7072
J . Org. Chem. 1997, 62, 7072-7073
Com bin ed Dir ected Or th o-,
Rem ote-Meta la tion a n d Cr oss-Cou p lin g
Str a tegies. Con cise Syn th eses of th e
Kin a m ycin Biosyn th etic Gr id An tibiotics
P h en a n th r ovir id in Aglycon a n d
Kin obscu r in on e
Shin-ichiro Mohri, Marijan Stefinovic, and
Victor Snieckus*
Guelph-Waterloo Centre for Graduate Work in Chemistry,
University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Received J une 20, 1997
The kinamycins constitute a class of polyketide-
derived1 antitumor antibiotics first isolated from Strep-
tomyces murayamaensis,2 in which the already consid-
erable biosynthetic and synthetic interest has been
accelerated by their recent structural revision from
N-cyanamides of benzo[b]carbazole to 5-diazobenzo[b]-
fluorenes 1.3,4 Extensive biosynthetic studies by Gould
and co-workers have placed a number of diverse con-
densed aromatics and heteroaromatics along the biosyn-
thetic grid to the kinamycins, including the benz[a]-
anthraquinone dehydrorabelomycin,5a WS-5995A (from
S. auranticolor),5b the phenanthroviridins 26 and 3,6,7 the
benzo[b]fluorenone, kinobscurinone (4a )8 and the corre-
sponding aminobenzo[b]fluorene, stealthin C,9 and pre-
kinamycin (4b).10 Structural uniqueness (2, 3) and
challenging biosynthetic questions8,9 have fueled syn-
thetic studies and have led to the synthesis of 3,11 4b,12
and the benzofluorenone 511 by Gould, Echavarren, and
Hauser, respectively. We report short and efficient syn-
theses of phenanthroviridin aglycon (3) and kinobscurino-
ne (4a ) which demonstrate the evolving utility of strat-
egies which link directed ortho-13 and remote-metalation14a
with transition metal catalyzed cross-coupling reac-
tions.14 Since 5 has been previously converted into 4a ,8
prekinamycin 4b,9,10,12 and stealthin C,9 this work also
constitutes total synthesis of these natural products.
The synthesis of phenanthroviridin aglycon (3), the
first naturally-occurring benzo[b]phenanthridine, was
initiated by the preparation of the oxaborole 715 from the
readily available benzyl alcohol 616 using a directed ortho-
metalation-trimethylborate quench protocol (Scheme 1).
F igu r e 1.
Sch em e 1
(1) Gould, S. J .; Tamayo, N.; Melville, C. R.; Cone, M. C. J . Am.
Chem. Soc. 1994, 116, 2207.
(2) Mithani, S.; Weeratunga, G.; Taylor, N. J .; Dmitrienko, G. I. J .
Am. Chem. Soc. 1994, 116, 2209.
(3) Sato, Y.; Gould, S. J . Tetrahedron Lett. 1985, 26, 4023.
(4) Sato, Y.; Gould, S. J . J . Am. Chem. Soc. 1986, 108, 4625.
(5) (a) Seaton, P. J .; Gould, S. J . J . Am. Chem. Soc. 1987, 109, 5282.
(b) Watanabe, M.; Date, M., Furukawa, S. Chem. Pharm. Bull. 1989,
37 (2), 292.
(6) Fendrich, G.; Zimmermann, W.; Gruner, J .; Auden, J . A. L. Eur.
Pat. Appl. EP 304, 400 (Cl.C07D221/18), 1989.
Suzuki-Miyaura cross-coupling17 of 7 with the versatile
bromojuglone 818 under anhydrous conditions19 furnished
the biaryl 9 in good yield. Simple dissolution of 9 in aque-
ous ammonia20 led directly to the hydroquinone 10 in
modest yield which, upon treatment with MnO2, was con-
verted into 11 by an oxidative cyclization which appears
to be unprecedented. Deprotection with BBr3 concluded
the synthesis of the phenanthroviridin aglycon 3 in five
steps from 7 and 15% overall yield which compares
favorably with the previous route achieved by Gould.10,21
The construction of the benzofluorenone 5 was formu-
lated on the basis of a key remote-metalation-carbamoyl
migration reaction (Scheme 2, 12, step 2) which, perforce,
necessitates prior silicon protection14b(step 1).
(7) Gore, M. P.; Gould, S. J .; Weller, D. D. J . Org. Chem. 1992, 57,
2774.
(8) Cone, M. C.; Hassan, A. M.; Gore, M. P.; Gould, S. J .; Borders,
D. B.; Alluri, M. R. J . Org. Chem. 1994, 59, 1923.
(9) (a) Gould, S. J .; Melville, C. R. Bioorg. Med. Chem. Lett. 1995,
5, 51. (b) For a recent synthesis of Stelathins A and B see: Koyama,
H.; Kamikawa, T. Tetrahedron Lett. 1997, 38, 3973.
(10) Gould, S. J .; Melville, C. R.; Cone, M. C.; Chen, J .; Carney, J .
R. J . Org. Chem. 1997, 62, 320.
(11) (a) Gould, S. J .; Chen, J .; Cone, M. C.; Gore, M. P.; Melville, C.
R.; Tamayo, N. J . Org. Chem. 1996, 61, 5720. (b) de Frutos, O.;
Echavarren, A. M. Tetrahedron Lett. 1996, 37, 8953.
(12) Hauser, F. M.; Zhou, M. J . Org. Chem. 1996, 61, 5722.
(13) Snieckus, V. Chem. Rev. 1990, 90, 879.
(14) (a) Wang, W.; Snieckus, V. J . Org. Chem. 1992, 57, 424. (b)
Fu, J .; Zhao, B.; Sharp, M. J .; Snieckus, V. J . Org. Chem. 1991, 56,
1683.
(17) J ung, M. E.; Hagenah, J . A. J . Org. Chem. 1987, 52, 1889.
(18) Brown, A. G.; Crimmin, M. J .; Edwards, P. D. J . Chem. Soc.,
Perkin Trans. 1 1992, 123.
(19) Fu, J .-M. Ph. D. Thesis, University of Waterloo, 1990. Oh-e,
T.; Miyaura, N.; Suzuki, A. Synlett 1990, 221. Watanabe, T.; Miyaura,
N.; Suzuki, A. Synlett 1992, 207.
(20) Echavarren, A. M.; Tamayo, N.; Cardenas, D. J . J . Org. Chem.
1994, 59, 6075. Gore, M. P.; Gould, S. J .; Weller, D. D. J . Org. Chem.
1992, 57, 2774.
(15) J ung, M. E.; J ung, Y. H. Tetrahedron Lett. 1988, 29, 2517.
(16) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
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