4-
naphthoquinone +5b). Compound 5b was prepared in
99% yield from compound 4b .1 g, 2.68 mmol) by the
same procedure as for compound 5a. Mp 242±2438C
.MeOH). IR .n, cm21, KBr): 3349 .OH), 1642.C vO),
1
1521 .NO2), 1340 .NO2). H NMR .d, ppm): 4.03 .s, 3H,
OCH3), 4.05 .s, 3H, OCH3), 7.52±7.58 .m, 5H, 4£Ar-H and
OH), 7.61±7.71 .m, 1H, Ar-H), 8.17 .dd, Jˆ8.2, 0.9 Hz, 1H,
Ar-H). 13C NMR .d, ppm): 57.00 .OCH3), 57.10 .OCH3),
108.21 .CH), 109.60 .CH), 119.60 .C), 123.90 .C), 125.00
.CH), 126.20 .C), 128.30 8C), 129.90 .CH), 133.00 .CH),
133.40 .CH), 149.50 .C), 152.00 .C), 153.40 .C), 155.20
.C), 180.80 .CvO), 180.80 .CvO). MS .m/z, %): 355 .M1,
29), 309 .100), 209 .67) 164 .70). Anal. Calcd for
C18H13NO7: C, 60.85; H, 3.69; N, 3.94. Found: C, 60.69;
H, 3.76; N, 4.06.
Procedure b. Oxygen was bubbled through a solution of
benzo[a]carbazole 7 .50 mg, 0.15 mmol) in 5 mL of 1,4-
dioxane for 15 min; excess of sodium hydroxide .50 mg)
was added and the mixture was stirred for 96 h. The solvent
was removed in vacuo and the residue dissolved in 30 mL of
dichloromethane and washed with 15 mL portions of water.
The organic layer was dried with anhydrous sodium sulfate
and concentrated in vacuo and, after preparative tlc of the
residue .eluant: 9:1 dichloromethane/methanol), 30 mg of
benzo[a]carbazol-5,6-dione 1a were isolated .55.1% yield).
1.1.7. 8,9-Dimethoxy-6,11-dihydro-5H-benzo[b]carba-
zol-6,11-dione +2b). A solution of compound 5b .130 mg,
0.36 mmol) in isopropanol .50 mL) was transformed into
compound 2b .97% yield) following the same procedure
as for compound 3a. Mp 279±2818C .MeOH). IR .n,
1.1.4. 2,3,8,9-Tetramethoxy-6,11-dihydro-5H-benzo[b]-
carbazol-6,11-dione +2a). NaBH4 .4 g, 106 mmol) was
added during 2h to a solution of 6,7-dimethoxy-2-.3,4-
dimethoxy-2-nitrophenyl)-3-hydroxy-1,4-naphthoquinone
.5a) .1 g, 2.40 mmol) in isopropanol .150 mL). The mixture
was stirred at room temperature for 4 h and then added to
water .200 mL). The resulting mixture was acidi®ed with
10% aqueous HCl solution .25 mL) and extracted into
chloroform .3£50 mL). The combined organic layers were
then dried with anhydrous sodium sulfate, ®ltered and
evaporated in vacuo to give 2,3,8,9-tetramethoxy-6,11-
dihydro-5H-benzo[b]carbazol-6,11-dione .2a) .0.88 g,
99% yield) as a red solid, mp 296±2988C .MeOH). IR .n,
1
cm21, KBr): 3280 .NH), 1653 .CvO). H NMR .d, ppm,
DMSO-d6): 3.93 .s, 3H, OCH3), 3.94 .s, 3H, OCH3), 7.30±
7.38 .m, 2H, 2£Ar-H), 7.40±7.43 .m, 3H, 3£Ar-H), 8.13 .d,
Jˆ8 Hz, 1H, Ar-H), 12.92 .s, 1H, NH). MS .m/z, %): 307
.M1, 100), 264 .8), 236 .10), 193 .10). Anal. Calcd for
C18H13NO4: C, 70.35; H, 4.26; N, 4.56. Found: C, 70.22;
H, 4.32; N, 4.71.
Acknowledgements
We thank the Xunta de Galicia and the Spanish Ministry of
Education and Culture .DGES) for ®nancial support.
1
cm21, KBr): 3215 .NH), 1642 .CvO). H NMR .d, ppm,
DMSO-d6): 3.84 .s, 6H, 2£OCH3), 3.94 .s, 6H, 2£OCH3),
6.93 .s, 1H, Ar-H), 7.50 .s, 2H, 2£Ar-H), 7.52.s, 1H, Ar-
H), 12.79 .s, 1H, NH). MS .m/z, %): 367 .M1, 100), 353
.46), 338 .24). Anal. Calcd for C20H17NO6: C, 65.39; H,
4.66; N, 3.81. Found: C, 65.46; H, 4.53; N, 3.72.
References
1. .a) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17,

J. Cruces et al. / Tetrahedron 58 ꢀ2002) 3015±3019
3019
175. .b). Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000,
1045.
6. .a) Beljanski, M. Eur. Pat. Appl. 373,986 .17.11.89), FR Appl.
88/15,845, 7 December 1988, p 7; Chem. Abstr. 1990, 113,
237846v. .b) Gribble, G. W. Natural Products Chemistry;
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1988; Vol. 1,
pp 123±162 Chapter 3.
2. For reviews on this topic see: .a) Gribble, G. W. The
Alkaloids; Brossi, A., Ed.; Academic: New York, 1990; Vol.
39, pp. 239±243 Chapter 7. .b) Husson, H.-P. The Alkaloids,
Chemistry and Pharmacology; Brossi, A., Ed.; Academic:
Orlando, 1985; Vol. 26, pp. 1±51 Chapter 1. .c) Chakraborty,
D. P. The Alkaloids, Chemistry and Pharmacology; Cordell,
G. A., Ed.; Academic: San Diego, 1993; Vol. 44, pp. 257±364
Â
7. Gonzalez, E.; Pindur, U.; Schollmeyer, D. J. Chem. Soc.,
Perkin Trans. 1 1996, 1767 and references therein.
8. Kobayasi, K.; Taki, T.; Kawakita, M.; Uchida, M.; Morikawa,
O.; Konishi, H. Heterocycles 1999, 51, 349.
9. .a) Ito, M. T.; Otani, M.; Nakagawa, A.; Iwai, Y.; Ohtani, M.;
È
Chapter 4. See also: .d) Knolker, J.-J.; Bauermeister, M.;
Â
Pannek, J.-B.; Wolpert, M. Synthesis 1995, 397. .e) Trecourt,
Â
F.; Mallet, M.; Mongin, F.; Queguiner, G. Tetrahedron 1995,
51, 11743. .f) Martarello, L.; Joseph, D.; Kirsch, G. Hetero-
Ã
Hata, T. J. Antibiot. 1970, 23, 315. .b) Hata, S.; Omura, S.;
Iwai, Y.; Nakagawa, A.; Otani, M. J. Antibiot. 1971, 24, 353.
Ã
.c) Omura, S.; Nakagawa, A.; Yamada, H.; Hata, T.; Furusaki,
A.; Watanabe, T. Chem. Pharm. Bull. 1971, 19, 2428.
Ã
.d) Omura, S.; Nakagawa, A.; Yamada, H.; Hata, T.; Furusaki,
A.; Watanabe, T. Chem. Pharm. Bull. 1973, 21, 931.
Ã
.e) Furusaki, A.; Matsui, M.; Watanabe, T.; Omura, S.;
È
cycles 1996, 43, 367. .g) Leese, T.; Dotz, K.-H. Bull. Soc.
Chim. Fr. 1997, 134, 503. .h) Echavarren, A. M.; Tamayo,
N.; de Frutos, O.; Garcia, A. Tetrahedron 1997, 53, 16835.
.i) Kobayshi, K.; Taki, T.; Kawakita, M.; Uchida, M.;
Morikawa, O.; Konishi, H. Heterocycles 1999, 51, 2 .
.j) Gribble, G. W.; Silva, R. A.; Saulnier, M. G. Synth.
Commun. 1999, 29, 729. .k) Shanmugasundaram, K.; Prasad,
K. J. R. Heterocycles 1999, 51, 2163. .l) de Koning, C. B.;
Michael, J. P.; Rousseau, A. L. J. Chem. Soc., Perkin Trans. 1
2000, 1705. .m) Meyer, K. U.; Pindur, U. J. Chem. Soc.,
Perkin Trans. 1 2001, 695. .n) Suresh, J. R.; Syam Kurnar,
U. K.; Junjappa, H. Tetrahedron 2001, 57, 781.
Nakagawa, A.; Hata, T. Isr. J. Chem. 1972, 10, 173.
.f) Sato, Y.; Geckle, M.; Gould, S. J. Tetrahedron Lett.
1985, 26, 4019. For a review on kynamicins see: .g) Gould,
S. J. Chem. Rev. 1997, 97, 2499.
10. Luo, Y.-L.; Chou, T.-C.; Cheng, C. C. J. Heterocycl. Chem.
1996, 33, 113 and references therein.
 Â
11. .a) Estevez, J. C.; Villaverde, M. C.; Estevez, R. J.; Castedo,
L. Heterocycles 1994, 38, 1 and references therein.
.b) Estevez, J. C.; Villaverde, M. C.; Estevez, R. J.; Castedo,
L. Tetrahedron 1994, 50, 2107 and references therein.
Â
Â
3. Cheng, C. C. Structural Aspects of Antineoplastic AgentsÐA
New Approach. Progress in Medicinal Chemistry; Ellis, G. P.,
West, G. B., Eds.; Elsevier: Amsterdam, 1988; Vol. 25,
pp. 35±83.
 Â
.c) Estevez, J. C.; Villaverde, M. C.; Estevez, R. J.; Castedo,
L. Tetrahedron 1993, 49, 2783 and references therein.
 Â
.d) Estevez, J. C.; Villaverde, M. C.; Estevez, R. J.; Castedo,
L. Tetrahedron 1995, 51, 4075 and references therein.
  Â
.e) Martõnez, E.; Estevez, J. C.; Estevez, R. J.; Villaverde,
M. C.; Castedo, L. Tetrahedron Lett. 1998, 39, 2175.
 Â
.f) Cruces, J.; Estevez, J. C.; Estevez, R. J.; Castedo, L.
Heterocycles 2000, 53, 1041.
4. .a) Kimura, M.; Shimizu, Y.; Dohmyou, M.; Nakajima, T.
Nippon Sanshigaku Zasshi 1990, 59, 92. .b) Yoshida, K.;
Oga, N.; Kadota, M.; Kubo, Y. Kochi Daigaku Rigakubu
Kiyo, Kagaku 1993, 14, 1. .c) Brown, D. E.; Leichter, L. M.
Eur. Pat. Appl. EP 292,322 .Cl. G03G5/06), 23 November
1988, GB Appl. 87/12,151, 22 May 1987, p 22. .d) Leichter,
L. M. Eur. Pat. Appl. EP 342,810 .Cl.C09B23/02), 23
November 1989, US Appl. 197,039, 20 May 1988. .e) Body,
G. T.; Tiers, G. V.; Francis, C. V.; Janulis, E. P.; Koshar, R. J.;
Leichter, L. M. PCT Int. Appl. WO 93 02,383 .Cl. G02F1/35),
12. .a) Kuznetsov, W. V.; Shcherbakova, I. V.; Dorofeenko, G. N.
Chem. Heterocycl. Compd. 1978, 13, 1183. .b) Elliot Jr., I. W.
J. Org. Chem. 1982, 47, 5398. .c) Carty, A.; Elliot, I. W.;
Lenior, G. M. Can. J. Chem. 1984, 62, 2435. .d) Meyer,
A. I.; Sielecki, T. M.; Crans, D. C.; Marshman, R. W.;
Nguyen, T. H. J. Am. Chem. Soc. 1992, 57, 3673.
4
February 1993, US Appl. 730,225, 15 July 1991.
.f) Enokida, T. Jpn. Kokai Tokkyo Koho, JP 06,228,554
[94,228,554] .Cl. C09K11/06), 16 August 1994, Appl. 93/
17,444, 4 February 1993.
Â
.e) Sotomayor, N.; Domõnguez, E.; Lete, E. J. Org. Chem.
1996, 61, 4062. .f) Munchhof, M. J.; Meyers, A. I. J. Org.
Chem. 1996, 61, 4607.
5. .a) Sharma, S. C. Orient. J. Chem. 1986, 2, 58. .b) Pappa, H.;
Segall, A.; Pizzorno, M. T.; Radice, M.; Amoroso, A.; Gutkin,
G. O. Farmaco 1994, 49, 333. .c) Buu-Hoi, Ng. Ph.; Hoan,
Ng.; Khoi, Ng. H. J. Org. Chem. 1949, 14, 492and references
therein. .d) Buu-Hoi, Ng. Ph.; Mangane, M.; Jacquignon, P.
J. Chem. Soc. 1967, 662. .e) Beisler, J. A. J. Med. Chem. 1971,
14, 1116. .f) Bair, K. W. US 4,910,218 .Cl. 514-443; A61K31/
38), 20 March 1990.
 Â
13. Castedo, L.; Estevez, R. J.; Saa, J. M.; Suau, R. J. Heterocycl.
Chem. 1982, 45, 657.
14. Aihara, J. L.; Ichikawa, H.; Tokiwa, H.; Okumura, Y. Bull.
Chem. Soc. Jpn 1990, 63, 2498.
15. Graham, J.; Ninan, A.; Reza, K.; Sainsbury, M.; Shertzer,
H. G. Tetrahedron 1992, 48, 7763.
16. Perrin, D. D.; Armarego, W. L. F. Puri®cation of Laboratory
Chemicals; Pergamon: Oxford, 1988.