J. Am. Chem. Soc. 1999, 121, 5589-5590
5589
enone 4 be developed, and would the conjugate addition proceed
with the requisite high diastereoselectivity?
Synthesis of (-)-Fumagillin
Douglass F. Taber,* Thomas E. Christos,
Arnold L. Rheingold,† and Ilia A. Guzei†
Department of Chemistry and Biochemistry,
UniVersity of Delaware, Newark, Delaware 19716
ReceiVed March 11, 1999
Angiogenesis is essential to solid tumor growth.1a,b Inhibitors
of angiogenesis are therefore under active investigation as
antineoplastic agents. Preliminary evidence has recently been put
forward that angiogenesis inhibitors also effectively inhibit the
growth of atherosclerotic plaque.1c Fumagillin 1, (eq 1) prepared
by fermentation, has been a primary lead compound in these
investigations. Semisynthetic derivatives such as TNP-470 2 are
currently in clinical trial as antitumor agents.2,3 Both fumagillin
14 and the related ovalicin 35 have been prepared by total
synthesis, and some preliminary structure-activity studies have
been reported.3 The recent discovery that methionine aminopep-
tidase-2 is the specific enzyme inhibited by fumagillin and
ovalicin2 and the elucidation by X-ray crystallography of the
binding mode of 1 to the enzyme6 make a convincing case for
the development of a flexible total synthesis.
This approach was particularly compelling because a potentially
simple route to the cyclohexenone 4 was available (Scheme 1).
Enone 4 could be derived from the cyclopentene 7 by ozonolysis
followed by aldol condensation. We had already demonstrated7
that addition of strong base to a haloalkene such as 9 would lead,
via the intermediate alkylidene carbene 10, to the C-H insertion
product and had also confirmed that this process proceeded with
retention of absolute configuration at the site of insertion. We
thought that it might be possible to extend this reaction to a simple
alkene such as 6. Bromination should give 8 and dehydrobromi-
nation would be expected to give 9, setting the stage for in situ
elimination and insertion.
Scheme 1
Retrosynthetic Analysis. We proposed to prepare fumagillin
1 by conjugate addition to the enantiomerically pure enone 4,
followed by oxygenation of the derived enolate. There were two
key questions with this approach: Could an efficient route to
* Corresponding author: (tel.) 302-831-2433; (fax) 302-831-6335; (e-mail)
† X-ray crystallography.
(1) (a) Folkman, J. in Cancer: Principles and Practices of Oncology, 5th
Ed., DeVita, V. T., Jr., Hellman, S., Rosenberg, S. A., Eds.; Lippincott-
Raven: Philadelphia, 1997; Vol. 2, pp 3075-3085. (b) Fan, T.-P.; Jaggar,
R.; Bicknell, R. Trends Pharmacol Sci. 1995 (February), 57. (c) Moulton, K.
S.; Heller, E.; Konerding, M. A.; Flynn, E.; Palinski, W.; Folkman, J.
Circulation 1999, 99, 1726.
(2) (a) Hasuike, T.; Hino, M.; Yamane, T.; Nishizawa, Y.; Morii, H.;
Tatsumi, N. Eur. J. Hemaet. 1997, 58, 293. (b) Dzube, B. J.; Vonroenn, J.
H.; Holdenwiltse, J.; Remick, S.; Cooley, T. P.; Cheung, T. W.; Sommodossi,
J. P.; Shriver, S. L.; Suckow, C. W.; Gills, P. S. RetroVirology 1997, 14, 78.
(c) Sin, N.; Meng, L.; Wang, M. Q. W.; Wen, J. J.; Bornmann, W. G.; Crews,
C. M. Proc. Natl. Acad. Sci. 1997, 94, 6099. (d) Griffith, E. C.; Su, Z.; Turk,
B. E.; Chen, S.; Chang, Y. H.; Wu, Z.; Biemann, K.; Liu, J. O. Chem. Biol.
1997, 4, 461.
(3) For leading references both to the isolation of fumagillin and to the
use of semisynthetic derivatives as antiangiogenic agents, see the following:
(a) Hanson, T. E. Antibiot. Chemother. (Washington, D.C.) 1951, 1, 54. (b)
Marui, S.; Itoh, Y.; Kosai, Y.; Sudo, K.; Kishimoto, S. Chem. Pharm. Bull.
1992, 40, 96. (c) Marui, S.; Kishimoto, S. Chem. Pharm. Bull. 1992, 40, 575.
(d) Marui, S.; Yamamoto, T.; Sudo, K.; Akimoto, H.; Kishimoto, S. Chem.
Pharm. Bull. 1995, 43, 588. (e) Dorey, G.; Leon, P.; Sciberras, S.; Leonce,
S.; Guilbaud, N.; Pierre, A.; Atassi, G.; Billington, D. C. Bioorg. Med. Chem.
Lett. 1996, 6, 3045. (e) Griffith, E. C.; Su, Z.; Niwayama, S.; Ramsay, C. A.;
Chang, Y.-H.; Liu, J. O. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 15183.
(4) For synthetic approaches to fumagillin, see the following: (a) Corey,
E. J.; Snider, B. B. J. Am. Chem. Soc. 1972, 94, 2549. (b) Kim, D.; Ahn, S.
K.; Bae, H.; Choi, W. J.; Kim, H. S. Tetrahedron Lett. 1997, 38, 4437.
(5) For syntheses of ovalicin, see the following: (a) Corey, E. J.; Dittami,
J. P. J. Am. Chem. Soc. 1985, 107, 256. (b) Bath, S.; Billington, D. C.; Gero,
S. D.; Quiclet-Sire, B.; Samadi, M. J. Chem. Soc., Chem. Commun. 1994,
1495. (c) Corey, E. J.; Guzman-Perez, A.; Noe, M. J Am. Chem. Soc. 1994,
116, 12109. (d) For a synthesis of FR65814, see the following: Amano, S.;
Ogawa, N.; Ohtsuka, M.; Chida, N. Tetrahedron 1999, 55, 2205.
(6) Liu, S.; Widom, J.; Kemp, C. K.; Crews, C. M.; Clardy, J. Science
(Washington, D.C.) 1998, 282, 1324.
Construction of enone 4. We have prepared 68 from (S)-
glycidol 11 (Scheme 2) by Grignard opening followed by
ketalization. The acetonide 6 was purified on a multigram scale
by distillation.
As we had hypothesized, bromination followed by exposure
to KHMDS nicely cyclized 6 to 7. This procedure required some
optimization. The ketal tended to participate in the bromination,
so it was necessary to effect bromination in ether at -78 °C and
then immediately add the KHMDS (freshly titrated) before
allowing the reaction to come to room temperature. Under these
conditions, cyclization proceeded in good yield. Ozonolysis
followed by aldol condensation then gave 4.
Conjugate addition to enone 8. The requisite side chain for
the conjugate addition was conveniently prepared in two steps
from dihydrofuran 12 (Scheme 3). Following the literature proce-
dure,9 lithiation of dihydrofuran followed by the addition of tri-
(7) For the efficient cyclization of haloalkenes, see (a) Taber, D. F.; Sahli,
A.; Yu, H.; Meagley, R. P. J. Org. Chem. 1995, 60, 6571. For earlier references
to the generation of alkylidene carbenes from haloalkenes, see the following:
(b) Erickson, K. L.; Wolinsky, J. J. Am. Chem. Soc. 1965, 87, 1143. (c)
Wolinsky, J.; Clark, G. W. J. Org. Chem. 1976, 41, 745. (d) Fisher, R. H.;
Baumann, M.; Koebrich, G. Tetrahedron Lett. 1974, 1207.
(8) Acetonide 7 was previously reported by Ohira: (a) Ohira, S.; Ishii, S.;
Shinohara, K.; Nozaki, H. Tetrahedron Lett. 1990, 31, 1039. (b) Ohira, S.;
Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun. 1992, 721.
(9) Le Menez, P.; Fargeas, V.; Poisson, J.; Ardisson, J.; Lallemand, J.-Y.;
Pancrazi, A. Tetrahedron Lett. 1994, 35, 7767.
10.1021/ja990784k CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/29/1999