Tandem Diels-Alder-manganese dioxide mediated oxidation reaction. A short route to marcanines

Article abstract of DOI:10.1016/j.tetlet.2008.06.107

An efficient synthesis of anthraquinones by a tandem Diels-Alder-decarboxylation-manganese dioxide mediated oxidation reaction was developed and applied to the regioselective synthesis of an azaanthraquinone.

Full text of DOI:10.1016/j.tetlet.2008.06.107

Tetrahedron Letters 49 (2008) 5268–5270
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tandem Diels–Alder-manganese dioxide mediated oxidation reaction.
A short route to marcanines
*
Sabrina Mekideche, Laurent Désaubry
UMR 7175-LC1, Université Louis Pasteur, CNRS, Department of Medicinal Chemistry, Faculté de Pharmacie, 74 Route du Rhin, BP 60024, 67401 Illkirch, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of anthraquinones by a tandem Diels–Alder-decarboxylation-manganese dioxide
mediated oxidation reaction was developed and applied to the regioselective synthesis of an
azaanthraquinone.
Received 15 May 2008
Revised 19 June 2008
Accepted 24 June 2008
Available online 28 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Azaanthraquinones
Tandem reactions
Diels–Alder
Anticancer natural products
Topoisomerase II inhibitors are highly efficacious antineoplastic
agents for various hematopoietic and solid tumors.1 However, their
usefulness is limited by their cardiotoxicity, and the search of new
topoisomerase II inhibitors with lower side effects remains an ac-
tive field of research.2 In a previous article, we presented electro-
chemical data that suggest that dielsiquinone (Fig. 1, 1), a potent
cytotoxic natural product related to anthracyclines, should be less
cardiotoxic than anthracyclines used in clinic, and may therefore
provide the basis for the development of safer anticancer drugs.3
In 1999, Suwanborirux reported the isolation of secondary metab-
olites related to dielsiquinone from the stem bark of Goniothalamus
marcanii, a rare small tree growing in Thailand.4 Among these,
marcanine D displayed cytotoxic activities superior to that of diels-
iquinone against a variety of tumor cells. Unfortunately, this com-
pound could not be isolated in sufficient amount to record a
complete 13C NMR spectrum and to characterize it unambiguously.
A NOE effect between the hydroxyl proton and the 4-methyl pro-
tons suggested that this compound should be 2, but on handling
trace amounts of material some errors may occur.
The identification of marcanine E (4) in the same extract from
the stem bark suggested that the structure of marcanine D might
also be 3. The uncertainty of its structure, coupled with its natural
scarcity and therapeutic potential, prompted us to undertake the
synthesis of 2 and 3.
Attempts to synthesize 2 according to the strategy that we
developed for 1 were unsuccessful.3 We now had to identify a
new way to create the heterocyclic core of these compounds. Our
new approach was based on the synthesis of naphthoquinones
by the base–catalyzed Diels–Alder reaction hydroxypyrone 8 with
quinones, which was recently developed by Tsuboi and co-
workers.5
The synthesis of quinone 7 started with acylation of known
amine 5 (two steps from commercial 2,5-dimethoxyacetophe-
none),6 followed by cyclization under basic conditions to yield
quinolone 6 (29% for two steps) (Scheme 1). Attempts to oxidize
6 to the quinone 7 with ceric ammonium nitrate under classical
conditions7 gave unsatisfactory yields (624%), due to an extensive
degradation of the compound. Use of silver(II) dipicolinate devel-
oped for acid-labile products slightly increased the yield to 34%.8
Gratifyingly, oxidative demethylation of 6 with phenyliodine(III)
bis(trifluoroacetate)9 in water afforded the quinone 7 in an 80%
yield.10
Figure 1. Dielsiquinone (1), proposed (2), and alternative (3) structures of
marcanine D and marcanine E (4).
* Corresponding author. Tel.: +33 390 244 141; fax: +33 390 244 310.
E-mail address: desaubry@chimie.u-strasbg.fr (L. Désaubry).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.107

S. Mekideche, L. Désaubry / Tetrahedron Letters 49 (2008) 5268–5270
5269
Scheme 1. Synthesis of Marcanine D.
Initial attempts to perform the tandem Diels–Alder-decarboxyl-
ation reaction of 3-hydroxypyrone 8 with quinone 7 afforded a
mixture of the adducts 2 and 3 with a regioselectivity of 8:92 albeit
with yields inferior to 45%.11 Similar good regioselectivities have
been observed in the Diels–Alder reaction of related azaanthraqui-
nones with other types of diene.12
The presence of dihydroquinone 10 in the reaction medium
indicated that these low yields stem from the oxidation of the
intermediate 9 by the starting quinone 7 (Scheme 2). In their syn-
thesis of naphthoquinones, Tsuboi and co-workers performed the
Compounds 2 and 3 were compared by HPLC–MS with an
authentic sample of marcanine D generously provided by Pr. Su-
wanborirux. Unfortunately, this sample had been too degradated
over time to prove unambigously the structure of marcanine D.
However, 2, but not 3, displayed the same retention time and the
same mass spectrum as one of the compounds present in this sam-
ple, which tends to confirm that the structure of marcanine D is
really 2.15
In conclusion, we described herein a concise synthesis of marca-
nines based on a new construction of anthraquinones by a tandem
Diels–Alder-decarboxylation-manganese dioxide mediated oxida-
tion reaction of quinone 7 with hydroxypyrone 8.
Diels–Alder reaction of hydroxypyrone
8 with unexpensive
quinones, which were used in excess to oxidize the adduct to the
corresponding naphthoquinone.5
Attempts to oxidize in situ 9 by DDQ were not satisfactory.
Inspired by the use of manganese dioxide in tandem oxidation/
olefination recently developed by Taylor et al.,13 we added over
4 h a solution of quinone 7 to a mixture of hydroxypyrone 8,
Cs2CO3, and MnO2, with the hope that the intermediate 9 would
be oxidized in situ by MnO2. As far as we know, such an in situ
MnO2 oxidation of a Diels–Alder adduct had never been described
previously. To our greater delight, this reaction proceeded with a
91% yield affording 2 and 3 in an 8:92 ratio.14
Acknowledgments
We would like to dedicate this Letter to Professor Miguel Yus
for his 65th birthday. We are extremely grateful to Pr. Khanit Su-
wanborirux for providing an authentic sample of marcanine D.
We thank Cyril Antheaume, Roland Graff and Patrick Wehrung
for NMR spectroscopic and mass spectrometric assistance.
The structure of 3 was confirmed by NOE between H-5 (d
7.57 ppm) and Me-4 (d 2.51 ppm) and by key HMBC correlations
from these protons and the C-10 carbonyl carbon at d 182 ppm
(Fig. 2).
References and notes
1. Minotti, G.; Menna, P.; Salvatorelli, E.; Cairo, G.; Gianni, I. Pharmacol. Rev. 2004,
56, 185–229.
2. Denny, W. A. Expert. Opin. Emerg. Drug. 2004, 9, 105–133.
3. Brisach-Wittmeyer, A.; Sani Souna Sido, A.; Guilini, P.; Désaubry, L.Bioorg. Med.
Chem. Lett. 2005, 15, 3609–3610.
4. Soonthornchareonnon, N.; Suwanborirux, K.; Bavovada, R.; Patarapanich, C.;
Cassady, J. M. J. Nat. Prod. 1999, 62, 1390–1394.
5. Komiyama, T.; Takaguchi, Y.; Tsuboi, S. Synlett 2006, 124–126.
6. Bandurco, V. T.; Schwender, C. F.; Bell, S. C.; Combs, D. W.; Kanojia, R. M.;
Levine, S. D.; Mulvey, D. M.; Appollina, M. A.; Reed, M. S.; Malloy, E. A.; Falotico,
R.; Moore, J. B.; Tobia, A. J. J. Med. Chem. 1987, 30, 1421–1426.
7. Castagnoli, N., Jr.; Shulgin, A. T.; Callery, P. S.; Jacob, P., III J. Org. Chem. 1976, 41,
3627–3629.
8. Syper, L.; Mlochowski, J.; Kloc, K. Tetrahedron 1983, 39, 781–786.
9. Tohma, H.; Morioka, H.; Harayama, Y.; Hashizume, M.; Kita, Y. Tetrahedron Lett.
2001, 42, 6899–6902.
10. Experimental procedure for the synthesis of quinone 7:
dimethoxyarene (99 mg, 0.4 mmol) and phenyliodine(III) bis(trifluoro-
acetate) (3.4 g, 0.8 mmol) in 2 ml of water and 50 l MeOH was sonicated at
A suspension of
6
l
rt for 1.5 h (the water of the bath was changed every 15 min to keep the
medium at rt). The medium was extracted with EtOAc, washed with brine,
dried over MgSO4, and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (CH2Cl2/acetone 9:1) to give 70 mg
(3.2 mmol, 80%) of quinone 7 as red crystals. 1H NMR (300 MHz, DMSO-d6):
Scheme 2. Proposed mechanism to explain the low yield of the Diels–Alder
reaction in absence of MnO2.
6.92 (d, J = 10.0 Hz, 1H), 6.83 (d, J = 10.0 Hz, 1H), 3.83 (s, 3H), 2.40 (1s, 3H); 13
C
NMR (75 MHz, DMSO-d6): 185.0, 179.6, 156.9, 150.7, 139.3, 135.6, 135.2, 133.8,
113.5, 59.0, 13.0. IR (KBr): 2921, 2854, 1511, 1519, 1364, 1223, 1035, 986, 933,
849 cmÀ1. Anal. Calcd for C11H9NO4: C, 60.27; H, 4.14; N, 6.39. Found: C, 60.22;
H, 4.21; N, 6.33.
11. Initial attempts to perform the Diels–Alder reaction of
performed in presence of Cs2CO3 in CHCl3 at rt for 3 h.
8 with 7 were
12. (a) Pérez, J. M.; Vidal, L.; Grande, M. T.; Menéndez, J. C.; Avendaño, C.
Tetrahedron 1994, 50, 7923–7932; (b) del Mar, M.; Avendaño, C.; Menéndez, J.
C. Tetrahedron 1997, 53, 11465–11480.
13. Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851–869.
14. Experimental procedure for the synthesis of 2 and 3: To a mixture of 3-hydroxy-
2-pyrone 8 (112 mg, 1 mmol), manganese dioxide (433 mg, 5 mmol), and
Cs2CO3 (19 mg, 0.1 mmol) in CHCl3 (4 ml) was added a solution of quinone 7
(110 mg, 0.5 mmol) in CHCl3 (5 ml) at r.t. over a period of 4 h by using a syringe
Figure 2. Key NOE and HMBC correlations of 3.

5270
S. Mekideche, L. Désaubry / Tetrahedron Letters 49 (2008) 5268–5270
pump. The mixture was stirred at rt for an additional 20 min, filtered on Celite
(washing with CHCl3), and concentrated. The residue was purified by silica gel
chromatography (CH2Cl2/EtOAc/toluene 8:1:1) to afford 130 mg (91%) of a
Compound 3: 1H NMR (300 MHz, DMSO-d6): 7.93 (s, 1H), 7.74 (dd, J = 8.4,
7.5 Hz, 1H), 7.57 (dd, J = 7.5, 1.0 Hz, 1H), 7.29 (dd, J = 8.4, 1.0 Hz, 1H), 3.87 (s,
3H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6): 181.5, 181, 160, 157, 151, 136,
135, 137, 133, 123, 119, 117, 114, 59, 13; UV (CH3CN) kmax 274, 302 nm; MS
(ESI): m/z 286.1 (M+H)+, 308.1 (M+Na)+, 593.0 (2M+Na)+.
mixture of adducts
2 and 3 in an 8:92 ratio as an orange solid. For
spectroscopic analyses of 2 and 3, pure samples were purified by RP-HPLC.
Compound 2: 1H NMR (400 MHz, DMSO-d6): 7.77 (dd, J = 8.0 Hz, 1H), 7.60 (d,
J = 7.2 Hz, 1H), 7.32 (t, J = 8.4 Hz, 1H), 3.88 (s, 3H), 2.49 (s, 3H); UV (DMSO) kmax
277, 306 nm; MS (ESI): m/z 286.1 (M+H)+, 308.1 (M+Na)+, 593.0 (2M+Na)+.
15. The difficulty to obtain a sample of the stem bark of Goniothalamus marcanii,
which is a rare tree growing in Thailand, prevented us to compare 2 and 3 with
a freshly extracted sample of marcanine D.