recently reported, as our initial effort toward this goal, the
synthesis of 11-desmethyllaulimalide8g (2, Figure 1).
Thus far, our efforts to define the pharmacophoric features
of laulimalide that influence its activity have focused on
modifications of the core macrocycle. However, little is
known about the role of the dihydropyran side chain
incorporating C23-C27 because so few analogues at this
position exist.8f This subunit could contribute to the activity
of laulimalide, but if not, variation of this unit could be used
to modulate the pharmacokinetics and ADME of promising
analogues. We sought to determine whether this ring could
be replaced with a simpler moiety that would be beneficial
with regard to both synthetic step count and biological
activity. The ideal strategy for rapidly synthesizing numerous
analogues at this position is to use a mild and selective
reaction at a late stage in the synthesis that would draw on
commercially available or easily prepared starting materials
for structural variety. Such a reaction is the olefin cross
metathesis process,11,12 which would simply require an
advanced laulimalide-like intermediate such as the C21-
C22 alkene 4 and a partner alkene bearing the desired
structural features of the new side chain (Scheme 1). We
Figure 1. Laulimalide, selected analogues, and their potencies for
inhibition of cancer cell proliferation.
Despite this unique therapeutic potential, laulimalide’s
scarce natural availability and instability are major obstacles
to its clinical development. The first steps toward addressing
these problems appeared in the form of several total syntheses
of laulimalide.7 Following this, the syntheses of various
nonnatural analogues have appeared in the literature.8 We
have previously reported a uniquely short synthesis of
laulimalide that provided the basis for accessing a first series
of analogues. These analogues were designed to avoid the
acid-catalyzed decomposition of laulimalide that leads to
isolaulimalide, a less active compound.8b The most potent
analogues, LA1 and LA2 (Figure 1), are more stable than
laulimalide and retain its mode of action.9 Significantly, they
act synergystically with both paclitaxel and 2-methoxyestra-
diol to a greater degree than laulimalide itself.10 More
recently, we have focused on the identification of structurally
simplified analogues that could be synthesized in a more step-
economical and cost-efficient manner yet retain the potency
and mode of action of the parent compound. We have
Scheme 1. Retrosynthesis of Laulimalide Side Chain
Analogues
(6) Trojanowski, J. Q.; Smith, A. B.; Huryn, D.; Lee, V. M.-Y. Expert
Opin. Pharmacother. 2005, 6, 683.
(7) (a) Ghosh, A. K.; Wang, Y. J. Am. Chem. Soc. 2000, 122, 11027.
(b) Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66, 8973. (c)
Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3, 213. (d) Paterson,
I.; DeSavi, C.; Tudge, M. Org. Lett. 2001, 3, 3149. (e) Mulzer, J.; O¨ hler,
E. Angew. Chem., Int. Ed. 2001, 40, 3843. (f) Evev, V. S.; Kaehlig, H.;
Mulzer, J. J. Am. Chem. Soc. 2001, 123, 10764. (g) Crimmins, M. T.;
Stanton, M. G.; Allwein, S. P. J. Am. Chem. Soc. 2002, 124, 13654. (h)
Williams, D. R.; Mi, L.; Mullins, R. J.; Stites, R. E. Tetrahedron Lett. 2002,
43, 4841. (i) Wender, P. A.; Hegde, S. G.; Hubbard, R. D.; Zhang, L. J.
Am. Chem. Soc. 2002, 124, 4956. (j) Nelson, S. G.; Chueng, W. S.; Kassick,
A. J.; Hilfiker, M. A. J. Am. Chem. Soc. 2002, 124, 13654. (k) Uenishi, J.;
Ohmi, M. Angew. Chem., Int. Ed. 2005, 44, 2756.
(8) (a) Ahmed, A.; Hoegenauer, K.; Enev, V. S.; Hanbauer, M.; Kaehlig,
H.; O¨ hler, E.; Mulzer, J. J. Org. Chem. 2003, 68, 3026. (b) Wender, P. A.;
Hegde, S. G.; Hubbard, R. D.; Zhang, L.; Mooberry, S. L. Org. Lett. 2003,
5, 3507. (c) Gallagher, B. M., Jr.; Fang, F. G.; Johannes, C. W.; Pesant,
M.; Tremblay, M. R.; Zhao, H.; Akasaka, K.; Li, X.-Y.; Liu, J.; Littlefield,
B. A. Bioorg. Med. Chem. Lett. 2004, 14, 575. (d) Paterson, I.; Bergmann,
H.; Menche, D.; Berkessel, A. Org. Lett. 2004, 6, 1293; 2006, 8, 1511
(erratum). (e) Gallagher, B. M., Jr.; Zhao, H.; Pesant, M.; Fang, F. G.
Tetrahedron Lett. 2005, 46, 923. (f) Paterson, I.; Menche, D.; Håkansson,
A. E.; Longstaff, A.; Wong, D.; Barasoain, I.; Bury, R. M.; D´ıaz, J. F.
Bioorg. Med. Chem. Lett. 2005, 15, 2243. (g) Wender, P. A.; Hilinski, M.
K.; Soldermann, N.; Mooberry, S. L. Org. Lett. 2006, 8, 1507.
(9) Mooberry, S. L.; Randall-Hlubek, D. A.; Leal, R. M.; Hegde, S. G.;
Hubbard, R. D.; Zhang, L.; Wender, P. A. P. Natl. Acad. Sci. U.S.A. 2004,
101, 8803.
envisioned that such a reaction could be accomplished
selectively at the C21 terminal alkene even in the presence
of numerous other sites of unsaturation in the molecule.
Although the synthesis of 4 would require a completely
revised synthetic route, the opportunity to improve and
generalize our earlier route and to access numerous analogues
through late-stage diversification provided compelling jus-
tification for embarking on this effort. Drawing conceptually
from our total syntheses of 1 and 2, we expected that 4 would
be convergently accessible from the less complex fragments
5 and 6 (Scheme 1). We provide herein the first report on
this strategy for the synthesis of laulimalide side chain
analogues.
(11) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J Am.
Chem. Soc. 2003, 125, 11360.
(10) Clark, E. A.; Hills, P. M.; Davidson, B. S.; Wender, P. A.; Mooberry,
S. L. Mol. Pharm. 2006, 3, 457.
(12) For cross metathesis in the amphidinolide series, see: Ghosh, A.
K.; Gong, G. J. Am. Chem. Soc. 2004, 126, 3704.
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Org. Lett., Vol. 8, No. 18, 2006