Synthesis of (-)-Fumagillin

Full text of DOI:10.1021/ja990784k

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)
taberdf@udel.edu.
† 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

5590 J. Am. Chem. Soc., Vol. 121, No. 23, 1999
Communications to the Editor
Scheme 3
Scheme 4
Scheme 2
butylstannyllithium gave an intermediate that was quenched with
methyl iodide to give the alcohol 13. Silylation then gave 14.
With the side chain in hand, we were ready to attempt conjugate
addition to the enone 4. There was some literature precedent10
for conjugate addition taking place anti to the oxygen of the
spirocyclic ether. In the event, conjugate addition/enolate trapping
proceeded smoothly to give 15 and its easily separated diastere-
omer in a 96:4 ratio.
in this case the â,γ-epoxy aldehyde from oxidation of 21. These
fears proved to be well-founded, as the aldehyde was indeed very
unstable. Direct homologation of the crude aldehyde, however,
delivered the desired alkene 22 in acceptable overall yield.
At this point, debenzoylation allowed us to compare our
synthetic (-)-fumagillol 23 with authentic material prepared from
Rubottom oxidation11 of the silyl enol ether 15 (Scheme 4)
suffered somewhat from competing epoxidation of the double
bond. The most serious difficulty with this procedure for enolate
hydroxylation, however, was the removal of the secondary OTES
group in the presence of the primary OTBS group. We finally
found that TBAF/THF buffered with solid NH4Cl, a reagent
combination recently developed in our laboratory,12 effected the
selective desilylation. Methylation of 17 followed by reduction
of the ketone provided 18 as a single diastereomer. Benzoylation
of 18 followed by hydrolysis then gave the triol 19.
At this point, we needed to convert the triol to the epoxide 20.
This transformation could proceed by inversion of the quaternary
center. While this might be possible, we elected instead to cleave
the diol to the ketone, then establish the epoxide using the
equatorial-selective13 sulfoxonium ylide. We had been concerned
that the intermediate â,γ-unsaturated ketone, from periodate
cleavage of diol 19, would be unstable. As it turned out, this
ketone could be handled without difficulty. Addition of the ylide
to this ketone led to epoxide 20 as a single diastereomer.
Following the literature precedent,4 peracid oxidation of 20 led
to 21, again as the only detected diastereomer. At this point we
were once again concerned about the stability of an intermediate,
1
natural fumagillin. The two were indentical by TLC, H NMR,
and 13C NMR. The synthetic material had [R]D ) -68.8° (lit.3
[R]D ) - 67.7°). Conversion of the C-10 diacid (prepared from
natural fumagillin) to the acid chloride4a followed by acylation
of the synthetic 23 led to synthetic 1, mp ) 193-195° (lit.3 mp
) 194-195° for natural material). This substance was identical
1
to natural fumagillin in all respects (TLC, H NMR, 13C NMR).
The synthetic material had [R]D ) - 27.0° (lit.3 [R]D ) - 26.2°).
Conclusion
The in situ bromination/dehydrobromination protocol intro-
duced here offers a potentially very flexible route from 1,1-
disubstituted alkenes to cyclopentenes. As (S)-glycidol is inex-
pensive on a commercial scale ($18/mole), and since the ketone
4 is nicely crystalline, we expect that 4 and its enantiomer will
become valuable chirons for natural product synthesis.
Acknowledgment. We thank Dr. Gordon Nichol for high-resolution
mass spectra and Dr. Martha Bruch for high resolution NMR spectra.
We thank Professor Jun Liu for a generous supply of natural fumagillin.
(10) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015.
(11) This now-classic reaction was originated simultaneously by three
research groups: (a) Rubottom, G. M.; Vazquez, M. A.; Pellagrina, D. R.
Tetrahedron Lett. 1974, 4319. (b) Hassner, A.; Reuss, R. H.; Pinnick, H. W.
J. Org. Chem. 1975, 40, 3427. (c) Brook, A. G.; Macrae, D. M. J. Organomet.
Chem. 1974, 77, C19.
Supporting Information Available: Experimental details, full char-
acterization data, and figure of the X-ray structure of a derivative of 16
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Taber, D. F.; Kanai, K. Tetrahedron 1998, 54, 11767.
(13) Cook, C. E.; Corley, R. C.; Wall, M. E. Tetrahedron Lett. 1965, 891.
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