First total synthesis of topopyrone C

Article abstract of DOI:10.1016/j.tetlet.2006.11.164

The first synthesis of topopyrone C, a natural compound and inhibitor of Topoisomerase I, has been carried out by Marschalk alkylation of 1-hydroxy-3,6,8-trimethoxyanthraquinone, followed by a Baker-Venkataraman chain elongation and an acid-catalyzed cyclization for the construction of the pyrone ring.

Full text of DOI:10.1016/j.tetlet.2006.11.164

Tetrahedron Letters 48 (2007) 1049–1051
First total synthesis of topopyrone C
Sonia Gattinoni, Lucio Merlini and Sabrina Dallavalle*
Dipartimento di Scienze Molecolari Agroalimentari, Universit a` di Milano, via Celoria 2, 20133 Milano, Italy
Received 30 October 2006; revised 17 November 2006; accepted 28 November 2006
Available online 22 December 2006
Abstract—The first synthesis of topopyrone C, a natural compound and inhibitor of Topoisomerase I, has been carried out by Mars-
chalk alkylation of 1-hydroxy-3,6,8-trimethoxyanthraquinone, followed by a Baker–Venkataraman chain elongation and an acid-
catalyzed cyclization for the construction of the pyrone ring.
Ó 2006 Elsevier Ltd. All rights reserved.
Nature continues to be an important source of new bio-
logically active compounds. Many useful drugs are of
OH
O
O
O
OH
O
O
OH
O
O
natural origin, or are obtained by skilful modification
R
R
1
of natural substances. We are interested in potential
O
inhibitors of topoisomerase I, an ubiquitous enzyme
HO
OH
HO
that plays an important role in DNA replication, tran-
scription, recombination, and repair.2 Inhibition of
1
Topopyrone A R=Cl
Topopyrone C R=H
3 Topopyrone B R=Cl
topoisomerase I can have important consequences for
3
chemotherapic treatment of tumors.
2
4 Topopyrone D R=H
Human topoisomerase I (top1) is the molecular target of
a diverse set of anticancer compounds, including camp-
tothecins, indolocarbazoles, and indenoisoquinolines.
Topopyrones A, B, C, and D selectively inhibit recombi-
nant yeast growth, depending on the expression of
human topoisomerase I. All these compounds showed
significant cytotoxic effects (in the range 0.7–20 lM)
4
5
These compounds bind to a transient top1-DNA cova-
lent complex and inhibit the resealing of a single-strand
break that the enzyme creates to relieve superhelical ten-
7
against a panel of tumor cell lines when tested in vitro.
6
sion in the duplex DNA. Other compounds, however,
that differ from camptothecins, can inhibit topoisomer-
ase I through an alternative mechanism, such as inhibi-
tion of the catalytic site.
Herein, we would like to disclose a route to the synthesis
of topopyrones which may also be amenable to the syn-
thesis of new derivatives. Our aim was to make these
compounds available for biological testing and for the
investigation of the structural requirements for anti-
tumor activity.
5
7
Recently, Kanai et al. have discovered four new specific
inhibitors of topoisomerase I, topopyrones A–D (1–4).
All four compounds were isolated from the culture
broth of a fungus, Phoma sp. BAUA2861, as well as
two of them from Penicillium sp. BAUA4206. Structural
elucidation showed that these compounds are of anthra-
The synthetic approach was based on the use of the
Marschalk alkylation reaction of 1-hydroxy-3,6,8-tri-
9
methoxyanthraquinone followed by a Baker–Venkata-
10
raman chain elongation
and an acid-catalyzed
8
quinone type, containing a fused 1,4-pyrone moiety.
cyclization for the construction of the pyrone framework.
The formation of 1-hydroxy-3,6,8-trimethoxyanthraqui-
none was initially envisioned to proceed through two
subsequent Diels–Alder cycloadditions of Brassard
diene (6) onto the commercially available 2,6-di-
chloro-1,4-benzoquinone (Scheme 1).
Keywords: Topopyrone C; Synthesis; Anthraquinone; Topoisomerase;
Marschalk reaction.
1
1
*
Corresponding author. Tel.: +39 2 5031 6818; fax: 39 2 5031 6801;
e-mail: sabrina.dallavalle@unimi.it
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.164

1050
S. Gattinoni et al. / Tetrahedron Letters 48 (2007) 1049–1051
O
OH
O
O
Cl
iii
Cl
OCH3
O
OCH OSi(CH )
Cl
O
O
3
3 3
i
ii
iv
O
OCH3
OCH3
v
OCH3
6
H CO
3
5
7
OH
O
OH
OCH O
OH
OCH3 O
OH
3
vi
+
H CO
OCH3
H3CO
OCH3
H3CO
OCH3
3
8
O
9
9
O
O
Scheme 1. Reagents and conditions: (i) CH(OCH
THF, ꢀ30 °C, 30 min, then rt, 1 h; (2) silica gel, CH
dichlorobenzoquinone, THF, ꢀ78 °C then rt, 2 h; (2) 130 °C, 10 h; (3) MeOH/HCl 10% 3:1 reflux, 30 min.; (vi) TsOCH
40 °C, 2 h, overall yield from 7: 42%; overall yield via route v: 40%.
3
)
3
, H
2
SO
4
, rt, 24 h, 88%; (ii) LDA, TMSCl, THF, ꢀ78 °C, 45 min, then 20 °C, 3 h, 100%; (iii) (1)
, 1 day, 82%; (iv) (1) 6, THF, rt, 2.5 h; (2) silica gel, CH Cl , 3 days; (v) (1) 2,6-
, Na CO , tetraglyme,
2
Cl
2
2
2
3
2
3
1
The first cycloaddition reaction, done at ꢀ30 °C, be-
tween 2,6-dichloro-1,4-benzoquinone and 6 gave the
naphthoquinone 7 as the major product, after a rather
cumbersome aromatization process, which required 24
medium.9c Purification of this and of the following crude
products required flash column chromatography using
silica gel previously deactivated with KH PO . Oxida-
2
4
tion of 10 to ketone 11 was first performed using pyrid-
1
2
hours of stirring with a large amount of deactivated
inium chlorochromate, as described by Krohn and
9
c
silica gel. The second Diels–Alder reaction, done at
room temperature, afforded a nonseparable mixture of
anthraquinones 8 and 9.
Vitz, with a 43% yield. We tried to improve the process
by using different oxidants and we found that a PCC
catalyzed (2 mol %) oxidation, using 1.05 equiv of
1
6
H IO in acetonitrile, gave the desired ketone in a
5
6
1
7
We then found that this procedure could be greatly sim-
plified by employing an excess of diene 6 to directly ob-
tain the mixture of 8 and 9 after pyrolysis, at 130 °C for
60% yield. (Scheme 2).
The phenolic hydroxy group was then acetylated with
acetic anhydride to give 12 (88%). The subsequent intra-
molecular acylation was initiated by LiH in boiling THF
to afford compound 13 in a 55% yield. The last step of
the synthesis was an acid-catalyzed cyclization, that
was achieved by simply dissolving phenolic b-diketone
13 in trifluoroacetic acid to obtain tri-O-methyltopo-
pyrone C 14 (76%).
1
3
1
0 h (Scheme 1, step v), without isolating the interme-
diate naphthoquinone. This mixture was then converted
into 1-hydroxy-3,6,8-trimethoxyanthraquinone 9 with
1
4
methyl para-toluenesulfonate in tetraglyme at 140 °C,
with an overall yield of 40% from 2,6-dichloro-1,4-
benzoquinone. Interestingly, this procedure proved to
be very selective, exclusively producing the 1-hydroxy
1
5
product.
The pyranone ring was probably formed by a reversible
hemiketal formation, involving the phenolic group
and the 3 -oxo group, followed by an irreversible water
Reduction of 9 with sodium dithionite under basic
conditions gave 1-hydroxy-3,6,8-trimethoxy-9,10-dihydro-
anthraquinone, which was alkylated in situ with acetal-
dehyde in the ortho position, relative to the phenolic
hydroxy group, and rapidly re-oxidized to quinone 10
0
elimination step. Demethylation of 14 with boron tri-
bromide afforded Topopyrone C 2 whose spectroscopic
data were consistent with the structure of the natural
1
8
(
30%) using hydrogen peroxide in an alkaline reaction
compound.
O
OCH O
OH OH
OCH3
O
O
OH
O
OCH3
O
O
O
O
3
vii
viii
ix
9
H CO
OCH3
H CO
OCH3
H CO
OCH3
3
3
3
11
12
10 O
OCH3
O
OH
O
O
OCH3
O
O
OH
O
O
O
xi
xii
x
O
O
H CO
OCH3
H CO
OCH3
HO
OH
3
3
2
13
O
14 O
OH, 0 °C; (2) CH
Scheme 2. Reagents and conditions: (vii) (1) NaOH, Na
CH CN, 0 °C, 30 min, then rt, 3 h, 60%; (ix) Ac
6%; (xii) BBr , CH
Cl, ꢀ60 °C, 90 min, 25%.
2
S
2
4
O , CH
3
3
CHO, 20 °C, 3 h; (3) H
O
2 2
, 0 °C, 30%; (viii) PCC, H
5 6
IO ,
3
O, Py, reflux, 10 h, 88%; (x) LiH, THF, reflux, 20 h, 55%; (xi) CF COOH, 0 °C, 20 min, rt, 10 min,
2 3
7
3
2

S. Gattinoni et al. / Tetrahedron Letters 48 (2007) 1049–1051
1051
When this work was already completed, a different
approach to the synthesis of Topopyrones B and D
was reported by Tan and Ciufolini.
The mixture was allowed to warm at room temperature,
stirred for 2 h, and then evaporated. The crude product
was pyrolyzed at 130 °C for 10 h. A solution of 3:1
MeOH/10% HCl (aq) was added to the residue and the
mixture was refluxed for 0.5 h, cooled, diluted with water,
and filtered. The solid was taken up with AcOEt and
filtered. The residue was extracted in a Soxhlet apparatus
1
9
Acknowledgment
with CH
dried, and evaporated to give 1.98 g of a mixture of
1,8-dihydroxy-3,6-dimethoxyanthraquinone (8) and
-hydroxy-3,6,8-trimethoxyanthraquinone (9). Without
further purification, the crude products were heated at
2 2
Cl and the two organic phases were joined,
We thank MIUR (FIRB Project 2001 and PRIN 2003)
for financial support.
1
1
40 °C in tetraglyme (74 mL) with Na
2 3
CO (1.05 g,
Supplementary data
9
.89 mmol) and methyl tosylate (1.9 mL, 13.18 mmol)
for 2 h. The mixture was cooled, diluted with water
250 mL), and filtered. The orange solid was purified by
flash chromatography (Et O/CH Cl ) to give 1.84 g of 1-
hydroxy-3,6,8-trimethoxyanthraquinone (9) (40%); mp
Experimental procedure and characterization data for
compounds 10,12–14 are provided. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2006.11.164.
(
2
2
2
1
2
55–256 °C; H NMR (300 MHz, CDCl
3
) d: 3.90 (3H, s,
–
OMe), 3.98 (3H, s, –OMe), 4.02 (3H, s, –OMe), 6.69 (1H,
d, 1Ar, J = 2.61 Hz), 6.80 (1H, d, 1Ar, J = 2.61 Hz), 7.29
(1H, d, 1Ar, J = 2.61 Hz), 7.45 (1H, d, 1Ar, J = 2.61 Hz),
References and notes
1
3.38 (1H, s, –OH).
16. Hunsen, M. Tetrahedron Lett. 2005, 46, 1651–1653.
17. Oxidation: solution of periodic acid (200 mg,
1
2
. Rivkin, A.; Chou, T.-C.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2005, 44, 2838–2850.
. (a) Wang, J. C. Ann. Rev. Biochem. 1985, 54, 665–697; (b)
Chen, A. Y.; Liu, L. F. Ann. Rev. Pharmacol. Toxicol.
A
0.88 mmol) in 6.6 mL of acetonitrile was stirred at room
temperature for 15 min. After cooling at 0 °C, 300 mg of
10 (0.84 mmol) and 10 mg of PCC in acetonitrile (1.6 mL)
were added. The solution was stirred at 0 °C for 30 min,
then at room temperature for 3 h. The reaction mixture
was then diluted with dichloromethane and washed with
1
994, 94, 194–218.
3
4
5
6
. DNA Topoisomerases in Cancer; Potmesil, M., Kohn, K.
W., Eds.; Oxford University Press: New York, 1991.
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Chem. 1985, 260, 14873–14878.
. Meng, L. H.; Liao, Z. Y.; Pommier, Y. Curr. Top. Med.
Chem. 2003, 3, 305–320.
1:1 brine:water, saturated aq Na
respectively, dried over anhydrous Na
trated to give the crude ketone. Purification by flash
chromatography (CH Cl /acetone 97:3) afforded pure 2-
acetyl-1-hydroxy-3,6,8-trimethoxyanthraquinone 11 (180 mg,
SO
olution, and brine,
2
3
SO , and concen-
2
4
. Staker, B. L.; Feese, M. D.; Cushman, M.; Pommier, Y.;
Zembower, D.; Stewart, L.; Burgin, A. B. J. Med. Chem.
2
2
1
2
005, 48, 2336–2345.
3
60%); mp 216–218 °C; H NMR (300 MHz, CDCl )
7
8
9
. Kanai, Y.; Ishiyama, D.; Senda, H.; Iwatani, W.; Taka-
hashi, H.; Konno, I.; Tokumasu, S.; Kanazawa, S. J.
Antibiot. 2000, 53, 863–872.
. Ishiyama, D.; Kanai, Y.; Senda, H.; Iwatani, W.; Taka-
hashi, H.; Konno, I.; Kanazawa, S. J. Antibiot. 2000, 53,
d: 2.55 (3H, s, MeCO), 3.97 (3H, s, –OMe), 3.99 (3H, s,
–OMe), 4.02 (3H, s, –OMe), 6.80 (1H, d, 1Ar,
J = 2.61 Hz), 7.32 (1H, s, 1Ar), 7.45 (1H, d, 1Ar,
J = 2.61 Hz), 13.48 (1H, s, –OH).
18. Topopyrone C: Compound 14 (20 mg, 0.05 mmol) was
dissolved in dry dichloromethane under nitrogen. After
8
73–878.
. (a) Marschalk, C.; Koenig, F.; Ourossoff, N. Bull. Soc.
Chim. Fr. 1936, 3, 1545–1575; (b) Krohn, K.; Hemme, C.
Liebigs Ann. Chem. 1979, 19–34; (c) Krohn, K.; Vitz, J.
Eur. J. Org. Chem. 2004, 1, 209–219.
cooling at ꢀ60 °C, BBr
3
was added (0.08 mL, 0.78 mmol)
and the mixture was stirred for 30 min, then allowed to
stand at room temperature. Water was added, the two
layers were separated and the aqueous phase was extracted
1
0. (a) Bbadhwar, I. C.; Kang, K. S.; Venkataraman, K. J.
Chem. Soc. 1932, 1107–1112; (b) Baker, W. J. Chem. Soc.
with dichloromethane, dried with Na
evaporated. The crude product was purified by chroma-
tography on silica gel deactivated with KH PO (acetone/
dichloromethane 2:8) to give Topopyrone C (2) (4 mg,
2 4
SO , filtered, and
1
933, 1381–1389.
2
4
1
1
1. Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455.
2. Procedure for preparing deactivated silica gel: 110 g of
1
6
25%); mp > 250 °C, H NMR (300 MHz, acetone-d ) d:
silica gel were suspended in 400 mL of 4% KH
2
PO
4
. After
2.58 (3H, s, Me), 6.47 (1H, s, CH@), 6.67 (1H, d, 1Ar,
J = 2.24 Hz), 7.18 (1H, d, 1Ar, J = 2.24 Hz), 7.43 (1H, s,
evaporation of water, silica was dried in the oven
overnight.
1
1Ar), 13.16 (1H, s, –OH), 14.11 (1H, s, –OH); H NMR
1
1
1
3. O’Malley, G. J.; Murphy, R. A., Jr.; Cava, M. P. J. Org.
Chem. 1985, 50, 5533–5537.
4. Sereda, G. A.; Akhvlediani, D. Tetrahedron Lett. 2003, 44,
6
(600 MHz, DMSO-d ) d: 2.55 (3H, s, Me), 6.62 (1H, s,
CH@), 6.64 (1H, d, 1Ar, J = 2.20 Hz), 7.10 (1H, d, 1Ar,
J = 2.20 Hz), 7.40 (1H, s, 1Ar), 11.30 (1H, s, –OH), 13.15
9
125–9126.
(1H, s, –OH), 14.18 (1H, s, –OH); HRMS/ESI negative:
ꢀ
5. Synthesis of 1-hydroxy-3,6,8-trimethoxyanthraquinone 9: A
solution of (1,3-dimethoxy-buta-1,3-dienyloxy)trimeth-
ylsilane (8.8 g, 43.9 mmol) in dry THF (16 mL) was added
dropwise at ꢀ78 °C to a solution of 2,6-dichloro-1,4-
benzoquinone (2.59 g, 14.6 mmol) in dry THF (26 mL).
calcd for C18
H
9
O
H
7
337.03538, found 337.03529 [MꢀH] ;
calcd for
C
18
ꢀ
8
O
7
Na 359.01732, found 359.01769
[Mꢀ2H+Na] ; calcd for C36
H O14Na 697.05997, found
18
ꢀ
697.061378 [2Mꢀ2H+Na] .
19. Tan, J. S.; Ciufolini, M. A. Org. Lett. 2006, 8, 4771–4774.