(+)-2. Interestingly, based on work by Ding and Jennings,
synthetic (-)-2 appears to be slightly more active than natural
(+)-2 (although a direct comparison is available only for a
single cell line).4 More recently, (-)-1 was also isolated from
the Togan sponge Cacospongia mycofijiensis by Northcote
and co-workers, who demonstrated the compound to be an
efficient promotor of tubulin assembly.5 This suggests that
(-)-1 inhibits cancer cell growth through the same mecha-
nism of action as Taxol or epothilones.6
lective epoxide opening with lithiated vinyl iodide 9. The
latter was to be obtained by Prins-type reaction of alkyne
10 to deliver a 4-iodotetrahydropyran derivative; the iodo
substituent would then be elaborated into the desired meth-
ylene group. Finally, 10 would be derived from epoxide 11
which, in turn, is accessible from (R)-aspartic acid.12 Acid
6 was envisaged to be accessed from a protected Z-vinyl
iodide via reaction with epichlorohydrin followed by conver-
sion of the resulting chlorohydrin to a new oxirane, epoxide
opening with lithiated diethylphosphite, and finally, HWE
reaction and ester hydrolysis.
While a number of stereoselective syntheses of (-)-17 and
(+)-28 have appeared in the literature, little work has been
reported on analogue structures and their biological activity.9
It also remains to be shown whether (-)-2 or (+)-2, like
(-)-1, may promote tubulin polymerization and stabilize
microtubules. Intrigued by the divergent stereochemistry of
natural (-)-1 and (+)-2 and in light of the distinct lack of
SAR data for these structures, we had initiated a program
on the synthesis of natural (-)-1 and (+)-2, their non-natural
counterparts (+)-1 and (-)-2, and analogue structures for
SAR studies, even before the recent discovery of the tubulin-
polymerizing activity of (-)-1. In this paper, we now report
on a new synthesis of (-)-210 and of dactylolide analogues
3-5 (Figure 1), all of which were found to have similar
antiproliferative activity and to induce tubulin polymerization
in vitro.
Scheme 2. Synthesis of Vinyl Iodide 9
Scheme 1. Retrosynthetic Analysis for (-)-2
The synthesis of vinyl iodide 9 started with the Cu-
mediated regioselective epoxide opening of 11 (available
from (R)-aspartic acid in three steps in 78% overall yield)12
with vinyl-MgBr in excellent yield (98%; Scheme 2).
Compound 12 was then elaborated into tetrahydropyran 13
(3) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc.
2002, 124, 11102.
(4) Ding, F.; Jennings, M. P. J. Org. Chem. 2008, 73, 5965.
(5) Field, J. J.; Singh, A. J.; Kanakkanthara, A.; Halafihi, T.; Northcote,
P. T.; Miller, J. H. J. Med. Chem. 2009, 52, 7328.
(6) For a review on microtubule-stabilizing natural products, see:
Altmann, K.-H.; Gertsch, J. Nat. Prod. Rep. 2007, 24, 327.
(7) (a) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem.
Soc. 2001, 123, 12426. (b) Smith, A. B., III; Safonov, I. G.; Corbett, R. M.
J. Am. Chem. Soc. 2002, 124, 11102. (c) Hoye, T. R.; Hu, M. J. Am. Chem.
Soc. 2003, 125, 9576. (d) Uenishi, J.; Iwamoto, T.; Tanaka, J. Org. Lett.
2009, 11, 3262. Studies toward (-)-1: (e) Loh, T.-P.; Yang, J.-Y.; Feng,
L.-C.; Zhou, Y. Tetrahedron Lett. 2002, 43, 7193. (f) Troast, D. M.; Porco,
J. A., Jr. Org. Lett. 2002, 4, 991. (g) Troast, D. M.; Yuan, J.; Porco, J. A.,
Jr. AdV. Synth. Catal. 2008, 350, 1701.
Our retrosynthesis for (-)-2 is outlined in Scheme 1 and
is centered around an intramolecular HWE reaction for the
closure of the 20-membered macrolide ring. The requisite
ꢀ-keto phosphonate/aldehyde percursor would be obtained
via esterification of acid 6 and alcohol 7, followed by silyl
ether cleavage and oxidation. While HWE-based macrocy-
clizations involving the formation of the CdC double bond
in R,ꢀ-unsaturated ketone units are well precedented in
natural product synthesis, they have not been used exten-
sively;11 in particular, and quite surprisingly, this strategy
has not been employed in the context of zampanolide or
dactylolide syntheses. Alcohol 7 was envisioned to be
accessible from protected (R)-glycidol 8 through regiose-
(8) (a) Smith, A. B., III; Safonov, I. G. Org. Lett. 2002, 4, 635. (b)
Aubele, D. L.; Wan, S. Y.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005,
44, 3485. (c) Sanchez, C. C.; Keck, G. E. Org. Lett. 2005, 7, 3053.
(9) A notable exception is the work by Uenishi et al. (ref 7d), who have
shown the C20 epimer of (-)-1 to be ca. 10-fold less active than (-)-1.
(10) For previous syntheses of (-)-2, see: (a) Louis, I.; Hungerford,
N. L.; Humphries, E. J.; McLeod, M. D. Org. Lett. 2006, 8, 1117. (b)
Reference 4.
(11) For examples, see: (a) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.
J. Am. Chem. Soc. 1982, 104, 2030. (b) Paterson, I.; Yeung, K.-S.
Tetrahedron Lett. 1993, 34, 5347. (c) Paterson, I.; Yeung, K.-S.; Watson,
C.; Ward, R. A.; Wallace, P. A. Tetrahedron 1998, 54, 11935. (d) Kadota,
I.; Hu, Y.; Packard, G. K.; Rychnovsky, S. D. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 11192. (e) Berger, G. O.; Tius, M. A. J. Org. Chem. 2007, 72,
6473.
(12) Frick, J. A.; Klassen, J. B.; Bathe, A.; Abramson, J. M.; Rapoport,
H. Synthesis 1992, 621.
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