A new route to benzo[4,5]cyclohepta[1,2-b]naphthalenes: Synthesis of radermachol

Article abstract of DOI:10.1021/ol0055869

Condensation of 3-phenylsulfonyl-1,3-isobenzofuranone (3) with benzocyclohept-6,7-en-5-ones such as 4 and 15 provides a straightforward, general method for synthesis of functionalized benzo[4,5]cyclohepta[1,2-b]naphthalenes (e.g., 5 and 16). This finding was used to achieve a brief and efficient preparation of 6,7-benzo-3,4-(1,4-dimethoxy-2,3-naphtho)-1,5-dioxosuberane (2), an established intermediate to the naturally occurring red pigment radermachol (1).

Full text of DOI:10.1021/ol0055869

ORGANIC
LETTERS
2
000
Vol. 2, No. 8
045-1047
A New Route to
Benzo[4,5]cyclohepta[1,2-b]naphthalenes:
Synthesis of Radermachol
1
‡
Frank M. Hauser* and Htwe Yin
Department of Chemistry, The UniVersity at Albany, State UniVersity of New York,
Albany, New York 12222
fh473@sarah.albany.edu
Received January 26, 2000
ABSTRACT
Condensation of 3-phenylsulfonyl-1,3-isobenzofuranone (3) with benzocyclohept-6,7-en-5-ones such as 4 and 15 provides a straightforward,
general method for synthesis of functionalized benzo[4,5]cyclohepta[1,2-b]naphthalenes (e.g., 5 and 16). This finding was used to achieve a
brief and efficient preparation of 6,7-benzo-3,4-(1,4-dimethoxy-2,3-naphtho)-1,5-dioxosuberane (2), an established intermediate to the naturally
occurring red pigment radermachol (1).
The isolation and structure elucidation of the red pigment
1
radermachol (1) was originally reported by Joshi et al.
Subsequently, the same group accomplished a total synthesis
of 1, in which the benzocycloheptadiene[1,2-b]-naphthalene
dione 2 was employed as a key intermediate.2
Scheme 1a
Since the use of benzcyclohepten-5-ones in the isobenzo-
furanone annulation had not been previously explored and
because this approach would provide a new route to benzo-
[4,5]cyclohepta[1,2-b]naphthalenes, we decided to investigate
Our work with the isobenzofuranone annulation suggested
that 5, a potential precursor to 2, might be readily prepared
through condensation of the phenylsulfonyl isobenzofura-
this approach.
To test the feasability of using the annulation methodology
to generate the objective ring system, the anion of the
phenylsulfonyl isobenzofuranone 3 was condensed with 8,9-
3
none 3 with the benzocyclohepten-5-one (4) (Scheme 1).
‡
Dedicated to the memory of the late Arthur G. Schultz (1942-2000).
(3) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178. For use of
this reaction in natural products syntheses, see: Hauser, F. M.; Mal, D. J.
Am. Chem. Soc. 1984, 106, 1098. Hauser, F. M.; Prasanna, S. Tetrahedron
1984, 40, 4711. Hauser, F. M.; Chakrapani, S.; Ellenberger, W. P. J. Org.
Chem. 1991, 56, 5248. Hauser, F. M.; Tommasi, R. A. J. Org. Chem, 1991,
56, 5758.
(1) Joshi, B. S.; Gawad, D. H.; Pelletier, S. W. Kartha, G.; Bhandary,
K. Tetrahedron Lett. 1984, 25, 5547.
2) Joshi, B. S.; Jiang, Q.; Rho, T.; Pelletier, S. W. J. Org. Chem. 1994,
(
5
3
9, 8220. Jiang, Q.; Joshi, B. S.; Pelletier, S. W. Tetrahedron Lett. 1991,
2, 5283.
1
0.1021/ol0055869 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/23/2000

4
dihydrobenzocyclohepten-5-one (4). Indeed, gram quantities
vinyl hydrogen. Proton decoupling established that the other
vinyl hydrogen was buried in the aromatic absorptions.
Apparently the presence of oxygen in the medium resulted
in oxidation of the hydroquinone 5a to the quinone 8, which
underwent tautomerization to 9 and then methylation.
Although we had seen this phenomena before and even
refined and capitalized on it for anthracycline syntheses,6
the facility of this transformation was nevertheless striking.
In fact, preparation of the dimethyl ether 5b, uncontaminated
with the unsaturated dimethyl ether 6, proved challenging.7
of the expected benzo[4,5]cyclohepta[1,2-b]naphthalene 5a
were produced in 85% yield. A distinctive feature of the H
1
NMR spectrum of 5a was the presence of multiplets at 3.13
and 3.27 ppm for the protons on the methylene groups at
C-12 and C-13.
Once it was established that the isobenzofuranone con-
densation provided the ring system, various methods for
introduction of a C-13 ketone functionality in 5a were
explored to complete construction of the intermediate 2. The
conceptualized plan, as outlined in Scheme 2, was to convert
Although epoxidation of 6 (MCPBA, CH
in 78% yield, attempted rearrangement of 7 with CF
or BBr failed to give the expected ketone 2. A possible
2
Cl
2
) produced
7
3
CO H
2
3
Scheme 2a
explanation is that, as shown in Figure 1, the ring system is
Figure 1. Three-dimensional representation of 7 showing the
cupped geometry.
cup-shaped and opening of the epoxide to form a carbocation
would result in additional ring strain. Moreover, attempted
reductive opening (H , Pd/BaSO ) of the epoxide in 7 was
2 4
also unsuccessful. In this case, the catalyst probably cannot
access the concave face.
Based on the expectation that regiospecific reductive
opening of a 12,13-epoxide or regioselective reductive
removal of a 12-hydroxyl group would be possible, the route
shown in Scheme 3 was explored. To access appropriately
functionalized intermediates, our previously developed pro-
cedure for oxidative tautomerization of quinones was ex-
5
a to the dimethyl ether derivative 5b and then introduce
6
ploited. Treatment of the hydroquinone 5a with Fetizon’s
C-12/C-13 unsaturation in 6, possibly through benzylic
bromination/dehydrobromination. It was anticipated that the
epoxide 7, derived from 6, would undergo regioselective
5
Scheme 3a
rearrangement to the objective ketone 2, as a result of
resonance stabilization by the neighboring methoxyl group.
We were pleased but not entirely surprised to discover that
the unsaturated compound 6 was directly formed in 46%
yield on attempted methylation of 5a with (CH
3 2 2
O) SO and
K
2
CO , thereby obviating the need for alternative methods
3
for introduction of C-12/C-13 unsaturation. Formation of 6
1
was confirmed by the H NMR spectrum. There were no
absorptions between 3.1 and 3.3 ppm for the protons on the
ethano bridge. Instead, a one-hydrogen doublet at 6.95 ppm
(J ) 12.4 Hz) was observed, indicating the presence of a
(
4) Ito, S.; Kasai, M.; Ziffer, H.; Silverton, J. V. Can. J. Chem. 1987,
5, 574.
5) Hauser, F. M.; Prasanna, S. Synthesis 1980, 621.
6
(
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Org. Lett., Vol. 2, No. 8, 2000

the monacetylated intermediate 11. Unexpectedly, 11 proved
Scheme 4a
resistant not only to epoxidation with MCPBA but also to
dihydroxylation (catalytic OsO with either TMNO or
4
t-BuOOH).
The route shown in Scheme 4, which leads directly to the
masked ketone 16, was investigated next. Ketalization of the
1
0
known 5,8-diketone 13 with ethylene glycol and PPTS
1
1
furnished exclusively the monoketal 14. Treatment of 14
with LDA and TMSCl produced the expected TMS ether,
which smoothly underwent oxidation with Pd(OAc) to the
2
unsaturated enone 15.
Condensation of 15 with the anion of the sulfone 3 gave
4 3
6a, which was directly methylated (Bu N F , CH
I, DMF)7
+
-
1
to furnish the dimethyl ether 16b (75% overall yield).
Hydrolysis of 16b (PPTS, acetone/water, 97%) produced 2,
1
13
which had physical and spectral properties ( H and C NMR)
2
identical to those reported by Joshi et al. The sequence
reported by them, involving acylation of 2 with dimethy-
1
2
lacryloyl chloride to 17, followed by demethylation and
cyclization furnished 1.
In summary, we have shown that condensation of benzo-
cycloheptenones with an isobenzofuranone provides straight-
forward access to functionalized benzocycloheptadiene[1,2-
b]naphthalenes.
Acknowledgment. This work was generously supported
by the National Cancer Institute of the National Institutes
of Health under grant CA 18141.
OL0055869
(9) In conjunction with the work described in this paper, condensation
of the anion of the isobenzofuranone 3 with the benzocycloheptenone i
was performed. This reaction produced, after incipient oxidation, the quinone
10 (15%), the bridged bicyclic product ii (7%), and iii (28%).
8
3
reagent in the presence of Et N directly furnished the
9
unsaturated quinone 10 in quantitative yield. As expected,
under reductive acetylation conditions, 10 was converted to
(
6) Hauser, F. M.; Takeuchi, C.; Yin, H.; Corlett, S. A. J. Org. Chem.
994, 59, 258 and references therein.
7) Ultimately, the dimethyl ether 5b was cleanly prepared in 75% yield
from 5a by rigorously removing oxygen from the reaction medium and
1
(10) Barltrop, J. A.; Johnson, A. J.; Meakins, G. D. J. Chem. Soc. 1951,
181.
(11) Even under forcing conditions, excess ethylene glycol and prolonged
reflux, only trace quantities of the bisketal were observed. This selectivity
is probably a consequence of relief of ring strain.
(
+
-
using an alternative methylation procedure (Bu4N F , CH3I, DMF). Slater,
G. P.; Haskins, R. H.; Hogge, L. R.; Nesbitt, L. R. Can. J. Chem. 1967,
4
5, 92.
8) Fetizon, M.; Golfiner, M. Compt. Rend. 1968, 267, 900.
(12) Our yield for the AlCl3 promoted acylation of 2 to 17 was only
13%, in contrast to the reported 69%.
(
Org. Lett., Vol. 2, No. 8, 2000
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