ORGANIC
LETTERS
2008
Vol. 10, No. 17
3813-3816
Total Synthesis of (-)-Kendomycin
Jason T. Lowe and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, Boston UniVersity,
590 Commonwealth AVenue, Boston, Massachusetts 02215
Received July 2, 2008
ABSTRACT
An enantioselective synthesis of (-)-kendomycin is described and is based on the application of the organosilane-based [4 + 2]-annulation
strategy for the assembly of the C1a-C10 fragment. An underutilized samarium(II) iodide-assisted cyclization (intramolecular Barbier-type
reaction) is employed to afford the protected macrocycle.
Kendomycin [(-)-TAN 2162] was originally isolated from
Streptomyces Violaceuber in 1996 by Funahashi and co-
workers.1 Initial screens of the compound revealed potent
endothelin receptor antagonist activity1 as well as its potential
as an antiosteoporotic agent.2 Subsequent reports indicated
that kendomycin exhibited effective antibacterial activity
against both Gram-positive and Gram-negative strains as well
as having enhanced cytotoxic activity toward several human
tumor cell lines (average GI50 < 0.10 µM).3 Recently, it has
been suggested that kendomycin mediates its cytotoxic
effects, in part, through proteasome inhibition.4
Kendomycin is a 16-membered conformationally restricted
macrocycle comprising a densely functionalized pyran ring
system and unique quinone methide chromophore through
a pseudo C-glycosidic bond and further tethered by an
aliphatic ansa system. The relative and absolute stereochem-
istry of kendomycin was confirmed by both single crystal
X-ray and advanced Mosher’s ester analysis.3
The biological profile of kendomycin crosses several
therapeutic areas, and its unique molecular architecture has
led to considerable interest by the synthetic community,
which culminated with two total syntheses5,6 in addition to
several fragment syntheses.7 Herein, we report an enanti-
oselective synthesis of kendomycin.
The synthetic plan for constructing kendomycin in-
tended to utilize an underdeveloped macrocyclization
involving an intramolecular Barbier-type reaction of 3
(5) Yuan, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720–
14721
.
(6) (a) Smith, A. B., III; Mesaros, E. F.; Meyer, E. A. J. Am. Chem.
Soc. 2005, 127, 6948–6949. (b) Smith, A. B., III; Mesaros, E. F.; Meyer,
E. A. J. Am. Chem. Soc. 2006, 128, 5292–5299
.
(1) (a) Funahashi, Y.; Kawamura, N.; Ishimaru, T. Japan Patent
08231551 [A2960910], 1996; Chem. Abstr. 1997, 126, 6553. (b) Funahashi,
Y.; Kawamura, N.; Ishimaru, T. Japan Patent 08231552, 1996; Chem. Abstr.
1996, 125, 326518.
(7) (a) Sengoku, T.; Uemura, D.; Arimoto, H. Chem. Lett. 2007, 36,
726–727. (b) Williams, D. R.; Shamim, K. Org. Lett. 2005, 7, 4161–4164.
(c) White, J. D.; Smits, H. Org. Lett. 2005, 7, 235–238. (d) Mulzer, J.;
Pichlmair, S.; Green, M. P.; Marques, M. M. B.; Martin, H. J. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 11980–11985. (e) Sengoku, T.; Arimoto, H.;
Uemura, D. Chem. Commun. 2004, n/a, 1220–1221. (f) Pichlmair, S.;
Marques, M. M. B.; Green, M. P.; Martin, H. J.; Mulzer, J. Org. Lett. 2003,
5, 4657–4659. (g) Marques, M. M. B.; Pichlmair, S.; Martin, H. J.; Mulzer,
J. Synthesis 2002, n/a, 2766–2770. (h) Martin, H. J.; Drescher, M.; Ka¨hlig,
H.; Schneider, S.; Mulzer, J. Angew. Chem., Int. Ed. 2001, 40, 3186–3188.
(i) Bahnck, K. B.; Rychnovsky, S. D. Chem. Commun. 2006, n/a, 2388–
2390.
(2) Su, M. H.; Hosken, M. I.; Hotovec, B. J.; Johnston, T. L. U.S. Patent
5728727 [A 980317], 1998; Chem. Abstr. 1998, 128, 239489.
(3) (a) Bode, H. B.; Zeeck, A. J. Chem. Soc., Perkin Trans. 1 2000,
n/a, 323–328. (b) Bode, H. B.; Zeeck, A. J. Chem. Soc., Perkin Trans. 1
2000, n/a, 2665–2670.
(4) Elnakady, Y. A.; Rohde, M.; Sasse, F.; Backes, C.; Keller, A.;
Lenhof, H. P.; Weissman, K. J.; Mueller, R. ChemBioChem. 2007, 8, 1261–
1272.
10.1021/ol801499s CCC: $40.75
Published on Web 08/13/2008
2008 American Chemical Society