Synthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazoles by oxidative cyclization of bisindolylmaleimides with a rhodium(III)-copper(II) catalytic system

Article abstract of DOI:10.1055/s-2005-869977

A novel catalytic protocol for the synthesis of a series of indolo[2,3-a]pyrrplo[3,4-c]carbazoles based on the bimetallic system RhCl ₃·3H₂O and Cu(OAc)₂·H ₂O in the presence of molecular oxygen was investigated

Full text of DOI:10.1055/s-2005-869977

PAPER
1959
Synthesis of Indolo[2,3-a]pyrrolo[3,4-c]carbazoles by Oxidative Cyclization of
Bisindolylmaleimides with a Rhodium(III)–Copper(II) Catalytic System
I
ndolo[2,3-
a
]
pyrr
e
olo[3,4-
c
]c
r
arbazole
n
s
by
O
xidati
h
ve Cyclizatio
a
n
rd Witulski,* Torsten Schweikert
Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Correnstr. 40, 48143 Münster, Germany
Fax +49(251)8336501; E-mail: witulski@uni-muenster.de
Received 12 January 2005; revised 9 March 2005
without light),8a,b,16 2,3-dichloro-5,6-dicyano-1,4-benzo-
Abstract: A novel catalytic protocol for the synthesis of a series of
indolo[2,3-a]pyrrolo[3,4-c]carbazoles based on the bimetallic sys-
tem RhCl3·3H2O and Cu(OAc)2·H2O in the presence of molecular
oxygen was investigated. The method was applied to the synthesis
quinone (DDQ),17 or with hypervalent iodine species such
as phenyliodine(III)bis(trifluoroacetate) (PIFA) and phe-
nyliodine(III)diacetate (PIDA).18 Furthermore, it was per-
of the glycosidated fluoroindolocarbazole 3 that was recently isolat- formed with stoichiometric amounts of Pd(OAc)2,8c,19
PdCl2,20 Pd(O2CCF3)2,21 or CuCl2.22 However, these
ed as a metabolite from feeding experiments of Saccharothrix aero-
colonigenes ATCC 39243 with fluorotryptophanes.
methods are not general with respect to the substitution
Key words: glycosides, rebeccamycin, catalysis, rhodium, copper
pattern of the bisindolylmaleimide and present a number
of other limitations: reactions with iodine necessitate high
dilution and long reaction times and cyclizations carried
out with DDQ maintain problems with the removal of the
DDQ by-products. Pd2+- or Cu2+-mediated oxidative cy-
clizations require one to five equivalents of the palladium
or copper salt and cause severe difficulties when the
formed Pd(0)- or Cu(0)-slurry has to be separated from
the often insoluble indolocarbazoles.
Considerable interest is devoted to the synthesis of indo-
lo[2,3-a]pyrrolo[3,4-c]carbazole derived natural products
and synthetic analogues thereof because of their diverse
spectrum of biological activities.1 For example, the alka-
loid staurosporine (1) was isolated from Streptomyces
staurosporeus (AM 2282).2,3 Its biological properties in-
clude antifungal,2a hypotensive,4 and platelet aggregation
activities,5 whilst its cytotoxic activity against protein ki-
nase C and other cycline-dependent kinases is one of the
most important aspects of its biological profile
(Figure 1).6 Rebeccamycin (2) is another important mem-
ber of this class of indolocarbazoles displaying a broad
spectrum of in vivo activity in tumor-bearing murine
models. Most importantly, rebeccamycin (2) is, like
camptothecin, a topoisomerase I poison.7,8 Recently, the
fluoroindolocarbazole 3 was identified as one of several
metabolites obtained from feeding experiments of Sac-
chrothrix aerocolonigenes ATCC 39243 cultures with 5-
fluorotryptophane and glucose.9 The fluoroindolocarba-
zole 3 is a quite selective topoisomerase I active agent and
was reported of being more potent than rebeccamycin (2)
in in vivo antitumor assays.9,10
H
N
O
O
H
N
O
N
N
H
N
N
Cl
Cl
O
O
OH
H3C
H
HO
H3CO
NHCH3
OH
H3CO
H
2: rebeccamycin
1: staurosporine
N
O
O
F
F
Despite numerous synthetic efforts towards the synthesis
of this class of compounds, a flexible and efficient access
to the aglycon indolocarbazole core is still an important
challenge. Several routes to the indolo[2,3-a]pyrrolo[3,4-
c]carbazole ring system have been reported.1,11–15
Amongst them, the most attractive approach is the oxida-
tive cyclization of readily available bisindolylmaleimides
to the corresponding indolocarbazoles and numerous syn-
thetic variants to perform this reaction have been ex-
plored. For example, the oxidative cyclization of
bisindolylmaleimides was carried out with iodine (with or
N
N
H
O
OH
HO
OH
HO
3
Figure 1
Recently, Wang et al. reported the oxidative cyclization of
bisindolylmaleimides with a Pd2+/Cu2+ Wacker-type reac-
tion system, where aglycons of rebeccamycin derivatives
were obtained in 58–88% yield.23 The catalytic system de-
scribed took advantage of the reoxidation of Pd(0) and
SYNTHESIS 2005, No. 12, pp 1959–1966
x
x.
x
x
.
2
0
0
5
Advanced online publication: 24.06.2005
DOI: 10.1055/s-2005-869977; Art ID: T00305SS
© Georg Thieme Verlag Stuttgart · New York

1960
B. Witulski, T. Schweikert
PAPER
Cu(0) by molecular oxygen making the process itself op- indolylmagnesium salt were necessary to effect the de-
erationally simple and amenable to a scale-up. However, sired reaction.
the bimetallic system used was only catalytic with respect
With the bisindolylmaleimides 6 in hand, rhodium(III)-
mediated cyclizations to the indolo[2,3-a]pyrrolo[3,4-
c]carbazoles 7 were studied (Scheme 2). Electrophilic
Rh(III)-species, such as Rh(tfa)3 in the presence of
to the palladium source, whilst a stoichiometric amount of
Cu2+ salt was still necessary to accomplish the desired re-
action.
We report herein our results on the use of a rhodium(III)– K2S2O8 or the redox-couple RhCl(PPh3)3/Cu2+, have pre-
copper(II) catalytic system to perform the oxidative cy- viously been used in oxidative carbonylations of arenes
clization of bisindolylmaleimides to appropriately substi- via an SEAr type C–H activation as the initiating step of
tuted indolo[2,3-a]pyrrolo[3,4-c]carbazoles and its the catalytic cycle.25,26 We therefore assumed that the
application in the synthesis of the potent topoisomerase I strong electrophilic nature of rhodium(III)-based catalysts
active agent 3.29
might also be of value to induce the cyclization to the
rebeccamycin-type indolocarbazole core starting from the
bisindolylmaleimides 6. In a first attempt, reactions of 6a
with stoichiometric quantities of Rh(tfa)3 in either trifluo-
roacetic acid or acetic acid at elevated temperatures were
studied to give the indolocarbazole 7a, albeit in a low
yield of 15% (Table 2). All further efforts to perform
these reactions with catalytic amounts of Rh(tfa)3 and
K2S2O8 as an additional oxidant led to the decomposition
of the starting bisindolylmaleimide 6a. Therefore, the less
electrophilic chlororhodium species RhCl3·3H2O and a
stoichiometric amount of a copper(II) salt as a possible
co-oxidant were investigated next.
The synthesis of the bisindolylmaleimides 6 was accom-
plished by the coupling of two equivalents of the indolyl-
based lithium salts of 5 with the 2,3-dibromomaleimides
4 in close analogy to the protocol of Ohkubo et al.
(Scheme 1 and Table 1).20
R1
R1
N
O
N
O
O
O
Br
Br
R2
R2
4
LiHMDS
+
Gratifyingly, the formation of the indolo[2,3-a]pyrro-
lo[3,4-c]carbazoles 7a–f could be accomplished when the
bisindolylmaleimides 6a–g were heated to 120 °C in the
presence of 10 mol% of RhCl3·3H2O and 1.1 equivalents
of Cu(OAc)2·H2O in DMF. Under these conditions, a full
conversion of the starting bisindolylmaleimides 6 was ob-
served and the cyclized products 7a–g were obtained in
reasonable to good yields after column chromatography
on silica gel (Table 2).
toluene,
–78 °C to r.t., then
12 h reflux
N
N
R2
H
H
R3
R3
(see Table 1)
N
H
6
R3
5
Scheme 1
Table 1 Synthesis of the Bisindolylmaleimides 6a–g
R1
Rh(TFA)3, AcOH, 120 °C
4
R1
5
R2
R3
H
H
H
H
H
H
Cl
6
Yield (%)a
or
O
N
10 mol% RhCl3·3H2O,
1.1 equiv Cu(OAc)2
80–120 °C, DMF
O
4a
4a
4a
4b
4b
4b
4b
CH3
CH3
CH3
5a
5b
5c
H
6a
6b
6c
6d
6e
6f
75
63
43
47
40
50
54
R2
R2
(for details see Table 2)
F
6
or
OCH3
F
N
N
5 mol% RhCl3·3H2O,
20 mol% Cu(OAc)2
O2 sparge
H
H
R3
R3
CH2Ph 5b
CH2Ph 5c
CH2Ph 5a
CH2Ph 5d
90–120 °C, DMF
(for details see Table 3)
7
OCH3
H
Scheme 2
H
6g
Although oxidative cyclizations towards indolocarba-
zoles have been described with copper(II) salts alone, the
use of a catalytic amount of RhCl3·3H2O was crucial to ac-
complish an efficient reaction. For example, the oxidative
cyclization of 6a to 7a was achieved in 73% yield in the
presence of 10 mol% RhCl3·3H2O and 1.1 equivalents of
Cu(OAc)2·H2O, whereas omitting the rhodium salt under
otherwise identical reaction conditions resulted in the sig-
nificant lower yield of 47%. Furthermore, the cyclization
of 6a was also induced by a stoichiometric amount of
RhCl3·3H2O. However, the lower yield of 25% of the in-
dolocarbazole 7a thus obtained makes clear that the bime-
a Yield refers to isolated product after column chromatography.
Adding the indoles 5 to a freshly prepared solution of
LiHMDS in toluene, followed by the addition of the N-
protected dibromomaleimides 4, gave the bisindolylmale-
imides 6 in moderate to good yields (40–75%). Although
the coupling of 5 to 4 needed elevated temperatures for its
completion, this protocol was more valuable than the use
of the corresponding indolylmagnesium bromides as de-
scribed by Steglich et al. in the synthesis of arcyriarubin
A and B.24 In this case more than four equivalents of the
Synthesis 2005, No. 12, 1959–1966 © Thieme Stuttgart · New York

PAPER
Indolo[2,3-a]pyrrolo[3,4-c]carbazoles by Oxidative Cyclization
1961
Table 3 Oxidative Cyclization of 6a,d,f to the Indolo[2,3-a]pyrro-
lo[3,4-c]carbazoles 7a,d,f in the Presence of RhCl3·3H2O (5 mol%),
Cu(OAc)2·H2O (20 mol%), and O2
Table 2 Oxidative Cyclization of 6a–g to Indolo[2,3-a]pyrrolo[3,4-
c]carbazoles 7a–g in the Presence of RhCl3·3H2O (10 mol%) and
Cu(OAc)2·H2O (1.1 equiv)
R1
R2
R3
Temp
(°C)
t
Yield
(%)a
7
R1
R2
R3
Temp
(°C)
t
Yield
(%)a
7
(h)
(h)
15b
73
47c
25d
58
54
73
74
78
44
7a
7d
7f
CH3
H
F
H
H
H
110
120
90
4.0
3.0
5.0
53
47
75
7a
7a
7a
7a
7b
7c
7d
7e
7f
CH3
CH3
CH3
CH3
CH3
CH3
CH2Ph
H
H
H
H
H
H
H
H
H
H
Cl
120
120
120
120
120
90
24
CH2Ph
CH2Ph
H
1.5
0.5
24
H
H
a Yield refers to isolated product after column chromatography.
H
F
3.0
3.0
9.5
3.0
0.5
6.0
its advantage from the work-up procedure: at the end of
the reaction the rhodium and copper salts retained their
initial oxidation state and could be easily separated from
the organic products by simple extraction.
OCH3
F
120
80
CH2Ph OCH3
A mechanistic rationale for the underlying oxidative cy-
clization of 6 to 7 is outlined in Scheme 3. Most likely the
cyclization is initiated by an electrophilic Rh(III) species
that is capable of inducing a cationic driven ring closure
(8a to 8b), and the overall process is based on three cou-
pled redox processes: the Rh(III)–Rh(I) couple and the
Cu(II)–Cu(0) redox pair, whilst in the catalytic version the
formed copper(0) is reoxidized to copper(II) by molecular
oxygen.
CH2Ph
CH2Ph
H
H
120
120
7g
a Yield refers to isolated product after column chromatography.
b The reaction was carried out in the presence of Rh(TFA)3 (1.1 equiv)
in HOAc.
c The reaction was carried out with Cu(OAc)2·H2O (1.1 equiv) and
without RhCl3·3H2O.
d The reaction was carried out with RhCl3·3H2O (1.1 equiv) and with-
out Cu(OAc)2·H2O.
O2
6
7
tallic system of Rh(III) and Cu(II) effects the underlying
reaction.
[CuII]
[Cu0]
– 2 H+
[RhIII
]
[RhI]
Notably, the reaction protocol still gave satisfactory re-
sults with the bisindolylmaleimides 6b, d, or g bearing
electron withdrawing substituents. Indeed, the electron
deficient indolocarbazoles 7b,d, as well as the aglycon of
rebeccamycin 7g were obtained in 58%, 73% and 44%
yield, respectively. Milder reaction conditions could be
applied with the electron rich bisindolylmaleimides 6c or
e. For these compounds temperatures of 80–90 °C were
ample for the completion of the reaction and the ring-clo-
sure products 7c and e were obtained in yields of 54% and
74%.
R1
O
N
O
[Rh]
R2
R2
R1
O
N
O
N
N
H
H
H
H
R3
R3
R2
R2
[Rh]
8b
N
N
Next, our attention was drawn to promote the oxidative
cyclization to the indolo[2,3-a]pyrrolo[3,4-c]carbazoles 7
by using catalytic amounts of Rh(III) and catalytic
amounts of Cu(II) salts in the presence of molecular oxy-
gen as a reliable reoxidant for the formed copper(0) by-
products (Table 3). For this purpose the bisindolylmale-
imides 6 were treated with 5 mol% RhCl3·3H2O and with
20 mol% Cu(OAc)2·H2O in DMF at 90–120 °C while
oxygen was introduced into the reaction mixture for the
whole reaction period (4–5 hours). The starting bisin-
dolylmaleimides 6a,d,f were completely consumed in this
truly catalytic protocol as indicated by TLC, and the prod-
ucts 7a,d,f were obtained in 53%, 47%, and 75% yield, re-
spectively. However, although the overall yields were
slightly lower in the catalytic version, the protocol gained
H
H
R3
R3
8a
Scheme 3
With the aim to complete the synthesis of the potent topo-
isomerase I active fluoroindolocarbazole 3 the obtained
cyclisation product 7b was N-glycosidated with 1-chloro-
2,3,4,6-tetra-O-benzyl-a-D-glucose in the presence of
powdered KOH in anhyd acetonitrile (73% yield), fol-
lowed by the removal of the benzyl protective groups via
hydrogenolysis with catalytic quantities of palladium on
charcoal (10% Pd/C, 1 atm H2, 64% yield) to give the
fluoroindolocarbazole glycoside 9 with high stereoselec-
tivity (Scheme 4).
Synthesis 2005, No. 12, 1959–1966 © Thieme Stuttgart · New York

1962
B. Witulski, T. Schweikert
PAPER
4a and b were synthesized according to literature procedures.27 Pe-
troleum ether refers to the fraction with bp 40–60 °C.
CH3
N
O
O
Bisindolylmaleimides 6a–g; General Procedure
1) KOH, α-D-Glc(OBn)4Cl,
Na2SO4, MeCN, r.t.
F
F
To a solution of HMDS (4.8 g, 29.7 mmol) in anhyd toluene (20
mL) was added BuLi (29.6 mmol; 18.5 mL of a 1.6 M solution in
hexanes) at –78 °C. The reaction mixture was brought to 0 °C and
thereafter again cooled to –78 °C. A solution of indole 5a–d (13.6
mmol) in anhyd toluene (40 mL) was added to the reaction mixture,
followed by stirring for 45 min at –78 °C. Thereafter, a solution of
4a or b (6.3 mmol) in anhyd toluene (20 mL) was added and the re-
sulting blue reaction mixture was kept for 20 min at r.t., followed by
heating to reflux for 12 h. The reaction mixture was poured into an
aq HCl (0.2 M; 150 mL), extracted with EtOAc (3 × 100 mL), and
the organic layer was washed with aq NaHCO3 (150 mL), H2O (150
mL) and brine (150 mL), dried (MgSO4), filtered through a plug of
Celite and concentrated. The residue was purified by column chro-
matography (silica gel; petroleum ether–EtOAc) with the exception
of 6c, where the crude product after aqueous work-up was washed
with cold MeOH, and 6f where the crude product was washed with
EtOAc.
(73%)
7b
N
N
2) 10% Pd/C, H2 (1 atm),
MeOH/CHCl3, 3 d, r.t.
(64%)
H
O
OH
HO
HO
OH
9
2 M KOH, 1 d, r.t.
(71%)
H
N
O
O
O
O
O
F
F
F
F
2,3-Bis(1H-indol-3-yl)-N-methylmaleimide (6a)
N
N
N
N
These data are in agreement with those published.24b
H
H
NH4(OAc),
2 h, 140 °C
(83%)
O
O
OH
Red solid; yield: 75%; mp > 260 °C.
OH
1H NMR (200 MHz, DMSO-d6): d = 11.65 (br s, 2 H), 7.74 (d,
J = 2.8 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 6.96 (t, J = 7.6 Hz, 2 H),
6.80 (d, J = 8.0 Hz, 2 H), 6.62 (t, J = 7.6 Hz, 2 H), 3.03 (s, 3 H).
HO
HO
HO
HO
OH
OH
2,3-Bis(5-fluoro-1H-indol-3-yl)-N-methylmaleimide (6b)
Red solid; yield: 63%; mp > 260 °C.
3
10
Scheme 4
IR (KBr): 3420, 3341, 3136, 1694, 1526, 1444, 1429, 1391, 1150,
1097, 934, 802, 616 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.80 (d, J = 2.2 Hz, 2 H), 7.85
(d, J = 2.8 Hz, 2 H), 7.38 (dd, J = 8.8, 4.7 Hz, 2 H), 6.82 (dt, J = 9.1,
2.5 Hz, 2 H), 6.39 (dd, J = 10.6, 2.6 Hz, 2 H), 3.03 (s, 3 H).
Hydrolysis of 9 with aqueous potassium hydroxide gave
the anhydride 10 in 71% yield. Finally, treatment of the
anhydride 9 with neat ammonium acetate in a sealed tube
at 140 °C without additional solvents gave the fluoroin- 13C NMR (100 MHz, DMSO-d6): d = 172.0 (s), 157.1 (d,
1JCF = 231.8 Hz, CF), 133.0 (s), 131.4 (d), 127.2 (s), 126.2 (d,
dolocarbazole 3 in 83% yield and completed the targeted
reaction sequence.
3
3JCF = 11.0 Hz, Cq), 113.3 (d, JCF = 10.3 Hz, CH), 110.3 (d,
2JCF = 26.4 Hz, CH), 106.1 (s), 105.9 (d, 2JCF = 29.3 Hz, CH), 24.4
In summary, the oxidative cyclization of bisindolylmale-
imides 6 to a set of indolocarbazoles 7 was accomplished
by the bimetallic catalytic system comprising catalytic
quantities of RhCl3·3H2O and either stoichiometric or cat-
alytic quantities of Cu(OAc)2·H2O and molecular oxygen.
Furthermore, this novel catalytic protocol was applied in
a six-step synthesis of the potent topoisomerase I active
fluoroindolocarbazole 3.
(q).
MS (EI, 70 eV): m/z (%) = 377 (1) [M+], 292 (1), 215 (15), 213 (13),
177 (1), 135 (100), 134 (22), 107 (32), 81 (6), 57 (8), 43 (17), 32 (8).
HRMS (ESI): calcd for C21H13F2N3NO2 [M + Na]+: 400.0868;
found: 400.0864.
2,3-Bis(5-methoxy-1H-indol-3-yl)-N-methylmaleimide (6c)
Red solid; yield: 43%; mp > 260 °C.
1H NMR (400 MHz, DMSO-d6): d = 11.55 (br s, 2 H), 7.79 (s, 2 H),
7.25 (d, J = 8.8 Hz, 2 H), 6.57 (dd, J = 8.9, 2.6 Hz, 2 H), 6.23 (d,
J = 2.5 Hz, 2 H), 3.10 (s, 6 H), 3.05 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 172.8 (s), 154.0 (s), 131.6 (s),
130.1 (d), 127.6 (s), 127.1 (s), 113.1 (d), 113.0 (d), 106.8 (s), 103.4
(d), 55.1 (q), 24.8 (q).
All reagents used were analytical grades and all solvents were puri-
fied by standard methods and distilled prior to use. Reaction mix-
tures were stirred magnetically and were monitored by TLC using
Polygram Sil G/UV254 silica plates from Macherey-Nagel & Co.
(Düren, Germany). Flash column chromatography was performed
with Merck silica gel 60 (40–60 mm). 1H and 13C NMR spectra were
recorded on Bruker AC200 and Bruker AMX400 using TMS
IR (KBr): 3448, 1771, 1685, 1636, 1437, 1275, 1261, 764, 750
cm–1.
MS (EI, 70 eV): m/z (%) = 401 (3) [M+], 356 (15), 341 (4), 255 (35),
213 (6), 183 (1), 149 (4), 145 (34), 130 (2), 116 (6), 91 (6), 89 (8),
77 (3), 73 (4).
HRMS (ESI): calcd for C23H19N3O4 [M + Na]+: 424.1268; found:
424.1255.
1
(d = 0.00, H) and CDCl3 (d = 77.0, 13C), or DMSO-d6 (d = 39.7,
13C) as internal standards. 13C NMR assignments were made on the
basis of DEPT experiments. Mass spectra were obtained on a Finni-
gan MAT 90 spectrometer (EI, 70 eV) and on a Quattro-LCZ from
Waters-Micromass (ESI). IR-spectra were recorded as solids in KBr
pellets on a Perkin–Elmer FT-IR spectrometer. Mps were recorded
on a Büchi apparatus, and are uncorrected. The dibromomaleimides
Synthesis 2005, No. 12, 1959–1966 © Thieme Stuttgart · New York

PAPER
Indolo[2,3-a]pyrrolo[3,4-c]carbazoles by Oxidative Cyclization
1963
3,4-Bis(5-fluoro-1H-indol-3-yl)-N-benzylmaleimide (6d)
Red solid; yield: 47%; mp 256–258 °C.
90 °C in the case of 7c and e) in a Schlenk tube with a screw cap
until TLC showed complete consumption of the bisindolylmaleim-
ide. Thereafter, the reaction mixture was poured into aq HCl (0.2 M;
20 mL), and was extracted with EtOAc (3 × 25 mL). The organic
phase was washed with aq NaHCO3 (25 mL), H2O (25 mL) and
brine (25 mL), dried (MgSO4), filtered through Celite and concen-
trated. The residue was purified by column chromatography (silica
gel; petroleum ether–EtOAc).
IR (KBr): 3392, 1756, 1690, 1627, 1582, 1527, 1483, 1462, 1432,
1400, 1346, 1298, 1186 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.88 (d, J = 2.7 Hz, 2 H), 7.91
(d, J = 2.7 Hz, 2 H), 7.36–7.41 (m, 6 H), 7.27–7.32 (m, 1 H), 6.84
(m, 2 H), 6.39 (dd, J = 10.5, 2.6 Hz, 2 H), 4.77 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 171.7 (s), 157.1 (d,
1JCF = 232.9 Hz, CF), 137.6 (s), 133.0 (s), 131.6 (d), 129.0 (d),
127.9 (d), 127.8 (d), 127.0 (s), 126.2 (d, 3JCF = 10.8 Hz, Cq), 113.3
12,13-Dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-6-
methyl-5,7(6H)-dione (7a)
These data are in agreement with those published.14d
3
2
(d, JCF = 10.1 Hz, CH), 110.4 (d, JCF = 25.7 Hz, CH), 106.0 (d,
4JCF = 4.1 Hz, Cq), 105.9 (d, 2JCF = 24.3 Hz, CH), 41.5 (t).
Yellow solid; yield: 73%; mp > 260 °C.
MS (EI, 70 eV): m/z (%) = 453 (100) [M+], 293 (14), 292 (46), 291
(19), 108 (10), 91 (16).
1H NMR (400 MHz, DMSO-d6): d = 11.70 (s, 2 H), 9.00 (d, J = 7.9
Hz, 2 H), 7.81 (d, J = 8.1 Hz, 2 H), 7.56 (t, J = 7.1 Hz, 2 H), 7.36 (t,
J = 7.1 Hz, 2 H), 3.18 (s, 3 H).
HRMS (EI, 70 eV): calcd for C27H17F2N3O2: 453.1289; found:
453.1287.
3,9-Difluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]car-
bazole-6-methyl-5,7(6H)-dione (7b)
Yellow solid; yield: 58%; mp > 260 °C.
2,3-Bis(5-methoxy-1H-indol-3-yl)-N-benzylmaleimide (6e)
Red solid; yield: 40%; mp 184–186 °C.
IR (KBr): 3462, 1700, 1653, 1540, 1476, 1380, 1275, 1262, 763
cm–1.
IR (KBr): 3374, 2935, 1757, 1694, 1624, 1583, 1526, 1400, 1352,
1282, 1248, 1213, 1164, 1117, 1071, 1034 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.73 (br s, 2 H), 8.56 (dd,
J = 9.7, 2.7 Hz, 2 H), 7.78 (dd, J = 8.9, 4.6 Hz, 2 H), 7.39 (m, 2 H),
3.06 (s, 3 H).
1H NMR (400 MHz, DMSO-d6): d = 11.62 (d, J = 2.3 Hz, 2 H), 7.84
(d, J = 2.7 Hz, 2 H), 7.34–7.39 (m, 4 H), 7.28–7.31 (m, 1 H), 7.24
(d, J = 8.8 Hz, 2 H), 6.56 (dd, J = 8.8, 2.5 Hz, 2 H), 6.21 (d, J = 2.5
Hz, 2 H), 4.77 (s, 2 H), 3.08 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): d = 172.0 (s), 153.6 (s), 137.8 (s),
131.2 (s), 129.9 (d), 129.1 (d), 128.1 (d), 128.0 (d), 127.8 (d), 126.9
(s), 126.8 (s), 112.7 (d), 106.3 (s), 103.0 (d), 54.7 (q), 41.6 (t).
13C NMR (100 MHz, DMSO-d6): d = 170.1 (s), 157.3 (d,
1JCF = 234.0 Hz, CF), 137.2 (s), 130.3 (s), 122.1 (d, 3JCF = 10.9 Hz,
Cq), 119.3 (s), 115.6 (d, 3JCF = 3.8 Hz, Cq), 115.1 (d, 2JCF = 25.3 Hz,
4
2
CH), 113.7 (d, JCF = 9.0 Hz, Cq), 109.5 (d, JCF = 25.4 Hz, CH),
23.8 (q).
MS (EI, 70 eV): m/z (%) = 477 (100) [M+], 343 (5), 330 (9), 317 (6),
316 (26), 315 (6), 301 (7), 300 (6).
MS (EI, 70 eV): m/z (%) = 375 (6) [M+], 261 (1), 228 (5), 187 (3),
172 (5), 149 (8), 139 (13), 116 (5), 106 (41), 91 (26), 84 (100), 79
(61), 77 (28).
HRMS (ESI): calcd for C21H11F2N3NO2 [M + Na]+: 398.0712;
found: 398.0712.
HRMS (EI, 70 eV): calcd for C29H23N3O4: 477.1689; found:
477.1695.
2,3-Bis(1H-indol-3-yl)-N-benzylmaleimide (6f)
These data are in agreement with those published.17a,28
3,9-Dimethoxy-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-
c]carbazole-6-methyl-5,7(6H)-dione (7c)
Yellow solid; yield: 54%; mp > 260 °C.
Red solid; yield: 50%; mp > 260 °C.
1H NMR (400 MHz, DMSO-d6): d = 11.68 (br s, 2 H), 7.77 (d,
J = 2.2 Hz, 2 H), 7.31–7.38 (m, 6 H), 7.24–7.29 (m, 1 H), 6.95 (t,
J = 7.5 Hz, 2 H), 6.78 (d, J = 8.3 Hz, 2 H), 6.61 (t, J = 7.6 Hz, 2 H),
4.75 (s, 2 H).
IR (KBr): 3463, 1844, 1684, 1653, 1559, 1481, 1274, 1261, 746
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.50 (br s, 2 H), 8.54 (d,
J = 2.6 Hz, 2 H), 7.69 (d, J = 8.8 Hz, 2 H), 7.18 (dd, J = 8.8, 2.6 Hz,
2 H), 3.91 (s, 6 H), 3.16 (s, 3 H).
2,3-Bis(7-chloro-1H-indol-3-yl)-N-benzylmaleimide (6g)
Red solid; yield: 54%; mp > 260 °C.
13C NMR (100 MHz, DMSO-d6): d = 169.7 (s), 154.4 (s), 137.7 (s),
129.1 (s), 121.6 (s), 118.2 (s), 115.8 (d), 115.0 (s), 112.4 (d), 105.7
(d), 55.0 (q), 23.1 (q).
MS (ESI): m/z (%) = 422 [M + Na]+.
HRMS (ESI): calcd for C23H17N3O4 [M + Na]+: 422.1111; found:
422.1118.
IR (KBr): 3330, 1759, 1696, 1619, 1564, 1532, 1432, 1398, 1340,
1296, 1205, 1179, 1144 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.13 (d, J = 2.2 Hz, 2 H), 7.83
(d, J = 2.9 Hz, 2 H), 7.26–7.35 (m, 5 H), 7.06 (d, J = 7.3 Hz, 2 H),
6.72 (d, J = 8.1 Hz, 2 H), 6.64 (t, J = 7.9 Hz, 2 H), 4.76 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 171.5 (s), 137.6 (s), 133.3 (s),
130.8 (d), 129.1 (d), 128.0 (d), 127.9 (d), 127.6 (s), 127.6 (s), 121.9
(d), 121.0 (d), 120.2 (d), 116.6 (s), 106.9 (s), 41.7 (t).
MS (EI, 70 eV): m/z (%) = 487 (92) [M+], 418 (4), 398 (4), 390 (6),
336 (4), 326 (6).
HRMS (ESI): calcd for C27H17Cl2N3O2 [M + Na]+: 508.0590:
found: 508.0592.
3,9-Difluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]car-
bazole-6-benzyl-5,7(6H)-dione (7d)
Yellow solid; yield: 73%; mp > 260 °C.
IR (KBr): 3408, 2924, 2854, 1748, 1698, 1628, 1584, 1483, 1383
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.77 (br s, 2 H), 8.55 (dd,
J = 9.7, 2.6 Hz, 2 H), 7.78 (dd, J = 8.9, 4.5 Hz, 2 H), 7.32–7.45 (m,
6 H), 7.25–7.31 (m, 1 H), 4.80 (s, 2 H).
Indolocarbazoles 7a–f; General Procedure Using Rh(III) as
Catalyst and Cu(II) as Re-oxidant
A solution of the bisindolylmaleimide 6a–f (0.12 mmol),
Cu(OAc)2·H2O (34 mg, 0.13 mmol), RhCl3·3H2O (4 mg, 0.005
mmol, 10 mol%) in DMF (10 mL) was heated to 120 °C (to 80–
13C NMR (100 MHz, DMSO-d6): d = 169.8 (s), 157.4 (d,
1JCF = 234.3 Hz, CF), 137.8 (s), 137.2 (s), 130.4 (s), 129.1 (d), 127.9
3
(d), 127.8 (d), 122.1 (d, JCF = 11.5 Hz, Cq), 119.0 (s), 115.8 (d,
Synthesis 2005, No. 12, 1959–1966 © Thieme Stuttgart · New York

1964
B. Witulski, T. Schweikert
PAPER
2
4JCF = 4.1 Hz, Cq), 115.3 (d, JCF = 25.7 Hz, CH), 113.8 (d,
3,9-Difluoro-12,13-dihydro-13-(b-D-glucopyranosyl)-5H-indo-
lo[2,3-a]pyrrolo[3,4-c]carbazole-6-methyl-5,7(6H)-dione (9)
Indolocarbazole 7b (451 mg, 1.20 mmol) was added to a suspension
of powdered KOH (228 mg, 4.07 mmol) and Na2SO4 (1.29 g, 9.06
mmol) in anhyd MeCN (10 mL) under a nitrogen atmosphere. The
reaction mixture was allowed to stir for 1 h at r.t. Then a solution of
2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl chloride (1.37 g, 2.40
mmol) in anhyd MeCN (20 mL) was added. The reaction mixture
was stirred at r.t. for 18 h, poured into aq (50 mL), and then extract-
ed with EtOAc (3 × 40 mL). The organic layer was washed with
H2O (40 mL), aq NaHCO3 (40 mL), H2O (40 mL) and brine (40
mL), dried (Na2SO4), filtered through a plug of Celite and concen-
trated. Purification by column chromatography (silica gel; petro-
leum ether–EtOAc, 3:1) afforded the benzyl protected 9.
3JCF = 8.8 Hz, CH), 109.3 (d, 2JCF = 25.0 Hz, CH), 41.1 (t).
MS (ESI): m/z (%) = 474 [M + Na]+.
HRMS (ESI): calcd for C27H15F2N3O2 [M + Na]+: 474.0125; found:
474.0128.
3,9-Dimethoxy-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-
c]carbazole-6-benzyl-5,7(6H)-dione (7e)
Orange solid; yield: 74%; mp > 260 °C.
IR (KBr): 3416, 3260, 2931, 1747, 1693, 1658, 1624, 1581, 1484,
1403, 1382 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.60 (br s, 2 H), 8.55 (d,
J = 2.6 Hz, 2 H), 7.74 (d, J = 8.7 Hz, 2 H), 7.25–7.46 (m, 5 H), 7.21
(dd, J = 8.8, 2.6 Hz, 2 H), 4.93 (s, 2 H), 3.92 (s, 6 H).
Yield: 784 mg (73%); yellow solid.
13C NMR (100 MHz, DMSO-d6): d = 170.2 (s), 154.4 (s), 138.1 (s),
135.6 (s), 130.1 (s), 129.1 (d), 127.7 (d), 127.7 (d), 122.4 (s), 118.7
(s), 116.9 (d), 116.0 (s), 113.3 (d), 106.5 (d), 56.0 (q), 41.1 (t).
MS (EI, 70 eV): m/z (%) = 475 (100) [M+], 460 (6), 453 (11), 432
(3), 415 (4), 292 (6), 237 (12), 92 (3), 73 (6).
Then palladium on charcoal (200 mg; 10% Pd/C) was added to a so-
lution of the benzyl protected 9 (600 mg, 0.67 mmol) in CHCl3–
MeOH (1:1; 20 mL). The mixture was stirred for 3 d in a hydrogen
atmosphere. Then the catalyst was filtered off, washed with MeOH
(60 mL) and the solvent was removed in vacuo. Purification by col-
umn chromatography (silica gel; EtOAc–MeOH, 50:1) afforded the
glycoside 9.
HRMS (EI, 70 eV): calcd for C29H21N3O4: 475.1532; found:
475.1539.
Yellow solid; yield: 233 mg (64%); mp 234–236 °C.
IR (KBr): 3329, 2925, 1745, 1690, 1624, 1586, 1482, 1380, 1326,
1288, 1249, 1188 cm–1.
12,13-Dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-6-ben-
zyl-5,7(6H)-dione (7f)
These data are in agreement with those published.17a,28
1H NMR (400 MHz, DMSO-d6): d = 11.76 (s, 1 H), 8.84 (dd,
J = 9.5, 2.5 Hz, 1 H), 8.77 (dd, J = 9.5, J = 2.6, 1 H), 8.03 (dd,
J = 9.5, 3.8 Hz, 1 H), 7.69 (dd, J = 8.9, 4.5 Hz, 1 H), 7.49 (m, 2 H),
6.30 (d, J = 8.8 Hz, 1 H), 6.10 (t, J = 3.9 Hz, 1 H), 5.42 (d, J = 4.6
Hz, 1 H), 5.16 (d, J = 5.5 Hz, 1 H), 4.95 (d, J = 5.5 Hz, 1 H), 3.95–
4.11 (m, 3 H), 3.82–3.86 (m, 1 H), 3.56–3.62 (m, 1 H), 3.46–3.52
(m, 1 H), 3.19 (s, 3 H).
Yellow solid; yield: 78%; mp > 260 °C.
1H NMR (400 MHz, DMSO-d6): d = 11.62 (br s, 2 H), 8.93 (d,
J = 8.0 Hz, 2 H), 7.74 (d, J = 8.1 Hz, 2 H), 7.52 (dt, J = 7.1, 1.3 Hz,
2 H), 7.38–7.41 (m, 2 H), 7.29–7.36 (m, 4 H), 7.23–7.27 (m, 1 H),
4.78 (s, 2 H).
13C (100 MHz, DMSO-d6): d = 170.1 (s), 170.0 (s), 157.5 (d,
1,11-Dichloro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-
c]carbazole-6-benzyl-5,7(6H)-dione (7g)
Yellow solid; yield: 44%; mp > 260 °C.
2
2JCF = 234.3 Hz), 157.5 (d, JCF = 234.3 Hz, CH), 139.2 (s), 137.8
3
(s), 131.0 (s), 129.5 (s), 122.1 (d, JCF = 11.5 Hz), 121.7 (d,
3JCF = 10.8 Hz), 120.8 (s), 119.1 (s), 118.5 (d, 4JCF = 4.1 Hz), 117.1
IR (KBr): 3422, 2926, 2761, 1694, 1598, 1492, 1455, 1405, 1388,
1357 cm–1.
1H NMR (400 MHz, CDCl3): d = 11.19 (br s, 2 H), 8.92 (d, J = 7.8
Hz, 2 H), 7.53–7.51 (m, 2 H), 7.41 (m, 2 H), 7.32–7.24 (m, 3 H),
7.21 (t, J = 7.8 Hz, 2 H), 4.91 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 169.7 (s), 137.5 (s), 137.4 (s),
129.2 (s), 128.6 (d), 128.5 (d), 127.5 (s), 125.9 (d), 123.9 (d), 123.7
(d), 121.1 (d), 119.9 (s), 116.7 (s), 116.0 (s), 41.4 (t).
4
2
2
(d, JCF = 4.7 Hz), 115.7 (d, JCF = 25.0 Hz), 115.3 (d, JCF = 25.7
3
3
Hz), 113.8 (d, JCF = 8.8 Hz), 113.8 (d, JCF = 8.8 Hz), 109.6 (d,
2JCF = 25.0 Hz), 109.6 (d, JCF = 25.7 Hz), 85.2 (d), 79.1 (d), 77.0
2
(d), 73.7 (d), 68.0 (d), 58.8 (t), 24.2 (q).
MS (ESI): m/z (%) = 560 [M + Na]+.
HRMS (ESI): calcd for C27H21F2N3O7 [M + Na]+: 560.1240; found:
560.1248.
HRMS (ESI): calcd for C27H15O2N3Cl2 [M + Na+]: 506.0434;
found: 506.0429.
3,9-Difluoro-11,12-dihydro-12-(b-D-glucopyranosyl)indolo[2,3-
a]carbazole-5,6-dicarboxylic Anhydride (10)
The glycoside 9 (193 mg, 0.36 mmol) was dissolved in aq KOH (2
M; 20 mL) at r.t. and the resulting solution was stirred overnight.
The solution was acidified with aq HCl (2 M) and extracted with
EtOAc–MEK (30 mL; 1:1) and the organic layer was washed with
brine (30 mL), dried (MgSO4) and concentrated. The residual solid
was washed with CHCl3 (40 mL) to obtain the anhydride 10 (130
mg).
Indolocarbazoles 7a,d,f; General Procedure Using Rh(III) as
Catalyst, Cu(II) as Co-catalyst and Oxygen as Re-oxidant
A 100 mL 3-necked flask was equipped with a condenser and was
charged with bisindolylmaleimide 6a, d or f (0.15 mmol),
RhCl3·3H2O (2 mg, 0.008 mmol, 5 mol%) Cu(OAc)2·H2O (16 mg,
20 mol%) and DMF (40 mL). The resulting suspension was heated
to 90–110 °C while oxygen was sparged into the reaction mixture.
The reaction was performed until TLC indicated the complete con-
sumption of the bisindolylmaleimide 6 (4 h). Thereafter, the reac-
tion mixture was poured into aq HCl (0.2 M; 40 mL) and extracted
with EtOAc (3 × 30 mL). The organic phase was washed with aq
NaHCO3 (30 mL), H2O (30 mL) and brine (30 mL), dried (MgSO4),
filtrated through a plug of Celite and concentrated in vacuo. The res-
idue was purified by column chromatography (silica gel; petroleum
ether–EtOAc) to give the indolocarbazoles 7a, 7d, and 7f in 53%,
47%, and 75% yield, respectively.
Orange solid; yield: 71%; mp > 260 °C.
IR (KBr): 3443, 3312, 2916, 1820, 1749, 1620, 1587, 1486, 1389,
1347, 1321, 1288 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.00 (br s, 1 H), 8.61 (dd,
J = 9.5, 2.6 Hz, 1 H), 8.55 (dd, J = 9.5, 2.6 Hz, 1 H), 8.09 (dd,
J = 9.2, 4.4 Hz, 1 H), 7.75 (dd, J = 8.8 Hz, J = 4.6 Hz, 1 H), 7.52–
7.58 (m, 2 H), 6.37 (d, J = 8.8 Hz, 1 H), 6.18 (br s, 1 H), 5.45 (br s,
1 H), 5.18 (d, J = 4.8 Hz, 1 H), 4.99 (d, J = 5.3 Hz, 1 H), 4.11 (d,
J = 11.0 Hz, 1 H), 3.96–4.02 (m, 2 H), 3.87 (d, J = 10.2 Hz, 1 H),
3.56–3.64 (m, 1 H), 3.40–3.48 (m, 1 H).
Synthesis 2005, No. 12, 1959–1966 © Thieme Stuttgart · New York

PAPER
Indolo[2,3-a]pyrrolo[3,4-c]carbazoles by Oxidative Cyclization
1965
13C NMR (100 MHz, DMSO-d6): d = 165.0 (s), 164.9 (s), 157.7 (d,
1JCF = 234.8 Hz), 139.1 (s), 139.1 (s), 137.7 (s), 131.8 (s), 130.4 (s),
121.7 (d, 3JCF = 11.5 Hz), 121.2 (d, 3JCF = 10.7 Hz), 119.8 (s), 118.4
(2) (a) Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya,
J.; Tsuchiya, H.; Takahashi, Y.; Masuma, R. J. Antibiot.
1977, 30, 275. (b) Furusaki, A.; Hashiba, N.; Matsumoto, T.
J. Chem. Soc., Chem. Commun. 1978, 800. (c) Schupp, P.;
Eder, C.; Proksch, P.; Wray, V. V.; Schneider, B.; Herderich,
M.; Paul, V. J. Nat. Prod. 1999, 62, 959.
4
4
(d, JCF = 3.8 Hz), 118.1 (s), 117.0 (d, JCF = 4.6 Hz), 116.3 (d,
2JCF = 25.2 Hz), 115.9 (d, 2JCF = 26.0 Hz), 114.4 (d, 3JCF = 9.2 Hz),
3
2
114.4 (d, JCF = 9.2 Hz), 108.8 (d, JCF = 25.2 Hz), 108.7 (d,
2JCF = 25.2 Hz), 85.2 (d), 79.2 (d), 76.9 (d), 73.9 (d), 68.0 (d), 58.7
(3) For total syntheses, see: (a) Link, J. T.; Raghavan, S.;
Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 552.
(b) Link, J. T.; Raghavan, S.; Gallant, M.; Chou, T. C.;
Ballas, L. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1996,
118, 2825. (c) Wood, J. L.; Stoltz, B. M.; Goodman, S. N. J.
Am. Chem. Soc. 1996, 118, 10656. (d) Wood, J. L.; Stoltz,
B. M.; Goodman, S. N.; Onwueme, K. J. Am. Chem. Soc.
1997, 119, 9652.
(4) Omura, S.; Iwai, Y.; Hirano, A. Japan Kokai 7873,501,
1978; Chem. Abstr. 1978, 89, 178086h.
(5) Oka, S.; Kodama, M.; Takeda, H.; Tomizuka, N.; Suzuki, H.
Agric. Biol. Chem. 1986, 50, 2723.
(6) (a) Hung, D. T.; Jamison, T. F.; Schreiber, S. L. Chem. Biol.
1996, 3, 623. (b) Tamaoki, T.; Nomoto, H.; Takahashi, I.;
Kato, Y.; Morimoto, M.; Tomita, F. Biochem. Biophys. Res.
Commun. 1986, 135, 397. (c) Yamada, S.; Hirota, K.;
Chida, K.; Kuroki, T. Biochem. Biophys. Res. Commun.
1988, 157, 9. (d) Fujita-Yamaguchi, Y.; Kathuria, S.
Biochem. Biophys. Res. Commun. 1988, 157, 955.
(e) Sanchez-Martinez, C.; Shih, C.; Zhu, G.; Li, T.; Brooks,
H. B.; Patel, B. K. R.; Schultz, R. M.; DeHahn, T. B.;
Spencer, C. D.; Watkins, S. A.; Ogg, C. A.; Considine, E.;
Dempsey, J. A.; Zhang, F. Bioorg. Med. Chem. Lett. 2003,
13, 3841.
(7) (a) Bush, J. A.; Long, B. H.; Cationo, J. J.; Bradner, W. T.;
Tomita, K. J. Antibiot. 1987, 40, 668. (b) Nettleton, D. E.;
Doyle, T. W.; Krishnan, B.; Matsumoto, G. K.; Clardy, J.
Tetrahedron Lett. 1985, 26, 4011. (c) Pommier, Y. Curr.
Med. Chem.: Anti-Cancer Agents 2004, 4, 429.
(t).
MS (ESI): m/z (%) = 547 [M + Na]+.
HRMS (ESI): calcd for C26H18F2N2NaO8 [M + Na]+: 547.0929;
found: 547.0937.
3,9-Difluoro-6,12,13-trihydro-13-(b-D-glucopyranosyl)-5H-in-
dolo[2,3-a]pyrrolo-[3,4-c]carbazole-5,7(6H)-dione (3)
In a Schlenk tube with screw cap, the anhydride compound 10 (65
mg, 0.12 mmol) was heated with ammonium acetate (1 g, 13.0
mmol) for 2 h at 140 °C. The mixture was cooled and extracted with
EtOAc–MEK (40 mL; 1:1) after the addition of H2O (20 mL). The
organic layer was washed with brine (20 mL), dried (MgSO4) and
concentrated. Purification by column chromatography (silica gel;
EtOAc–MeOH, 50:1) afforded the fluoroindolocarbazole 3.
These data are in agreement with those published.9
Yellow solid; yield: 51 mg (83%); mp 257–259 °C.
IR (KBr): 3330, 2924, 2854, 1746, 1712, 1621, 1586, 1482, 1621,
1586, 1482, 1390, 1325, 1287 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.74 (s, 1 H), 11.21 (s, 1 H),
8.84 (dd, J = 9.6, 2.5 Hz, 1 H), 8.76 (dd, J = 9.6, 2.5 Hz, 1 H), 8.00
(dd, J = 9.4, 4.3 Hz, 1 H), 7.67 (dd, J = 8.8, 4.5 Hz, 1 H), 7.43–7.48
(m, 2 H), 6.28 (d, J = 9.0 Hz, 1 H), 6.07 (t, J = 3.7 Hz, 1 H), 5.39 (d,
J = 4.3 Hz, 1 H), 5.14 (d, J = 5.5 Hz, 1 H), 4.93 (d, J = 5.5 Hz, 1 H),
4.06–4.10 (m, 1 H), 3.94–4.01 (m, 2 H), 3.81–3.83 (m, 1 H), 3.55–
3.60 (m, 1 H), 3.45–3.51 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 171.5 (s), 171.4 (s), 157.5 (d,
(d) Voldoire, A.; Moreau, P.; Sancelme, M.; Matulova, M.;
Léonce, S.; Pierré, A.; Hickman, J.; Pfeiffer, B.; Renard, P.;
Dias, N.; Bailly, C.; Prudhomme, M. Bioorg. Med. Chem.
2004, 12, 1955. (e) Woo, M. H.; Vance, J. R.; Otero Marcos,
A. R.; Bailly, C.; Bjornsti, M.-A. J. Biol. Chem. 2002, 277,
3813. (f) Moreau, P.; Anizon, F.; Sancelme, M.;
Prudhomme, M.; Sevère, D.; Riou, J.-F.; Goossens, J.-F.;
Hénichart, J.-P.; Bailly, C.; Labourier, E.; Tazzi, J.; Fabbro,
D.; Meyer, T.; Aubertin, A. M. J. Med. Chem. 1999, 42,
1816. (g) Bailly, C.; Riou, J.-F.; Colson, P.; Houssier, C.;
Rodrigues-Pereira, E.; Prudhomme, M. Biochemistry 1997,
36, 3917. (h) Faul, M. M.; Sullivan, K. A.; Grutsch, J. L.;
Winneroski, L. L.; Shih, C.; Sanchez-Martinez, C.; Cooper,
J. T. Tetrahedron Lett. 2004, 45, 1095.
1
1JCF = 234.0 Hz), 157.5 (d, JCF = 234.0 Hz), 139.1 (s), 137.7 (s),
131.1 (s), 129.6 (s), 122.2 (d, 3JCF = 10.7 Hz), 121.8 (d, 3JCF = 11.5
4
Hz), 121.8 (s), 120.1 (s), 118.4 (d, JCF = 3.8 Hz), 117.1 (d,
4JCF = 4.6 Hz), 115.6 (d, 2JCF = 25.2 Hz), 115.2 (d, 2JCF = 25.2 Hz)
3
3
113.8 (d, JCF = 8.4 Hz), 113.8 (d, JCF = 8.4 Hz), 109.7 (d,
2JCF = 25.2 Hz), 109.7 (d, 2JCF = 25.2 Hz), 85.2 (d), 79.1 (d), 77.0
(d), 73.7 (d), 68.0 (d), 58.8 (t).
HRMS (ESI): calcd for C26H19F2N3O7 [M + Na+]: 546.1083; found:
546.1084.
Acknowledgment
Financial support of this work by the Fonds der Chemischen
Industrie is gratefully acknowledged.
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