Efficient synthesis of the first n-methyloxoarcyriaflavin including an original central seven-membered cycle

Article abstract of DOI:10.1055/S-0029-1218626

A new route to the first N-methyloxoarcyriaflavin was designed. The compound was obtained by a palladium-catalyzed Stille cross-coupling reaction, followed by an electrophilic cyclization onto a C-2 indolic position as a key step. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/S-0029-1218626

PAPER
783
Efficient Synthesis of the First N-Methyloxoarcyriaflavin Including an
Original Central Seven-Membered Cycle
S
A
ynthesis of the
F
i
u
rst
N
-Methyl
r
oxoarcy
é
riaflavin lie Bourderioux, Aziz Ouach, Valérie Bénéteau, Jean-Yves Mérour, Sylvain Routier*
Institut de Chimie Organique et Analytique, (1) Université d’Orléans, (2) UMR CNRS 6005, Rue de Chartres, B.P. 6759,
5067 Orléans Cedex 2, France
4
Fax +33(2)38417281; E-mail: sylvain.routier@univ-orleans.fr
Received 7 September 2009; revised 19 November 2009
In continuation of our work, it appeared as a challenge to
design compound 1 (Scheme 1), a bisindolic analogue of
compounds of type III. Currently, only few bisindolic
compounds bearing a central seven-membered ring have
been synthesized. The two main compounds are homoar-
cyriaflavin (V) and arcyriacyanin A (VI) (Figure 2). Ho-
moarcyriaflavin was obtained by a double 1,4-Michael
addition starting from a bisindolic scaffold and dibromo-
maleimide in basic medium, whereas three ways of syn-
thesis were described for arcyriacyanin A, two out of three
including Heck palladium-catalyzed reactions.
Abstract: A new route to the first N-methyloxoarcyriaflavin was
designed. The compound was obtained by a palladium-catalyzed
Stille cross-coupling reaction, followed by an electrophilic cycliza-
tion onto a C-2 indolic position as a key step.
Key words: indole, tropone, palladium, electrophilic cyclization,
rearrangement
7
8
Over the last decades, several groups have been interested
in the synthesis of diverse indolocarbazoles because of
their diverse biological and pharmacological activities.1
Among them, the naturally occurring arcyriaflavin A (I)
H
(
(
Figure 1) exhibits moderate cyclin-dependent kinases
CDKs) inhibition. With the aim of finding more potent
H
N
N
O
O
2
O
O
activities against cancer cells, the structure of arcyriafla-
vin A (I) has been modulated, mainly by replacement of
one of the indole cores by diverse (hetero)aromatic3
moities: thiophene, azaindole, naphthalene, phenyl, etc.,
NH
N
H
N
H
N
H
4
or by design of unfused indolocarbazole analogues. In
homoarcyriaflavin (V)
arcyriacyanin A (VI)
another study of our own, we introduced a carbonyl group
between the indole moiety and a phenyl group, leading to
Figure 2 Bisindoles bearing a seven-membered central ring
5
compounds of type III. The tropone core, a central seven-
membered ring, was directly inspired by caulersine (IV), In this article, we describe an original synthesis of the first
a natural bisindolic molecule isolated from the alga Caul- N-methyloxoarcyriaflavin (1) in only few efficient steps
6
erpa serrulata.
starting from the well known 3-bromo-4-indolyl-N-meth-
9
ylmaleimide (4) and indole-2-carboxylic acid methyl es-
ter (5).10 During the course of this work, an unexpected
rearranged 4-ethylidene b-carboline 2 was isolated,
whose structure has been confirmed by a different syn-
thetic pathway (Scheme 1).
H
H
N
O
N
O
O
O
Ar
5
Following our previous strategy, the central tropone of
N
H
N
N
H
H
the N-methyloxoarcyriaflavin (1) can be generated
through an intramolecular electrophilic cyclization in C-2
of an indole. The opened bisindolic precursor 3 would be
formed by a Stille cross-coupling reaction between 3-bro-
mo-4-indolyl-N-methylmaleimide (4) and a C-3 tin deriv-
ative of 5.
arcyriaflavin A (I)
modulated structure (II)
of arcyriaflavin A
MeO
O
X
O
O
R1
R2
NH
N
H
N
We began with the synthesis of the stannylated esters 8
and 9, as building blocks for the cross-coupling reaction
(Scheme 2). The esterification of the commercially avail-
able indole-2-carboxylic acid was conducted in refluxing
methanol for 24 hours with either 1.2 equivalents of acetyl
chloride or 1.5 equivalents of sulfuric acid to afford 5 in
R2
H
O
O
oxophenylarcyriaflavins (III)
caulersine (IV)
1
2
R , R = H, OH
X = O, NH, NMe, NCH2CH2NMe2
Figure 1 Arcyriaflavin A and modulated-structure compounds
9
6 and 99% yield, respectively.11
SYNTHESIS 2010, No. 5, pp 0783–0790
x
x
.
x
x
.2
0
1
0
The iodination was performed at room temperature using
KOH as a base and provided 6 in an excellent yield after
Advanced online publication: 22.12.2009
DOI: 10.1055/s-0029-1218626; Art ID: T17409SS
Georg Thieme Verlag Stuttgart · New York
©

7
84
A. Bourderioux et al.
PAPER
Me
N
Me
N
O
O
O
O
HO
N
H
N
H
N
H
N
H
O
O
1
3
Me
N
O
O
O
HN
+
OMe
N
Me
Br
N
H
O
O
N
N
H
MOM
2
4
5
Scheme 1 Retrosynthetic pathway toward N-methyloxoarcyriaflavin (1)
I
SnMe3
OMe
a
c
OMe
OMe
N
N
R
N
R
H
O
O
O
5
6, R = H, 95%
8, R = H, quant
9, R = MOM, 68%
b
7
, R = MOM, 93%
Scheme 2 Reagents and conditions: a) KOH (4.0 equiv), DMF, r.t., 10 min, then I , DMF, r.t., 1.25 h, 95%; b) NaH (1.3 equiv), DMF, 0 °C,
2
3
0 min, then MOMCl (4.0 equiv), 0 °C to r.t., 2 h, 93%; c) from 6, Sn Me (1.2 equiv), Pd(PPh ) (0.1 equiv), toluene, reflux, 6 h, 8 (quant);
2 6 3 4
from 7, Sn Me (1.5 equiv), Pd(PPh ) (0.2 equiv), toluene, reflux, 8 h, 9 68%.
2
6
3 4
5
only 1.25 hours. Compound 6 was then protected using a (Scheme 3). Starting from 8, hydrodestannylation oc-
large excess of MOMCl (4.0 equiv) from 0 °C to room curred and 5 was isolated, whereas the palladium-
temperature for two hours, affording 7 in 93% yield.12 catalyzed coupling reaction of 4 with 9 afforded 10 quan-
First attempts of halogen–metal exchange carried out on titatively.
compound 6 with Sn Bu led only to a mixture of starting
2
6
At this stage two strategies can be adopted: first removing
the indolic nitrogen atom protecting group of 10 and then
performing the saponification of the ester; or proceeding
the opposite way. We envisioned in the first place the
MOM cleavage of 10 in acidic media and isolated 11 in
material and compound 5. The exchange was then tried
with Sn Me , which afforded compound 8 as a crude
2
6
product quantitatively; attempts to purify led to the cleav-
age of the stannyl group on the chromatographic column
(
either with silica gel or neutral aluminum oxide). Using
9
0% yield (Scheme 3). To obtain the acid function needed
the same conditions, compound 7 led to 9 in 47% yield. It
appears that 9 was less sensitive than 8 and could be puri-
fied by flash chromatography on silica gel. However, 20%
of compound 9 was destannylated during the purification.
for the electrophilic cyclization, several conditions were
attempted. As indicated in Table 1 (entries 1–3), Lewis
12
5
acid conditions, saponification in diluted basic media
13
and transesterification assay appeared as unfruitful.
An increase of the quantities of both Sn Me6 and
2
Facing failures with traditional systems, we turned our at-
tention to unconventional methods. In a previous work
Pd(PPh ) produced 9 in an improved yield of 68%.
3
4
Having the coupling partners 8 and 9 in hand, we next
tried the Stille cross-coupling reaction with unprotected
indole derivative 4 under previously optimized conditions
concerning the deprotection of carbamates with Bu NF,
4
we observed, in some cases, a quantitative hydrolysis of
Me
Me
Me
X
O
O
N
N
O
O
O
N
O
O
O
a
c
d
Br
HO
MeO
N
N
N
N
R
H
H
N
N
H
N
H
O
H
H
O
O
1
1
0 R = MOM, quant
1 R = H, 90%
3 X = NMe, 75%
12 X = O
4
b
1 60%
Scheme 3 Reagents and conditions: a) 9 (1.5 equiv), CuI (0.1 equiv), PdCl (PPh ) (0.2 equiv), dioxane, reflux, 3.5 h, quant; b) aq 2 N HCl,
2
3 4
MeOH, reflux, 16 h, 90%; c) LiOOH (5.0 equiv), dioxane, 0 °C to r.t., 1 h, then reflux, 4.5 h, 75%; d) from 3, PPA, P O , 130 °C, 4 h, 60%.
2
5
Synthesis 2010, No. 5, 783–790 © Thieme Stuttgart · New York

PAPER
Synthesis of the First N-Methyloxoarcyriaflavin
785
Table 1 Synthesis of the Acid 3 Starting from the Ester 11
Entry
Conditions
Time
0.5 h
14.5 h
3 d
Yield (%)
11 (95)
1
2
3
4
5
6
BBr (25.0 equiv), CH Cl , 0 °C, then r.t.
3
2
2
KOH 15% (3.6 equiv), acetone, r.t.
11 (60)
Ti(Oi-Pr) (0.5 equiv), CH =CHCH OH, reflux
11 (86)
4
2
2
Bu NF (1 M in THF, 20 equiv), microwave, 140 °C
0.25 h
89 h
3 (55)
4
LiOOH (5.0 equiv), THF, 0 °C, then r.t.
3 (19) + 12 (13)
3 (19) + 12 (24)
a) LiOOH (5.0 equiv), THF, 0 °C, then r.t.
b) heating to 70 °C
a) 1 h
b) 15.5 h
7
a) LiOOH (5.0 equiv), dioxane, 0 °C to r.t.
b) heating to reflux
a) 1 h
b) 4.5 h
3 (75)
1
4
ester functions as a side-reaction. Indeed, using Bu NF liberated amide reacted thus with the acid to form the ther-
4
in large excess and heating the mixture with microwaves modynamically stable b-carboline.
for 15 min led to 3 in 55% yield (entry 4).
Trying to prove this structure, and also to facilitate the
In parallel, we also tried LiOOH, prepared from LiOH/ NMR analysis, we treated 14 with hydrogen over Pd/C in
1
5
H O (entries 5–7). This method presents two advan- order to reduce the double bond. Despite a long reaction
2
2
tages: a less basic media than with KOH or LiOH; the use time, the expected hydrogenated compound 15 was never
–
of the nucleophilic character of the HOO anion. Because observed. Instead, an unexpected decarboxylation oc-
of this nucleophilicity, the maleimide part was opened and curred and compound 2 was the sole isolated product in
first attempts led to a mixture of 3/12 in a 6:4 ratio as well 40% yield. Unfortunately, NMR 2D experiments were
as degradation due to the long reaction time (entry 5). Op- still not satisfactory to confirm the structure of 2.
timizing the conditions afforded compound 3 alone in the
best yield of 75% without any trace of 12 (entry 7).
So, we decided to prepare 2 in an unequivocal route
(
Scheme 5; method B, see experimental). Such a structure
The last step of the synthesis was the electrophilic cycliza- suggests an aldolization/crotonization sequence between
tion onto position C-2 of the indole. Our usual conditions, formylindole and a b-carboline. Starting from the ketoglu-
5
BF ·Et O at reflux in dichloroethane, led to an insepara- tyric acid and phenylhydrazine, the indole 16 was ob-
3
2
1
6
ble mixture of 1 and an unidentified compound. Fortu- tained under Fischer type conditions in 68% yield and a
nately, the cyclization could be conducted in a mixture of further MOM protection led easily to 17 in 90% yield
polyphosphoric acid and P O , providing the final and (Scheme 5).
2
5
pure compound 1 in 60% yield.
A double saponification generated the diacid 18 in 88%
In a second set of experiments, we wanted to try the other yield, which was involved in a direct condensation of
strategy consisting of hydrolyzing first the ester function aqueous methylamine in refluxing n-propanol to afford
17
of the protected compound 10 (Scheme 4). But in pres- the expected carboline 19 in a good yield. Nevertheless,
ence of the methoxymethyl group, the saponification did all attempts to realize the condensation between 19 and 3-
not afford the expected protected acid 13. Instead, the re- formyl-N-Boc-indole (aldolization or Knovenaegel con-
action led to a surprising rearranged product, which was densation) failed.
suspected, after complete analysis to be 14, nevertheless
with ambiguous structural assignment due to a poor solu-
bility in NMR solvents. This compound 14 was presum-
ably formed by maleimide opening in basic media. The
We next envisioned performing such a reaction on the di-
ester 17. In the presence of sodium hydride (5.0 equiv)
and using a slight excess of 3-formyl-N-Boc-indole (20),
18
the alkene 21 was isolated in 68% yield (Scheme 5).
Me
Me
Me
O
d
N
c
O
O
N
O
N
O
O
O
a
2
H
b
a
HO
b
3
N
N
3'
O
O
4'
2'
5'
4
7
Me
RO
Me
N
N
NH
5
NH
14 46%
6
H
6'
O
Me
7'
O
1
1
0 R = Me
3 R = H
2 40%
Scheme 4 Reagents and conditions: a) from 10, aq 45% KOH (3.6 equiv), acetone, r.t., 21 h, then concd HCl, r.t. 12 h, 46%; b) Pd/C, H (50
2
psi), DMF, 3 d, 40%.
Synthesis 2010, No. 5, 783–790 © Thieme Stuttgart · New York

7
86
A. Bourderioux et al.
PAPER
O
CO2Et
CO2Et
CO2H
CO2H
b
c
N
Me
N
R
N
N
O
R
R
1
1
6 R = H
7 R = MOM 90%
18 R = MOM 88%
19 R = MOM 75%
a
O
O
c
X
d
EtO
H
a
2
b
3
N
d
f
O
17
4'
3'
2 92%
CHO
2'
4
Me
5'
7
NH
5
6
6'
N
7'
Boc
21 X = OH 68%
2 X = NHMe 85%
e
2
20
Scheme 5 Reagents and conditions: a) NaH (1.2 equiv), MOMCl (1.5 equiv), DMF, 0 °C to r.t. 6.5 h, 90%; b) KOH (2.2 equiv), H O–EtOH
2
(
1:1), THF, 50 °C, 8 h, 88%; c) MeNH (4.0 equiv), H O–PrOH, reflux, 12 h, 75%; d) NaH (5.0 equiv) 1 h, then 20 (1.2 equiv), r.t., THF, 15
2
2
h, 68%; e) EDCI (1.1 equiv), HOBt (1.1 equiv), 30 min, then MeNH (1.2 equiv), DMF, r.t., 5 h, 85%; f) Et N (cat.), MeOH, r.t., 2 h, 92%.
2
3
During the reaction, a mono and regioselective saponifi- 3-Iodo-1-methoxymethyl-1H-indole-2-carboxylic Acid Methyl
Ester (7)
cation occurred concomitantly. The E-configuration of
To a suspension of NaH (690 mg, 17.3 mmol, 60% in oil) in DMF
the double bond was established by NMR experiment, by
(
48 mL), under argon and at 0 °C, was added over 50 min a solution
1
3
1
measurement of the long-range hetero C– H coupling
of 6 (4.0 g, 13.3 mmol) in DMF (48 mL). The mixture was stirred
at 0 °C for 0.5 h and MOMCl (4.0 mL, 53.1 mmol) was added drop-
wise. The solution was then stirred for 2 h and quenched with iced
3
19
constant, between H and CO ( J = 3.0 Hz). Then,
b
d
H,CO
the amidification of 21 in the presence of methylamine led
under peptidic conditions to the amide 22 in 85% yield.20 H O (10 mL). The precipitate was filtered through a Millipore filter,
2
Fortunately, the spontaneous cyclization of 22 occurred in washed with H
O (2 × 30 mL), and dried under vacuum to give 7 as
2
a white solid (4.3 g, 93%); mp 61–62 °C; R = 0.38 (PE–EtOAc,
the presence of a catalytic amount of triethylamine in
methanol at room temperature and led to 2 in 92% yield.
f
9
:1).
–
1
IR (NaCl): 3020, 2953, 1712, 1654, 1500 cm .
After analysis, all data were in concordance with the pre-
viously supposed compound. The supposed b-carboline
structure of compound 2 was thus confirmed, as well as
the synthetic sequence starting from 10, leading to 14 and
then to 2 (Scheme 4).
1
H NMR (250 MHz, CDCl ): d = 3.26 (s, 3 H, CH OCH ), 4.00 (s,
3
3
2
3
7
H, CO CH ), 5.94 (s, 2 H, CH OCH ), 7.27–7.31 (m, 1 H, H-5),
2 3 3 2
.43 (t, J = 7.1 Hz, 1 H, H-6), 7.52 (d, J = 8.5 Hz, 1 H, H-7), 7.60
(
d, J = 8.2 Hz, 1 H, H-4).
13C
NMR (62.9 MHz, CDCl3): d = 51.9 (CO CH ), 56.3
2
3
In conclusion, we have reported here the synthesis of the (CH OCH ), 70.4 (C-3) 75.7 (CH OCH ), 111.3 (CH-7), 122.4
3
2
,
3
2
first N-methyloxoarcyriaflavine in only four efficient (CH-5), 124.2 (CH-4), 126.9 (CH-6), 128.7 (C
), 130.7 (C ), 139.1
q
q
(
C ), 161.7 (CO CH ).
steps involving a Stille cross coupling and a final electro-
q
2
3
+
philic cyclization. Our investigations provided an unex- IS-MS: m/z = 363.5 [M + NH ] .
4
pected b-carboline which was synthesized by another
3
-Trimethylstannyl-1H-indole-2-carboxylic Acid Methyl Ester
straightforward route. All structures were confirmed and
further investigations are in progress using these two orig-
inal structures for designing new potential antitumor
drugs.
(
8)
To a solution of 6 (250.0 mg, 0.83 mmol) in distilled toluene (10
mL) was added Sn Me (0.20 mL, 1.00 mmol). After degassing the
mixture with argon for 0.5 h, Pd(PPh ) (96 mg, 0.08 mmol) was in-
2
6
3
4
troduced. The flask was immersed in a preheated oil bath (125 °C)
and the mixture was refluxed for 5.5 h. The solution was quenched
with a mixture of hexane/sat. aq KF (1:1, 20 mL) and stirred for 0.5
h. The salts were filtered over Celite and the organic layer dried un-
der vacuum to afford crude 8 as an orange solid (366 mg, quant);
Rf = 0.64 (PE–EtOAc, 9:1).
1H and 13C NMR spectra were recorded on a Bruker Avance 500,
4
00, or DPX 250 instruments using CDCl or DMSO-d . The chem-
3 6
ical shifts are reported in ppm (d scale) and all J values are in Hz.
Melting points are uncorrected. IR absorption spectra were recorded
on a Perkin-Elmer FT PARAGON 1000 PC and values are reported
–
1
1
in cm . MS spectra (ion spray) were performed on a Perkin-Elmer
SCIEX API 300 spectrometer. HRMS analyses were realized by the
Centre Régional de Mesures Physiques de l’Ouest (CRMPO,
Rennes) or by the Centre Régional de Mesure Physique (CRMP,
Clermont Ferrand). Monitoring of the reactions was performed us-
ing silica gel TLC plates (Merck 60 F254). Spots were visualized by
UV light at 254 and 365 nm. Column chromatography was per-
formed using silica gel 60 (40–63 mm, Merck). Petroleum ether (PE)
used refers to the fraction boiling in the range 30–60 °C.
H NMR (250 MHz, CDCl ): d = 0.41 [t, J = 28.0 Hz, 9 H,
3
Sn(CH ) ], 3.94 (s, 3 H, CO CH ), 7.14 (t, J = 7.5 Hz, 1 H, H-5),
3
3
2
3
7.28–7.40 (m, 1 H, H-6), 7.45 (d, J = 8.1 Hz, 1 H, H-7), 7.81 (d,
J = 8.3 Hz, 1 H, H-4), 9.1 (br, 1 H, NH).
3-Trimethylstannyl-1-methoxymethyl-1H-indole-2-carboxylic
Acid Methyl Ester (9)
Compound 9 was obtained as described for 8 starting from 7 (1.0 g,
2.90 mmol), toluene (50 mL), Sn Me (0.9 mL, 4.35 mmol),
2
6
Pd(PPh ) (670 mg, 0.58 mmol), and refluxing for 8 h. After treat-
3
4
Synthesis 2010, No. 5, 783–790 © Thieme Stuttgart · New York

PAPER
Synthesis of the First N-Methyloxoarcyriaflavin
787
1
3
ment with aq KF, a purification by chromatography on silica gel
C NMR (62.9 MHz, DMSO-d ): d = 24.1 (NCH ), 51.8
6
3
(
6
PE, then PE–EtOAc, 98:2) afforded 9 as a colorless oil (752 mg,
8%); R = 0.49 (PE–EtOAc, 9:1).
(CO CH ), 105.5 (C -3¢), 110.9 (C -3), 111.9 (CH-7¢), 112.7 (CH-
2 3 q q
7), 119.8 (CH-5¢), 120.3 (CH-4¢), 120.4 (CH-5), 121.1 (CH-4),
121.9 (CH-6¢), 124.5 (C
1
(CO CH ), 170.5 (NC=O), 171.4 (NC=O).
f
–
1
q
), 124.9 (C-9¢ + CH-6), 126.2 (C
q
-9 + C ),
q
IR (NaCl): 3000, 2950, 1714 cm .
30.4 (CH-2¢), 133.1 (C ), 136.1 (C -8), 136.2 (C -8¢), 161.4
q q q
1
H NMR (250 MHz, CDCl ): d = 0.39 [t, J = 27.2 Hz, 9 H,
3
2 3
Sn(CH ) ], 3.30 (s, 3 H, CH OCH ), 3.91 (s, 3 H, CO CH ), 5.97 (s,
3
3
3
2
2
3
+
+
–
IS-MS: m/z = 400.5 [M + H] , 422.5 [M + Na] , 398 [M – H] .
2
1
H, CH OCH ), 7.18 (t, J = 7.5 Hz, 1 H, H-5), 7.38 (t, J = 7.7 Hz,
H, H-6), 7.56 (d, J = 8.5 Hz, 1 H, H-7), 7.83 (d, J = 7.9 Hz, 1 H,
3 2
3
-[4-(1H-Indol-3-yl)-1-methyl-2,5-dioxo-2,5-dihydro-1H-pyr-
H-4).
rol-3-yl]-1H-indole-2-carboxylic Acid (3)
To aq 1 M LiOH (1.25 mL, 1.25 mmol) cooled to 0 °C was added
dropwise H O (0.63 mL). The mixture was stirred at 0 °C for 0.5 h,
then added dropwise at 0 °C to a solution of 10 (100 mg, 0.25 mmol)
in dioxane (4 mL). The mixture was warmed up to r.t. over 1 h and
refluxed for 4.5 h. After cooling to r.t., the solution was diluted with
H O (20 mL), acidified with concd HCl (6 mL) and stirred over-
night at r.t. The precipitate was extracted with EtOAc (3 × 30 mL).
The combined organic layers were washed with H O (50 mL), dried
1
3
C NMR (62.9 MHz, CDCl ): d = –6.5 [Sn(CH ) ], 51.6
2 3 3 2 3 2
3
3 3
(
CO CH ), 56.1 (CH OCH ), 75.0 (CH OCH ), 111.1 (CH-7),
2
2
1
1
21.1 (CH-5), 123.8 (C ), 124.4 (CH-4), 125.5 (CH-6), 133.1 (C ),
q q
33.5 (C ), 140.9 (C ), 162.6 (CO CH ).
q
q
2
3
IS-MS: m/z = 380.5, 382.5, 384.5, 386.5, 388.5 [M + H] for 116Sn,
+
1
18
120
122
124
Sn, Sn, Sn, and Sn isotopes.
2
3
-[4-(1H-Indol-3-yl)-1-methyl-2,5-dioxo-2,5-dihydro-1H-pyr-
2
(
MgSO ), filtered through a plug of cotton wool, and evaporated un-
rol-3-yl]-1-methoxymethyl-1H-indole-2-carboxylic Acid Meth-
4
der vacuum to afford 11 as an orange solid (73 mg, 75%); R = 0.48
(
IR (KBr): 3342, 3059, 2928, 1759, 1697, 1446, 1385, 1245 cm–1.
1
yl Ester (10)
f
EtOAc–MeOH, 8:2); mp 223–225 °C (dec.).
A solution of 4 (27.0 mg, 0.09 mmol), 9 (52 mg, 0.13 mmol), and
CuI (2.0 mg, 0.01 mmol) in dioxane (5 mL) was degassed under ar-
gon for 0.5 h. Then PdCl (PPh ) (12.0 mg, 0.02 mmol) was added
2
3 2
H NMR (500 MHz, DMSO-d ): d = 3.05 (s, 3 H, NCH ), 6.59 (t,
6
3
and the flask was immersed in a preheated oil bath (120 °C). The
mixture was refluxed under argon for 3.75 h, then cooled to r.t., and
filtered over Celite. The filtrate was evaporated and the crude prod-
uct purified by chromatography on silica gel (PE–CH Cl , 1:1, then
J = 8.1 Hz, 1 H, H-5¢), 6.70 (d, J = 8.1 Hz, 1 H, H-4¢), 6.77 (t,
J = 7.6 Hz, 1 H, H-5), 6.94 (t, J = 8.1 Hz, 1 H, H-6¢), 6.99 (d, J = 8.1
Hz, 1 H, H-4), 7.12 (t, J = 7.7 Hz, 1 H, H-6), 7.31 (d, J = 8.1 Hz, 1
H, H-7¢), 7.41 (d, J = 8.3 Hz, 1 H, H-7), 7.92 (d, J = 2.9 Hz, 1 H, H-
2
2
PE–CH Cl –EtOAc, 2:2:1) to provide 10 as an ochre solid (40 mg,
2
2
2
¢), 11.75 (br s, 1 H, NHind¢), 12.13 (br s, 1 H, NHind).
13C NMR (62.9 MHz, DMSO-d
): d = 24.1 (NCH ), 105.5 (C
10.2 (C -3), 111.9 (CH-7¢), 112.6 (CH-7), 119.8 (CH-5¢), 120.2
quant); R = 0.44 (PE–EtOAc, 6:4); mp 181–183 °C (dec.).
f
–
1
6
3
q
-3¢),
IR (KBr): 3320, 2951, 1754, 1715, 1695, 1634, 1531 cm .
1
q
1
H NMR (250 MHz, DMSO-d ): d = 3.06 (s, 3 H, NCH ), 3.17 (s, 3
6
3
(CH-5), 120.4 (CH-4¢), 120.7 (CH-4), 121.8 (CH-6¢), 124.4 (CH-6),
H, CH OCH ), 3.75 (s, 3 H, CO CH ), 5.88–6.06 (m, 2 H,
3
2
2
3
125.0 (C -9¢), 126.4 (C -9), 130.2 (CH-2¢), 132.9 (C -a), 135.8 (C -
q
q
q
q
CH OCH ), 6.52 (t, J = 7.5 Hz, 1 H, H-5¢), 6.69 (d, J = 8.2 Hz, 1 H,
3
2
8), 136.1 (C -8¢), 139.9 (C -b), 142.4 (C -2), 162.4 (CO H), 170.5
q
q
q
2
H-4¢), 6.80 (t, J = 7.5 Hz, 1 H, H-5), 6.89–6.96 (m, 2 H, H-4/H-6¢),
.20 (t, J = 7.7 Hz, 1 H, H-6), 7.32 (d, J = 7.9 Hz, 1 H, H-7¢), 7.71
d, J = 8.2 Hz, 1 H, H-7), 8.03 (d, J = 1.9 Hz, 1 H, H-2¢), 11.86 (br
s, 1 H, NH).
(
NC=O), 171.5 (NC=O).
7
(
IS-MS: m/z = 384 [M – H]–.
Indolo[2¢,3¢-3,4]indolo[2¢,3¢-6,7]cyclohepta[1,2-c]-1-methylpyr-
rol-1,3,9-trione (1)
To a mixture of polyphosphoric acid (5.0 g, large excess) and P O
(770 mg, large excess), heated to 130 °C, was added 11 (50 mg,
0.13 mmol). After heating for 4 h at 130 °C and cooling to r.t., the
1
3
C NMR (62.9 MHz, DMSO-d ): d = 24.2 (NCH ), 52.1
6
3
(
(
1
+
1
CO CH ), 55.4 (CH OCH ), 74.3 (CH OCH ), 105.2 (C -3¢), 111.5
2 3 3 2 3 2 q
2
5
CH-7), 112.0 (CH-7¢), 113.6 (C -3), 119.7 (CH-5¢), 120.1 (CH-4¢),
q
21.1 (CH-4), 121.3 (CH-5), 122.0 (CH-6¢),124.1 (C ), 125.1 (C -9
q q
C -9¢), 125.5 (CH-6), 127.3 (C -2), 130.5 (CH-2¢), 132.7 (C ),
q
q
q
mixture was diluted with H O (50 mL) and neutralized to pH 7 with
sat. aq NaHCO (70 mL). The aqueous layer was extracted with
2
36.1 (Cq-8¢), 138.0 (C -8), 161.7 (CO CH ), 170.6 (NC=O), 171.3
NC=O).
q 2 3
3
(
EtOAc (3 × 50 mL). The combined organic layers were washed
+
+
–
with H O (3 × 50 mL), dried (MgSO ), and filtered through a plug
IS-MS: m/z = 461.5 [M + NH ] , 466.5 [M + Na] , 442.5 [M – H] .
2
4
4
of cotton wool. Removal of the solvents afforded 1 as an orange sol-
id (29 mg, 60%); R = 0.14 (PE–CH Cl –EtOAc, 9:9:2); mp 193–
3
-[4-(1H-Indol-3-yl)-1-methyl-2,5-dioxo-2,5-dihydro-1H-pyr-
f
2
2
1
95 °C (dec.).
rol-3-yl]-1H-indole-2-carboxylic Acid Methyl Ester (11)
To a solution of 10 (1.0 g, 2.26 mmol) in MeOH (150 mL) was add-
ed aq 6 N HCl (100 mL). The mixture was refluxed for 18 h and then
cooled to r.t. The precipitate was filtered through a Millipore filter,
IR (KBr): 3228, 2923, 1766, 1705, 1550, 1493, 1459, 1387 cm–1.
1
H NMR (500 MHz, DMSO-d ): d = 3.12 (s, 3 H, NCH ), 7.33 (t,
6
3
J = 7.1 Hz, 2 H, H-5), 7.55 (t, J = 7.1 Hz, 2 H, H-6), 7.75 (d, J = 8.0
Hz, 2 H, H-7), 9.11 (d, J = 8.5 Hz, 2 H, H-4), 13.06 (br s, 2 H, NH).
washed with H O (3 × 30 mL), and then dissolved in EtOAc (4 × 50
2
mL). The combined organic layers were dried (MgSO ), filtered
4
1
3
through a plug of cotton wool, and evaporated under vacuum to give
C NMR (62.9 MHz, DMSO-d ): d = 24.3 (NCH ), 112.7 (2 × CH-
6
3
1
1 as an orange solid (827 mg, 92%); R = 0.32 (PE–CH Cl –
7), 114.3 (2 × C -3), 121.3 (2 × CH-5), 123.9 (2 × C -9), 125.0
f
2
2
q
q
EtOAc, 9:9:2); mp 251–253 °C (dec.).
(2 × C ), 127.6 (2 × CH-4), 127.7 (2 × CH-6), 138.6 (2 × C -8),
q
q
1
40.3 (2 × C -2), 167.9 (C=O), 170.0 (2 × NC=O).
q
IR (KBr): 3373, 3283, 1759, 1717, 1693, 1635, 1543, 1385, 741
–
1
·+
cm .
HRMS: m/z calcd for C H N O : 367.09569; found [M ]:
22 13 3 3
1
367.0961.
H NMR (500 MHz, DMSO-d ): d = 3.07 (s, 3 H, NCH ), 3.73 (s, 3
6
3
H, CO CH ), 6.56–6.62 (m, 2 H, H-4¢/H-5¢), 6.79 (t, J = 7.5 Hz, 1
H, H-5), 6.94 (t, J = 7.6 Hz, 1 H, H-6¢), 7.02 (d, J = 8.1 Hz, 1 H, H-
4
7
(
2
3
(
Z)-2-(1H-Indol-3-yl)-2-(9-methoxymethyl-2-methyl-1,3-(2H)-
dioxo-4,9-dihydro-1H-pyrido[3,4-b]indol-4-ylidene)acetic Acid
14)
), 7.16 (t, J = 7.6 Hz, 1 H, H-6), 7.33 (d, J = 8.1 Hz, 1 H, H-7¢),
.44 (d, J = 8.3 Hz, 1 H, H-7), 7.96 (d, J = 2.7 Hz, 1 H, H-2¢), 11.78
br s, 1 H, NHind¢), 12. 31 (br s, 1 H, NHind).
(
To a solution of 10 (150 mg, 0.34 mmol) in acetone (7.5 mL) was
added 0.5 mL of aq KOH (69 mg, 1.23 mmol). The mixture was
Synthesis 2010, No. 5, 783–790 © Thieme Stuttgart · New York

7
88
A. Bourderioux et al.
PAPER
stirred at r.t. for 21 h. After evaporation of the acetone, the mixture
After filtration and reduction of the volatiles under reduced pres-
sure, silica gel column chromatographic purification (PE–EtOAc,
was diluted with H O (15 mL), then acidified with concd HCl (15
2
mL), and stirred overnight at r.t. The precipitate was filtered
6:4) gave 17 as a colorless oil (1.04 g, 90%); R = 0.45 (PE–EtOAc,
f
through a Millipore filter, washed with H O (2 × 20 mL), and puri-
6:4).
2
fied by chromatography on silica gel (EtOAc, then EtOAc–MeOH,
IR (ATR diamond): 2981, 1733, 1701, 1333, 1227 cm–1.
6
:4) to give 14 as a brown solid (67 mg, 46%); R = 0.21 (EtOAc–
f
1
H NMR (250 MHz, DMSO-d ): d = 1.18 (t, J = 7.2 Hz, 3 H), 1.33
t, J = 7.2 Hz, 3 H), 3.13 (s, 3 H), 4.04–4.11 (m, 4 H), 4.27–4.36 (q,
MeOH, 8:2); mp 157–159 °C (dec.).
6
(
–
1
IR (KBr): 3393, 2930, 1757, 1686, 1648, 1575, 1476 cm .
J = 7.2 Hz, 2 H), 5.91 (s, 2 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.40 (t,
J = 7.7 Hz, 1 H), 7.71 (d, J = 8.2 Hz, 1 H), 7.77 (d, J = 7.9 Hz, 1 H).
1
H NMR (250 MHz, DMSO-d ): d = 3.21 (s, 3 H, CH OCH ), 3.27
6
3
2
(
s, 3 H, NCH ), 6.05 (s, 2 H, CH OCH ), 6.37 (d, J = 7.8 Hz, 1 H,
13
3
3
2
C NMR (62.9 MHz, CDCl ): d = 13.7 (CH ), 14.0 (CH ), 30.5
2 2 2 2 2
3
3
3
H-4), 6.47 (t, J = 7.5 Hz, 1 H, H-5), 6.75 (t, J = 7.2 Hz, 1 H, H-5¢),
(
CH ), 55.2 (CH ), 60.1 (CH ), 60.5 (CH ), 74.1 (CH ), 111.1 (CH),
6
.97 (t, J = 7.5 Hz, 1 H, H-6¢), 7.09 (t, J = 7.7 Hz, 1 H, H-6), 7.31
1
18.1 (C ), 120.5 (CH), 120.8 (CH), 125.1 (C ), 125.6 (CH), 126.6
q q
(
(
1
d, J = 8.2 Hz, 1 H, H-7¢), 7.44–7.55 (m, 3 H, H-2¢/H-4¢/H-7), 11.67
(
C ), 138.2 (C ), 161.2 (C=O), 163.7 (C=O).
q q
br s, 1 H, NH).
IS-MS: m/z = 320 [M + H]+.
3
C NMR (62.9 MHz, DMSO-d ): d = 26.4 (NCH ), 55.2
6
3
+
HRMS: m/z calcd for C H NO + Na [M + Na ]: 342.1317; found:
(
(
CH OCH ), 73.7 (CH OCH ), 110.2 (C ), 111.2 (CH-7), 111.8
CH-7¢), 113.9 (C ), 119.5 (CH-5¢), 120.0 (CH-5), 120.6 (CH-4¢),
17 21
5
3
2
3
2
q
3
42.1332.
q
1
2
21.5 (C -3), 121.6 (CH-6¢), 122.1 (C -9), 123.4 (CH-4), 123.8 (C -
q
q
q
3
-Carboxymethyl-1-methoxymethyl-1H-indole-2-carboxylic
), 125.5 (CH-6), 125.9 (C -9¢), 130.3 (CH-2¢), 136.4 (C -8¢), 139.7
q
q
Acid (18)
(
C -8), 159.4 (NC=O), 164.9 (NC=O).
q
A solution of the diester 17 (200 mg, 0.62 mmol) in H O (5 mL) and
EtOH (5 mL) was stirred for 8 h at r.t. in the presence of NaOH (55
IS-MS: m/z = 428 [M – H]–.
2
mg, 1.37 mmol). H O (10 mL) was added and the suspension was
2
(
4
E)-4-[(1H-Indol-3-yl)methylene]-9-methoxymethyl-2-methyl-
,9-dihydro-1H-pyrido[3,4-b]indole-1,3(2H)-dione (2)
extracted with CH Cl (3 × 15 mL). The aqueous phase was acidi-
2
2
fied by the addition of concd HCl. The resulting white solid was fil-
Method A: To a solution of 14 (50 mg, 0.12 mmol) in DMF (30 mL)
was added Pd/C 10% (41 mg, 0.04 mmol). The mixture was stirred
4
over Celite and washed with EtOAc (60 mL). The organic layer was
washed with brine (3 × 50 mL) and H O (50 mL), dried (MgSO ),
and filtered through a plug of cotton wool. Removal of solvents pro-
tered to give 18 (140 mg, 88%); mp >260 °C.
–
1
IR (ATR diamond): 2934, 1707, 1655, 1446, 1235, 1171 cm .
d in a steel bomb at r.t. under H (50 psi). The solution was filtered
2
1
H NMR (400 MHz, DMSO-d ): d = 3.12 (s, 3 H), 4.03 (s, 2 H),
6
2
4
5.91 (s, 2 H), 7.16 (dd, J = 7.6, 7.2 Hz, 1 H), 7.36 (dd, J = 8.0, 7.2
Hz, 1 H), 7.66 (d, J = 7.6 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 12.72
vided 2 as an orange solid (18 mg, 40%).
(
br s, 2 H).
Method B: To a stirred solution of compound 22 (100 mg, 0.23
13
C NMR (100.6 MHz, CDCl ): d = 30.6 (CH ), 55.3 (CH ), 74.1
2 q
3
2
3
mmol) in MeOH (5 mL) at r.t. was added a catalytic amount of Et N
3
(CH ), 111.1 (CH), 118.5 (C ), 120.5 (CH), 120.6 (CH), 125.2
(
3 drops) and the reaction mixture was stirred for 2 h. The precipi-
(
CH), 126.1 (C ), 126.8 (C ), 138.2 (C ), 163.0 (C ), 172.2 (C ).
q q q q q
tate was filtered through a Millipore filter, washed with MeOH (5
mL), and dried under reduced pressure to provide pure compound 2
IS-MS: m/z = 262 [M – H]–.
as an orange solid (82 mg, 92%); R = 0.44 (PE–EtOAc, 1:1); mp
f
9
-Methoxymethyl-2-methyl-4,9-dihydro-1H-pyrido[3,4-b]in-
2
30–232 °C (dec.).
dole-1,3(2H)-dione (19)
A solution of compound 18 (100 mg, 0.38 mmol) and a 4.0 molar
ratio of MeNH (40% in H O, 130 mL, 1.52 mmol) in H O–PrOH (6
mL, 1:2) was stirred at r.t. for 4 h and then heated at 90 °C for 12 h.
The mixture was cooled to r.t. and the solvents were removed under
reduced pressure. The crude product was recrystallized from
MeOH–PE to yield 19 as a white solid (73 mg, 77%); mp 166–
–
1
IR (KBr): 3278, 2925, 1672, 1632, 1488, 1372 cm .
1
H NMR (500 MHz, DMSO-d ): d = 3.23 (s, 3 H, CH OCH ), 3.36
2
2
2
6
3
2
(
s, 3 H, NCH ), 6.11 (s, 2 H, CH OCH ), 7.29–7.35 (m, 2 H, H-5¢/
3
3
2
H-6¢), 7.47 (t, J = 7.6 Hz, 1 H, H-5), 7.55–7.59 (m, 2 H, H-6/H-7),
.83 (d, J = 8.5 Hz, 1 H, H-7), 7.99 (d, J = 6.6 Hz, 1 H, H-4¢), 8.39
d, J = 8.3 Hz, 1 H, H-4), 8.65 (s, 1 H, H ), 9.33 (d, J = 2.1 Hz, 1 H,
7
(
b
1
68 °C.
H-2¢), 12.28 (br s, 1 H, NH).
–
1
1
3
IR (ATR diamond): 2934, 1706, 1655, 1447, 1342, 1108 cm .
C NMR (100.6 MHz, DMSO-d ): d = 26.5 (NCH ), 55.5
6
3
(
(
1
6
(
CH OCH ), 73.9 (CH OCH ), 111.5 (C -3¢), 112.3 (CH-7), 112.7
1
3
2
3
2
q
H NMR (250 MHz, DMSO-d ): d = 2.39 (s, 3 H), 3.11 (s, 3 H),
6
CH-7¢), 114.7 (C ), 117.8 (CH-4), 121.4 (C -9), 121.5 (CH-5¢),
q
q
3.70 (s, 2 H), 5.96 (s, 2 H), 7.11 (dd, J = 7.2, 7.5 Hz, 1 H), 7.24 (dd,
J = 8.2, 7.2 Hz, 1 H), 7.52 (d, J = 8.2 Hz, 1 H), 7.57 (d, J = 7.5 Hz,
1 H).
21.6 (C ), 122.2 (C -2), 122.3 (CH-4), 122.7 (CH-5), 123.0 (CH-
q q
¢), 126.7 (CH-6), 129.0 (C -9¢), 132.8 (CH ), 135.1 (CH-2¢), 136.1
C -8¢), 140.5 (C -8), 158.5(NC=O), 163.6 (NC=O).
q
b
q q
13
C NMR (62.9 MHz, CDCl ): d = 24.4 (CH ), 33.2 (CH ), 55.0
3
3
2
·
+
HRMS: m/z calcd for C H N O : 385.14931; found [M ]:
2
3
19
3
3
(CH ), 73.6 (CH ), 110.8 (CH), 112.0 (C ), 119.0 (CH), 120.0 (CH),
1
3
2
q
3
85.14264.
23.0 (CH), 126.5 (C ), 133.8 (C ), 136.6 (C ), 164.9 (C ), 172.8
q q q q
(
Cq).
3
-Ethoxycarbonylmethyl-1-methoxymethyl-1H-indole-2-car-
IS-MS: m/z = 258 [M + H]+.
boxylic Acid Ethyl Ester (17)
Compound 16 (1.0 g, 3.63 mmol) was slowly added to a suspension
of NaH (175 mg, 4.35 mmol, 60% in oil) in DMF (10 mL) at 0 °C.
The mixture was stirred for 15 min at 0°C and then at r.t. for 15 min.
Chloromethyl methyl ether (415 mL, 5.44 mmol) was added drop-
wise at 0 °C and the reaction mixture was stirred for 30 min at 0 °C
(
E)-3-[3-Ethoxy-1-(1H-indol-3-yl)-3-oxoprop-1-en-2-yl]-1-
methoxymethyl-1H-indole-2-carboxylic Acid (21)
A solution of compound 17 (1.0 g, 3.13 mmol) in THF (5 mL) was
added under argon and at 0 °C to a suspension of NaH (627 mg,
1
at r.t. for 1 h and a solution of aldehyde 20 (922 mg, 3.76 mmol) in
THF (5 mL) was added dropwise. The mixture was stirred at r.t. for
5.65 mmol, 60% in oil) in THF (20 mL). The mixture was stirred
and then 6 h at r.t. The mixture was diluted with H O (15 mL) and
2
extracted with EtOAc (3 × 25 mL). The combined organic layers
were washed with H O (10 mL), brine (10 mL), and dried (Na SO ).
2
2
4
Synthesis 2010, No. 5, 783–790 © Thieme Stuttgart · New York

PAPER
Synthesis of the First N-Methyloxoarcyriaflavin
789
1
5 h. EtOH (2 mL) and then 50% aq AcOH (5 mL) were added. Af- References
ter extraction with EtOAc (2 × 30 mL), the organic layers were
washed with sat. aq NaHCO (20 mL), dried (MgSO ), filtered, and
concentrated under reduced pressure. The crude residue was
washed with Et O (3 × 10 mL) and the precipitate filtered through a
Millipore filter to give 21 as a yellow solid (885 mg, 68%); mp 206–
2
(
1) (a) Sanchez, C.; Mendez, C.; Salas, J. A. Nat. Prod. Rep.
006, 23, 1007. (b) Knölker, H.-J.; Reddy, K. R. In The
3
4
2
Alkaloids, Vol. 65; Cordell, G. A., Ed.; Elsevier Academic
Press: New York, 2008, 1–430.
2
(
2) (a) 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. (b) Zhu, G.; Conner, S. E.; Zhou, X.; Shih, C.; Li,
T.; Anderson, B. D.; Brooks, H. B.; Campbell, R. M.;
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.
08 °C.
–
1
IR (ATR diamond): 3395, 2976, 1679, 1587, 1430, 1321 cm .
1
H NMR (400 MHz, DMSO-d ): d = 1.12 (t, J = 7.2 Hz, 3 H,
6
CO CH CH ), 3.19 (s, 3 H, CH OCH ), 4.01–4.09 (m, 2 H,
2
2
3
3
2
CO CH CH ), 6.16–6.32 (m, 3 H, H-2¢/ CH OCH ), 6.87–6.91 (t,
2
2
3
3
2
J = 7.5 Hz, 1 H, H-6¢), 7.06–7.11 (m, 3 H, H-6/H-5/H-7¢), 7.14–
7
7
.18 (t, J = 8.2 Hz, 1 H, H-5¢), 7.28–7.30 (d, J = 8.8 Hz, 1 H, H-4¢),
.55 (d, J = 8.2 Hz, 1 H, H-7), 7.70 (d, J = 8.8 Hz, 1 H, H-4), 8.04
(
1
s, 1 H, H ), 11.35 (br s, 1 H, NH).
(3) (a) 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, J. Bioorg. Med. Chem. Lett. 2003, 13, 3835.
b
3
C NMR (100.6 MHz, DMSO-d ): d = 14.2 (CO CH CH ), 54.6
3 2 2 2 3 3 2 q
6
2
2
3
(
1
5
CH OCH ), 59.3 (CO CH CH ), 73.6 (CH OCH ), 110.7 (C -3¢),
11.0 (CH-7), 111.7 (CH-4¢), 114.2 (C ), 117.6 (CH-4), 119.4 (CH-
q
), 119.7 (CH-6), 119.8 (CH-6¢), 121.5 (C -9), 121.7 (CH-3¢), 122.1
q
(
1
CH-5¢), 125.2 (C ), 126.6 (C -2), 127.3 (CH-2¢), 128.6 (CH ),
q
q
b
(
b) Engler, T. A.; Furness, K.; Malhotra, S.; Sanchez-
35.1 (C ), 136.0 (C ), 137.0 (C ), 165.5 (C=O ), 168.2 (C=O ).
q q q c d
Martinez, C.; Shih, C.; Xie, W.; Zhu, G.; Zhou, X.; Conner,
S.; Faul, M. M.; Sullivan, K. A.; Kolis, S. P.; Brooks, H. B.;
Patel, B.; Schultz, R. M.; DeHahn, T. B.; Kirmani, K.;
Spencer, C. D.; Watkins, S. A.; Considine, E. L.; Dempsey,
J. A.; Ogg, C. A.; Stamm, N. B.; Anderson, B. D.; Campbell,
R. M.; Vasudevan, V.; Lytle, M. L. Bioorg. Med. Chem. Lett.
+
HRMS: m/z calcd for C H N O + Na [M + Na ]: 441.1426;
found: 441.1436.
2
4
22
2
5
(
E)-Ethyl 3-(1H-Indol-3-yl)-2-(1-methoxymethyl-2-methyl-
carbamoyl-1H-indol-3-yl)acrylate (22)
To a stirred solution of compound 21 (100 mg, 0.24 mmol) in DMF
2
003, 13, 2261. (c) Zhu, G.; Conner, S.; Zhou, X.; Shih, C.;
(7 mL) at 0 °C were slowly added HOBt (39 mg, 0.28 mmol) and
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. (d) Routier,
S.; Peixoto, P.; Mérour, J.-Y.; Coudert, G.; Dias, N.; Bailly,
C.; Pierré, A.; Léonce, S.; Caignard, D.-H. J. Med. Chem.
EDCI (51 mg, 0.26 mmol). The reaction mixture was stirred under
inert atmosphere for 30 min. MeNH (2 M in THF) (144 mL, 0.29
mmol) was added to the above mixture dropwise over 5 min and
stirred for 5 h at r.t. The mixture was diluted with H O (3 mL) and
extracted with EtOAc (3 × 15 mL). The combined organic layers
were washed with H O (10 mL), brine (2 mL), dried (MgSO ), and
filtered. Concentration under vacuum and silica gel column chro-
matographic purification [CH Cl –MeOH (1%)] gave 22 as a yel-
low solid (87 mg, 85%); R = 0.45 (CH Cl –MeOH, 9:1); mp 120–
2
2
2
005, 48, 1401. (e) Routier, S.; Mérour, J.-Y.; Dias, N.;
2
4
Lansiaux, A.; Bailly, C.; Lozach, O.; Meijer, L. J. Med.
Chem. 2006, 49, 789.
2
2
(4) (a) Caballero, E.; Adeva, M.; Calderon, S.; Sahagun, H.;
Tomé, F.; Medarde, M.; Fernandez, J. L.; Lopez-Lazaro, M.;
Ayuso, M. J. Bioorg. Med. Chem. 2003, 11, 3413.
(b) Pews-Davtyan, A.; Tillack, A.; Ortinau, S.; Rolfs, A.;
Beller M, Org. Biomol. Chem. 2008, 6, 992. (c) Levy, D.
E.; Wang, D.-X.; Lu, Q.; Chen, Z.; Perumattam, J.; Xu, Y.-
j.; Liclican, A.; Higaki, J.; Dong, H.; Laney, M.; Mavunkel,
B.; Dugar, S. Bioorg. Med. Chem. Lett. 2008, 18, 2390.
f
2
2
1
22 °C (dec.).
–
1
IR (ATR diamond): 3394, 2976, 1678, 1588, 1431, 1367 cm .
1
H NMR (400 MHz, DMSO-d ): d = 1.30 (t, J = 7.2 Hz, 3 H,
6
CO CH CH ), 2.84 (d, J = 7.2 Hz, 3 H, CH NH), 3.29 (s, 3 H,
2
2
3
3
CH OCH ), 4.20–4.38 (m, 2 H, CO CH CH ), 5.89–5.96 (m, 2 H,
CH OCH ), 6.25 (s, 1 H, H-2¢), 7.01–7.07 (m, 2 H, H6¢/HNCH ),
7
7
(
3
2
2
2
3
3
2
3
(
5) (a) Bourderioux, A.; Routier, S.; Bénéteau, V.; Mérour, J.-Y.
Tetrahedron Lett. 2005, 46, 6071. (b) Bourderioux, A.;
Routier, S.; Bénéteau, V.; Mérour, J.-Y. Tetrahedron 2007,
.20–7.27 (m, 3 H, H-4¢/H-7¢/H-5), 7.30–7.34 (m, 2 H, H-6/H-5¢),
.59 (d, J = 8.8 Hz, 1 H, H-7), 7.87 (d, J = 8.0 Hz, 1 H, H-4), 8.47
br s, 1 H, NH), 8.53 (s, 1 H, Hb).
63, 9465. (c) Bourderioux, A.; Bénéteau, V.; Mérour, J.-Y.;
1
3
C NMR (100.6 MHz, DMSO-d ): d = 14.3 (CO CH CH ), 26.3
Baldeyrou, B.; Ballot, C.; Lansiaux, A.; Bailly, C.;
Le Guével, R.; Guillouzo, C.; Routier, S. Org. Biomol.
Chem. 2008, 6, 2108.
6
2
2
3
(NHCH ), 55.9 (CH OCH ), 61.2 (CO CH CH ), 75.1 (CH OCH ),
3 3 2 2 2 3 3 2
1
1
11.0 (CH-7), 111.2 (C ), 111.5 (CH-5), 114.3 (C ), 117.1 (C ),
q q q
18.2 (CH-4), 121.1 (CH-6), 121.16 (CH-7¢), 121.2 (CH-6¢), 123.0
(6) Su, J.-Y.; Zhu, Y.; Zeng, L.-M.; Xu, X.-H. J. Nat. Prod.
1997, 60, 1043.
(7) Mahboobi, S.; Burgemeister, T.; Dove, S.; Kuhr, S.; Popp,
A. J. Org. Chem. 1999, 64, 8130.
(
1
CH-4¢), 124.7 (CH-5¢), 125.2 (C ), 127.1 (CH-2¢), 127.6 (C ),
q
q
30.3 (C ),135.1 (C ), 135.4 (CH ), 138.1 (C ), 162.8 (C=O ), 168.8
q
q
b
q
c
(C=Od).
+
(8) Brenner, M.; Mayer, G.; Terpin, A.; Steglich, W. Chem. Eur.
J. 1997, 3, 70.
HRMS: m/z calcd for C H N O + Na (M + Na ): 454.1743;
found: 454.1762.
2
5
25
3
4
(
9) (a) Steglich, W.; Steffan, B.; Kopanski, L.; Eckhardt, G.
Angew. Chem., Int. Ed. Engl. 1980, 19, 459. (b) Brenner,
M.; Rexhausen, H.; Steffan, B.; Steglich, W. Tetrahedron
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
1
988, 44, 2887. (c) Faul, M. M.; Sullivan, K. A.;
Winneroski, L. L. Synthesis 1995, 1511.
(
(
10) Cruz, M. D.; Jimenez, F.; Delgado, F.; Tamariz, J. Synlett
2006, 749.
11) Martin, T.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1
Acknowledgment
We thank the Canceropôle Grand Ouest and the Association pour la
Recherche contre le Cancer (ARC) for the financial support.
1988, 235.
Synthesis 2010, No. 5, 783–790 © Thieme Stuttgart · New York

7
90
A. Bourderioux et al.
PAPER
(17) Yang, X.; Xu, X.; Ji, H. F. J. Phys. Chem. B. 2008, 112,
(
(
(
(
12) Mouaddib, A.; Joseph, B.; Hasnaoui, A.; Mérour, J.-Y.
Tetrahedron Lett. 1999, 40, 5853.
7196.
13) Seebach, D.; Hungerbühler, E.; Naef, R.; Schnurrenberger,
P.; Weidmann, B.; Züger, M. Synthesis 1982, 138.
14) Jacquemard, U.; Bénéteau, V.; Lefoix, M.; Routier, S.;
Mérour, J.-Y.; Coudert, G. Tetrahedron 2004, 60, 10039.
15) (a) Lucas, H.; Basten, J. E. M.; Van Dinther, T. G.;
Meuleman, D. G.; Van Aelst, S. F.; Van Boeckel, C. A. A.
Tetrahedron 1990, 46, 8207. (b) Lopin, C.; Jacquinet, J.-C.
Angew. Chem. Int. Ed. 2006, 45, 2574.
(18) Conchon, E.; Aboab, B.; Golsteyn, R. M.; Cruzalegui, F.;
Edmonds, T.; Léonce, S.; Pfeiffer, B.; Prudhomme, M. Eur.
J. Med. Chem. 2006, 41, 1470.
(19) (a) Vögeli, U.; Von Philipsborn, W.; Nagarajan, K.; Nair, M.
D. Helv. Chim. Acta 1978, 61, 607. (b) Chezal, J. M.;
Delmas, G.; Mavel, S.; Elakmaoui, H.; Métin, J.; Diez, A.;
Blache, Y.; Gueiffier, A.; Rubiralta, M.; Teulade, J.-C.;
Chavignon, O. J. Org. Chem. 1997, 62, 4085.
(20) Wakchaure, P. B.; Easwar, S.; Puranik, V. G.; Argade, N. P.
Tetrahedron 2008, 64, 1786.
(
16) (a) Robinson, J. R.; Good, N. E. Can. J. Chem. 1957, 35,
1
578. (b) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka,
H. Chem. Pharm. Bull. 1988, 36, 2248.
Synthesis 2010, No. 5, 783–790 © Thieme Stuttgart · New York