Synthesis of the tetracyclic core of anthracycline antibiotics by an intramolecular dehydro diels-alder approach

Article abstract of DOI:10.1021/ol035168e

(Matrix presented) A conceptually new approach to the tetracyclic core of the anthracycline antibiotics is reported. With use of this approach, the 7,8,9,10-tetrahydronaphthacene-5,12-dione skeleton has been synthesized in three steps, from commercially available reagents, in yields of up to 85%.

Full text of DOI:10.1021/ol035168e

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3119-3121
Synthesis of the Tetracyclic Core of
Anthracycline Antibiotics by an
Intramolecular Dehydro Diels−Alder
Approach
David Rodr´ıguez, Luis Castedo, Domingo Dom´ınguez, and Carlos Saa´*
Departamento de Qu´ımica Orga´nica e Unidade Asociada o´ CSIC,
Facultade de Qu´ımica, UniVersidade de Santiago de Compostela,
15782 Santiago de Compostela, Spain
qocsaa@usc.es
Received June 24, 2003
ABSTRACT
A conceptually new approach to the tetracyclic core of the anthracycline antibiotics is reported. With use of this approach, the 7,8,9,10-
tetrahydronaphthacene-5,12-dione skeleton has been synthesized in three steps, from commercially available reagents, in yields of up to 85%.
Since the early 1970s, anthracycline antibiotics1 such as the
well-known doxorubicin (1) and daunorubicin (2) have been
widely used as clinically effective antitumor agents against
acute leukemia, Hodgkin’s disease, lymphomas, breast
carcinomas, and sarcomas (Figure 1).2 During this time, the
(3),3 has led to the development of many methods for the
synthesis of natural and nonnatural anthracyclines.4
In most, the tetracyclic core of the antibiotic is synthesized
by addition to anthraquinones5 (ring D formation) or by
intermolecular Diels-Alder reactions forming the B or C
ring.3f,6 Although it has long been claimed that cobalt and
rhodium-mediated [2+2+2] inter- and intramolecular cy-
clizations should be capable of simultaneous formation of
(1) (a) Priebe, W. Anthracycline Antibiotics: New Analogues, Method
of DeliVery, and Mechanisms of Action; ACS Symp. Ser. No. 574; American
Chemical Society: Washington, DC, 1995. (b) Arcamone, F. Doxorubicin;
Academic Press: New York, 1980. (c) El Khadem, H. S. Anthracycline
Antibiotics; Academic Press: New York, 1982.
(2) (a) Weis, R. B.; Sarosy, G.; Clagget-Carr, K.; Russo, M.; Leyland-
Jones, B. Cancer Chemother. Pharmacol. 1986, 18, 185-197. (b) Weiss,
R. B. Semin. Oncol. 1992, 19, 670-686. (c) Lown, J. W. Chem. Soc. ReV.
1993, 165-176.
(3) Di Marco, A.; Casazza, A. M.; Giuliani, F.; Pratesi, G.; Arcamone,
F.; Bernadi, L.; Franchi, G.; Giradino, P.; Patelli, B.; Penco, S. Cancer
Treat. Rep. 1978, 62, 375-380.
(4) (a) Arcamone, F.; Cassinelli, G. Curr. Med. Chem. 1988, 5, 391-
419. (b) Thomson, R. H. In The Total Synthesis of Natural Products;
ApSimon, J., Ed.; Wiley: New York, 1992; pp 311-531. (c) Krohn, K.
Angew. Chem., Int. Ed. Engl. 1986, 25, 790-807. (d) Wulff, W. D.; Su, J.;
Tang, P.-C.; Xu, Y.-C. Synthesis 1999, 415-422. (e) Hauser, F. M.;
Ganguly, D. J. Org. Chem. 2000, 65, 1842-1849. (f) Achmatowicz, O.;
Szechner, B. J. Org. Chem. 2003, 68, 2398-2404.
Figure 1. Anthracycline antibiotics.
search for anthracyclines with greater potency and less
cardiotoxicity, such as the 4-demethoxy derivative idarubicin
(5) Krohn, K. Tetrahedron 1990, 46, 291-318.
10.1021/ol035168e CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/01/2003

Scheme 1a
a Reagents and conditions: (a) Phenylacetylene, n-BuLi, THF, -78 °C to rt, 100%. (b) Toluene, sealed tube, 160 °C, 12 h, 61% (6), 18%
(7), 8% (8). (c) Toluene/Et3N, sealed tube, 150 °C, 80% (6), 16% (9). (d) (i) Phenylacetylene, n-BuLi, THF, -78 °C, 15 min; (ii)
trimethylsilylacetylene, n-BuLi, THF, -78 °C to rt, 1 h; (iii) KOH, MeOH, rt, 95% (3 steps). (e) o-Xylene/Et3N, sealed tube, 205 °C, 12
h, 29% (11), 23% (12).
rings B and C,7 it is only quite recently that a Co-mediated
route of this kind has been patented.8
performed in the presence of triethylamine as cosolvent, it
proceeded almost quantitatively, affording an 80% yield of
diol 6 and a 16% yield of the previously undetected
naphthacenedione 9.14 By contrast, heating a toluene solution
of 5 in the presence of catalytic amounts of CF3CO2H led
to the formation of a complex mixture of unidentified
compounds.15
Having recently studied the intramolecular dehydro Diels-
Alder (IDDA) reactions of diarylacetylene systems in which
a three-carbon spacer linking the reacting 2π and 4π moieties
allowed the synthesis of the tetracyclic core of the benzo-
[b]fluorene antibiotics,9 we envisaged that the addition of
one more atom to the linker would give access to the benzo-
[b]anthracene nucleus, the basic skeleton of anthracyclines.
Here we report the first synthesis of the benzo[b]anthracene
skeleton by simultaneous formation of rings B and C by
means of an IDDA reaction.10
Scheme 2a
We first prepared diol 511 by reacting commercially
available phthaldehyde 4 with 2.1 equiv of lithium phenyl-
acetylide (Scheme 1). This provided a quantitative yield of
a diastereomeric mixture of diols that coeluted in column
chromatography.
Gratifyingly, when a toluene solution of 5 was heated at
160 °C in a sealed tube, the easily oxidizable naphthacenediol
6 was isolated as a mixture of diastereoisomers in 61% yield,
along with minor amounts of ketones 7 (18%) and 8 (8%).12
We then investigated the effect of the acidity or basicity of
the medium on the reaction course.13 When the reaction was
a Reagents and conditions: (a) (i) Ethynylcyclohexene, n-BuLi,
THF, -78 °C, 15 min; (ii) ethylethynyl ether, n-BuLi, -78 °C to
rt, 62% (for 13); trimethylsilylacetylene, n-BuLi, -78 °C to rt, 94%
(for 14). (b) KOH (aq), THF, MeOH, rt, 100%. (c) Toluene/Et3N,
sealed tube, 150 °C, 12 h, 52% (16), 36% (17). (d) MnO2, CH2Cl2,
rt, 100%.
(6) (a) Farin˜a, F.; Noheda, P.; Paredes, M. C. J. Org. Chem. 1993, 58,
7406-7415. (b) Allen, J. G.; Hentemann, M. F.; Danishefsky, S. J. J. Am.
Chem. Soc. 2000, 122, 571-575. (c) Hottop, T.; Gutke, H.-J.; Murahashi,
S.-I. Tetrahedron Lett. 2001, 42, 3343-3346.
(7) (a) For Co, see: Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl.
1984, 23, 539-556. (b) For Rh, see: Mu¨ller, E.; Beissner, C.; Ja¨ckle, H.;
Langer, E.; Muhm, G. O.; Sauerbier, M.; Segnitz, A.; Streichfuss, D.;
Thomas, R. Liebig, Ann. Chem. 1971, 754, 64-89.
(8) Kreye, P.; Groth, U.; Eckenberg, P. Ger. Offen. 19708496, 1998.
(9) (a) Rodr´ıguez, D.; Castedo, L.; Dom´ınguez, D.; Saa´, C. Tetrahedron
Lett. 1999, 40, 7701-7704. (b) Rodr´ıguez, D.; Navarro, A.; Castedo, L.;
Dom´ınguez, D.; Saa´, C. Org. Lett. 2000, 2, 1497-1500. (c) Rodr´ıguez, D.;
Navarro, A.; Castedo, L.; Dom´ınguez, D.; Saa´, C. J. Org. Chem. 2003, 68,
1938-1946.
Since it is well-established that alkynyl ketones undergo
IDDA reactions under milder conditions and afford higher
yields than alcohols,9b,13a we also oxidized diol 5 to the
(10) Synthesis of the related benzo[a]anthracene nucleus and its applica-
tion to the synthesis of angucyclinone antibiotics has been recently reported,
being the key step in the simultaneous formation of three rings via a cobalt-
mediated [2+2+2] cycloaddition of a triyne: Kalogerakis, A.; Groth, U.
Org. Lett. 2003, 5, 843-844.
(12) The side products may have arisen, in part, from reaction with
oxygen present in the solvent. When the toluene was degassed prior to use,
the yields of 7 and 8 decreased to 6% and 2%, respectively. Assignment of
the structures was supported by the observation of an HMBC correlation
between the ketone of the carbonyl group and the singlet corresponding to
the hydrogen placed in the peri position.
(11) Straub, H.; Hambrecht, J. Synthesis 1975, 425-426.
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Org. Lett., Vol. 5, No. 17, 2003

corresponding diketone by treatment with excess activated
MnO2 (not shown in Scheme 1). However, all attempts to
cyclize the diketone under thermal or catalyzed conditions
(CH3CO2H, Et3N, ZnCl2, AlCl3) led to its decomposition.
To obtain a product without the phenyl substituent, we
first synthesized the asymmetric diol 10 in 95% yield by
sequential treatment of phthaldehyde with lithium phenyl-
acetylide and lithium trimethylsilylacetylide followed by
KOH treatment and desilylation. However, as feared, the lack
of a terminal substituent on one of the alkynes hampered its
cyclization:9a heating an o-xylene/Et3N solution of 10 in a
sealed tube at 205 °C afforded only a 29% yield of diol 11
and a 23% yield of quinone 12.
Finally, cyclohexene derivatives 13 and 14 were prepared
from 4 by sequential addition of the corresponding acetylides,
and cyclohexene 15 by desilylation of 14. Alkynyl ether 13,
which would allow direct introduction of an oxygen sub-
stituent, unfortunately proved do be thermally unstable,
decomposing under the cylization reaction conditions. In the
case of 14, cyclization was prevented by its bulky trimeth-
ylsilyl group, no evolution being observed after heating 14
at 180 °C for 24 h. To our delight, however, desilylated diol
15 reacted smoothly at 150 °C,16 affording a clean mixture
of diol 16 (52%) and quinone 1717 (36%) (due to the
complexity of the spectrum of 16, its identity was confirmed
by quantitative oxidation to 17). Once again, diketone
derivatives of 14 and 15 (not shown) were easily prepared
but decomposed when subjected to cyclization conditions.
In conclusion, we have demonstrated the utility of IDDA
reactions for the synthesis of the 7,8,9,10-tetrahydronaph-
thacene-5,12-dione skeleton of the anthracycline antibiotics,
which was obtained in high yields and just three steps from
commercially available phthaldehyde.
(13) (a) Danheiser, R. L.; Gould, A. E.; Ferna´ndez de la Pradilla, R.;
Helgason, A. L. J. Org. Chem. 1994, 59, 5514-5515. (b) Rodr´ıguez, D.;
Navarro, A.; Castedo, L.; Dom´ınguez, D.; Saa´, C. J. Am. Chem. Soc. 2001,
123, 9178-9179. (c) Rodr´ıguez, D.; Navarro, A.; Castedo, L.; Dom´ınguez,
D.; Saa´, C. Tetrahedron Lett. 2002, 43, 2717-2720.
(14) Naphthacenedione 9 was formed during the course of the reaction
and not by oxidation of diol 6: when 6 was heated under the same reaction
conditions, no evolution was observed. A plausible mechanism for the
obtention of the minor products is depicted below: The first step is the
formation of the intermediate allene I, being the most favorable process
the isomerization (aromatization) via two consecutive [1, 2]-hydrogen shifts
to give diol 6 (see ref 9c). The loss of water in allene I followed by
rearomatization would lead to phenol III, which can tautomerize to ketone
8 or react with any adventitious oxygen present in the mixture to form the
intermediate IV, which would easily evolve to the quinone 9. Several
pathways involving molecular oxygen could be suggested for the transfor-
mation of I or II to the hydroxy ketone 7
Acknowledgment. We thank the Ministerio de Ciencia
y Tecnolog´ıa (Spain) and the European Regional Develop-
ment Fund for financial support under project BQU2002-
02135. D. Rodr´ıguez also thanks the Universidad de Santiago
de Compostela (Sapin) for a postdoctoral grant.
Supporting Information Available: Experimental pro-
1
cedures and spectral data for 5-9 and 13-17; H and 13C/
DEPT spectra for 13-17. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL035168E
(16) Due to the fact that no loss of aromaticity is required during the
cycloaddition process, cyclohexene derivatives react under milder conditions
than the corresponding aryl derivatives (15, 150 °C vs 10, 205 °C).
(17) Compound 17 has been previously reported, but not its spectroscopic
data: Semmelhack, M. F.; Neu, T.; Foubelo, F. J. Org. Chem. 1994, 59,
5038-5047.
.
(15) Reaction of 5 in HBr or HCl/t-BuOH has previously been reported
to afford 12-bromo- or 12-chloro-5-phenylnaphthacene; see ref 11.
Org. Lett., Vol. 5, No. 17, 2003
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