Benzo[b]fluorenes via indanone dianion annulation. A short synthesis of prekinamycin

Article abstract of DOI:10.1021/ol0629768

Figure presented A rapid construction of benzo[b]fluorenones via reaction of 1-indanone dianions with phthalate diesters is described. Its utility is illustrated with a concise synthesis of prekinamycin.

Full text of DOI:10.1021/ol0629768

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1223-1225
Benzo[b]fluorenes via Indanone Dianion
Annulation. A Short Synthesis of
Prekinamycin
Vladimir B. Birman,* Zhufeng Zhao, and Lei Guo
Department of Chemistry, Washington UniVersity, Campus Box 1134,
One Brookings DriVe, St. Louis, Missouri 63130
birman@wustl.edu
Received December 8, 2006
ABSTRACT
A rapid construction of benzo[b]fluorenones via reaction of 1-indanone dianions with phthalate diesters is described. Its utility is illustrated
with a concise synthesis of prekinamycin.
The benzo[b]fluorene family of natural products comprises
two major subgroups: the kinamycin antibiotics 1 and their
aromatic congeners, 2-5,1 and the dimeric lomaiviticins 6
(Figure 1). Kinamycins2,3 are strongly active against Gram-
positive bacteria. Lomaiviticins, in addition to their potent
antibacterial activity, exhibit powerful cytotoxicity against
a wide range of cancer cell lines.4
kinamycins has been published only recently.10,11 The chal-
lenges posed by the stereochemical complexity of lomaivi-
Synthetic efforts in this area have resulted in the prepara-
tion of several naturally occurring aromatic benzo[b]fluor-
enes5-7 and model compounds.8,9 The first total synthesis of
(1) For reviews of biosynthesis, history of structure determination, and
synthetic studies, see: (a) Gould, S. J. Chem. ReV. 1997, 97, 2499. (b)
Marco-Contelles, J.; Molina, M. T. Curr. Org. Chem. 2003, 7, 1433. (c)
Kumamoto, T.; Ishikawa, T.; Omura, S. J. Synth. Org. Chem. Jpn. 2004,
62, 49.
(2) Isolation of kinamycins, their antibiotic activity, and the original
structure determination: (a) Ito, S.; Matsuya, T.; Omura, S.; Otani, M.;
Nakagawa, A.; Takeshima, H.; Iwai, Y.; Ohtani, M.; Hata, T. J. Antibiot.
1970, 23, 315. (b) Hata, T.; Omura, S.; Iwai, Y.; Nakagawa, A.; Otani, M.;
Ito, S.; Matsuya, T. J. Antibiot. 1971, 24, 353. (c) Omura, S.; Nakagawa,
A.; Yamada, H.; Hata, T.; Furusaki, A.; Watanabe, T. Chem. Pharm. Bull.
1971, 19, 2428. (d) Omura, S.; Nakagawa, A.; Yamada, H.; Hata, T.;
Furusaki, A.; Watanabe, T. Chem. Pharm. Bull. 1973, 21, 931.
(3) Structure revision of kinamycins: (a) Gould, S. J.; Tamayo, N.;
Melville, C. R.; Cone, M. C. J. Am. Chem. Soc. 1994, 116, 2207. (b)
Mithani, S.; Weeratunga, G.; Taylor, N. J.; Dmitrienko, G. I. J. Am. Chem.
Soc. 1994, 116, 2209.
(4) He, H.; Ding, W.-D.; Bernan, V. S.; Richardson, A. D.; Ireland, C.
M.; Greenstein, M.; Ellestad, G. A.; Carter, G. T. J. Am. Chem. Soc. 2001,
123, 5362.
(5) Synthesis of prekinamycin: Hauser, F. M.; Zhou, M. J. Org. Chem.
1996, 61, 5722.
Figure 1. Benzo[b]fluorene natural products.
10.1021/ol0629768 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/01/2007

ticins still remain to be overcome.12 Conceivably, both
kinamycins and lomaiviticins could be accessed via oxidative
dearomatization of aromatic precursors in a manner remi-
niscent of their probable biosynthesis.1a To explore the
biogenetically patterned approach to these targets, we
required a concise and flexible synthesis of the benzo[b]-
fluorenone core. Although a number of synthetic approaches
to this tetracycle have been described in the literature,5-8
the existing schemes were deemed to be too lengthy to be
suitable for the preparation of an early synthetic intermediate.
In this communication, we report a new method for the
synthesis of functionalized benzo[b]fluorene derivatives,
which compares favorably with the earlier routes. To
demonstrate its utility, we also describe a short and high-
yielding total synthesis of prekinamycin.13 Apart from its
significance as the direct biosynthetic precursor of kinamy-
cins, prekinamycin and its derivatives have recently been
used to elucidate the mechanism of action of diazobenzo-
fluorene antibiotics.14
We realized that 5,10-dihydroxy-benzo[b]fluoren-11-one
11,8a,b,15 containing the essential structural elements of
kinafluorenone 5, could be assembled in a single step via
sequential bisacylation of indanone dianion 816 with a
phthaloyl biselectrophile, e.g., dimethyl phthalate 9 (Scheme
1). It is surprising that this exceedingly simple approach to
the benzo[b]fluorene natural products has not been previously
described.17 Because both of the requisite starting materials
Scheme 1. Synthesis of the Model Benzo[b]fluorenone 11
were commercially available chemicals, the idea was im-
mediately put to the test. A solution of the dianion generated
by treatment of 1-indanone with 2.2 equiv of LDA was
treated with dimethyl phthalate producing a bright purple
solution. Upon the usual workup, the orange tetracycle 11
was isolated in 46% yield by precipitation and recrystalli-
zation (Table 1, entry 1).
Table 1. Optimization of Indanone Dianion Annulationa
total solvent
entry
base, solvent
equiv of 9
volume, mL
yield, %
1
2
3
4
5
6
7
8
9
LDA, THF
LDA, THF
LDA, THF
LDA, THF
LDA, THF
LDA, THF
LDA, Et2O
LHMDS, THF
KHMDS, THF
LTMP, THF
1.0
1.0
0.8
1.2
0.8
0.8
0.8
0.8
0.8
0.8
4.4
3.4
3.4
3.4
1.8
1.5
3.4
2.6
4.8
3.4
46
65
77
60
71
60
65
26
0
(6) Synthesis of stealthins: (a) Gould, S. J.; Melville, C. R.; Cone, M.
C.; Chen, J.; Carney, J. R. J. Org. Chem. 1997, 62, 320. (b) Koyama, H.;
Kamikawa, T. J. Chem. Soc., Perkin Trans. 1 1998, 203.
(7) Syntheses of kinobscurinone: (a) Gould, S. J.; Melville, C. R. Bioorg.
Med. Chem. Lett. 1995, 5, 51. (b) Mohri, S.-i.; Stefinovic, M.; Snieckus,
V. J. Org. Chem. 1997, 62, 7072.
(8) (a) Mal, D.; Hazra, N. K. Tetrahedron Lett. 1996, 37, 2641. (b)
Williams, W.; Sun, X.; Jebaratnam, D. J. Org. Chem. 1997, 62, 4364. (c)
de Frutos, O.; Echavarren, A. M. Tetrahedron Lett. 1997, 38, 7941. (d)
Qabaja, G.; Jones, G. B. J. Org. Chem. 2000, 65, 7187.
10
80
(9) For a review of existing approaches, see refs 1b and c.
(10) Enantioselective total synthesis of kinamycin C: Lei, X.; Porco, J.
A., Jr. J. Am. Chem. Soc. 2006, 128, 14790.
a Conditions: 1.0 mmol of 7, 2.25 mmol of base, -78 to 0 °C; 0.8-1.2
mmol of 9 added at -78 °C.
(11) For synthetic studies towards kinamycins, see: (a) Kumamoto, T.;
Tabe, N.; Yamaguchi, K.; Ishikawa, T. Tetrahedron Lett. 2000, 41, 5693.
(b) Kumamoto, T.; Tabe, N.; Yamaguchi, K.; Yagishita, H.; Iwasa, H.;
Ishikawa, T. Tetrahedron 2001, 57, 2717. (c) Kitani, Y.; Morita, A.;
Kumamoto, T.; Ishikawa, T. HelV. Chim. Acta 2002, 85, 1186. (d) Zhao,
Z.; Guo, L.; Birman, V. B. Abstracts of Papers, 231st ACS National
Meeting, Atlanta, GA, March 26-30, 2006; American Chemical Society:
Washington, DC, 2006; ORGN 473.
(12) For synthetic studies toward lomaiviticins, see: (a) Nicolaou, K.
C.; Denton, R. M.; Lenzen, A.; Edmonds, D. J.; Li, A.; Milburn, R. R.;
Harrison, S. T. Angew. Chem., Int. Ed. 2006, 45, 2076. (b) Freed, J. D.
Ph.D. Thesis, Harvard University, 2005. (c) Pongdee, R. Ph.D. Thesis, Texas
A&M University, 2003.
(13) (a) Isolation of the “original prekinamycin”: Seaton, P. J.; Gould,
S. J. J. Antibiot. 1989, 42, 189. (b) Reassignment of the name “prekina-
mycin” to the compound prepared by Hauser and Zhou (ref 5): Gould, S.
J.; Chen, J.; Cone, M. C.; Gore, M. P.; Melville, C. R.; Tamayo, N. J. Org.
Chem. 1996, 61, 5720. (c) Structure revision of the original prekinamycin:
Proteau, P. J.; Li, Y.; Chen, J.; Williamson, R. T.; Gould, S. J.; Laufer, R.
S.; Dmitrienko, G. I. J. Am. Chem. Soc. 2000, 122, 8325.
(14) Feldman, K. S.; Eastman, K. J. J. Am. Chem. Soc. 2005, 127, 15344.
(15) Compound 11 was first prepared long before the discovery of benzo-
[b]fluorenones in nature: (a) Koelsch, C. F. J. Am. Chem. Soc. 1945, 67,
159. (b) Bader, A. R.; Ettlinger, M. G. J. Am. Chem. Soc. 1953, 75, 730.
(16) Trost, B. M.; Latimer, L. H. J. Org. Chem. 1977, 42, 3212.
(17) Condensation of 1-indanone with phthaldialdehyde leading to benzo-
[b]fluorenone has been reported, although the mechanism is not likely to
involve the dianion formation: (a) Thiele, J.; Schneider, J. Liebigs Ann.
1909, 369, 287. (b) Streitwieser, A., Jr.; Brown, S. M. J. Org. Chem. 1988,
53, 904.
Optimization of the reaction conditions was undertaken
next. Concentrations of the reactants had a marked effect
on the yields (Table 1, entries 1 and 2; 3, 5, and 6). Higher
yields were obtained when dimethyl phthalate was used as
the limiting reagent (entries 2-4). Changing the solvent to
diethyl ether was not beneficial (cf. entries 3 and 7).
Commercially available bases, such as LHMDS or KHMDS
(entries 8 and 9) or commercial LDA, were considerably
inferior to freshly prepared LDA. Lithium tetramethylpip-
eridide (LTMP), on the other hand, produced a slightly
improved yield (entry 10).
With a substantial quantity of the model tetracycle 11 in
hand, we examined the installation of the diazo group at C11.
Previously, this transformation was accomplished in moder-
ate yields via hydrazone formation followed by oxidation
with Fetizon’s reagent.5,8b The following alternative proce-
dure appears to be more convenient (Scheme 2). Crude
tosylhydrazone 12a easily prepared by refluxing 11 in ethanol
with tosylhydrazide was directly oxidized with CAN to yield
1224
Org. Lett., Vol. 9, No. 7, 2007

minor regioisomer, 17b could be detected in the supernatant
solution. Previously, compound 17a was utilized in the
synthesis of prekinamycin5 and stealthin C.6a Benzofluo-
renone 20, which serves as an intermediate in our ongoing
synthetic studies toward kinamycins,10e was produced in an
analogous fashion from indanone 1919 in 55-60% yield.
Refluxing 17a with MsNHNH2 in ethanol produced crude
mesylhydrazone 21. Its global demethylation with excess
Scheme 2. Installation of the Diazo Group
20
BBr3 in dichloromethane, followed by treatment of the
crude reaction mixture with triethylamine under an air
atmosphere, gave rise to prekinamycin 2 in 85% overall yield
(Scheme 4). The NMR spectra of the synthetic prekinamycin
matched exactly those found in the literature.5
Scheme 4. Synthesis of Prekinamycin
the unstable quinone derivative 13a, which underwent
transformation into the desired diazoquinone 148b rapidly
upon treatment with triethylamine or slowly on storage.
Chromatographic separation of 14 from the p-toluenesulfinic
acid byproduct, however, proved to be somewhat inconve-
nient. Therefore, the analogous procedure was developed
employing mesylhydrazide instead of tosylhydrazide, which
eliminated the purification problems and led to an improved
yield of 14. Even more conveniently, 12b could be subjected
to triethylamine under an air atmosphere, directly producing
14 in 91% overall yield.
Having thus optimized the preparation of the model
diazoquinone 14, we turned our attention to the synthesis of
prekinamycin. Application of our newly developed annula-
tion methodology to this target necessitated the use of an
unsymmetrical phthalate diester (cf. 1518), which might
conceivably lead to regioselectivity problems (Scheme 3).
In conclusion, a new, rapid approach to benzo[b]fluorene
derivatives has been developed, which provides a convenient
synthetic access to prekinamycin and its unnatural analogues
and thus should facilitate their biological study. Studies aimed
at the total synthesis of kinamycins via the biogenetically
patterned dearomatization strategy are currently underway
in our laboratory.
Scheme 3. Regioselectivity Issue
Acknowledgment. Acknowledgment is made to the
Donors of the American Chemical Society Petroleum
Research Fund for partial support of this research. Mass
spectrometry was provided by the Washington University
Mass Spectrometry Resource, an NIH Research Resource
(Grant No. P41RR0954).
However, we predicted that the desired regioisomer would
predominate because the reaction was presumed to com-
mence with the nucleophilic attack of the more reactive
â-position of the indanone dianion on the more reactive ester
moiety of 15. Indeed, the reaction of 15 with indanone 185
led to the desired product 17a in 67-81% yields (based on
15) using LTMP as the base. At most trace amounts of the
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0629768
(19) Nichols, D. E.; Barfknecht, C. F.; Long, J. P.; Standridge, R. T.;
Howell, H. G.; Partyka, R. A.; Dyer, D.C. J. Med. Chem. 1974, 17, 161.
(20) McOmie, J. F. W.; Watts, M. L.; West, D. E. Tetrahedron 1968,
24, 2289.
(18) (a) Harland, P. A.; Hodge, P. Synthesis 1982, 223. (b) Gupta, D.
N.; Hodge, P.; Hurley, P. N. J. Chem. Soc., Perkin Trans. 1 1989, 391.
Org. Lett., Vol. 9, No. 7, 2007
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