ORGANIC
LETTERS
2007
Vol. 9, No. 15
2915-2918
Total Synthesis of Isoprekinamycin:
Structural Evidence for Enhanced
Diazonium Ion Character and Growth
Inhibitory Activity toward Cancer Cells
Wei Liu,† Matthew Buck,† Nan Chen,† Muhong Shang,† Nicholas J. Taylor,†,‡
Jalil Asoud,† Xing Wu,§ Brian B. Hasinoff,§ and Gary I. Dmitrienko*,†
Department of Chemistry, UniVersity of Waterloo, Waterloo,
Ontario, Canada, N2L 3G1, and Faculty of Pharmacy,
UniVersity of Manitoba, Winnipeg, Manitoba, Canada, R3T 2N2
Received May 31, 2007
ABSTRACT
The structurally novel diazobenzo[a]fluorene antibiotic isoprekinamycin (IPK) has been synthesized for the first time employing a Suzuki
coupling of a brominated AB ring synthon with a boronate ester representing the D ring, followed by anionic cyclization and appropriate
functional group manipulations. The first indication that the diazobenzo[a]fluorene system exhibits in vitro anticancer activity is provided and
X-ray crystallographic evidence for enhancement of diazonium ion character as a consequence of intramolecular H-bonding is described.
The kinamycins, first believed to be N-cyanobenzo[b]-
carbazoles 1,1 but now known to be diazobenzo[b]fluorenes
2,2,3 are of current interest because of their antibacterial
activity and an in vitro cytotoxicity profile against cancer
cells suggestive of a mode of action different than that of
anticancer agents in current clinical use.4 The discovery of
the lomaiviticins 6, which are dimeric analogues of the
kinamycins possessing potent cytotoxicity against a range
of cancer cell lines, has heightened interest in these unusual
natural products.5 A number of synthetic strategies have been
disclosed,6 most notably a total synthesis of the biosynthetic
precursor 7,7 model studies toward a total synthesis of
lomaiviticin B,8 and recent total syntheses of kinamycin C
(2C)9 and its methyl ether.10
Isoprekinamycin (IPK), first assigned structure 3,11 is now
recognized to be the diazobenzo[a]fluorene 4.12 The previ-
(5) 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, 5362-5363.
* Address correspondence to this author.
† University of Waterloo.
(6) Gould, S. J. Chem. ReV. 1997, 97, 2499-2509.
‡ Deceased, November 2006.
(7) (a) Hauser, F.; Zhou, M. J. J. Org. Chem. 1996, 61, 5722-5723. (b)
Birman, V. B.; Zhao, Z.; Guo, L. Org. Lett. 2007, 9, 1223-1225.
(8) 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-
2081.
§ University of Manitoba.
(1) Omura, S.; Nakagawa, A.; Yamada, H.; Hata, T.; Furusaki, A. Chem.
Pharm. Bull. 1973, 21, 931-940.
(2) Gould, S. J.; Tamayo, N.; Melville, C. R.; Cone, M. C. J. Am. Chem.
Soc. 1994, 116, 2207-2208.
(9) Lei, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2006, 128, 14790-14791.
(10) Kumamoto, T.; Kitani, Y.; Tsuchiya, H.; Yamaguchi, K.; Seki, H.;
Ishikawa, T. Tetrahedron 2007, 63, 5189-5199.
(11) Seaton, P. J.; Gould, S. J. J. Antibiot. 1989, 42, 189-197.
(12) Proteau, P. J.; Li, J.; Williamson, T. R.; Gould, S. J.; Laufer, R. S.;
Dmitrienko, G. I. J. Am. Chem. Soc. 2000, 122, 8325-8326.
(3) Mithani, S.; Weeratunga, G.; Taylor, N. J.; Dmitrienko, G. I. J. Am.
Chem. Soc. 1994, 116, 2209-2210.
(4) Hasinoff, B. B.; Wu, X.; Yalowich, J. C.; Goodfellow, V.; Laufer,
R. S.; Adedayo, O.; Dmitrienko, G. I. Anticancer Drugs 2006, 17, 825-
837.
10.1021/ol0712374 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/22/2007