Total synthesis of (±)-biphyscion

Article abstract of DOI:10.1021/ol990758r

(Matrix presented) A regiospecific total synthesis of (±)-biphyscion (1) is described. A novel aspect of the plan was construction of the bianthraquinone ring system from a biphenyl intermediate through the use of a one-pot, double isobenzofuranone condensation.

Full text of DOI:10.1021/ol990758r

ORGANIC
LETTERS
1999
Vol. 1, No. 4
671-672
Total Synthesis of (±)-Biphyscion
Frank M. Hauser* and Polivina Jolicia F. Gauuan
Department of Chemistry, State UniVersity of New York at Albany,
Albany, New York 12222
fh473@sarah.albany.edu
Received June 23, 1999
ABSTRACT
A regiospecific total synthesis of (±)-biphyscion (1) is described. A novel aspect of the plan was construction of the bianthraquinone ring
system from a biphenyl intermediate through the use of a one-pot, double isobenzofuranone condensation.
Although a large number of naturally occurring bianthra-
quinones have been identified,1 there has been only modest
synthetic work on this class of compounds.2 In conjunction
with our interest in developing new routes to these natural
products, we have explored a one-pot, double isobenzofura-
none annelation3 on the biphenyl 6b (Scheme 2), and in so
doing, have accomplished the first total synthesis of the 7,7′-
linked bianthraquinone biphyscion (1).4
the yield of the needed iodoresorcinol 3a, iodination of 2a
and its acetoxy and methyl ether derivatives was studied
(Scheme 1).5 The 4-methoxy derivative 2b, prepared in 96%
Scheme 1
yield through regioselective methylation [(CH3O)2SO2/K2CO3/
CH2Cl2] of 2a, proved to be the best substrate. Iodination
(NIS, CH2Cl2, rt) of 2b consistently gave a 2.8:1 ratio of
the 3-iodo to 5-iodo compounds, 3a and 3b. The iodo isomers
could be separated; however, it proved experimentally
As shown in Scheme 2, an initial goal of the plan was
preparation of the symmetrical biphenyl 4 through Ullman
coupling of the protected iodoresorcinol 3a. To maximize
(1) (a) For an extensive list on naturally occurring bianthraquinones,
see: ; Academic Press: New York, 1971; Vol. I, Chapter 5. (b) Thompson,
R. H. Naturally Occurring Quinones, 2nd ed.; Chapman and Hall: New
York, 1987; Vol. 3, Chapter 3.
(2) Only two examples of bianthraquinone syntheses have been reported,
and both were based on the use of emodin or a derivative thereof. Ullman
reaction of the trimethyl ether derivative of 5-bromoemodin was employed
to synthesize the 5,5′-linked bianthraquinone skyrin: Tanaka, O.; Kaneko,
C. Chem. Pharm. Bull. 1955, 3, 284. Biomimetic coupling of emodin with
K3Fe(CN)6 affords an unnatural 4,7′-linked bianthraquinone (30%) and a
trace (0.28%) of the 5,5-linked bianthraquinone, skyrin: Kato, T.; Hozumi,
T. Chem. Pharm. 1972, 20, 1574.
(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.; Tommassi, R. A. J. Org. Chem,
1991, 56, 5758. Hauser, F. M.; Zhou, M. J. Org. Chem. 1996, 61, 5722.
Hauser, F. M.; Xu, Y. Org. Lett. In press.
(4) Gluchoff, K.; Arpin, N.; Dangy-Caye, M.; Lebreton, P.; Steglich,
W.; To¨pfer, E.; Pourrat, M.; Regerat, F.; Deruaz, D. C. R. Seances Acad.
Sci., Ser. 3 1972, 274, 1739. Steglich, W.; To¨pfer-Petersen, E.; Reininger,
W.; Gluchoff, K.; Arpin, N. Phytochemistry 1972, 11, 3299.
(5) The details of this study will be published elsewhere.
10.1021/ol990758r CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/08/1999

expeditious to effect methylation [(CH3O)2SO2, K2CO3,
acetone] of the mixture and then perform chromatographic
separation of the isomers. The overall yield of the iodoresor-
cinol 3a from the resorcinol 2a was 63%.
Although steric hindrance can be a problem in Ullman
reactions,6 coupling of 3a with copper bronze proceeded as
expected to afford the biphenyl 4 in good yield (73%)
(Scheme 2). Fabrication of phenylsulfonyl isobenzofuranone
tetrathiophenylated product 5 in 55% yield.7 Longer reaction
times gave less of the tetrathiophenylated product and more
of the di- and trithiophenylated products.
Brief treatment of 5 with CF3CO2H/H2O provided a
quantitative yield of the 3-thiophenylated biphthalide 6a as
a mixture of diastereoisomers in a 1:2:1 ratio. The biphthalide
6a was oxidized (MCPBA, K2CO3, CH2Cl2)8 to the sulfone
6b (100% yield).9,10 Since the chirality at two of the three
chiral centers in 6b would be lost in the next step, the
diastereomeric mixture was used in further transformations.
The dianion of 6b, generated with 4 equiv of LiOtBu, was
reacted with the cyclohexenone 7a. Analysis of the 1H NMR
spectrum of the initially received condensation product, as
well as TLC, indicated that a complex mixture had been
formed. Nevertheless, we decided to explore oxidative
transformation of the hydroanthracene intermediate, since this
might afford some insight into the reaction outcome. To this
end, we employed the procedure previously developed by
us to specifically accomplish this type of oxidative conver-
sion.11 We were quite pleased to discover that treatment of
the condensation product with Ag2CO3 on Celite in the
presence of Et3N afforded the expected bianthraquinone 8a
in 23% yield.
Scheme 2
Having established that the double condensation can be
used to construct bianthraquinones, we undertook preparation
of the naturally occurring bianthraquinone biphyscion (1).
As in the previous sequence, the dianion of 6b was generated
with 4 equiv of LiOtBu and then reacted with the cyclohex-
enone 7b. Oxidation (Ag2CO3 on Celite, Et3N, CH2Cl2) of
the bihydroanthracene condensation intermediate gave the
bianthraquinone 8b in 36% yield. Regiospecific demethyl-
ation of 8b with MgI212 afforded biphyscion (1) in 70% yield.
1
The H and 13C NMR spectra were identical with those
reported for biphyscion (1).
Acknowledgment. This work was generously supported
by the National Cancer Institute and the National Institute
of General Medical Sciences of the National Institutes of
Health (CA 18141)
OL990758R
(7) Hauser, F. M.; Rhee, R. P.; Weinreb, S. M.; Dodd, J. H. Synthesis
1980, 73.
(8) The use of a buffered medium is crucial to obtaining a high yield of
the sulfone. Without K2CO3, the yield was only 70%.
(9) The diastereoisomeric ratio was unaltered during oxidation.
(10) The sulfone diastereoisomers were separated. The 1H and 13C NMR
spectra of the most polar and the least polar isomers indicated that they
fragments from the o-methyl carboxylate functionalities in
4 proved to be challenging, and several methods were
explored for this key construction. Ultimately, it was found
that brief treatment of 4 with 6 equiv of LDA (5 min, -78
°C) and 4.4 equiv of (PhS)2 consistently afforded the
were C-2 symmetric. The isomer of intermediate polarity gave 1H and 13
C
spectra indicating that all the protons and all the carbons were different.
(11) Hauser, F. M.; Takeuchi, C.; Yin, H.; Corlett, S. A. J. Org. Chem.
1994, 59, 258-259.
(12) Arkley, V.; Attenburrow, G. I.; Gregory, G. I.; Walker, T. J. Chem.
Soc. 1962, 1260. Gregory, G. I.; Holton, P. J.; Robinson, H.; Walker, T. J.
Chem. Soc. 1962, 1269. Bycroft, B. W.; Holton, P. J.; Roberts, J. C. J.
Chem. Soc. 1963, 4868. Hauser, F. M.; Sengupta, D.; Corlett, S. A. J. Org.
Chem. 1994, 59, 1967.
(6) Ullman, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174. Bringman, G.;
Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977. Fanta,
P. E. Synthesis 1974, 9. Fanta, P. E. Chem. ReV. 1964, 64, 613. Fanta, P.
E. Chem. ReV. 1946, 38, 139.
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Org. Lett., Vol. 1, No. 4, 1999