Synthetic Approach to Hypoxyxylerone, Novel Inhibitor of Topoisomerase I

Article abstract of DOI:10.1021/ol026454d

(Equation Presented) A potential route to the topoisomerase I inhibitor hypoxyxylerone is demonstrated by a highly convergent synthesis of the penta(O-methyl) derivative. The key step in the approach is an anionic homo-Fries rearrangement, little used to

Full text of DOI:10.1021/ol026454d

ORGANIC
LETTERS
2002
Vol. 4, No. 18
3139-3142
Synthetic Approach to Hypoxyxylerone,
Novel Inhibitor of Topoisomerase I
Arnaud Piettre, Emmanuel Chevenier, Christine Massardier, Yves Gimbert,* and
Andrew E. Greene*
UniVersite´ Joseph Fourier de Grenoble, Chimie Recherche (LEDSS),
38041 Grenoble Cedex, France
yVes.gimbert@ujf-grenoble.fr
Received July 2, 2002
ABSTRACT
A potential route to the topoisomerase I inhibitor hypoxyxylerone is demonstrated by a highly convergent synthesis of the penta(O-methyl)
derivative. The key step in the approach is an anionic homo-Fries rearrangement, little used to date in natural product synthesis and employed
here for the first time with a dinaphthalenic substrate, to access the pentacyclic system of hypoxyxylerone.
DNA topoisomerases play a fundamental role in the replica-
tion, transcription, and recombination of DNA.1 These
ubiquitous enzymes, which create single- or double-strand
breaks (topoisomerases I and II, respectively), are the cellular
targets of important antibiotic and anticancer drugs.2
potential route to the novel in vitro topoisomerase I inhibitor
hypoxyxylerone (1) is disclosed that should allow access not
only to the natural product but also to derivatives with greater
bioavailability (Figure 1).6
Over the past 10 years, the number of topoisomerase I
inhibitors has grown considerably and now includes some
60 structurally diverse compounds obtained from a variety
of sources.3 Very few of these substances, however, dem-
onstrate in vivo antitumor activity; except for camptothecin
and related compounds,4 only certain indolocarbazoles have
to date provided encouraging results.5 In this paper, a
* Email for A.E.G.: andrew.greene@ujf-grenoble.fr.
Figure 1. Hypoxyxylerone.
(1) Froelich-Ammon, S. J.; Osheroff, N. J. Biol. Chem. 1995, 270,
21429-21432. Wang, J. C. Annu. ReV. Biochem. 1996, 65, 635-691.
(2) Wang, H.-K.; Morris-Natschke, S. L.; Lee, K.-H. Med. Res. ReV.
1997, 17, 367-425. Recently, another type has been identified: Hania, R.;
Caron, P. R.; Wang, J. C. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 3653-
3657. Goulaic, H.; Roulon, T.; Flamand, O.; Grondard, L.; Lavelle, F.; Riou,
J.-F. Nucleic Acids Res. 1999, 27, 2443-2450.
(3) Bailly, C. Curr. Med. Chem. 2000, 7, 39-58. Long, B. H.;
Balasubramanian, B. N. Exp. Opin. Ther. Patents 2000, 10, 635-666.
(4) Garcia-Carbonero, R.; Supko, J. G. Clin. Cancer Res. 2002, 8, 641-
661. Kehrer, D. F.; Soepenberg, O.; Loos, W. J.; Verweij, J.; Sparreboom,
A. Anticancer Drugs 2001, 12, 89-128.
(5) Gescher, A. Biochem. Pharmacol. 1998, 31, 721-728. Gescher, A.
Crit. ReV. Oncol. Hematol. 2000, 34, 127-135.
Hypoxyxylerone was isolated by Edwards and co-workers
from the fungus Hypoxylon fragiforme in 1991 and was
shown to possess the dibenzo[b,h]xanthene ring system,
previously unknown among natural products.7 This substance,
which is responsible for the green coloration in strains of
(6) See: Gimbert, Y.; Chevenier, E.; Greene, A. E.; Massardier, C.;
Piettre, A. EP 01 402 551 4, 2001.
10.1021/ol026454d CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/16/2002

Hypoxylon, was later found to be an in vitro inhibitor of
topoisomerase I.6 It lacks in vivo solubility, however, and
thus the preparation of more soluble derivatives, in addition
to the novel pentacyclic compound itself, seemed a worth-
while pursuit. Scheme 1 summarizes retrosynthetically our
envisioned approach to hypoxyxylerone.
naphthyl-naphthyl partners, nor even phenyl-naphthyl ones.
It appeared, though, to be ideally suited for use in this
approach since a hydroxymethyl group was present in the
final product.
A salient advantage of the homo-Fries rearrangement (and
the Fries) is that it offers convergency. For the preparation
of the homo-Fries substrate 4, the similarly complex and
similarly substituted naphthalene units 5 and 6 were neces-
sary (Figure 2). While structures closely related to each had
Scheme 1. Retrosynthesis of Hypoxyxylerone
Figure 2. Naphthalene precursors.
previously been prepared,10 the syntheses suffer from low
yields and/or poor reproducibility, and thus a number of
modifications have been introduced.
For the synthesis of the naphthalene unit 5, methyl 3,5-
dimethoxyphenylacetate (7), easily obtained on a large scale
as described by Gaudry and co-workers,11 was used as the
starting material (Scheme 2). Hydrolysis of 7, followed by
exposure of the resulting acid to oxalyl chloride, provided
acid chloride 8. Conversion of this substance into naphthalene
10 could be accomplished in 67% yield by successive
Scheme 2a
The key reaction in our planned approach was an anionic
homo-Fries rearrangement to convert ester 4 into the di-
naphthyl ketone 3, which might then be transformed into
xanthone 2 by debenzylation and cyclization. It was hoped
that this xanthone could then be reduced to access hy-
poxyxylerone and derivatives. The anionic homo-Fries
rearrangement,8 like the anionic Fries rearrangement,9 had
been used in synthesis, but had never been applied to
(7) Edwards, R. L.; Fawcett, V.; Maitland, D. J.; Nettleton, R.; Shields,
L.; Whalley, A. J. S. J. Chem. Soc., Chem. Commun. 1991, 1009-1010.
(8) Horne, S.; Rodrigo, R. J. Chem. Soc., Chem. Commun. 1992, 164-
166. Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994,
116, 8402-8408. Lampe, P. F.; Hugues, C. K.; Biggers, C. K.; Smith, S.
H.; Hu, H. J. Org. Chem. 1996, 61, 4572-4581. Couture, A.; Deniau, E.;
Lebrun, S.; Grandclaudon, P. J. Chem. Soc., Perkin Trans. 1 1999, 7, 789-
794.
a (a) K2CO3, MeOH-H2O, 20 °C, 16 h. (b) (COCl)2, DMF (cat.),
toluene, 0 f 20 °C, 2 h. (c) (MeO2C)2CHNa, THF, 60 °C, 16 h.
(d) MeSO3H, 20 °C, 4 h. (e) TBDMSCl, imidazole, DMF, 20 °C,
14 h. (f) DMS, K2CO3, acetone, reflux, 16 h. (g) KF, HBr (cat.),
DMF, 20 °C, 45 min. (h) BnBr, K2CO3, DMF, 20 °C, 4 h. (i) 10%
KOH, EtOH, reflux, 18 h.
3140
Org. Lett., Vol. 4, No. 18, 2002

treatment with sodium dimethyl malonate and methane-
sulfonic acid. The reported procedure (magnesium dimethyl
malonate, phosphoric acid-phosphorus pentoxide) proceeded
in only 36% yield.12 This naphthalene was found to be highly
susceptible to oxidation, and therefore it was best used
directly. Selective tert-butyldimethylsilylation of the more
accessible hydroxyl in 10, followed by methylation of the
one remaining, delivered the fully protected naphthalene 11
in 63% yield. After silyl f benzyl protecting group exchange
to afford 12,13 saponification led to the desired acid 5. The
overall yield of 5 from ester 7 was 21% for the nine steps
(84%/step).
resultant acid 15 with potassium acetate in acetic anhydride,
according to the procedure outlined by Rizzacasa and
collaborators,16 than through the Giles approach that involved
Stobbe condensation with dimethyl succinate and cyclization
with sodium acetate in acetic anhydride (51% versus 30%
overall yield). Compound 16 so obtained was next converted,
as described by Lown and co-workers,17 with methanol and
potassium carbonate in acetone into naphthol 17, which was
methylated (rather than isopropylated14) and then reduced
to provide alcohol 18 in excellent yield.
The acetate of 18, obtained conventionally, was dibromi-
nated to provide the highly substituted naphthalene 19.
Mono-debromination of 19 was effected by exposure to
trifluoroacetic acid and 1,2,4-trimethoxybenzene (TMB) in
refluxing dichloromethane14 to give a difficult to separate
mixture of the desired product18 together with TMB and
5-bromo-TMB. Fortunately, purification of the mono bro-
mide could be easily accomplished after saponification to
naphthol 6. This esterification partner of acid 5 was thus
obtained in nine steps from aldehyde 13 with an overall yield
of 29% (87%/step).
The second unit, naphthalene 6, was synthesized by
substantially modifying the procedure described by Giles and
collaborators14 (Scheme 3). It was found that ester 16 could
Scheme 3a
The anionic homo-Fries substrate, ester 4, could readily
be formed by Mitsunobu coupling of the naphthalene units
5 and 6 (Scheme 4). The key acyl transfer proceeded
Scheme 4a
a (a) Benzene, 20 °C, 12 d. (b) Ac2O, AcOK, reflux, 15 min. (c)
MeOH-acetone, K2CO3, 35 °C, 3 h. (d) DMS, K2CO3, acetone,
reflux, 16 h. (e) LiAlH4, THF, 20 °C, 1 h. (f) Ac2O, pyr., 50 °C,
1.5 h. (g) Br2, AcOH, 20 °C, 20 min. (h) CF3CO2H, 1,2,4-TMB,
CH2Cl2, reflux, 12 h. (i) 1% KOH, MeOH, 20 °C, 30 min.
be better obtained from 3,5-dimethoxybenzaldehyde (13) by
reaction with ylide 1415 followed by cyclization of the
(9) Miller, J. A. J. Org. Chem. 1987, 52, 322-323. Horne, S.; Rodrigo,
R. Ibid. 1990, 55, 4520-4522. Horne, S.; Rodrigo, R. J. Chem. Soc., Chem.
Commun. 1991, 1046-1048.
(10) See, for example: Yamaguchi, M.; Okuma, S.; Nakamura, S.;
Minami, T. J. Chem. Soc., Perkin Trans. 1 1990, 183-190. Harris, T. M.;
Wittek, J. J. Am. Chem. Soc. 1975, 11, 3270-3277. Dodd, J. H.; Weinreb,
S. M. Tetrahedron Lett. 1979, 38, 3593-3596. Carpenter, T. A.; Evans, G.
E.; Leeper, F. J.; Stauton, J.; Wilkinson, M. R. J. Chem. Soc., Perkin Trans.
1 1984, 1043-1050. Cameron, D. W.; Feutrill, G. I.; Pannan, L. J. H. Aust.
J. Chem. 1987, 40, 1737-1745.
(11) Viviani, F.; Gaudry, M.; Marquet, A. J. Chem. Soc., Perkin Trans.
1 1990, 1255-1261.
(12) Birch, A. J.; Donovan, F. W. Aust. J. Chem. 1955, 8, 529-534.
(13) The benzyl group could not be directly introduced in 10 because of
the unavoidable occurrence of C-4 benzylation.
a (a) DEAD, PPh3, THF, 20 °C, 4 h. (b) n-BuLi, THF, -55 f
-45 °C, 1.5 h. (c) Ag2O, MeI, CH2Cl2, 20 °C, 7 d. (d) H2, Pd(OH)2/
C, EtOH-CH2Cl2, 16 h. (e) KOH, MeOH, reflux, 12 h.
smoothly, following optimization, to afford naphthonaph-
thone 20 in a reproducible 50-60% yield. In view of the
steric encumbrance at the carbonyl site in 4, the efficiency
(14) Giles, R. G. F.; Green, I. V.; Knight, L. S.; Lee Son, V. R.; Mitchell,
P. R. K.; Yorke, S. C. J. Chem. Soc., Perkin Trans. 1 1994, 853-866.
Org. Lett., Vol. 4, No. 18, 2002
3141

of the free hydroxyl group, followed by hydrogenolysis of
the benzyl group in the presence of Pearlman’s catalyst and
cyclization in methanolic KOH. Xanthone 2 could be
obtained pure by simple trituration in 91% overall yield. It
is worth pointing out that this B-ring O- attack on the pro
D-ring is essential in order to achieve the desired regio-
chemical outcome in the cyclization; pro D-ring O- attack
on the B-ring results in the formation of the regioisomeric
xanthone.
Scheme 5a
Because exposure of the xanthol derived from 2 to
solvolytic conditions failed to generate the dienone ether
motif of hypoxyxlerone, a reduction-oxidation strategy was
pursued (Scheme 5). Thus, the B-ring methoxyl in xanthone
2 was selectively demethylated (possible because of carbonyl
adjacency) with lithium chloride in DMF,19 and the carbonyl
was reduced with excess borane in dichloromethane. Silyla-
tion of the free OH in 22 set the stage for Saegusa-Ito
dehydrosilylation20 with palladium(II) acetate, which gave
penta(O-methyl) hypoxyxylerone 23 in 50% overall yield.21
This highly convergent first approach to hypoxyxylerone
and congeners, which features a novel naphthyl-naphthyl
anionic homo-Fries reaction, is reasonably short and ef-
ficient: 18 linear steps with an overall yield of 5% (85%/
step). Further developments will be publish in due course.
Acknowledgment. We thank Professor Y. Valle´e and Dr.
A. Commerc¸on for their interest in our work, Dr. J-F. Riou
for the biological testing, and Dr. F. Robert for some
preliminary experiments. Financial support from the CNRS
(UMR 5616) and Aventis and fellowship awards (to E.C.
and C.M.) from Aventis are gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and full characterization for the preparation of
compound 23 from 5 and 6 and biological test protocol for
23. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL026454D
a (a) LiCl, DMF, 110 °C, 13 h. (b) BH3‚Me2S, CH2Cl2, reflux,
48 h. (c) TMSOTf, CH2Cl2, 2,6-lutidine, 0 °C, 2.5 h. (d) Pd(OAc)2,
MeCN, reflux, 12 h.
(16) Rizzacasa, M. A.; Sargent, M. V. Aust. J. Chem. 1987, 40, 1737-
1743.
(17) Liu, J.; Diwu, Z.; Lown, J. W. Synthesis 1995, 914-916.
(18) Despite considerable effort, we were unable to realize direct,
selective monobromination at C-2. Bromination reagents reacted selectively
at the more electron-rich C-5 center, and ortho-metalation reactions were
nonselective.
(19) Nakanishi, T.; Suzuki, M. Org. Lett. 1999, 7, 985-989. The correct
solvent is DMF and not DMSO.
of this first reported naphthonaphthone preparation through
an anionic homo-Fries reaction was particularly satisfying.
Conversion of 20 into xanthone 2 was effected without
purification of intermediates by methylation (Ag2O, CH3I)
(20) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 49, 3671-3675.
(21) This fully OH-protected hypoxyxylerone was found to be an inhibitor
of topoisomerase I in vitro, albeit less active than the natural product. For
the test protocol, see Supporting Information.
(15) Doulut, S.; Dubuc, I.; Rodriguez, M.; Vecchini, F.; Fulcrand, H.;
Barelli, H.; Checler, F.; Bourdel, E.; Aumelas, A.; Lallement, J.-C.; Kitabgi,
P.; Costentin, J.; Martinez, J. J. Med. Chem. 1993, 36, 1369-1375.
3142
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