Synthesis of the naphthalene portion of the rubromycins.

Article abstract of DOI:10.1021/ol016220e

[reaction: see text]. A synthesis of a reduced version of the naphthazarin found in the rubromycin class of natural products is reported. The naphthalene ring system is formed via a Doetz reaction with a symmetrical alkyne. Differentiation between the C1'

Full text of DOI:10.1021/ol016220e

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2661-2663
Synthesis of the Naphthalene Portion of
the Rubromycins
Xu Xie and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
marisa@sas.upenn.edu
Received June 1, 2001
ABSTRACT
A synthesis of a reduced version of the naphthazarin found in the rubromycin class of natural products is reported. The naphthalene ring
system is formed via a Do1tz reaction with a symmetrical alkyne. Differentiation between the C1′ and C3′ groups of the Do1tz adduct is achieved
by selective oxidation since the two methylene groups possess different oxidation potentials.
γ-Rubromycin (1),1 purpuromycin (2),2 heliquinomycin,3 and
the griseorhodins4 are a set of structurally related pigments
consisting of naphthazarin and isocoumarin ring structures
linked through a 5,6-spiroketal. The synthesis of this unique
class of antitumor antibiotic compounds has not yet been
achieved, although they display a range of biological activity.
γ-Rubromycin (1) exhibits activity against the reverse
transcriptase of human immunodeficiency virus-15 and
against human telomerase, which is overproduced in cancer
cells.6 Purpuromycin (2) is a potential topical agent for
vaginal infections,7 and heliquinomycin is an inhibitor of
DNA helicase.3
As part of an effort toward the synthesis of this group of
natural products,8 a highly convergent assembly of the
hexaoxonaphthyl system was desired. Even though a linear
elaboration from 1,5-naphthalene diol has been attempted,
difficulties in installing the correct oxygenation were en-
countered.9 In our approach we have elected to employ a
Do¨tz reaction to provide a rapid and convergent synthesis
of the naphthalene core.10 Utilization of a Do¨tz reaction
would allow for the ready assembly of analogues by simple
variation of the chromium carbene component.11
For a direct synthesis of the naphthazarin precursor, an
oxygen-substituted alkyne 6a would be ideal in a Do¨tz
cyclization with chromium carbene 5. Although such alkynes
(1) Brockmann, H.; Zeeck, A. Chem. Ber. 1970, 103, 1709-1726.
(2) (a) Coronelli, C.; Pagani, H.; Bardone, M. R.; Lancini, G. C. J.
Antibiot. 1974, 27, 161-168. (b) Bardone, M. R.; Martinelli, E.; Zerilli, E.
F.; Coronelli, C. Tetrahedron 1974, 30, 2747-2754.
(3) (a) Chino, M.; Nishikawa, K.; Umekita, M.; Hayashi, C.; Yamazaki,
T.; Tsuchida, T.; Sawa, R.; Hamada M.; Takeuchi, T. J. Antibiot. 1996,
49, 752-757. (b) Chino, M.; Nishikawa, K.; Tsuchida, T.; Sawa, R.;
Nakamura, H.; Nakamura, K. T.; Muraoka, M. Y.; Ikeda, D.; Naganawa,
H.; Sawa, T.; Takeuchi, T. J. Antibiot. 1997, 50, 143-146. (c) Chino, M.;
Nishikawa, K.; Yamada, A.; Oshono, M.; Sawa, T.; Hanaoka, F.; Ishizuka,
M.; Takeuchi, T. J. Antibiot. 1998, 51, 480-486.
(4) The griseorhodins possess a methyl group in place of the methyl
ester group on the isocoumarin and also differ from γ -rubromycin with
respect to the oxygenation of the spiroketal cores. (a) Eckardt, K.; Tresselt,
D.; Ihn, W. J. Antibiot. 1978, 31, 970-973. (b) Stroshane, R. M.; Chan, J.
A.; Rubalcaba, E. A.; Garretson, A. L.; Aszalos, A. A.; Roller, P. P. J.
Antibiot. 1979, 32, 197-204. (c) Suetsuna, K.; Osajima, Y. Agric. Biol.
Chem. 1989, 53, 241-242. (d) Panzone, G.; Trani, A.; Ferrari, P.; Gastaldo,
L.; Colombo, L. J. Antibiot. 1997, 50, 665-670.
Figure 1.
(5) Goldman, M. E.; Salituro, G. S.; Bowen, J. A.; Williamson, J. M.;
Zink, L.; Schleif, W. A.; Emini, E. A. Mol. Pharmacol. 1990, 38, 20-25.
10.1021/ol016220e CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/24/2001

can undergo Do¨tz cyclization reactions, steric differentiation
between a suitably protected alcohol and the methylene group
would likely not be sufficient to provide a selective process.12
As such, a symmetric alkyne diol 6b, for which the issue of
regioselection is not a concern, was selected instead (Figure
2). Differentiation of the two termini from the alkyne can
Scheme 1a
a (a) (i) Br2, AcOH, (ii) NaH, BnBr; 86%; (b) (i) mCPBA, (ii)
KOH, (iii) NaH, BnBr; 61%; (c) (i) nBuLi, (ii) Cr(CO)6, (iii)
Me3OBF4; 60-90%; (d) THF, Ac2O, 53%; (e) TBAF, THF, 31%;
(f) PPTS, (MeO)2CMe2; (g) PPTS, acetone.
Figure 2.
be accomplished after the Do¨tz cyclization (C1′ vs C3′) on
naphthol 4.
optimized, provided the unstable naphthol derivative 12.
Further treatment with dimethoxypropane and PPTS provided
the seven-membered ketal 13. At this point, isomerization
to the thermodynamically more stable six-membered ketal
14, in which C1′ and C3′ are differentiated, was expected to
occur.
Unfortunately, equilibration of seven-membered ketal 13
to six-membered ketal 14 did not proceed, even though
molecular mechanics calculations16 of 15 and 16 (Scheme
2) indicated a significant stabilization (9.4 kcal/mol) of the
The initial implementation of this strategy is shown in
Scheme 1. Fischer chromium carbene intermediate 9 with
benzyl ether protecting groups was selected as the precursor
for the Do¨tz reaction with the aim of effecting a late stage
global deprotection via hydrogenation. Starting with com-
mercially available vanillin (7), Fischer chromium carbene
intermediate 9 was produced using a modified protocol.13
Subjection of 9 to alkyne 1014 in the presence of heat and
Ac2O15 produced the Do¨tz adduct 11 in 40-50% yield.
Removal of the silyl ethers using TBAF, which was not
(6) Ueno, T.; Takahashi, H.; Oda, M.; Mizunuma, M.; Yokoyama, A.;
Goto, Y.; Mizushina, Y.; Sakaguchi, K.; Hayashi, H. Biochemistry 2000,
39, 5995-6002.
Scheme 2. Calculated Relative Energies for 15 and 16
(MM2*)
(7) Trani, A.; Dallanoce, C.; Pranzone, G.; Gianbattisita, R.; Ripamonti,
F.; Goldstein, B. P.; Ciabatti, R. J. Med. Chem. 1997, 40, 967-971.
(8) Syntheses of these compounds have not yet been reported. For efforts
towards construction of the spiroketal core, see: (a) Capecchi, T.; de Koning,
C. B.; Michael, J. P. Tetrahedron Lett. 1998, 39, 5429-5432. (b) Capecchi,
T.; de Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin Trans. 1 2000,
2681-2688. For syntheses of the isocoumarin portion, see: (c) Thrash, T.
P.; Welton, T. D.; Behar, V. Tetrahedron Lett. 2000, 41, 29-31. (d) Waters,
S. P.; Kozlowski, M. C. Tetrahedron Lett. 2001, 42, 3567-3570.
(9) (a) Terada, A.; Tanoue, Y.; Hatada, A.; Sakamoto, H. Bull. Chem.
Soc. Jpn. 1987, 60, 205-213. (b) Tanoue, Y.; Terada, A.; Tsuboi, T.;
Hayashida, T.; Tsuge, O. Bull. Chem. Soc. Jpn. 1987, 60, 2927-2930. (c)
Tanoue, Y.; Terada, A.; Seto, I.; Umeza, Y.; Tsuge, O. Bull. Chem. Soc.
Jpn. 1988, 61, 1221-1224. (d) Tanoue, Y.; Terada, A. Bull. Chem. Soc.
Jpn. 1991, 64, 2295-2297.
six-membered derivative. From studies in a model system
lacking functionalization on the left-hand aromatic ring of
the naphthalene, where isomerization of the respective six-
(10) In the synthesis of fredericamycin, which possesses a similar
naphthazarin, such a construction has been shown to be successful: (a)
Boger, D. L.; Jacobson, I. C. J. Org. Chem. 1991, 56, 2115-2122. (b)
Boger, D. L.; Hueter, O.; Mbiya, K.; Zhang, M. J. Am. Chem. Soc. 1995,
117, 11839-11849.
(11) For reviews see: (a) Harrington, P. J. Transition Metals in Total
Synthesis; Wiley: New York, 1990; p 364. (b) ComprehensiVe Organo-
metallic Chemistry II; Abel, E. W., Stone, F. A. G., Wilkinson, G., Eds.;
Pergamon: Oxford, 1995; p 155. (c) Do¨tz, K. H.; Tomuschat, P. Chem.
Soc. ReV. 1999, 28, 187.
(12) For a discussion of mechanism and regioselectivity factors, see:
Hegedus, L. S. Transition Metals in The Synthesis of Complex Organic
Molecules, 2nd ed.; University Science Books, Sausalito, CA, 1999.
(13) Boger, D. L.; Jacobson, I. C. J. Org. Chem. 1990, 55, 1919-1928.
Deprotonation of the benzylic ethers of 9 by the aryllithium intermediate
could be attenuated by using 1.05 equiv of high-purity freshly titrated nBuLi,
performing the lithiation rapidly at low temperature (<15 min at -78 °C)
and adding the Cr(CO)6 in one portion at low temperature. The use of freshly
prepared Meerwein’s reagent was also found to be absolutely necessary to
obtain 9 efficiently (>90% yield over several trials).
(14) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190-
6191.
2662
Org. Lett., Vol. 3, No. 17, 2001

membered ketal did occur, it appears that steric hindrance
from the peri-benzyl ether groups prevents ready isomer-
ization of the ketal to the required hydroxyl in 13.
Since the steric bias against formation of the desired six-
membered ketal 14 (Scheme 1) prevented selective func-
tionalization of the two methyleneoxy groups, an alternate
approach based on the differences in chemical reactivity of
these two groups was utilized (Scheme 3). It has been shown
the fiVe oxidizable benzyloxy groups is modified. From
aldehyde 18 it is possible to generate two isomeric naphtha-
zarin fragments in which the naphthazarin methoxy group
of the natural products is present at C7′ (22, as in the natural
products) or at C6′ (24, see Scheme 4).
Scheme 4a
Scheme 3a
a (a) (i) 10 mol % (2-NO2-C6H4Se)2, H2O2, (ii) KOH; (b) BnBr,
K2CO3, 48% from 18.
For the synthesis of the natural product precursor 22,
aldehyde 18 was reduced and the alkoxide trapped as the
MOM ether to provide 19. The silyl group was removed and
the resultant benzylic alcohol was oxidized to the aldehyde
with the Dess-Martin periodinane. Baeyer-Villiger oxida-
tion was initially troublesome, but buffered mCPBA was
found to cleanly form the respective formate ester. Hydrolysis
of this formate ester intermediate with NH3 in EtOH
generated unstable phenol 21, which was directly benzylated
to provide naphthazarin derivative 22.
Synthesis of an isomeric C6′ methoxy derivative will allow
the importance and exact placement of the C7′ methoxy
functional group to be assessed with respect to biological
activity. With intermediate 18 available, such a derivative
can be readily generated. As such, aldehyde 18 was subjected
to Baeyer-Villiger oxidation. In this case, the optimal
oxidant proved to be H2O2 with bis(2-nitrophenyl)diselenide
as a catalyst. After hydrolysis of the formate ester intermedi-
ate with KOH, the resultant unstable phenol 23 was protected
to provide the isomeric reduced naphthazarin 24.
In conclusion, a general synthesis of highly oxygenated
naphthalene derivatives is presented, culminating in the
preparation of reduced naphthazarin precursors suitable for
the synthesis of the rubromycin group of natural products
including the rubromycins, purpuromycin, heliquinomycin,
and the griseorhodins. In addition, a strategy to differentiate
benzylic groups on highly substituted aromatic substrates by
taking advantage of differences in oxidation potentials is
demonstrated.
a (a) BnBr, K2CO3, 81%; (b) DDQ, CH2Cl2-H2O, 80%; (c) (i)
NaBH4, (ii) MOMCl, 85%; (d) (i) TBAF, (ii) Dess-Martin, 90%;
(e) (i) mCPBA, NaHCO3, CH2Cl2, (ii) NH3, EtOH; (f) BnBr,
K2CO3, 55% from 20.
that oxidation of benzene derivatives possessing two benzylic
methylenes can be halted after oxidation to the monoalde-
hyde.17 In addition, methoxy groups on benzene derivatives
show a powerful effect in directing the regiochemistry of
oxidation to para-methyleneoxy substituents over meta-
methyleneoxy substituents, presumably by attenuating the
oxidation potential via resonance effects.17
Protection of the remaining phenol in the Do¨tz adduct 11
with benzyl bromide yielded 17 in which the two TBSOCH2
groups now possess different oxidation potentials (Scheme
3). As a result of the electron-donating nature of the C7′
methoxy group, the C3′ group is more electron-rich and
hence more readily oxidized. Treatment of 17 with DDQ
effects clean formation of aldehyde 18 in which only one of
Acknowledgment. Financial support was provided by the
University of Pennsylvania Research Foundation, Pharmacia
Upjohn, Merck Research Laboratories, and DuPont.
(15) For the use of Ac2O as a cosolvent in Do¨tz reactions, see: (a)
Yamashita, A.; Scahill, T. A.; Toy, A. Tetrahedron Lett. 1985, 26, 2969-
2972. (b) Yamashita, A.; Toy, A.; Scahill, T. A. J. Org. Chem. 1989, 54,
3625-3634. (c) Boger, D. L.; Jacobson, I. C. Tetrahedron Lett. 1989, 30,
2037-2040.
(16) (a) MacroModel, V4.0, V5.0 V6.0; Still, W. C.; Columbia Univer-
sity. (b) Mohamdi, F.; Richards, N. G.; Guida, W. C.; Liskamp, R.; Lipton,
M.; Caufield, C.; Chang, G.; Hendrickson, T., Still, W. C. J. Comput. Chem.
1990, 11, 440.
Supporting Information Available: Experimental details
and characterization of all new compounds is provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Wang, W.; Li, T.; Attardo, G. J. Org. Chem. 1997, 62, 6598-6602.
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