Synthesis of benzo analogs of oxoarcyriaflavins and caulersine

Article abstract of DOI:10.1016/j.tet.2007.06.118

In the course of a program aimed at designing new antitumor agents, we were interested in the synthesis of mixed structures of maleimidophenyl carbazoles and natural product caulersine as potential CDK inhibitors. This was performed through an efficient f

Full text of DOI:10.1016/j.tet.2007.06.118

Tetrahedron 63 (2007) 9465–9475
Synthesis of benzo analogs of oxoarcyriaflavins and caulersine
*
Aurelie Bourderioux, Sylvain Routier, Valerie Beneteau and Jean-Yves Merour
*
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
´
Institut de Chimie Organique et Analytique, UMR-CNRS 6005, Universite d’Orleans, B.P. 6759, 45067 Orleans Cedex 2, France
´
´
Received 1 June 2007; revised 26 June 2007; accepted 27 June 2007
Available online 30 July 2007
Abstract—In the course of a program aimed at designing new antitumor agents, we were interested in the synthesis of mixed structures of
maleimidophenyl carbazoles and natural product caulersine as potential CDK inhibitors. This was performed through an efficient four-step
sequence starting from indole or 3-formyl-N-Boc indole. 5H-Benzocycloheptaindol-6-one derivatives equipped with a fused maleimide
(oxophenylarcyriaflavins) or a methyl ester (benzo analog of caulersine) on the central tropone ring were thus obtained.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
acceptor hydrogen bonding groups (NH/C]O), well known
to be essential to interact with the ATP binding pocket. For
this purpose, we chose to increase the size of the central
ring from C-6 to C-7, incorporating as well a ketone func-
tionality (VIII). This original structure can be related to (i)
homoarcyriaflavins (V), a patented tyrosine kinase inhibi-
tor,6 (ii) a natural marine product caulersine7 (VI) for which
no biological data are available, and (iii) a suberenone
series8 (VII) developed in our laboratory some years ago
(Fig. 2). In order to evaluate the indole tropone core on its
own, without the additional maleimide moiety, we achieved
as well the synthesis of IX, a phenyl analog of caulersine.
Since the isolation and characterization of rebeccamycin I in
1985, much attention has been paid by the scientific commu-
nity to this alkaloid and the whole series of natural or syn-
thetic indolocarbazoles (ICZs).1 Indeed, rebeccamycin I
was found to be active against leukemia and melanoma im-
planted in mice and proved to be a lead compound to develop
topoisomerase I inhibitors but aglycones of ICZs exhibit dif-
ferent activities (Fig. 1). For example, natural product arcyr-
iaflavin A II is active against HCMV and inhibits CDK4/
Cyclin D1 (IC50¼140 nM).2 Interestingly, Cyclin Depen-
dent Kinases (CDKs), as key enzymes for the progression
through each stage of the cell division cycle, are major tar-
gets to prevent uncontrolled cellular proliferation.3
The retrosynthetic pathway to access type VIII and type IX
compounds is shown in Scheme 1.9 The tropone central ring
would result from an electrophilic cyclization of an acylium
Recently, Zhu and Sanchez-Martinez developed a series of
(hetero)arylanalog of arcyriaflavin A II endowed with note-
worthyCDK4/cyclin D1inhibitoryactivities(IC50<100 nM).4
H
H
N
N
O
O
O
O
As part of our research program aimed at designing modified
aglycones of ICZs as potential anticancer agents, we re-
cently evaluated a series of naphtho and phenyl carbazoles
III and IV.5 Most of these compounds showed good cyto-
toxic activities (L1210, CEM) and DNA intercalation.
Among both series, one derivative (IV, R1¼OH, R2¼H)
proved to inhibit a test set of kinases (CDK1 and 5, GSK-
3) in the submicromolar range.
N
H
N
N
Cl
N
H
H
Cl
O
II : Arcyriaflavin A
OH
OH
OMe
HO
R2
N
O
O
I : Rebeccamycin
R2
N
R1
Following these preliminary results, we wanted to modulate
the biological target of the phenyl carbazole series from
DNA intercalation to CDKs’ inhibition by a slight modifica-
tion of the planarity and the addition of a close pair of donor/
O
O
N
H
R1
III : naphtocarbazoles
N
H
* Corresponding authors. Tel.: +33 02 38494853; fax: +33 02 38417281;
e-mail addresses: sylvain.routier@univ-orleans.fr; valerie.beneteau@
univ-orleans.fr
IV : phenyl carbazoles
Figure 1. Most representative indolocarbazoles and derivatives.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.118

9466
A. Bourderioux et al. / Tetrahedron 63 (2007) 9465–9475
H
N
O
the addition reaction, and the last 1 equiv serves for rearoma-
tization. Indeed, in our hands, the use of 4 equiv of magne-
siated indole with 3,4-dibromomaleimide 3 in THF at
room temperature afforded the bromomaleimidoindole 5
in a very satisfying 89% yield (Table 1, entry 2). Yet, the
need for such an excess of magnesiated indole proved to
be a major drawback for this reaction considering the further
involvement of more elaborated indolic starting materials.
Replacing the Grignard base for LiHMDS appeared as
a good alternative in order to reduce the required amount
of the indolic derivative. Applying the same procedure
(entry 1) but adding one additional equivalent of base for
the maleimide nitrogen led to the formation of the desired
product 5 in 31% yield (Table 1, entry 3). A further increase
of the amount of base (5.3 equiv) and shifting from THF to
toluene allowed the isolation of 5 in 84% yield (Table 1,
entries 4 and 5).
O
MeO
H
N
O
N
H
N
H
O
N
H
V : Homoarcyriaflavin
VI : caulersine
R
N
O
N 1 or 2
VII: R=H, OCH3
O
CO2CH3
X
N
O
R
O
N
N
H
R
N
O
O
O
R1
IX: phenyl analogue
of caulersine
O
O
a
Br
+
VIII: oxophenyl arcyriaflavins
X=O, NR2
N
H
Br
Br
N
H
Figure 2. Natural (VI) or synthetic (V, VII) models and targeted compounds
(VIII and IX).
1
2: R=CH3
3: R=H
4: R=CH3
5: R=H
CO2CH3
Br
intermediate onto C-2 of the indole moiety. Acid derivatives
(X, XI) would arise from a palladium cross-coupling be-
tween 2-formylphenyl boronic acid or a stannylated counter-
part and a bromoindolic partner (XII or XIII), followed by
an oxidation step. 3-Bromomaleimide indole XII would be
formed from indole and 3,4-dibromomaleimide. Meanwhile,
3-bromoacrylate indole XIII would result from a Wittig type
reaction from 3-formylindole.
CHO
b
Ph3P=CH-CO2CH3
+
N
Boc
N
Boc
6
7
Scheme 2. (a) See Table 1, entries 1–5. (b) NBS (1.6 equiv), K2CO3
(2.5 equiv), CH2Cl2, 0 ꢀC to rt, 30 h, 94%.
Z'
Z
Z'
Z'
CO2H
Z
Z
Br
R2
+
N
R1
N
CHO
N
H
O
H
R2=B(OH)2,SnBu3
XII: Z,Z'=COXCO,X=NH,NCH3,R1=H
XIII: Z=H,Z'=CO2CH3,R1=Boc
X: Z,Z'=COXCO,X=O,NH,NCH3
XI: Z=H,Z'=CO2CH3
VIII: Z,Z'=COXCO,X=O,NH,NCH3
IX: Z=H,Z'=CO2CH3
Scheme 1. Retrosynthetic pathway for type VIII and type IX compounds.
2. Results and discussion
As far as the synthesis of phenyl caulersine is considered, the
bromomethyl acrylate functionality of compound 7 could re-
sult from a Wittig type reaction from N-Boc-3-formylindole
613 and an in situ prepared bromo phosphoylide.14 The re-
quired (Z)-isomer could be obtained in an excellent 94%
yield after recrystallization from methanol to remove traces
of the minor (E)-isomer.
2.1. Access to the bromide derivatives
type XII and type XIII
Monoindolyl maleimide bromide 410 was obtained in 91%
yield from indole 1 and 3,4-dibromo-N-methyl maleimide
2 using a known procedure in the presence of LiHMDS
(2.1 equiv) in THF (Scheme 2 and Table 1, entry 1).11 The
access to its demethylated counterpart 5 had briefly been
mentioned previously. Faul in 1995 and then Davioud-
Charvet in 1998 reported the isolation of 5 or its chloro an-
alog from unprotected 3,4-dibromo(or dichloro)maleimide
and 4 equiv of the bromide magnesium salt of indole.12 Ac-
tually, to synthesize 5 from indole and 3, at least 3 equiv of
magnesiated indole salt is required because 1 equiv is con-
sumed by the maleimide nitrogen, 1 equiv is needed for
2.2. Palladium catalyzed cross-couplings
The next step involved a palladium cross-coupling between
bromomaleimidoindole 4 or 5 or bromoacrylate indole 7 and
commercially available 2-formylphenyl boronic acid 8.
Suzuki coupling between 7 and 8 turned out to be very effi-
cient in the presence of Pd(PPh3)4 and K2CO3 in a mixture of
dioxane and water and led to 9 (Scheme 3).

A. Bourderioux et al. / Tetrahedron 63 (2007) 9465–9475
9467
Table 1. Experimental conditions for anionic reaction (entries 1–5), Suzuki reactions (entries 6–10), preparation of stannylated benzaldehyde (entries 11–13),
and Stille reactions (entry 14)
Entry
Reagent
Conditions
Time
Product
(yield,a %)
1
2
3
4
5
1 (1.0 equiv)
1 (4.0 equiv)
1 (1.7 equiv)
1 (1.7 equiv)
1 (1.7 equiv)
(a) LiHMDS (2.1 equiv), THF, ꢁ15 ꢀC
(a) 45 min
(b) 1 h
(a) 2 h
(b) 1 h
(a) 45 min
(b) 2 h
(a) 45 min
(b) 2 h 15
(a) 1 h
4 (91)
5 (89)
5 (31)
5 (76)
5 (84)
(b) 2 (1.0 equiv), THF, ꢁ15 to 0 ꢀC
(a) EtMgBr (4.0 equiv), THF, 60 ꢀC
(b) 3 (1.0 equiv), THF, rt
(a) LiHMDS (3.5 equiv), THF, ꢁ15 ꢀC
(b) 3 (1.0 equiv), THF, ꢁ15 ꢀC, 1 h 30 min and then 0 ꢀC, 30 min
(a) LiHMDS (5.3 equiv), THF, ꢁ15 ꢀC
(b) 3 (1.0 equiv), THF, ꢁ15 ꢀC, 15 min and then rt, 2 h
(a) LiHMDS (5.3 equiv), toluene, ꢁ15 ꢀC
(b) 3 (1.0 equiv), THF, ꢁ15 ꢀC, 15 min and then rt, 2 h
(b) 3 h 45 min
6
7
4
4
8 (1.5 equiv), K2CO3 (1.8 equiv), Pd(OAc)2 (0.1 equiv), diox/H2O (85/15), reflux
8 (1.5 equiv), K2CO3 (1.8 equiv), Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv), diox/H2O
(85/15), reflux
6 h
4 h
10 (72)
10 (74)
8
9
10
4
5
5
8 (1.5 equiv), K2CO3 (1.8 equiv), Pd(PPh3)4 (0.1 equiv), diox/H2O (85/15), reflux
8 (1.5 equiv), K2CO3 (1.8 equiv), Pd(PPh3)4 (0.1 equiv), diox/H2O (85/15), reflux
8 (1.5 equiv), K2CO3 (1.8 equiv), Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv), diox/H2O
(85/15), reflux
5 h
3 h 30 min
3 h
10 (59)
11 (27)
11 (33)
11
12
12
12
Sn2Bu6 (1.1 equiv), PdCl2(PPh3)2 (0.1 equiv), THF, reflux
(a) Sn2Bu6 (1.1 equiv), PdCl2(PPh3)2 (0.1 equiv), THF, reflux
(b) LiCl (0.5 equiv), THF, reflux
48 h
13 (30)
13 (54)
(a) 24 h
(b) 24 h
24 h
13
12
5
Sn2Bu6 (1.1 equiv), Pd(PPh3)4 (0.1 equiv), toluene, reflux
13 (57)
11 (54)
14
13 (1.5 equiv), PdCl2(PPh3)2 (0.1 equiv), CuI (0.1 equiv), dioxane, reflux
24 h
Yields are given in isolated products and fully characterized by IR, 1H NMR, 13C NMR, and MS.
a
CO2CH3
CHO
9 and 10). In order to optimize the formation of 11, we
shifted from a Suzuki cross-coupling reaction to a Stille
coupling involving trialkylstannane 13. To prepare 13,15
we performed a Pd-catalyzed halogen–tin exchange from
2-bromobenzaldehyde 12 using the known procedures. The
use of PdCl2(PPh3)2 as a catalyst16 led to a mixture of start-
ing material and stannylated product 13, the reaction would
not evolve further after 48 h (Table 1, entry 11). When lith-
ium chloride (0.5 equiv) was added after 24 h, the stannyl-
ated product 13 was obtained in 54% yield (Table 1, entry
12). Using Pd(PPh3)4 instead of PdCl2(PPh3)2, and shifting
from THF to toluene, allowed the isolation of 13 in approxi-
mately the same yield (57%, Table 1, entry 13).17 The
Stille coupling between 13 and 5 was then performed in
standard conditions. Using 1.5 equiv of 13, 0.2 equiv of
PdCl2(PPh3)2, and 0.1 equiv of copper(I) iodide in dioxane
at room temperature for 24 h allowed the isolation of 11 in
54% yield (Table 1, entry 14). Actually, both routes (Suzuki,
one step or Stille, two steps) allowed the synthesis of the un-
protected diaryl maleimide 11 from 5 in nearly the same
yield (33 and 31%, respectively). Even if the efficiency of
either type of coupling is modest, they would not require
the use of a protecting group on both nitrogens.
CO2CH3
Br
a
N
Boc
9
N
Boc
7
R
N
R
N
O
O
CHO
O
O
Br
b
N
H
N
H
10, R = CH3
11, R = H
4, R = CH3
5, R = H
SnBu3
Br
c
CHO
CHO
13
12
Scheme 3. (a) 2-Formylphenyl boronic acid 8 (2 equiv), K2CO3 (4 equiv),
Pd(PPh3)4 (0.1 equiv), diox/H2O, 70 ꢀC, 2 h, 89%. (b) See Table 1, entries
6–10 and 14. (c) See Table 1, entries 11–13.
In ligandless conditions, previously used by us for a similar
coupling,5 bromo compound 4, heated in a mixture of diox-
ane and water in the presence of the boronic acid (1.5 equiv),
potassium carbonate (1.8 equiv), and palladium acetate
(0.1 equiv), afforded the desired coupled product 10 in
72% yield (Table 1, entry 6). In the presence of triphenyl-
phosphine (0.2 equiv) as a ligand, the yield proved nearly
the same (Table 1, entry 7). Changing the catalytic system
for palladium tetrakis triphenylphosphine (0.1 equiv) de-
creased the yield to 59% (Table 1, entry 8).
2.3. Electrophilic reaction
The next step was aimed at generating a C-2 indolic carbonyl
function. To do so, several useful methods are available from
a carboxylic acid function through the generation of an acyl-
ium ion, which can undergo a Friedel–Crafts type reaction
at electron rich C-2 position of NH indoles via a direct attack
or a C-3 attack followed by rearrangement.8,18
The same coupling starting from demethylated compound 5
proved more challenging. Indeed, whatever Pd[0] catalytic
system used, the yield never exceeded 33% (Table 1, entries
The oxidation step from aldehydes 9–11 was achieved using
sodium chlorite and sulfamic acid in a cold mixture of diox-
ane and water for a few minutes (Scheme 4).19 Especially for

9468
A. Bourderioux et al. / Tetrahedron 63 (2007) 9465–9475
the formation of acids 14 and 15, we noticed that a careful
control of both temperature and reaction time is required
in order to avoid degradation of the reaction mixture. Acids
14 and 15 were thus obtained in 81 and 62% yield, respec-
tively. Acid 18 was quantitatively generated by the same
way without purification.
O
N
O
Br
a
16
N
H
O
21
Scheme 5. (a) NBS (15 equiv), THF, 0 ꢀC to rt, 4 days, 55%.
R
N
R
O
O
N
R'
O
O
alkylate selectively the indolic or the maleimido nitrogen.
Indeed, 16 could be efficiently alkylated on the indolic nitro-
gen using sodium hydride as a base and 2-dimethylami-
noethyl chloride as the electrophilic partner in DMF at
95 ꢀC (Scheme 6). An efficient and selective N-alkylation
of the maleimide moiety of 17 proved more problematic.
The best conditions found were the use of potassium carbon-
ate as a base in a mixture of DMF and toluene (1/1) at 65 ꢀC.
Thus, monoalkylated product 23 was isolated in 34% yield,
accompanied with a few amount of dialkylated compound
24 (9% yield). Adding NaI (0.1 equiv) and changing potas-
sium carbonate for sodium hydride led to the same global
yield (43%) but decreased the chemoselectively (ratio 23/
24¼3/7).
b
N
H
N
H
O
10, R = CH3, R' = CHO
11, R = H, R' = CHO
16, R = CH3
17, R = H
a
a
14, R = CH3, R' = CO2H
15, R = H, R' = CO2H
CO2CH3
CO2CH3
R'
d
N
H
O
N
R
20
9, R = Boc, R' = CHO
a
c
18, R = Boc, R' = CO2H
19, R = H, R' = CO2H
In order to selectively introduce the N,N-dimethylaminoethyl
chain on the maleimide nitrogen, we planned to perform
a trans-imidification from 16, by reaction with a large excess
of N,N-dimethylethylene diamine in DMF at 160 ꢀC in
a sealed tube. Surprisingly, an unexpected product corre-
sponding to the reduction of the carbonyl function (25) was
isolated in 41% yield (Table 2, entry 4). When the same
reaction was carried out in forcing conditions using the amine
as the solvent at reflux for 22 h, product 26 was obtained in
48% yield (Table 2, entry 5). It corresponds to the reduced
productwith theaminoalkyl chain on the maleimide nitrogen.
Scheme 4. (a) NH2SO3H (8 equiv), NaClO2 (2.2 equiv), dioxane/water,
5 ꢀC, from 10 (1 min): 14, 81%; from 11 (1 min): 15, 62%; from 9
(10 min): 18, quantitative. (b) BF3$Et2O (40 equiv), DCE, reflux, from 14
(5 h 30 min): 16, 89%; from 15 (20 h): 17, 86%. (c) TFA, CH2Cl2, r.t.,
24 h, 19, 26%. (d) PPSE (see Section 4), CH3NO2, reflux, 10 min, 44%
from 18.
Tropone ring closure was then performed using a large
excess of BF3$Et2O in refluxing dichloroethane from acids
14 and 15, leading to pentacycles 16 and 17 in 89 and
86% yield, respectively. The same cyclization type reaction
from 18 required the preliminary removal of the Boc protec-
tive group. This was achieved using trifluoroacetic acid in
dichloromethane in a very disappointing 26% yield. Then,
the electrophilic cyclization was tried using polyphosphoric
acid (PPA) or a mixture of trifluoroacetic anhydride and
acid, both conditions resulting in the degradation of the reac-
tion mixture. We assumed that we needed cyclization condi-
tions that could both remove the Boc group and generate the
acylium ion in milder conditions. This was performed using
trimethylsilyl polyphosphate (PPSE) in nitromethane. In-
deed, compound 20 was obtained from 18 in 44% yield.
We previously observed that the introduction of the amino-
alkyl chain on the maleimide nitrogen was more efficient
from the cyclic anhydride than from the N-methylmale-
imide. Anhydride 27 was then generated from 16 using aque-
ous potassium hydroxide in acetone at room temperature,
Table 2. Reactions performed on 16, 17, and 27
Entry Reactant Conditions
Products
(yield, %)
1
2
3
16
16
17
NBS (15 equiv), THF, 0 ꢀC to
rt, 4 days
Cl(CH2)2N(CH3)2 (2.5 equiv), NaH 22 (84)
(5.1 equiv), DMF 95 ꢀC, 9 h
Cl(CH2)2N(CH3)2 (2 equiv), K2CO3 23 (34), 24 (9)
(1.0 equiv), DMF/toluene 1/1,
65 ꢀC, 24 h
20 (56)
2.4. Functionalization of compounds 16 and 17
In a related indolocarbazole series, a direct and chemoselec-
tive bromination or nitration in para position of the indolic
nitrogen could be achieved using N-bromosuccinimide and
nitric acid, respectively.20 Applied to 16, the bromination
conditions (Scheme 5 and Table 2, entry 1) led to 21 in
55% yield. The position of the bromine atom could be con-
firmed by 2D NMR experiments (COSY, HMBC). An at-
tempt of electrophilic nitration (HNO3 in Et2O) led to an
untractable mixture of products.
4
16
N,N-Dimethylethylene diamine
(16 equiv), DMF in a sealed tube,
160 ꢀC, 22 h
25 (41)
5
6
16
16
N,N-Dimethylethylene diamine
(65 equiv), reflux, 22 h
Aq KOH (40 equiv), acetone,
rt, 24 h and then
26 (48)
27 (quant)
aq HCl, rt, 12 h
7
8
27
27
N,N-Dimethylethylene diamine
(14 equiv), DMF in a sealed
tube, 160 ꢀC, 18 h
N,N-Dimethylethylene diamine
(114 equiv), reflux, 64 h
23 (59)
26 (86)
Having in mind the introduction of solubilizing side chains
on the heterocyclic core of 16 and 17, we envisaged to

A. Bourderioux et al. / Tetrahedron 63 (2007) 9465–9475
9469
R
N
equipped with a fused maleimide or a methyl ester on the
central tropone ring. Maleimido pentacycles could be
mono- or bis-alkylated with a solubilizing N,N-dimethyl
aminoethyl side chain, while an unexpected reduction of
the cyclic ketone was observed in some cases. Further explo-
ration is in progress to elucidate this unusual reactivity.
O
O
O
b or c
16 or 17
N
R'
22, R=CH3, R'=(CH2)2N(CH3)2
23, R=(CH2)2N(CH3)2, R'=H
24, R=R'=(CH2)2N(CH3)2
R
Preliminary biological results on compounds 16, 17, 21–26
showed disappointing CDK (1 or 5) inhibitions (>2 mM)
meanwhile derivative 23 exhibited a noteworthy micromolar
cytotoxicity (F1 epithelial biliary cell line IC50 2 mM after
48 h). New developments on the topic will be reported in
due course.
O
N
O
d or e
16
g
H
N
H
H
4. Experimental section
4.1. Chemistry
25, R=CH3
26, R=(CH2)2N(CH3)2
O
O
O
h
1H and 13C NMR spectra were recorded on a Bruker Avance
DPX 250 or 500 instrument using CDCl3 or DMSO-d6. The
chemical shifts are reported in parts per million (d scale) and
all J values are in hertz. Melting points are uncorrected. IR
absorption spectra were recorded on a Perkin–Elmer FT
f
16
N
H
O
27
Scheme 6. For reagents and conditions, see Table 2, entries 2–8.
PARAGON 1000 PC and values were reported in cmꢁ1
.
MS spectra (Ion Spray) were performed on a Perkin–Elmer
SCIEX API 300. HRMS were carried out by the Centre
followed by recyclization in acidic medium (Table 2, entry
6). In the same conditions, it appeared that the N,N-dimethyl-
aminoethyl chain could be introduced on the top part of
the molecule affording 23 (Table 2, entry 7). In forcing
conditions (Table 2, entry 8), derivative 26, with a deoxy-
genated central ring, could be isolated in 86% yield.
Indeed, in the case of more electrophilic anhydride com-
pared to N-methylmaleimide, the imidification occurs be-
fore the reduction.
ꢀ
Regional de Mesures Physiques de l’Ouest (CRMPO, Ren-
nes) on a High Resolution Mass Spectrometer with double
focalization Varian Mat 311 using Electronic Impact. Mon-
itoring of the reactions was performed using silica gel TLC
plates silica Merck 60 F254. Spots were visualized by UV
light at 254 and 365 nm. Column chromatographies were
performed using silica gel 60 (40–63 mm, Merck). Only
the non-available products are described (not found in
CAS online).
To our knowledge, this reduction of a cyclic aromatic ketone
by an alkyldiamine (primary and tertiary) is unprecedented.
We are currently undergoing investigations in order to eluci-
date a possible mechanism. According to preliminary re-
sults, it is noteworthy that the maleimide or anhydride
moiety (Michael acceptors) seems necessary for the reduc-
tion to occur since neither benzophenone 28, nor suberenone
29, nor (1H-indol-2-yl)-phenyl-methanone 3021 (Fig. 3) can
be reduced in the presence of the diamine.
4.2. 3-Bromo-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione
(5)
Under argon, at room temperature, indole 1 (0.802 g,
6.8 mmol) was dissolved in dry toluene (16 mL). After cool-
ing to ꢁ15 ꢀC, a solution of LiHMDS (1 M in hexane,
22 mL, 21.8 mmol,) was added dropwise and then the mix-
ture was stirred for 1 h. A solution of 3,4-dibromomaleimide
3 (1.043 g, 4.1 mmol) in THF (6 mL) was added dropwise at
ꢁ15 ꢀC. After stirring 15 min at ꢁ15 ꢀC, 1 h at 4 ꢀC, and 2 h
30 min at room temperature, the reaction was hydrolyzed
with an aqueous hydrochloric acid solution (0.3 N, 50 mL)
and the product extracted with EtOAc (50 mL and then
4ꢂ20 mL). The combined organic layers were washed
with brine (50 mL) and concentrated under reduced pres-
sure. The crude orange residue was precipitated with cooled
MeOH (5 mL), the solid was filtered, and dried to afford
compound 5 as an orange compound (1.002 g, 84%). Rf (pe-
troleum ether/EtOAc 6/4) 0.42; mp: 160–162 ꢀC (dec); IR
N
H
O
29
O
28
N
H
O
30
1
(KBr, cmꢁ1) n 3343, 1772, 1028, 815, 755, 741; H NMR
Figure 3.
(DMSO-d6, 250 MHz) d 7.14 (t, 1H, J¼7.0 Hz, H5), 7.22
(t, 1H, J¼6.8 Hz, H6), 7.50 (d, 1H, J¼7.8 Hz, H7), 7.89 (d,
1H, J¼8.1 Hz, H4), 8.03 (d, 1H, J¼3.0 Hz, H2), 11.34 (br
s, 1H, NHmal), 12.09 (br s, 1H, NHindole); 13C NMR
(DMSO-d6, 62.9 MHz) d 103.7 (Cq), 112.3 (CH), 114.6
(Cq), 120.4 (CH), 122.2 (CH), 122.4 (CH), 124.5 (Cq),
3. Conclusion
We were able to elaborate an efficient four-step syn-
thetic route to 5H-benzocycloheptaindol-6-one derivatives

9470
A. Bourderioux et al. / Tetrahedron 63 (2007) 9465–9475
131.1 (CH), 136.5 (Cq), 138.0 (Cq), 167.5 (CO), 170.2
(CO); MS (IS) m/z: 291–293 [M+H]+, 308–310 [M+NH4]+.
4.5. 3-(2-Formylphenyl)-4-(1H-indol-3-yl)-1-methyl-
1H-pyrrole-2,5-dione (10)
4.3. 3-(2-Bromo-2-methoxycarbonyl ethenyl)-indole-
1-carboxylic acid tert-butyl ester (7)
A solution of compound 4 (201 mg, 0.66 mmol), K2CO3
(162 mg, 1.18 mmol), PPh3 (37 mg, 0.13 mmol), and 2-for-
mylphenyl boronic acid 8 (149 mg, 0.98 mmol) in dioxane/
water (5 mL/1 mL) was degassed under argon for 30 min.
After addition of Pd(OAc)2 (19 mg, 0.07 mmol), the reac-
tion mixture was immediately placed in a pre-heated oil
bath at 100 ꢀC and refluxed for 4 h. After cooling at room
temperature and filtration over Celite, the solvents were re-
moved under reduced pressure. The resulting red oil was pu-
rified by flash chromatography (petroleum ether/CH2Cl2, 1/
1 and then petroleum ether/EtOAc/CH2Cl2, 1/1/2) to afford
compound 10 as an orange solid (162 mg, 74%). Rf (EtOAc/
CH2Cl2 1/9) 0.38; mp: 225–227 ꢀC; IR (KBr, cmꢁ1) n 3558,
2774, 1757, 1683, 1388, 750; 1H NMR (DMSO-d6,
250 MHz) d 3.05 (s, 3H, CH3), 6.21 (d, 1H, J¼8.2 Hz,
H7ind), 6.63 (t, 1H, J¼7.7 Hz, H5ind), 7.03 (t, 1H,
J¼7.7 Hz, H6ind), 7.32–7.36 (m, 1H, H3F), 7.40 (d, 1H,
J¼8.0 Hz, H7ind), 7.61–7.65 (m, 2H, H4/5F), 7.93–7.96 (m,
1H, H6F), 8.07 (s, 1H, H2ind), 10.00 (s, 1H, CHO), 11.99
(br s, 1H, NH); 13C NMR (DMSO-d6, 62.9 MHz) d 24.2
(CH3), 104.2 (Cq), 112.3 (CH), 120.2 (CH), 120.3 (CH),
122.3 (CH), 124.0 (Cq), 126.3 (Cq), 129.0 (CH), 129.4
(CH), 131.4 (CH), 131.9 (CH), 133.1 (Cq), 133.8 (CH),
134.6 (Cq), 134.7 (Cq), 136.6 (Cq), 170.9 (CO)mal, 171.1
(CO)mal, 191.9 (CO)ald; MS (IS) m/z: 348.3 [M+NH4]+.
At ꢁ20 ꢀC, a solution of methyl(triphenyl phosphoranylide-
ne)acetate (5.45 g, 16.3 mmol) in dry CH2Cl2 (100 mL) was
treated with recrystallized NBS (3.19 g, 17.9 mmol). After
stirring at ꢁ20 ꢀC for 30 min, N-Boc-3-formylindole (2 g,
8.16 mmol) and K2CO3 (3.76 g, 27.2 mmol) were succes-
sively added. The reaction mixture was then stirred for
30 h while allowing the temperature to reach the ambient
condition. After filtration through a pad of Celite, the filtrate
was concentrated in vacuo. The mixture of (E)- and (Z)-iso-
mer was purified by column chromatography on silica gel
(PE/AcOEt, 9.5/0.5). The single (Z)-isomer 7 was obtained
by recrystallization in hot MeOH as a colorless solid
(2.93 g, 94%). Rf (petroleum ether/EtOAc, 9/1) 0.47; mp:
116 ꢀC; IR (KBr, cmꢁ1) n 1737 (C]O), 1672 (C]O),
1
1448, 1395, 1354, 1244, 1126, 1097; H NMR (CDCl3,
250 MHz) d 1.71 (s, 9H, 3ꢂCH3), 3.93 (s, 3H, OCH3),
7.33 (dd, 1H, J¼J0¼7.2 Hz, Har), 7.40 (dd, 1H,
J¼J0¼7.2 Hz, Har), 7.74 (d, 1H, J¼7.2 Hz, Har), 8.17 (d,
1H, J¼7.2 Hz, Har), 8.50 (s, 1H, ]CH), 8.81 (s, 1H,
]CH); 13C NMR (CDCl3) d 28.1 (3ꢂCH3), 53.5 (OCH3),
84.9 (C(CH3)3), 111.6 (Cq), 114.5 (Cq), 115.4 (CH), 118.3
(CH), 123.4 (CH), 125.3 (CH), 128.3 (CH), 129.8 (Cq),
131.3 (CH), 134.6 (Cq), 149.2 (CO), 163.7 (CO). HRMS
ꢃ
(EI) calcd for C17H18NO479Br (M+ ): 379.04192; found:
4.6. 3-(2-Formylphenyl)-4-(1H-indol-3-yl)-1H-pyrrole-
2,5-dione (11)
379.0424.
4.4. 3-[2-(2-Formyl-phenyl)-2-methoxycarbonyl eth-
enyl]-indole-1-carboxylic acid tert-butyl ester (9)
From 8: same procedure as described for compound 10, start-
ing from 5 and 8. Compound 11 was obtained as an orange
solid in 33% yield. From 13: a solution containing compound
5 (260 mg, 0.89 mmol), tributylstannylbenzaldehyde 13
(530 mg, 1.34 mmol), and CuI (12 mg, 0.09 mmol) in diox-
ane (20 mL) was degassed under argon for 30 min. After
addition of PdCl2(PPh3)2 (13 mg, 0.18 mmol), the reaction
mixture was immediately placed in a pre-heated oil bath at
120 ꢀC and refluxed for 8 h. After cooling at room tempera-
ture and filtration over Celite, the solvents were removed un-
der reduced pressure. The resulting red oil was purified by
flash chromatography (petroleum ether/CH2Cl2, 1/1 and
then petroleum ether/CH2Cl2/EtOAc, 1/1/2). The recovered
solid was dissolved in acetonitrile (50 mL) and washed
with petroleum ether (5ꢂ50 mL) to afford, after removal of
the solvents under reduced pressure, compound 11 as an or-
ange solid (152 mg, 54%). Rf (petroleum ether/EtOAc, 1/1)
0.41; mp: 189–193 ꢀC (dec); IR (KBr, cmꢁ1) n 3431, 3019,
A solution of 7 (500 mg, 1.3 mmol) in dioxane (25 mL) was
treated with 2-formylphenyl boronic acid 8 (394 mg,
2.6 mmol) and K2CO3 (724 mg, 5.2 mmol). Water
(7.5 mL) was added and the mixture was degassed for
20 min. Pd(PPh3)4 (151 mg, 10 mol %) was added, the flask
was immediately immersed in a pre-heated oil bath, and the
reaction mixture was stirred at 70 ꢀC for 2 h. After cooling to
room temperature, water was added (25 mL) and the product
was extracted with EtOAc (3ꢂ20 mL). The organic layer
was dried over MgSO4 and the solvents were removed in va-
cuo. The product was purified by column chromatography
on silica gel (petroleum ether/EtOAc, 9/1 and then 8.5/1.5)
to afford 9 as a yellow solid (475 mg, 89%). Rf (petroleum
ether/EtOAc, 9/1) 0.20; mp: 74 ꢀC; IR (KBr, cmꢁ1) n 3168
ðCsp2 ꢁ HÞ, 2981 ðCsp3 ꢁ HÞ, 2843 ðCsp3 ꢁ HÞ, 2744
ðCsp2 ꢁ H aldehydeÞ, 1763–1694 (3ꢂC]O), 1624, 1597,
1569, 1455, 1435, 1150, 1085; 1H NMR (CDCl3,
250 MHz) d 1.51 (s, 9H, 3ꢂCH3), 3.80 (s, 3H, OCH3),
6.41 (s, 1H, ]CH), 7.30–7.39 (m, 3H, Har), 7.61 (dd, 1H,
J¼J0¼7.3 Hz, Har), 7.69–7.77 (m, 2H, Har), 8.07–8.11 (m,
2H, Har), 8.26 (s, 1H, ]CH), 10.06 (s, 1H, CHO); 13C
NMR (CDCl3) d 27.9 (3ꢂCH3), 52.4 (OCH3), 84.2
(C(CH3)3), 114.7 (Cq), 115.1 (CH), 118.4 (CH), 123.3
(CH), 125.2 (CH), 126.9 (CH), 127.5 (Cq), 128.9 (CH),
129.4 (CH), 129.6 (Cq), 130.8 (CH), 132.0 (CH), 133.9
(Cq), 134.6 (Cq), 134.8 (CH), 140.1 (Cq), 148.6 (CO),
167.1 (CO), 191.2 (CHO). HRMS (EI) calcd for
C20H15NO5 ([MꢁC4H8]+.): 349.09502; found: 349.0935.
1
2927, 2855, 1713, 756; H NMR (DMSO-d6, 250 MHz)
d 6.23 (d, 1H, J¼7.8 Hz, H4ind), 6.62 (t, 1H, J¼7.8 Hz,
H5ind), 7.02 (t, 1H, J¼7.2 Hz, H6ind), 7.31–7.34 (m, 1H,
H3F), 7.39 (d, 1H, J¼8.2 Hz, H7ind), 7.60–7.63 (m, 2H, H4/
5F), 7.92–7.96 (m, 1H, H6F), 8.02 (d, 1H, J¼3.0 Hz, H2ind),
10.00 (s, 1H, CHO), 11.15 (br s, 1H, NH maleimide); 11.96
(br s, 1H, NH indole); 13C NMR (DMSO-d6, 62.9 MHz)
d 104.1 (Cq), 112.3 (CH), 120.1 (CH), 120.3 (CH), 122.2
(CH), 124.1 (Cq), 127.3 (Cq), 129.2 (CH), 129.4 (CH),
131.4 (CH), 131.7 (CH), 133.0 (Cq), 133.7 (CH), 134.7
(Cq), 134.9 (Cq), 136.5 (Cq), 172.1 (CO)mal, 172.2 (CO)mal
,
191.9 (CO)ald; MS (IS) m/z: 334.5 [M+NH4]+, 339.5
[M+Na]+.

A. Bourderioux et al. / Tetrahedron 63 (2007) 9465–9475
9471
4.7. 2-Tributylstannylbenzaldehyde (13)15
H4/5ind), 6.97–7.00 (m, 2H, H6ind/3F), 7.28 (t, 1H,
J¼7.4 Hz, H4F), 7.36 (d, 1H, J¼8.0 Hz, H7ind), 7.43 (t,
1H, J¼7.6 Hz, H5F), 7.84 (d, 1H, J¼2.1 Hz, H2ind), 8.07
(d, 1H, J¼7.8 Hz, H6F), 10.87 (br s, 1H, NH), 11.85 (br s,
1H, NH); 13C NMR (DMSO-d6, 62.9 MHz) d 104.3 (Cq),
111.9 (CH), 119.5 (CH), 120.7 (CH), 121.7 (CH), 124.6
(Cq), 128.5 (CH), 129.4 (Cq), 129.9 (CH), 130.1 (CH),
130.3 (Cq+CH), 130.4 (Cq), 130.5 (CH), 132.0 (Cq),
A solution containing 2-bromobenzaldehyde 12 (500 mg,
2.7 mmol) and hexabutylditin (1.724 g, 2.97 mmol) in dry
toluene (10 mL) was degassed under argon for 30 min. After
addition of Pd(PPh3)4 (312 mg, 0.27 mmol), the reaction
mixture was immediately placed in a pre-heated oil bath
at 100 ꢀC and refluxed for 24 h. After cooling at room tem-
perature, hexane (10 mL) and a saturated aqueous solution
of KF (10 mL) were added. After 30 min stirring, a filtration
over Celite was carried out, the organic layer was separated,
and the solvents were evaporated under reduced pressure.
The resulting residue was purified by flash chromatography
(petroleum ether/EtOAc, 98/2) to afford compound 13 as
a colorless oil (614 mg, 57%). Rf (petroleum ether/EtOAc,
136.3 (Cq), 169.8 (CO)acid, 171.8 (CO)mal, 173.0 (CO)mal
MS (IS) m/z: 333 [M+H]+, 350 [M+NH4]+.
;
4.10. 1H-Benzo[5,6]pyrrolo[30,40:3,4]cyclohept[1,2-b]-
indole-2-methyl-1,3,8(2H,9H)-trione (16)
BF3$Et2O (11 mL, 86.62 mmol) was added dropwise to a so-
lution of acid 14 (745 mg, 2.17 mmol) in dichloroethane
(120 mL). The mixture was refluxed for 5 h 30 min before
quenching with iced water (100 mL). The aqueous layer
was extracted three times with CH2Cl2 (2ꢂ60 mL). The
combined organic layers were washed with an aqueous sat-
urated solution of NaHCO3 (120 mL) and then with water
(3ꢂ120 mL). After drying over MgSO4, the solvents were
removed under reduced pressure to yield 16 (626 mg,
89%) as a brown solid. Rf (petroleum ether/EtOAc, 1/1)
0.67; mp 230–233 ꢀC (dec); IR (KBr, cmꢁ1) n 3272, 1768,
1
98/2) 0.43; H NMR (DMSO-d6, 250 MHz) d 0.80 (t, 9H,
J¼7.2 Hz, CH3), 0.99 (t, 6H, J¼8.0 Hz, CH2–Sn), 1.19–
1.28 (m, 6H, CH2), 1.38–1.46 (m, 6H, CH2), 7.56–7.65
(m, 3H, Harom), 7.99 (d, 1H, J¼6.4 Hz, Harom), 10.0 (s,
1H, CHO).
4.8. 2-[2,5-Dihydro-4-(1H-indol-3-yl)-1-methyl-2,5-
dioxo-1H-pyrrol-3-yl]benzoic acid (14)
The aldehyde 10 (899 mg, 2.72 mmol) was dissolved in a
mixture of dioxane and water (115 mL/30 mL). After cool-
ing to 5 ꢀC, sulfamic acid (2.143 g, 22.07 mmol) was added.
A solution of sodium chlorite (151 mg, 6.0 mmol) in water
(3 mL) was slowly introduced with accurate control of the
temperature. After 1 min, the reaction was quickly quenched
with a mixture of water (50 mL), brine (50 mL), and EtOAc
(150 mL). The aqueous layer was extracted with EtOAc
(3ꢂ75 mL). The combined organic layers were washed
with water (3ꢂ150 mL), dried over magnesium sulfate,
and concentrated under reduced pressure. A mixture of
EtOAc/CH2Cl2 (1/1) was added to the crude brown residue,
the precipitate formed was filtered, and washed thoroughly
(EtOAc/CH2Cl2, 1/1) till a red solid was obtained. The fil-
trate was evaporated to dryness to afford compound 14 as
a brown solid (762 mg, 81%). Rf (EtOAc) 0.27; mp:
135 ꢀC (dec); IR (KBr, cmꢁ1) n 3323, 1785, 1698, 1385,
1
1703, 1388, 750; H NMR (DMSO-d6, 500 MHz) d 3.09
(s, 3H, CH3), 7.32 (t, 1H, J¼7.7 Hz, H12), 7.51 (t, 1H,
J¼7.3 Hz, H11), 7.67 (d, 1H, J¼8.3 Hz, H10), 7.84 (d, 1H,
J¼7.5 Hz, H6), 7.93 (d, 1H, J¼7.7 Hz, H5), 8.46 (d, 1H, J¼
8.1 Hz, H7), 8.72 (d, 1H, J¼8.3 Hz, H13), 8.86 (d, 1H,
J¼8.3 Hz, H4), 13.04 (br s, 1H, NH); 13C NMR (DMSO-
d6, 62.9 MHz) d 24.1 (CH3), 111.3 (Cq), 112.8 (CH),
121.8 (CH), 123.8 (Cq), 125.0 (CH), 126.4 (CH), 126.9
(CH), 128.1 (Cq), 129.3 (CH), 130.2 (2CH), 130.9 (Cq),
131.7 (CH), 137.1 (Cq), 138.0 (Cq), 141.1 (Cq), 168.9
(C]O)mal, 170.1 (CO)mal, 179.8 (CO)cycle. HRMS (EI)
ꢃ
calcd for C20H12N2O3: 328.08479; found: 328.0855 (M)+ .
4.11. 1H-Benzo[5,6]pyrrolo[30,40:3,4]cyclohept-
[1,2-b]-indole-1,3,8(2H,9H)-trione (17)
1
747; H NMR (DMSO-d6, 500 MHz) d 3.02 (s, 3H, CH3),
Same procedure as described for compound 16, starting
from the acid 15. After 20 h, compound 17 was isolated as
an orange solid in 86% yield. Rf (petroleum ether/EtOAc,
6/4) 0.56; mp: 272–275 ꢀC (dec); IR (KBr, cmꢁ1) n 3274,
1778, 1723, 1582, 1018, 748; 1H NMR (DMSO-d6,
250 MHz) d 7.33 (t, 1H, J¼7.2 Hz, H12), 7.51 (t, 1H,
J¼7.2 Hz, H11), 7.67 (d, 1H, J¼8.2 Hz, H10), 7.84–7.97
(m, 2H, H5/6), 8.52 (d, 1H, J¼7.0 Hz, H4), 8.72 (d, 1H,
J¼7.7 Hz, H13), 8.87 (d, 1H, J¼8.4 Hz, H7), 11.48 (br s,
1H, NH(2)), 13.06 (br s, 1H, NH(9)); 13C NMR (DMSO-d6,
62.9 MHz) d 111.5 (Cq), 112.8 (CH), 121.8 (CH), 124.0
(Cq), 126.1 (Cq), 126.5 (CH), 127.0 (CH), 128.5 (Cq),
129.3 (CH), 130.4 (CH), 130.5 (CH), 131.6 (Cq), 131.8
6.43 (d, 1H, J¼8.3 Hz, H4ind), 6.65 (t, 1H, J¼7.6 Hz,
H5ind), 7.02 (t, 1H, J¼7.6 Hz, H6ind), 7.07 (d, 1H,
J¼7.6 Hz, H3F), 7.37–7.42 (m, 2H, H4F/7ind), 7.50 (t, 1H,
J¼7.8 Hz, H5F), 7.97 (d, 1H, J¼2.8 Hz, H2ind), 8.04 (d,
1H, J¼7.6 Hz, H6F), 11.87 (br s, 1H, NH); 13C NMR
(DMSO-d6, 62.9 MHz) d 24.0 (CH3), 104.1 (Cq), 112.1
(CH), 119.9 (CH), 120.4 (CH), 122.0 (CH), 124.4 (Cq),
129.0 (CH), 130.0 (Cq), 130.1 (CH), 130.6 (CH), 130.7
(CH), 130.8 (Cq), 131.6 (Cq), 131.7 (CH), 131.9 (Cq),
136.4 (Cq), 168.1 (CO)acid, 170.3 (CO)mal, 171.5 (CO)mal
MS (IS) m/z: 345.3 [MꢁH]ꢁ.
;
4.9. 2-[2,5-Dihydro-4-(1H-indol-3-yl)-2,5-dioxo-
1H-pyrrol-3-yl]benzoic acid (15)
(CH), 137.6 (Cq), 138.0 (Cq), 141.2 (Cq), 170.4 (CO)mal,
171.6 (CO)mal, 180.3 (CO)cycle. HRMS (EI) calcd for
ꢃ
C19H10N2O3: 314.06914; found: 314.0697 (M)+ .
Compound 15 was obtained as described for compound 14
starting from aldehyde 11 as an orange solid in 62% yield af-
ter flash chromatography (petroleum ether/EtOAc, 7/3 and
then EtOAc/MeOH, 8/2). Rf (EtOAc) 0.60; mp: 129–
132 ꢀC (dec); IR (KBr, cmꢁ1) n 3386, 1762, 1708, 1624,
4.12. 3-[2-(2-Carboxy-phenyl)-2-methoxycarbonyl-
ethynyl]-indole-1-carboxylic acid tert-butyl ester (18)
A solution of 9 (500 mg, 1.2 mmol) in a mixture of dioxane
(12 mL) and water (4 mL) was treated at 0 ꢀC with
1
745; H NMR (DMSO-d6, 250 MHz) d 6.56–6.63 (m, 2H,

9472
A. Bourderioux et al. / Tetrahedron 63 (2007) 9465–9475
ꢃ
NH2SO3H (955 mg, 9.8 mmol) and NaClO2 (279 mg,
3.1 mmol) successively. After 10 min stirring at 0 ꢀC, the re-
action mixture was hydrolyzed with water (30 mL) and the
product extracted with EtOAc (3ꢂ25 mL). The organic layer
was washed twice with brine (50 mL), dried over MgSO4,
and the solvents were removed in vacuo to afford quantita-
tively 18 as a cream foamy solid. Rf (petroleum ether/EtOAc,
5/5) 0.42; 1H NMR (CDCl3, 250 MHz) d 1.50 (s, 9H,
3ꢂCH3), 3.75 (s, 3H, OCH3), 6.43 (s, 1H, ]CH), 7.26–
7.34 (m, 3H, Har), 7.52 (ddd, 1H, J¼J0¼7.6 Hz, J00¼1.2 Hz,
Har), 7.62 (ddd, 1H, J¼J0¼7.4 Hz, J00¼ 1.5 Hz, Har), 7.70–
7.74 (m, 1H, Har), 8.02 (s, 1H, ]CH), 8.05–8.08 (m, 1H,
Har), 8.23 (dd, 1H, J¼7.7 Hz, J0¼1.5 Hz, Har); MS (IS)
(EI) calcd for C19H13NO3 (M+ ): 303.08954; found:
303.0903.
4.15. 1H-Benzo[5,6]pyrrolo[30,40:3,4]cyclohept[1,2-b]in-
dole-12-bromo-2-methyl-1,3,8(2H,9H)-trione (21)
To a solution of compound 16 (100 mg, 0.30 mmol) in dry
THF (5 mL) at 0 ꢀC was added dropwise a solution of recrys-
tallized NBS (544 mg, 3.05 mmol) in THF (5 mL). The reac-
tion mixture was stirred at room temperature for 3 days. An
additional portion of NBS (271 mg, 1.52 mmol) was added
and the mixture was stirred for another 24 h. Water
(10 mL) and a saturated aqueous solution of Na2S2O3
(20 mL) were added. After extractions with EtOAc
(3ꢂ50 mL), the combined organic layers were washed
with water (100 mL) and concentrated under reduced pres-
sure. The crude residue was precipitated with EtOAc
(2 mL), to afford, after filtration and drying, compound 21
as an orange solid (69 mg, 55%). Rf (petroleum ether/EtOAc,
8/2) 0.30; mp 316–320 ꢀC (dec); IR (KBr, cmꢁ1) n 3277,
1765, 1711, 1576, 1479, 1445, 1389, 768; 1H NMR
(DMSO-d6, 250 MHz) d 3.11 (s, 3H, CH3), 7.63 (br s, 2H,
H10/11), 7.84–7.99 (m, 2H, H5/6, 8.48 (d, 1H, J¼7.6 Hz,
H7), 8.87 (d, 1H, J¼7.8 Hz, H4), 8.94 (s, 1H, H13), 13.22
(br s, 1H, NH); 13C NMR (DMSO-d6, 62.9 MHz) d 25.0
(CH3), 110.7 (Cq), 114.4 (Cq), 114.9 (CH), 125.3 (Cq),
126.0 (Cq), 128.4 (Cq), 128.5 (CH), 129.6 (2CH), 130.4
(CH), 130.7 (CH), 132.2 (CH), 136.7 (Cq), 137.4 (Cq),
ꢃ
m/z: 422.5 [M+H]+ .
4.13. 2-[2-(1H-Indol-3-yl)-1-methoxycarbonyl-ethynyl]-
benzoic acid (19)
Compound 18 (55 mg, 126 mmol) in a mixture of CH2Cl2
(5 mL) and TFA (1 mL) was stirred at room temperature
for 24 h. Water (10 mL) was added and the product was ex-
tracted with CH2Cl2 (2ꢂ10 mL). The organic phase was
dried over MgSO4 and the solvents were removed in vacuo.
The product was purified by column chromatography on sil-
ica gel (3% MeOH in CH2Cl2) to afford 19 (11 mg, 26%). Rf
(CH2Cl2/MeOH, 95/5) 0.40; 1H NMR (DMSO-d6,
250 MHz) d 3.51 (s, 3H, OCH3), 6.18 (d, 1H, J¼2.7 Hz,
]CH–N), 7.07 (dd, 1H, J¼J0¼6.7 Hz, Har), 7.14 (dd, 1H,
J¼J0¼7.9 Hz, Har), 7.28 (d, 1H, J¼7.3 Hz, Har), 7.35 (d,
1H, J¼7.3 Hz, Har), 7.53–7.59 (m, 3H, Har), 7.96 (s, 1H,
]CH), 8.07 (d, 1H, J¼7.3 Hz, Har), 11.38 (s, 1H, NH),
12.68 (br s, 1H, CO2H).
141.7 (Cq), 169.3 (CO)mal, 170.3 (CO)mal, 180.2 (CO)cycle
HRMS (EI) calcd for C20H11N2O3Br: 405.99530; found:
.
ꢃ
405.9939 (M)+ .
4.16. 1H-Benzo[5,6]pyrrolo[30,40:3,4]cyclohept-
[1,2-b]indole-9-dimethylaminoethyl-2-methyl-
1,3,8(2H,9H)-trione (22)
4.14. 5,6-Dihydro-benzo[5,6]cyclohept[1,2-b]-
indole-6-one-11-carboxylic acid methyl ester (20)
To a suspension of NaH (8 mg, 0.20 mmol, 60% in oil) in
DMF (2 mL) was added dropwise at 0 ꢀC a solution of com-
pound 16 (51 mg, 0.15 mmol) in dry DMF (2 mL). After
30 min, a mixture of NaH (23 mg, 0.58 mmol, 60% in
oil) and 2-chloro-N,N-dimethylethylamine hydrochloride
(57 mg, 0.38 mmol) in DMF (1 mL) was added and the reac-
tion mixture was stirred at 95 ꢀC for 9 h. After cooling, iced
water (20 mL) was added, the precipitate formed was fil-
tered, and washed with water (2ꢂ10 mL). The solid was
then dissolved in CH2Cl2 and the organic layer was dried
over MgSO4. After evaporation of the solvent, compound
22 was isolated as a brown solid (51 mg, 84%). Rf (petro-
leum ether/EtOAc, 4/6) 0.49; mp: 119–121 ꢀC (dec); IR
(KBr, cmꢁ1) n 2924, 1764, 1706, 1622, 1439, 1385, 744;
1H NMR (DMSO-d6, 500 MHz) d 2.06 (s, 6H, CH3–N),
2.54 (t, 2H, J¼6.1 Hz, CH2–NMe2), 3.10 (s, 3H, CH3–
Nmal), 4.72 (t, 2H, J¼5.9 Hz, CH2–Nind), 7.34 (t, 1H,
J¼7.6 Hz, H12), 7.54 (t, 1H, J¼7.7 Hz, H11), 7.78–7.88
(m, 3H, H5/6/10), 8.11 (d, 1H, J¼7.8 Hz, H7), 8.51 (d, 1H,
J¼8.3 Hz, H13), 8.58 (d, 1H, J¼8.0 Hz, H4); 13C NMR
(DMSO-d6, 125.8 MHz) d 20.2 (CH3–Nmal), 42.0 (CH2–
Nind), 45.5 (2CH3–NCH2), 58.8 (CH2–NMe2), 111.3 (CH),
112.0 (Cq), 122.0 (CH), 122.6 (Cq), 125.5 (CH), 126.6
(2Cq), 126.7 (CH), 128.8 (CH), 129.0 (CH), 130.5 (CH),
130.6 (Cq), 131.1 (CH), 138.8 (Cq), 140.0 (Cq), 141.1
A mixture of hexamethyldisiloxane (4.44 mL, 20.9 mmol)
and P2O5 (1.05 g, 7.4 mmol) in CH2Cl2 (40 mL) was re-
fluxed for 45 min. After cooling to room temperature, the
volatiles were removed in vacuo. CH3NO2 (4 mL) was
added to the residue, followed by a solution of 18
(373 mg, 1.2 mmol) in CH3NO2 (6 mL). The mixture was
heated at reflux for 10 min while the color turned from
red to brown. After cooling, CH3NO2 was removed at re-
duced pressure. The residue was partitioned between water
(15 mL) and EtOAc (15 mL). The organic layer was washed
with brine (10 mL), dried over MgSO4, and the solvents
were removed under vacuum. The product crystallized
from MeOH to afford a yellow solid (165 mg, 44%). Rf (pe-
troleum ether/EtOAc, 7/3) 0.50; mp: 229 ꢀC; IR (KBr,
cmꢁ1) n 3263 (NH), 1719 (CO), 1705 (CO), 1610, 1572,
1541, 1479, 1380, 1333, 1284; 1H NMR (DMSO-d6)
d 3.98 (s, 3H, OCH3), 7.34 (dd, 1H, J¼J0¼7.1 Hz, Har),
7.53 (dd, 1H, J¼J0¼7.5 Hz, Har), 7.68 (d, 1H, J¼8.4 Hz,
Har), 7.75–7.93 (m, 3H, Har), 8.27 (d, 1H, J¼8.1 Hz, Har),
8.34 (s, 1H, ]CH), 8.79 (dd, 1H, J¼7.8 Hz, J0¼1.9 Hz,
Har); 13C NMR (DMSO-d6) d 52.8 (OCH3), 113.1 (CH),
117.3 (Cq), 121.1 (CH), 121.6 (CH), 124.7 (CH), 126.0
(Cq), 127.3 (CH), 128.9 (CH), 130.4 (CH), 130.5
(Cq), 130.9 (CH), 131.9 (CH), 132.7 (Cq), 135.5 (Cq),
137.6 (Cq), 137.8 (Cq), 170.4 (CO), 177.9 (CO). HRMS
(Cq), 169.2 (CO)mal, 170.1 (CO)mal, 184.7 (CO)cycle
.

A. Bourderioux et al. / Tetrahedron 63 (2007) 9465–9475
9473
HRMS (EI) calcd for C24H21N3O3: 399.15829; found:
H11), 7.80–7.88 (m, 3H, H5/6/10), 8.13 (d, 1H, J¼8.5 Hz,
H4), 8.53 (d, 1H, J¼7.5 Hz, H13), 8.59 (d, 1H, J¼6.4 Hz,
H7); 13C NMR (DMSO-d6, 62.9 MHz) d 35.9 (CH2–Nmal),
42.1 (CH2–Nind), 45.0 (2CH3–NCH2mal), 45.5 (2CH3–
NCH2ind), 56.3 (CH2–NMe2mal), 58.8 (CH2–NMe2ind),
111.4 (CH), 111.9 (Cq), 122.1 (CH), 122.5 (Cq), 125.5
(CH), 126.3 (Cq), 126.5 (Cq), 126.8 (CH), 128.9 (CH),
129.0 (CH), 130.4 (Cq), 130.6 (CH), 131.2 (CH), 138.8
ꢃ
399.1563 (M)+ .
4.17. 1H-Benzo[5,6]pyrrolo[30,40:3,4]cyclohept[1,2-b]-
indole-2-dimethylaminoethyl-1,3,8(2H,9H)-trione (23)
From 17: 2-chloro-N,N-dimethylethylamine hydrochloride
(46 mg, 0.32 mmol) was stirred in toluene (5 mL) at room
temperature in the presence of K2CO3 (87 mg, 0.63 mmol)
for 15 min. This organic solution was then washed with wa-
ter (3ꢂ5 mL) before drying over MgSO4. This solution was
added dropwise at 65 ꢀC to a suspension of 17 (50 mg,
0.16 mmol) and K2CO3 (22 mg, 0.16 mmol) in dry DMF
(20 mL). The resulting mixture was heated for 24 h at
65 ꢀC. After cooling, water (20 mL) and brine (10 mL)
were added. The product was extracted with EtOAc
(3ꢂ30 mL). The combined organic layers were then washed
with water (4ꢂ40 mL), dried over MgSO4, and evaporated
under reduced pressure. The crude residue was purified
by flash chromatography (EtOAc and then EtOAc/MeOH,
8/2) to afford compound 23 as a light brown solid
(21 mg, 34%). From 27: a solution of compound 27
(36 mg, 0.16 mmol), N,N-dimethylethylenediamine (207 mg,
2.34 mmol), and DMF (0.75 mL) was heated at 160 ꢀC for
18 h in a sealed tube. After cooling, water (5 mL) was added
and the pH was adjusted to 1 with a hydrochloric acid solu-
tion (1 N, 10 mL). The acidic aqueous medium was washed
with EtOAc (2ꢂ30 mL) before neutralization (pH 8) with
an aqueous solution of NaHCO3 (8 mL). The product was
then extracted with EtOAc (5ꢂ50 mL). The combined or-
ganic layers were washed with water and brine, dried over
MgSO4, and the solvent was removed under reduced pres-
sure. Compound 23 was obtained as a light brown solid
(26 mg, 59%). Rf (EtOAc/MeOH, 9/1) 0.36; mp: 195–
197 ꢀC dec; IR (KBr, cmꢁ1) n 3448, 2944, 1769, 1702,
(Cq), 140.2 (Cq), 141.1 (Cq), 168.9 (CO)mal, 169.9 (CO)mal
184.7 (CO)cycle. HRMS (EI) calcd for C27H28N4O3:
,
ꢃ
456.21614; found: 456.2149 (M)+ .
4.19. 1H-Benzo[5,6]pyrrolo[30,40:3,4]cyclohept[1,2-b]-
indole-2-methyl-1,3(2H,9H)-dione (25)
In a sealed tube, a solution of 16 (51 mg, 0.14 mmol) and
N,N-dimethylethylenediamine (201 mg, 2.28 mmol) in
DMF (0.75 mL) was heated at 160 ꢀC for 22 h. After cooling
to room temperature, water was added (15 mL), the pH was
adjusted to 8 with 1 N HCl, and the product was extracted
with EtOAc (3ꢂ30 mL). The combined organic layers
were washed with water (3ꢂ50 mL) and the solvent was
evaporated in vacuo. The product was purified by flash chro-
matography (petroleum ether/EtOAc, 3/7 and then EtOAc/
MeOH, 9/1). Compound 25 was obtained as a red solid
(19 mg, 41%). Rf (EtOAc/MeOH, 9/1) 0.91; mp: 94–97 ꢀC
(dec); IR (KBr, cmꢁ1) n 3336, 2925, 1761, 1690, 1587,
1
1439, 1386, 747; H NMR (DMSO-d6, 500 MHz) d 3.09
(s, 3H, CH3), 3.93 (s, 2H, CH2(cycle)), 7.11 (dt, 1H,
J¼7.5 Hz, J0¼1.1 Hz, H12), 7.16 (dt, 1H, J¼7.5 Hz,
J0¼1.1 Hz, H11), 7.36–7.40 (m, 2H, H5/7), 7.44 (d, 1H,
J¼7.9 Hz, H10), 7.51 (dt, 1H, J¼7.5 Hz, J0¼1.3 Hz, H6),
7.87 (d, 1H, J¼8.1 Hz, H4), 8.05 (d, 1H, J¼7.9 Hz, H13),
12.12 (br s, 1H, NH); 13C NMR (DMSO-d6, 125.8 MHz)
d 23.8 (CH3), 33.4 (CH2)cycle, 104.7 (Cq), 111.8 (CH)7,
120.7 (CH), 121.2 (CH), 122.2 (CH), 124.6 (Cq), 126.2
(CH), 127.1 (Cq), 128.6 (CH), 128.7 (CH), 129.1 (Cq),
130.5 (CH), 134.7 (Cq), 135.4 (Cq), 136.6 (Cq), 140.9
(Cq), 170.2 (CO)mal, 170.8 (CO)mal; MS (IS) m/z: 332.5
[M+NH4]+, 337.5 [M+Na]+. HRMS (EI) calcd for
1
1474, 747; H NMR (DMSO-d6, 250 MHz) d 2.22 (s, 6H,
CH3–NCH2), 2.57 (m, 2H, CH2–NMe2), 3.76 (t, 2H,
J¼6.2 Hz, CH2–Nmal), 7.35 (t, 1H, J¼7.6 Hz, H12), 7.52 (t,
1H, J¼8.5 Hz, H11), 7.68 (d, 1H, J¼8.2 Hz, H10), 7.85–
7.99 (m, 2H, H5/6), 8.52 (d, 1H, J¼7.8 Hz, H4), 8.75 (d,
1H, J¼8.7 Hz, H13), 8.89 (d, 1H, J¼8.2 Hz, H7), 13.12 (s,
1H, NH); 13C NMR (DMSO-d6, 62.9 MHz) d 36.0 (CH2–
Nmal), 45.1 (2CH3–NCH2), 56.4 (CH2–NMe2), 111.4 (Cq),
112.9 (CH), 121.9 (CH), 123.9 (Cq), 125.2 (Cq), 126.4
(CH), 127.1 (CH), 128.3 (Cq), 129.4 (CH), 130.4 (CH),
130.6 (CH), 131.1 (Cq), 132.0 (CH), 137.5 (Cq), 138.1
(Cq), 141.4 (Cq), 169.0 (CO)mal, 170.1 (CO)mal, 180.2
(CO)cycle. HRMS (EI) calcd for C23H19N3O3: 385.14264;
ꢃ
C20H14N2O2: 314.10553; found: 314.1055 (M)+ .
4.20. 1H-Benzo[5,6]pyrrolo[30,40:3,4]cyclohept[1,2-b]-
indole-2-dimethylaminoethyl-1,3(2H,9H)-dione (26)
A solution of 27 (100 mg, 0.32 mmol) in N,N-dimethylethyl-
enediamine (4 mL) was heated at reflux for 64 h. After cool-
ing to room temperature, water was added (10 mL) and the
pH was adjusted to 9 by addition of concd HCl (0.5 mL).
The product was extracted by EtOAc (5ꢂ10 mL). The com-
bined organic layers were washed with water (20 mL). Dry-
ing over MgSO4 and removal of the solvents afforded
compound 26 (102 mg, 86%) as a brown solid. Rf (petroleum
ether/EtOAc, 6/4) 0.26; mp: 165–168 ꢀC (dec); IR (KBr,
cmꢁ1) n 3398, 3050, 2948, 1758, 1694, 1465, 1400, 744;
1H NMR (DMSO-d6, 500 MHz) d 2.22 (s, 6H, CH3–
NCH2), 2.54 (t, 2H, J¼6.6 Hz, CH2–NMe2), 3.71 (t, 2H,
J¼6.6 Hz, CH2–Nmal), 3.94 (s, 2H, CH2(cycle)), 7.11 (t, 1H,
J¼7.5 Hz, H12), 7.16 (t, 1H, J¼7.5 Hz, H11), 7.36–7.41 (m,
2H, H5/7), 7.44 (d, 1H, J¼8.1 Hz, H10), 7.51 (t, 1H,
J¼7.6 Hz, H6), 7.87 (d, 1H, J¼7.7 Hz, H4), 8.05 (d, 1H,
J¼7.9 Hz, H13), 12.15 (br s, 1H, NH); 13C NMR (DMSO-
d6, 125.8 MHz) d 33.4 (CH2)cycle, 35.7 (CH2–Nmal), 45.2 (2
ꢃ
found: 385.1422 (M)+ .
4.18. 1H-Benzo[5,6]pyrrolo[30,40:3,4]cyclohept-
[1,2-b]indole-2,9-bis(dimethylaminoethyl)-1,3,8-
(2H,9H)-trione (24)
Compound 24 was concomitantly isolated in the reaction
leading to 23 from 17. After the flash chromatography, com-
pound 24 was obtained as an orange solid (9%). Rf (EtOAc/
MeOH, 9/1) 0.07; mp: 91–92 ꢀC (dec); IR (KBr, cmꢁ1) n
1
3056, 2940, 1765, 1702, 1398, 742; H NMR (DMSO-d6,
250 MHz) d 2.06 (s, 6H, CH3–NCH2ind), 2.23 (s, 6H,
CH3–NCH2mal), 2.50 (m, 4H, CH2–NMe2(ind+mal)), 3.75 (t,
2H, J¼6.6 Hz, CH2–Nmal), 4.75 (t, 2H, J¼6.6 Hz, CH2–
Nind), 7.36 (t, 1H, J¼7.5 Hz, H12), 7.55 (t, 1H, J¼8.2 Hz,

9474
A. Bourderioux et al. / Tetrahedron 63 (2007) 9465–9475
5, pp 235–248; (e) Huwe, A.; Mazitschek, R.; Giannis, A.
Angew. Chem., Int. Ed. 2003, 42, 2122–2138; (f) Blagden, S.;
de Bono, J. Curr. Drug Targets 2005, 6, 325–335; (g) Collins,
I.; Garrett, M. D. Curr. Opin. Pharmacol. 2005, 5, 366–373.
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B. D.; Brooks, H. B.; Morris Campbell, R.; Considine, E.;
Dempsey, J. A.; Faul, M. M.; Ogg, C.; Patel, B.; Schultz,
R. M.; Spencer, C. D.; Teicher, B.; Watkins, S. A. J. Med.
Chem. 2003, 46, 2027–2030; (b) Zhu, G.; Conner, S. E.; Zhou,
X.; Chan, H.-K.; Shih, C.; Engler, T. A.; Al-awar, R. S.;
Brooks, H. B.; Watkins, S. A.; Spencer, C. D.; Schultz, R. M.;
Dempsey, J. A.; Considine, E. L.; Patel, B. R.; Ogg, C. A.;
Vasudevan, V.; Lytle, M. L. Bioorg. Med. Chem. Lett. 2004,
14, 3057–3061; (c) Zhu, G.; Conner, S.; Zhou, X.; Shih, C.;
Brooks, H. B.; Considine, E.; Dempsey, J. A.; Ogg, C.; Patel,
B.; Schultz, R. M.; Spencer, C. D.; Teicher, B.; Watkins, S. A.
Bioorg. Med. Chem. Lett. 2003, 13, 1231–1235; (d) Sanchez-
Martinez, C.; Shih, C.; Faul, M. M.; Zhu, G.; Paal, M.;
Somoza, C.; Li, T.; Kumrich, C. A.; Winneroski, L. L.; Xun,
Z.; Brooks, H. B.; Patel, B. K. R.; Schultz, R. M.; DeHahn,
T. B.; Spencer, C. D.; Watkins, S. A.; Considine, E.; Dempsey,
J. A.; Ogg, C. A.; Campbell, R. M.; Anderson, B. A.; Wagner,
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CH3–NCH2), 56.7 (CH2–NMe2), 104.7 (Cq), 111.9 (CH),
120.8 (CH), 121.3 (CH), 122.3 (CH), 124.6 (Cq), 126.3
(CH), 126.8 (Cq), 128.7 (2CH), 129.1 (Cq), 130.6 (CH),
134.6 (Cq), 135.5 (Cq), 136.7 (Cq), 141.1 (Cq), 170.1
(CO)mal, 170.7 (CO)mal; MS (IS) m/z: 372.5 [M+H]+.
HRMS (EI) calcd for C23H21N3O2: 371.16338; found:
ꢃ
371.1625 (M)+ .
4.21. Benzo[5,6]furo[30,40:3,4]cyclohept[1,2-b]-
indole-1,3,8(9H)-trione (27)
A solution of compound 16 (120 mg, 0.37 mmol) and KOH
(819 mg, 14.62 mmol) in acetone (3 mL) and water (2 mL)
was stirred at room temperature for 24 h. After removal of
acetone invacuo, water was added (10 mL), followed by con-
centrated hydrochloric acid (2 mL) till pH 1. The solution
was stirred 12 h at room temperature. The product was ex-
tracted with EtOAc (4ꢂ30 mL). The combined organic
layers were washed with water (3ꢂ40 mL), dried over
MgSO4, and the solvent was removed under reduced pres-
sure. Compound 27 was thus obtained quantitatively
(117 mg) as a light brown solid. Rf (EtOAc/petroleum ether,
1/1) 0.68; mp: 220–223 ꢀC (dec); IR (KBr, cmꢁ1) n 3258,
1825, 1755, 1588, 1259, 746; 1H NMR (DMSO-d6,
250 MHz, ppm) d 7.40 (t, 1H, J¼7.8 Hz, H12), 7.56 (t, 1H,
J¼7.6 Hz, H11), 7.72 (d, 1H, J¼8.0 Hz, H10), 7.93–8.06
(m, 2H, H5/6), 8.57 (d, 1H, J¼8.0 Hz, H4), 8.69 (d, 1H,
J¼8.4 Hz, H13), 8.85 (d, 1H, J¼8.0 Hz, H7), 13.35 (s, 1H,
NH); 13C NMR (DMSO-d6, 62.9 MHz) d 110.4 (Cq), 113.3
(CH), 122.6 (CH), 123.7 (Cq), 125.7 (CH), 126.6 (Cq),
127.4 (CH), 127.6 (Cq), 129.8 (CH), 130.1 (CH), 131.5
(CH), 132.5 (Cq), 132.6 (CH), 137.5 (Cq), 138.1 (Cq),
ꢀ
5. (a) Routier, S.; Peixoto, P.; Merour, J.-Y.; Coudert, G.; Dias, N.;
Bailly, C.; Pierre, A.; Leonce, S.; Caignard, D.-H. J. Med.
ꢀ
ꢀ
Chem. 2005, 48, 1401–1413; (b) Routier, S.; Merour, J.-Y.;
Dias, N.; Lansiaux, A.; Bailly, C.; Lozach, O.; Meijer, L.
J. Med. Chem. 2006, 49, 789–799.
6. Mahboobi, S.; Burgemeister, T.; Dove, S.; Kuhr, S.; Popp, A.
J. Org. Chem. 1999, 64, 8130–8137.
7. (a) Su, J.-Y.; Zhu, Y.; Zeng, L.-M.; Xu, X.-H. J. Nat. Prod.
1997, 60, 1043–1044; (b) Fresneda, P. M.; Molina, P.; Saez,
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M. A. Synlett 1999, 1651–1653; (c) Wahlstrom, N.;
141.7 (Cq), 164.1 (CO)anh, 165.0 (CO)anh, 179.9 (CO)cycle
HRMS (EI) calcd for C19H9NO4: 315.05316; found:
.
Stensland, B.; Bergman, J. Tetrahedron 2004, 60, 2147–2153;
(d) Miki, Y.; Aoki, Y.; Miyatake, H.; Minematsu, T.; Hibino,
H. Tetrahedron Lett. 2006, 47, 5215–5218.
ꢃ
315.0537 (M)+ .
ꢀ
ꢀ
8. Joseph, B.; Alagille, D.; Merour, J.-Y.; Leonce, S. Chem.
Pharm. Bull. 2000, 48, 1872–1876.
ꢀ ꢀ ꢀ
9. Bourderioux, A.; Routier, S.; Beneteau, V.; Merour, J.-Y.
Acknowledgements
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10. Brenner, M.; Rexhausen, H.; Steffan, B.; Steglich, W.
Tetrahedron 1988, 44, 2887–2892.
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ꢀ
ˆ
We thank the Canceropole Grand Ouest, and the Association
pour la Recherche contre le Cancer (ARC) for the financial
support of this work. We thank Dr. C. Guillouzo (Rennes,
INSERM U-522) for the cytotoxity evaluation and Dr. L.
Meijer (Roscoff, CNRS) for the CDK inhibition testing.
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