10942
J. Am. Chem. Soc. 2001, 123, 10942-10953
Total Synthesis of (+)-Phorboxazole A Exploiting the Petasis-Ferrier
Rearrangement
Amos B. Smith, III,* Kevin P. Minbiole, Patrick R. Verhoest, and Michael Schelhaas
Contribution from the Department of Chemistry, Monell Chemical Senses Center, and Laboratory for
Research on the Structure of Matter, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
ReceiVed June 29, 2001
Abstract: A highly convergent, stereocontrolled total synthesis of the potent antiproliferative agent (+)-
phorboxazole A (1) has been achieved. Highlights of the synthesis include: modified Petasis-Ferrier
rearrangements for assembly of both the C(11-15) and C(22-26) cis-tetrahydropyran rings; extension of the
Julia olefination to the synthesis of enol ethers; the design, synthesis, and application of a novel bifunctional
oxazole linchpin; and Stille coupling of a C(28) trimethyl stannane with a C(29) oxazole triflate. The longest
linear sequence leading to (+)-phorboxazole A (1) was 27 steps, with an overall yield of 3%.
Marine sponges comprise a rich source of architecturally
the phorboxazoles to the level of premier medicinal targets.
Bioassays against the National Cancer Institute panel of 60
human solid tumor cell lines revealed extraordinary activity
against the entire panel;2 the mean GI50 value was 1.58 × 10-9
M for both 1 and 2.3a Some cell lines were completely inhibited
at the lowest level tested.2 Particularly noteworthy, phorboxazole
A (1) inhibited the human colon tumor cell line HCT-116 and
the breast cancer cell line MCF7 with GI50 values of 4.36 ×
10-10 M and 5.62 × 10-10 M, respectively. These data place
the phorboxazoles in the company of the spongistatins,1a
collectively the most potent cytostatic agents discovered to date.
Although the precise biochemical mode of action remains
undefined, (+)-phorboxazole A (1) is known to arrest the cell
cycle in S phase but does not inhibit tubulin polymerization or
interfere with the integrity of microtubules. Unfortunately,
further biological analysis is not possible, because access to the
producing sponge is currently restricted.4 Thus, the phorboxa-
zoles will be only available via total synthesis. Not surprisingly,
the novel architecture combined with the impressive bioactivity
has attracted wide attention in the synthetic community,5
including our own interest.6 In 1998, Forsyth and co-workers4
published the first total synthesis of (+)-phorboxazole A (1);
shortly thereafter, Evans and Fitch reported completion of (+)-
complex, biomedically important natural products; examples
include the spongistatins, discodermolide, and the tedanolides.1
Despite the structural complexity, the scarcity of these molecules
in conjunction with their medicinal importance continues to
prompt intense synthetic campaigns. During a recent search for
novel marine antifungals, Searle and Molinski2 identified a
methanolic extract from the sponge Phorbas sp. which displayed
significant activity against Candida albicans. Bioassay-guided
extraction, flash chromatography, and subsequent reverse-phase
HPLC afforded two isomeric macrolides termed (+)-phorboxa-
zoles A (1) and B (2). The structures of the phorboxazoles,
including relative and absolute stereochemistry, were determined
via a combination of NMR analyses, degradation studies, and
synthetic correlations.3
(4) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc.
1998, 120, 5597.
(5) (a) Lee, C. S.; Forsyth, C. J. Tetrahedron Lett. 1996, 37, 6449. (b)
Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1997, 62, 5672. (c) Ahmed, F.;
Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183. (d) Ye, T.; Pattenden, G.
Tetrahedron Lett. 1998, 39, 319. (e) Pattenden, G.; Plowright, A. T.; Tornos,
J. A.; Ye, T. Tetrahedron Lett. 1998, 39, 6099. (f) Paterson, I.; Arnott, E.
A. Tetrahedron Lett. 1998, 39, 7185. (g) Wolbers, P.; Hoffmann, H. M. R.
Tetrahedron 1999, 55, 1905. (h) Misske, A. M.; Hoffmann, H. M. R.
Tetrahedron 1999, 55, 4315. (i) Williams, D. R.; Clark, M. P.; Berliner,
M. A. Tetrahedron Lett. 1999, 40, 2287. (j) Williams, D. R.; Clark, M. P.
Tetrahedron Lett. 1999, 40, 2291. (k) Wolbers, P.; Hoffmann, H. M. R.
Synthesis 1999, 797. (l) Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago,
K. J. Org. Lett. 1999, 1, 87. (m) Wolbers, P.; Misske, A. M.; Hoffmann,
H. M. R. Tetrahedron Lett. 1999, 40, 4527. (n) Wolbers, P.; Hoffmann, H.
M. R.; Sasse, F. Synlett 1999, 11, 1808. (o) Pattenden, G.; Plowright, A. T.
Tetrahedron Lett. 2000, 41, 983. (p) Schaus, J. V.; Panek, J. S. Org. Lett.
2000, 2, 469. (q) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2,
1217. (r) Williams, D. R.; Clark, M. P.; Emde, U.; Berliner, M. A. Org.
Lett. 2000, 2, 3023. (s) Greer, P. B.; Donaldson, W. A. Tetrahedron Lett.
2000, 41, 3801. (t) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.;
Cho, P. S. Angew. Chem., Int. Ed. 2000, 39, 2533. (u) Huang, H.; Panek,
J. S. Org. Lett. 2001, 3, 1693.
The bioactivity profile of the phorboxazoles proved excep-
tional. In addition to the antifungal activity, the phorboxazoles
displayed antibiotic activity against saccharomyces carlsber-
ensis. However, it was the antiproliferative activity that elevated
(1) (a) Spongistatin: Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C.
L.; Boyd, M. R.; Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem. 1993, 58,
1302. (b) Discodermolide: Gunasekera, S. P.; Gunasekera, M.; Longley,
R. E.; Schulte, G. K. J. Org. Chem. 1990, 55, 4912. Correction: Gunasekera,
S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K. J. Org. Chem. 1991,
56, 1346. (c) Tedanolide: Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili,
G.; Hossain, M. B.; van der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251.
(2) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
(3) (a) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J.
Am. Chem. Soc. 1996, 118, 9422. (b) Molinski, T. F. Tetrahedron Lett.
1996, 37, 7879.
10.1021/ja011604l CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/13/2001