5722
J . Org. Chem. 1996, 61, 5722
Sch em e 1a
Tota l Syn th esis of th e Str u ctu r e P r op osed
for P r ek in a m ycin
Frank M. Hauser* and Maotang Zhou
Department of Chemistry, The University at Albany, State
University of New York, Albany, New York 12222
Received May 29, 1996
Synthetic work by several groups led to revision of the
structure initially proposed for prekinamycin to 1.1 We
have achieved a brief regiospecific preparation of 1 based
on use of our phthalide annelation methodology.2 In
accomplishing this preparation, we have established that
the anion of the phthalide 5 readily undergoes condensa-
tions with indenones such as 4, a class of compounds not
previously investigated as acceptors.3
As indicated in Scheme 1, the indenone 4 needed for
the phthalide annelation was prepared from the dihy-
drocoumarin 2. Intramolecular Friedel-Crafts rear-
rangement4 of 2 (AlCl3/NaCl, 180 °C, 1 h), followed by
methylation (DMSO4, K2CO3, acetone), furnished 3 in
60% overall yield. As a class of compounds, indenones
are unstable materials,5 and attempted application of a
procedure previously established to convert indanones to
indenones6 gave only a modest yield of 4 from 3. Ulti-
mately we were able to prepare 4 in satisfactory yield
(75%) via conversion of 3 to the silyl enol ether (TMSTf,
Et3N), followed by treatment with Pd(OAc)2.7
Condensation of the anion of the phthalide sulfone 5
with the indenone 4 regiospecifically furnished the benz-
[b]fluorene ketone 6 (73%). In initial work, 6 was
converted to the hydrazone. Treatment with Fetizon’s
reagent (Ag2CO3 on Celite) in the presence of triethy-
lamine oxidatively transformed both the hydroquinone
to the quinone8 and the hydrazone to the diazomethine
moiety9 (IR 2096 cm-1), providing an overall one-pot, two-
step conversion to 7 in 66% yield. Although the diazo
compound 7 was reasonably stable, attempted cleavage
of the O-methyl groups with BBr3, TMSI, or MgI2‚OEt2
a
Reagents: (a) NaCl/AlCl3, ∆; (b) Me2SO4, K2CO3; (c) TMSTf,
Et3N; (d) Pd(OAc)2; (e) 5, LiOBu-t; (f) NH2NH2, EtOH; (g) Ag2CO3,
Celite; (h) BBr3; (i) MeI, DMF, K2CO3.
to afford 1 instead produced a complex mixture of
decomposition products. On the basis of this finding, it
appeared that O-demethylation would be required prior
to introduction of the diazomethine moiety.
Treatment of 6 with BBr3 gave 8, which was sequen-
tially reacted with hydrazine and Ag2CO3 on Celite to
furnish 1, the structure reported for prekinamycin.10 The
spectral properties (IR and 1H NMR) for 1 were not
identical with those reported in the literature.11 How-
1
ever, the UV and H NMR spectra were identical with
another, previously uncharacterized metabolite from
Streptomyces murayamaensis, thus implying that the
spectral properties for the material identified as preki-
namycin are in error. This finding has prompted a
reinvestigation of the natural product reported to be 1,
and this work is described in the following communica-
tion.
Ack n ow led gm en t. We are indebted to Professor
Steven Gould for providing the UV comparison of our
synthetic 1 with the natural product previously assigned
this structure and also for establishing that our material
matches an uncharacterized kinamycin metabolite.
This work was generously supported by the National
Cancer Institute and the National Institute of General
Medical Sciences of the National Institutes of Health.
(1) (a) Echavarren, A. M.; Tamayo, N.; Paredes, C. Tetrahedron Lett.
1993, 34, 4713. (b) Gould, S. J .; Tamayo, N.; Melville, C. R.; Cone, M.
C. J . Am. Chem. Soc. 1994, 116, 2207. (c) Mithani, S.; Weeratunga,
G.; Taylor, N. J .; Dmitrienko, G. I. J . Am. Chem. Soc. 1994, 116, 2209.
(2) 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.; Ellen-
berger, W. P. J . Org. Chem. 1991, 56, 5248. Hauser, F. M.; Tommassi,
R. A. J . Org. Chem, 1991, 56, 5758.
(3) While this work was in progress, condensation of an indenone
with a (phenylsulfonyl)isobenzofuranone was reported. Mal, D.; Hazra,
N. K. Tetrahedron Lett. 1996, 37, 2641.
(4) For the rearrangement of dihydrocoumarins to indanones, see:
Loudon, J . D.; Razdan, R. K. J . Chem. Soc. 1954, 4299.
(5) Galatsis, P.; Manwell, J . J .; Blackwell, J . M. Can. J . Chem. 1994,
72, 1656.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all compounds (17 pages).
J O9609891
(6) Bellamy, F. D.; Chazan, J . B.; Ou, K. Tetrahedron 1983, 39, 2803.
(7) This widely used procedure developed by Saegusa et al. for the
preparation of R,â-unsaturated enones has not previously been used
to prepare indenones from indanones. Ito, Y.; Hirao, T.; Saegusa, T.
J . Org. Chem. 1978, 43, 1011.
(8) Balogh, V.; Fetizon, M.; Golfier, M. J . Org. Chem. 1971, 36, 1339.
(9) Fetizon, M.; Golfier, M.; Milcent, R.; Papadakis, I. Tetrahedron
1975, 31, 165.
(10) Because of insolubility, we were not able to fully characterize
either the demethylated compound 8, the hydrazone intermediate, or
1. However, methylation of synthetic 1 afforded the methyl ether 7,
which we had been able to fully characterize. Furthermore, acetylation
of 1 (Ac2O, Py, DMAP) produced a characterizable diacetate and the
spectral properties (IR, 1H and 13C NMR) of this compound were also
not identical to the diacetate reported in the literature.11
(11) Seaton, P. J .; Gould, S. J . J . Antibiot. 1989, 42, 189.
S0022-3263(96)00989-9 CCC: $12.00 © 1996 American Chemical Society
Hauser, Frank M.
