While demonstrating attractive anticancer properties, the
development of these marine-derived natural products as
potential therapeutics remains in its infancy due primarily
to their low natural abundance. Here, we describe our
initial foray into the chemistry of PTX-2 that has culmi-
nated in a convergent entry to the CDEF tetracyclic
heterocycle.
Scheme 1. Synthetic Strategy for a Model CDEF-Tetracycle
To prioritize our efforts directed toward a chemical
synthesis of PTX-2, we began with an analysis of its com-
plex with G-actin (Figure 1B) and the limited structureÀ
activity relationships established for the pectenotoxin
family.4 In short, the C- and H-rings play important roles
in binding, while the AB spiroketal appears to serve as a
scaffolding element to ensure proper orientation of these
subunits. Not surprisingly, this role is significantly affected
by the C7 stereochemistry, with the C7(R) isomers demon-
strating markedly enhanced activities.5 The oxidation state
of C43 also plays an important role in modulating the
cytotoxicity of the pectenotoxins; apparently, there exists
insufficient molecular features on G-actin to accommo-
date higher oxidation states at C43.5 In sum, these struc-
tural studies provide insight into the roles that each region
of the natural product play in binding to G-actin: The AB-
ring system and the 1,3-diene appear to play scaffolding
roles to properly orient the CDEF- and GH-subunits for
binding. Because of the central role that the CDEF-tetra-
cycle plays and its presence inall known pectenotoxins, our
initial chemical studies focused on this subunit.6,7
As highlighted in Scheme 1, the CDEF tetracyclic region
of PTX-2 (1) is quite complex and is composed of stereo-
chemically distinct tetrahydrofurans, a central bridged
bicyclic acetal, and three tertiary ethers. To date, a variety
of approaches to this system have been reported that
embrace chemistry spanning hydrazone alkylation, car-
bonyl addition, Julia olefination, and aldol chemistry.
Additionally, a strategy reported by Roush targeted con-
vergent assembly of this subunit via annulation of the
C- and F-rings about a central DE-ring precursor.7a
We opted to pursue a strategy to tetracycle 2 that was
distinct from these previously described approaches, em-
bracing metal-mediated site-selective and stereoselective
coupling of a suitably functionalized TMS-alkyne 3 with
a tricyclic aldehyde 4. Overall, reductive cross-coupling
followed by stereoselective epoxidation and acid-catalyzed
ring closure was targeted as a general convergent annula-
tion strategy for union of a functionalized DEF-tricycle
with the “northern” C1ÀC14 subunit. The requisite cou-
pling partner 4 was then reasoned to be accessible by
oxidative functionalization of 5, itself derived from a
head-to-tail dimerization of commercially available lina-
lool in a fashion to forge the C20ÀC21 bond.
(4) (a) Allingham, J. S.; Miles, C. O.; Rayment, I. J. Mol. Bio. 2007,
371, 959–970. (b) Allingham, J. S.; Klenchin, V. A.; Rayment, I. Cell.
Mol. Life Sci. 2006, 63, 2119–2134. (c) Espina, B.; Rubiolo, J. A. FEBS
2008, 275, 6082–6088.
(5) (a) Espina, B.; Louzao, M. C.; Ares, I. R.; Fonfrıa, E. W.;
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M. R.; Miles, C. O.; Yasumoto, T.; Botana, L. Cell. Physiol. Biochem.
2007, 19, 283–292. (c) See also ref 4a.
(6) For total syntheses of PTX-4 and PTX-8, see: (a) Evans, D. A.;
Rajapakse, H. A. Angew. Chem., Int. Ed. 2002, 41, 4569–4573. (b) Evans,
D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41,
4573–4576.
(7) For partial synthesis, and studies toward the syntheses of the
pectenotoxins, see: (a) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3,
1949–1952. (b) Paquette, L. A.; Peng, X.; Bondar, D. Org. Lett. 2002, 4,
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€
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a simple sequence of robust functional group manipula-
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