Photochemically induced synthesis of the topoisomerase i inhibitors indeno [1,2-c]isoquinoline-5,11-diones

Article abstract of DOI:10.1055/s-0031-1290751

A convenient synthesis of indeno[1,2-c]isoquinoline-5,11-diones has been achieved using combinational photochemical and carbocationic cyclization tactics. The synthetic route involved first the construction of adequately functionalized N-styryl benzamides via Suzuki-Miyaura cross-coupling reaction with enol phosphate combined with a six - electron photocyclization process. The assembling of the title compounds was readily ensured through sequential carbocationic annulation reaction and ultimate oxidation of a latent hydroxy functionality. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290751

LETTER
▌1047
letter
Photochemically Induced Synthesis of the Topoisomerase I Inhibitors
Indeno[1,2-c]isoquinoline-5,11-diones
Mélanie Dubois,a,b Eric Deniau,a,b Axel Couture,*a,c Pierre Grandclaudona,b
a
Univ Lille Nord de France, 59000 Lille, France
b
USTL, Laboratoire de Chimie Organique Physique, EA CMF 4478, Bâtiment C3(2), 59655 Villeneuve d’Ascq Cedex, France
c
CNRS, UMR 8181 ‘UCCS’, Bâtiment C3(2), 59655 Villeneuve d’Ascq Cedex, France
Fax +33(3)20436309; E-Mail: axel.couture@univ-lille1.fr
Received: 13.01.2012; Accepted after revision: 15.02.2012
by SOCl2-induced Friedel–Crafts reaction,3e,10 the later
tolerating the presence of substituents on the differentiat-
ed aromatic rings.
Abstract: A convenient synthesis of indeno[1,2-c]isoquinoline-
5,11-diones has been achieved using combinational photochemical
and carbocationic cyclization tactics. The synthetic route involved
first the construction of adequately functionalized N-styryl benz-
amides via Suzuki–Miyaura cross-coupling reaction with enol
phosphate combined with a six-π-electron photocyclization pro-
cess. The assembling of the title compounds was readily ensured
through sequential carbocationic annulation reaction and ultimate
oxidation of a latent hydroxy functionality.
O
O
MeO
MeO
Me
R
N
N
O
Key words: enols, phosphates, cross-coupling, electrocyclic reac-
O
O
tions, lactams
O
1
(NCS 314622)
Since the discovery by the National Cancer Institute that
NSC 314622,1 a representative example of the class of in-
denoisoquinolines 1, displays good inhibition capacities
on topoisomerase I but less toxicity than indimitecan and
indotecan (Figure 1),2 several structure–activity relation-
ships and pharmacomodulations have led to the develop-
ment of constitutionally diverse analogues with improved
pharmacological activities.2a,3 Novel insights have been
namely gleaned regarding the contributions of the inde-
none and isoquinolone rings, of the environmentally di-
verse aromatic units, and lactam side chain toward
biological activity.4,5 The indenoisoquinolines, which are
found to inhibit the religation reaction by intercalating at
the DNA cleavage site,4a have also garnered interest as
they offer certain advantages over camptothecins, includ-
ing the greater chemical stability of the compounds them-
selves and of the drug–enzyme–DNA cleavage
complexes.6 Among the over 400 indenoisoquinolines
evaluated two have been selected for preclinical trials.3h,7
As a consequence the development of synthetic method-
ologies that may have versatility for the construction of
multifarious substituted and unsubstituted indenoisoquin-
olines continues unabated, and alternative methods are
currently the object of synthetic endeavor.8 To date the
most convenient routes to these highly fused compounds
containing a planar tetracyclic hetero ring system are
based upon the condensation of benzo[d]indeno[1,2-b]py-
randiones with primary amines3b,c,f,g or upon condensation
of Schiff bases with homophthalic anhydrides followed
O
(CH2)3
N
R =
R =
MeO
MeO
R
N
O
N
indimitecan
O
(CH2)3
N
O
indotecan
O
Figure 1 Structures of indenoisoquinolinedione topo I inhibitors
They can also been accessed from suitably substituted ar-
ylated isoquinolones assembled by ring-closing-metathe-
sis reaction of polyenic benzamides11 or through a
dilithiated toluamide–benzonitrile cyclization process.3d
All these methods generally proceed in satisfactory yields
but they suffer from several drawbacks associated with
the elaboration of structurally diverse precursors,3,9 the re-
quirement of mandatory stereodefined intermediates,10
a
point at issue,12 and with the presence of competing meta-
lation sites.3d
In this paper we wish to delineate an alternative and tacti-
cally new synthetic approach to these highly condensed
indenoisoquinolinediones 1a–c. This new route, which is
depicted in retrosynthetic Scheme 1, hinges upon the pho-
toinduced electrocyclic ring closure of aromatic enamides
2a–c as the key step to secure the creation of the lactam
unit, that is, ring B in titled compounds 1a–c. The use of
enamides to form isoquinoline alkaloids photochemically
was pioneered by G. R. Lenz and I. Ninomiya and has
proved to be very fruitful later.13 The photocyclization
process does not require any specific structural adjust-
ments, often occurs without additional reagents and then
is particularly interesting in the context of green chemis-
try.
SYNLETT 204012, 237, 1047–1051
Advanced online publication: 05.04.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290751; Art ID: ST-2012-B0035-L
© Georg Thieme Verlag Stuttgart · New York

1048
M. Dubois et al.
LETTER
O
R3
O
O
Bn
R1
R2
Bn
R1
R2
Bn
N
N
B
R1
R2
R4
N
R3
R4
C
R3
OMe
2a–c
OH
O
R4
OH
1a–c
3a–c
4a,b
O
Bn
R1
R2
N
via enol phosphates
O
OMe
Scheme 1 Retrosynthetic analysis
Subsequent chemical manipulation of the latent benzylic vors intermediate 9 vs. 10 (Scheme 3); (ii) initial electro-
hydroxy functionality of photochemical adducts 3a–c cyclic ring closure is followed by a suprafacial [1,5] shift
should ensure the ultimate creation of the five-membered of the methoxy group. This migration is immediately ac-
oxonucleus C. Beforehand installation of the functional- companied by loss of a methanol molecule to provide a
ized styrene unit in 2a–c, one of the major synthetically straightforward access to the dehydrolactams 3a–c. As a
challenging task would be performed on reliance with consequence this photocyclization process can be per-
Suzuki–Miyaura cross-coupling reaction involving enol formed with unsymmetrically substituted opened models,
phosphates deriving from the parent N-acetylbenzamides for example, compound 2c; (iii) the photochemical pro-
4a,b.
cess can then be cleanly performed under anaerobic con-
ditions then ruling out undesirable photo-oxidation of
sensitive functionalities and by-passing the formation of
dihydrolactams structurally related to 11 which would im-
pose an additional oxidation step, a subject of controver-
sy.12a A carefully degassed methanolic solution of
enamides 2a–c (2·10–3 M) was then placed in a quartz ves-
sel and irradiated in a Rayonet RPR photoreactor
equipped with 254 nm lamps for one hour. Gratifyingly,
removal of the solvent and flash column chromatography
delivered very satisfactory yields of a single compound
which was identified as the demethoxylated isoquinolone
3a–c.19 Interestingly, the benzylic hydroxymethyl group
was spared upon the photostimulated annulation process,
and no trace of the dihydrolactam 11 could be detected in
the residual photoproduct. Subsequent PDC oxidation of
the hydroxy benzylic function proceeded uneventfully to
provide excellent yields of the aromatic carboxaldehyde
derivatives 12a–c (Scheme 3, Table 1). All attempts to ac-
cess the targeted models 12a–c through a reverse se-
quence, that is, oxidation of the opened models 2a–c prior
to photocyclization, met with no success probably due to
the sensitivity of the carboxaldehyde function under the
defined photolytic conditions. With compounds 12a–c in
hand we were only two steps away from the targeted title
compounds. The creation of the five-membered unit C
embedded in the tetracyclic framework was secured
through an intramolecular acid-mediated carbocationic
enelactam–carboxaldehyde cyclization to provide the hy-
droxylated cyclization adducts 13a–c, a class of com-
pounds endowed with promising chemotherapeutic
properties.20 Lastly, standard oxidation of the (bi)benzylic
hydroxy group of 13a–c delivered very satisfactory yields
of the targeted indenoisoquinolinediones 1a–c (Scheme 3,
Table 1).21
The first facet of the synthesis which is outlined in
Scheme 2 was then the elaboration of the aromatic en-
amides 2a–c. Initially the benzoic acids 5a,b were effi-
ciently converted into the free-NH benzamides 6a,b via
their acid chlorides. Subsequent deprotonation and cap-
ture of the transient amide salt with acetyl chloride deliv-
ered very satisfactory yields of the N-acetyl-o-
methoxybenzamides derivatives 4a,b. At this stage we
surmised that these quite structurally simple compounds
would possess the appropriate functionalities required for
installation of a tailor-made styrene unit through a palla-
dium cross-coupling reaction. It has been demonstrated
that enol phosphates, deriving from N-alkylamides, are ef-
fective substrates for cross-coupling reactions and provid-
ed that the model compounds are further equipped with
electron-withdrawing groups on nitrogen atoms.14 The
N,N-diacylated compounds 4a–c fulfill these structural
requirements. They were then exposed to KHMDS in
THF at –78 °C, and the resulting potassium enolate was
intercepted with diphenyl chlorophosphate to give rise
to transient sensitive vinyl phosphate 7.14c Subsequent
Suzuki–Miyaura cross-coupling of 7 with adequately sub-
stituted oxaborole 8a,b15 under anhydrous conditions al-
lowed the installation of the styrene unit with the
concomitant connection of the mandatory hydroxymethyl
appendage. The ring-opening of cyclic boronic acids16
with enol phosphates is unprecedented and should be of
interest for alternative synthetic planning. Compounds
2a–c, candidates for the planned photoinduced electron
cyclization process were obtained in quite satisfactory
yields (Table 1).17 The presence of the phenolic methoxy
group in the starting compounds 2a–c deserves some
comments. It originated from the following premises: (i)
upon photolysis the methoxy group forces the hexatriene–
cyclohexadiene ring-closure to be regiospecific18 and fa-
Synlett 2012, 23, 1047–1051
© Georg Thieme Verlag Stuttgart · New York

LETTER
Photochemical Synthesis of Indeno[1,2-c]isoquinoline-5,11-diones
1049
O
O
O
Bn
R1
R2
R1
R2
R1
R2
Bn
1. SOCl2
2. BnNH2
N
1. NaH, THF
2. MeCOCl
O
OH
OMe
N
H
89–92%
47–65%
OMe
4a,b
OMe
5a,b
6a,b
R3
R4
O
B
R3
1. KHMDS, THF
2.
8a,b
O
OH
O
R4
Bn
O
Bn
Cl
P
R1
R2
Na2CO3, Pd(PPh3)4
DME
R1
R2
OPh
N
N
O
O
PhO
P
OPh
61–69%
PhO
OMe
OMe
7
2a–c
OH
Scheme 2 Synthesis of starting aromatic enamides 2a–c
OMe O
OMe O
Bn
N
Bn
H
N
R3
R4
R3
R4
R2
R2
R3
H
R1
R1
H
H
Bn
R4
O
OH
OH
N
10
11
R1
R2
N
hν (254 nm)
MeOH, Ar
OMe
2a–c
OH
O
O
R1
R2
Bn
R1
R2
Bn
N
R3
R4
R3
R4
OMe
51–64%
OH
N
3a–c
9
OH
N
O
O
O
PDC
CH2Cl2
PDC
CH2Cl2
R1
R2
Bn
Bn
R1
R2
Bn
R1
R2
HCl
acetone
N
R3
R4
68–82%
71–87%
72–81%
R3
R3
HO
O
R4
R4
O
12a–c
13a–c
1a–c
Scheme 3 Photocyclization of enamides 2a–c and synthesis of indeno[1,2-c]isoquinoline-5,11-diones 1a–c
In conclusion we have devised a tactically new synthetic struction of the isoquinolinone template from tailor-made
approach to a variety of indenoisoquinolinediones. This N-styrylbenzamides as the key step. We believe that this
new route which offers special advantages including high work provides a strong incentive for the elaboration of
regioselectivity, procedural simplicity, and mildness of structurally modified alkaloids as well as their biogeneti-
reaction conditions, hinges upon the photoinduced con- cally related congeners.
Table 1 Isoquinoline Derivatives Synthesized
R1
R2
R3
R4
Enamide
Boronic acid
Yield of isoquinoline derivatives (%)
4a
4a
4b
H
H
8a
8b
8a
H
H
2a 61
2b 69
2c 64
3a 54
3b 51
3c 64
12a 87
12b 86
12c 71
13a 82
13b 68
13c 70
1a 81
1b 72
1c 77
H
H
OMe
H
OMe
H
OMe
OMe
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1047–1051

1050
M. Dubois et al.
LETTER
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Acknowledgment
This research was supported by the CNRS and by MENESR.
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methoxybenzamide (2a): pale yellow solid; mp 147–148
°C. 1H NMR (300 MHz, C6D6): δ = 1.82 (br s, 1 H), 3.21 (s,
3 H), 4.33 (d, J = 11.7 Hz, 1 H), 4.73 (br s, 1 H), 5.16 (br s,
2 H), 6.30 (br s, 1 H), 6.64 (br s, 1 H), 6.82–7.34 (m, 10 H),
7.36–7.64 (m, 3 H) ppm. 13C NMR (75 MHz, C6D6): δ =
52.6, 54.8, 62.3, 110.8, 112.3, 120.2, 121.4, 125.3, 127.4 (2
× CH), 128.5 (2 × CH), 128.7, 129.7, 129.9, 130.1, 132.6,
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Synlett 2012, 23, 1047–1051
© Georg Thieme Verlag Stuttgart · New York

LETTER
Photochemical Synthesis of Indeno[1,2-c]isoquinoline-5,11-diones
1051
H), 4.30 (d, J = 13.3 Hz, 1 H), 4.94 (d, J = 14.8 Hz, 1 H), 5.45
(20) (a) Jagtap, P. G.; Baloglu, E.; Southan, G. J.; Mabley, J. G.;
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(d, J = 14.8 Hz, 1 H), 6.39 (s, 1 H), 6.83 (d, J = 6.6 Hz, 2 H),
7.12–7.22 (m, 4 H), 7.32 (t, J = 7.3 Hz, 1 H), 7.42–7.61 (m,
4 H), 7.70 (t, J = 7.5 Hz, 1 H), 8.55 (d, J = 8.0 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 48.2, 62.3, 108.1, 125.3,
125.9, 126.9, 127.1, 127.2, 127.6 (2 × CH), 127.7, 128.3,
128.4 (2 × CH), 129.6, 129.7, 132.6, 133.4, 136.2, 137.5,
140.0, 141.1, 163.3 ppm. Anal. Calcd for C23H19NO2: C,
80.92; H, 5.61; N, 4.10. Found: C, 80.72; H, 5.84; N, 3.85.
(21) For compound 1a (mp 211–212 °C; lit. 202–205 °C), see:
Wawzonek, S. Org. Prep. Proced. Int. 1982, 14, 16.
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Synlett 2012, 23, 1047–1051

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