Enantioselective Approaches to Potential
MetAP-2 Reversible Inhibitors
Vincent Rodeschini, Pierre Van de Weghe,
Emmanuel Salomon, Ce´line Tarnus, and
Jacques Eustache*
Laboratoire de Chimie Organique et Bioorganique associe´
au CNRS, Universite´ de Haute-Alsace, Ecole Nationale
Supe´rieure de Chimie de Mulhouse, 3, Rue Alfred Werner,
F-68093 Mulhouse Cedex, France
FIGURE 1. Some fumagillin analogues.
similar lines and would like to report our synthetic efforts
in this area. In particular we wish to describe a short
enantioselective synthesis of the trifluoromethyl ketone
3 (Figure 1) from simple prochiral precursors. The
trifluoromethyl group in 3 was expected to increase the
stability of the aminal assumed to be formed during the
interaction with the enzyme, thus leading to stronger
inhibition.3a Compound 3 also features a simplified side
chain as compared to TNP-470 and fumagalone, lacking
the double bond distal from the cyclohexyl ring, and the
9,10-epoxide (see Figure 1 for numbering). We have
previously shown that these modifications did not sig-
nificantly affect MetAP-2 inhibition in the case of ir-
reversible fumagillin analogues.4
Received December 3, 2004
In our initial approach (Schemes 1-3), we had envis-
aged introducing the C9-C16 side chain by conjugate
addition of an appropriate organometallic reagent to an
intermediate R,â-unsaturated trifluoromethyl ketone.
The latter, in turn, was to be prepared by a short
sequence involving palladium-catalyzed methoxycar-
bonylation of a vinyltriflate and trifluoromethylation of
the resulting R,â-unsaturated ester (or the corresponding
R,â-unsaturated aldehyde). Little data is available re-
garding the addition of carbon nucleophiles to simple R,â-
unsaturated trifluoromethyl ketones. Addition of meth-
ylmagnesium bromide on (E)-1,1,1-trifluoro-dodec-3-en-
2-one was reported to proceed in a 1,2 fashion (apparently
even in the presence of Cu(I) iodide).5 On the other hand,
addition of Grignard reagents to acyclic or alicyclic
â-alkoxy-R,â-unsaturated trifluoromethyl ketones or to
1,1,1-trifluoro-4-phenyl-but-3-en-2-one yielded products
of 1,4-addition.6 In our case we reasoned that the
increased bulk around the carbonyl group as compared
to acyclic, R-nonsubstituted, R,â-unsaturated trifluoro-
methyl ketones should favor 1,4-attack.
Enantioselective deprotonation of 4-substituted cyclohex-
anones and highly stereoselective conjugate addition of
higher order mixed cuprates were the key steps in a concise
synthesis of fumagalone-related molecules. The origin of the
(low) biological activity of the new compounds as compared
to fumagalone is briefly discussed.
Angiogenesis inhibitors based on the fumagillin struc-
ture, exemplified by TNP-470 (1, Figure 1), are generally
believed to exert their biological effects through irrevers-
ible inhibition of methionine aminopeptidase 2 (MetAP-
2).1,2 Althought TNP-470 has shown therapeutic benefits
in clinical studies, toxic side effects are a serious limiting
factor. It has been suggested that these unwanted side
effects may be partly linked to the irreversible character
of the inhibition and the presence of reactive groups in
the molecule. As a result, several types of MetAP-2
reversible inhibitors were recently prepared and shown
to have antiproliferative properties on endothelial cells
(EC).3 In particular, fumagalone (2, Figure 1), derived
from fumagillol by semi-synthesis, significantly inhibits
MetAP-2 and shows a very good antiproliferative activity
toward EC.3a
The requisite chiral vinyltriflate was prepared as
shown in Scheme 1. Asymmetric deprotonation of 4-tert-
(3) (a) Zhou, G.; Tsai, C. W.; Liu, J. O. J. Med. Chem. 2003, 46,
3452-3454. (b) Wang, J.; Sheppard, G. S.; Lou, P.; Kawai, M.;
BaMaung, N.; Erickson, S. A.; Tucker-Garcia, L.; Park, C.; Bouska,
J.; Wang, Y.-C.; Frost, D.; Tapang, P.; Albert, D. H.; Morgan, S. J.;
Morowitz, M.; Shusterman, S.; Maris, J. M.; Lesniewski, R.; Henkin,
J. Cancer Res. 2003, 63, 7861-7869. (c) Sendzik, M.; Janc, J. W.;
Cabuslay, R.; Honigberg, L.; Mackman, R. L.; Magill, C.; Squires, N.;
Waldeck, N. Bioorg. Med. Chem. Lett. 2004, 14, 3181-3184.
(4) Rodeschini, V.; Boiteau, J.-G.; Van de Weghe, P.; Tarnus, C.;
Eustache, J. J. Org. Chem. 2004, 69, 357-373.
As part of an ongoing program aimed at discovering
new MetAP-2 inhibitors, we have been working along
* To whom correspondence should be addressed. Tel: ++33 3 89
33 6858. Fax: ++33 3 89 33 6860.
(1) (a) Liu, S.; Widom, J.; Kemp, C. W.; Crews, C. M.; Clardy, J.
Science 1998, 282, 1324-1327. (b) Sin, N.; Meng, L.; Wang, M. Q. W.;
Wen, J. J.; Bornmann, W. G.; Crews, C. M. Proc. Natl. Acad. Sci.
U.S.A., 1997, 94, 6099-6103. (c) Griffith, E. C.; Su, Z.; Turk, B. E.;
Chen, S.; Chang, Y.; Wu, Z.; Biemann, K.; Liu, J. O. Chem. Biol. 1997,
4, 461-471.
(5) Ogawa, K.; Nagai, T.; Nomomura, M.; Takagi, T.; Koyama, M.;
Ando, A.; Miki, T.; Kumadaki, I. Chem. Pharm. Bull. 1991, 39, 1707-
1712.
(2) However, recent data suggest that MetAP-2 inhibition does not
necessarily correlate with antiangiogenic activity. Kim, S.; LaMon-
tagne, K.; Sabio, M.; Sharma, S.; Versace, R. W.; Yusuff, N.; Phillips,
P. E. Cancer Res. 2004, 64, 2984-2987.
(6) (a) Coles, S. J.; Mellor, J. M.; El-Sagheer, A. H.; E. E. E. Salem,
M.; Metwally, R. N. Tetrahedron 2000, 56 , 10057-10066. (b) Andrew,
R. J.; Mellor, J. M. Tetrahedron 2000, 56, 7261-7266.
10.1021/jo047858h CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/18/2005
J. Org. Chem. 2005, 70, 2409-2412
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