A R T I C L E S
Vanderwal et al.
The fascinating structure and biological activity of FR182877,
as well as the intriguing reactivity of its strained olefin, would
generally prove sufficient to motivate synthetic studies toward
this natural product. However, we were further inspired to
undertake chemical studies on FR182877 when we pondered
its structural origin. We sought to answer the following
question: Can the unique architecture of FR182877 arise
spontaneously from a polyunsaturated precursor by a cascade
of cyclizations?
Figure 1. Initially reported structure for FR182877 [(+)-1] and the natural
enantiomer [(-)-1].
lines.6b Promising preliminary in vivo results in mouse models6b
indicate that this natural product has potential as a chemothera-
peutic agent or as a lead compound.
Taken together, these attributes have led to considerable
interest in FR182877 as an objective for research in organic
synthesis. Studies toward this target have been reported by our
laboratory,7 Armstrong,8 Clarke9 and Nakada.10 Our recent
preliminary communication11 describing the first synthesis of
(+)-FR182877 was followed shortly after by a report from
Evans and Starr describing a synthesis of the natural enantiomer
through a closely related approach.12
FR182877 was isolated from the fermentation broth of
Streptomyces sp. No9885. Its constitution and relative stereo-
chemistry were elucidated via a combination of NMR and X-ray
crystallographic methods, and its absolute stereochemistry was
proposed to be as shown for (+)-1 (Figure 1) based upon
advanced Mosher ester analysis.6d A recent revision of its
absolute stereochemistry by the Fujisawa scientists corroborated
our discovery that the initial assignment was incorrect.11-14
The strained bridgehead olefin, which is implicated in
FR182877’s biological activity (see below), is particularly
reactive. This moiety undergoes smooth conjugate additions with
primary or secondary amines under neutral conditions, and with
alcohols under basic conditions.15 The olefin of this vinylogous
carbonate is also highly susceptible to oxidation by molecular
oxygen.6d Interestingly, the resulting epoxide lacks microtubule-
stabilizing activity, suggesting that the strained olefin of
FR182877 could be a site of reactivity if covalent processes
are involved in its mechanism of action.
FR182877 is a member of a growing family of secondary
metabolites that bind and stabilize cellular microtubules. Other
members of this important family of natural products include
Taxol, the epothilones, discodermolide, the sarcodictyins and
eleutherobin, and laulimalide.16 That this novel compound shows
microtubule-stabilizing activity on the same order of magni-
tude as Taxol suggests that it may prove clinically useful, or
could serve as a lead for the development of new anticancer
therapeutics.
Results and Discussion
1. A Synthetic Approach Based upon Biosynthetic Con-
siderations. Our consideration of the structural origin of
FR182877 led to a general hypothesis in which the complex
hexacycle might derive from a linear, polyunsaturated compound
via a macrocyclization event and two cycloaddition reactions
in either of two possible orders. As depicted in Scheme 1,
tetraenal 2 could undergo a sequence of type I intramolecular
Diels-Alder reaction17,18 to afford 3, a Knoevenagel19 macro-
cyclization to afford the 12-membered ring of 4, and subsequent
transannular hetero Diels-Alder20,21 cycloaddition of the electron-
poor enone 4-π system with the trisubstituted olefin to afford
FR182877 after lactonization.22 An alternative ordering of events
would entail an intramolecular condensation of 2 to afford the
polyunsaturated 19-membered ring 6, followed by two transan-
nular Diels-Alder reactions:23,24 the first a carbocyclic cycload-
dition, succeeded by the same hetero Diels-Alder reaction
shown in the first sequence.
(16) (a) For a recent proposal of a common pharmacophore that unites paclitaxel,
the epothilones, eleutherobin, discodermolide, and a paclitaxel analogue,
see: Ojima, I.; Chakravarty, S.; Inoue, T.; Lin, S.; He, L.; Horwitz, S. B.;
Kuduk, S. D.; Danishefsky, S. J. Proc. Natl. Acad. Sci. U.S.A. 1999, 96,
4256-4261. (b) For a recent review focusing on solution and tubulin-bound
conformations of small-molecule microtubule-stabilizing compounds, see:
Jime´nez-Barbero, J.; Amat-Guerri, F.; Snyder, J. P. Curr. Med. Chem.:
Anti-Cancer Agents, 2002, 2, 91-122.
(17) For reviews of the intramolecular Diels-Alder reaction, see: (a) Oppolzer,
W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10-23. (b) Brieger, G.; Bennett,
J. N. Chem. ReV. 1980, 80, 63-97. (c) Fallis, A. G. Can. J. Chem. 1984,
62, 183-234. (d) Ciganek, E. Org. React. 1984, 32, 1-374. (e) Taber, D.
F. Intramolecular Diels-Alder and Alder Ene Reactions; Springer-Verlag:
Berlin, 1984. (f) Craig, D. Chem. Soc. ReV. 1987, 16, 187-238. (g) Roush,
W. R. In AdVances in Cycloaddition; Curran, D. P. Ed.; JAI Press:
Greenwich, Connecticut, 1990; Vol. 2, pp 91-146. (h) Roush, W. R. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 5, pp 513-550.
(18) For studies of the intramolecular Diels-Alder reaction to yield hydrindene
structures, see: (a) Roush, W. R. J. Org. Chem. 1979, 44, 4008-4010. (b)
Roush, W. R.; Ko, A. I.; Gillis, H. R. J. Org. Chem. 1980, 45, 4264-
4267. (c) Roush, W. R.; Gillis, H. R. J. Org. Chem. 1980, 45, 4267-4268.
(d) Roush, W. R.; Gillis, H. R.; Ko, A. I. J. Am. Chem. Soc. 1982, 104,
2269-2283. (e) Roush, W. R.; Essenfeld, A. P.; Warmus, J. S. Tetrahedron
Lett. 1987, 28, 2447-2450.
(19) For reviews of the Knoevenagel reaction, see: (a) Jones, G. Org. React.
1967, 15, 204-599. (b) Tietze, L. F.; Beifuss, U. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 2, pp 341-394.
(20) For excellent discussions of inverse electron demand and hetero Diels-
Alder reactions, see: (a) Boger, D. L. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 5,
pp 451-512. (b) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder
Methodology In Organic Synthesis; Academic Press: San Diego, 1987.
(c) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1-120. (d)
Tietze, L. F.; Kettschau, G.; Gewert, J. A.; Schuffenhauer, A. Curr. Org.
Chem. 1998, 2, 19-62.
(21) For reviews of the tandem Knoevenagel-hetero Diels-Alder reaction, see:
(a) Tietze, L. F. In SelectiVity, A Goal for Synthetic Efficiency, Proceedings
of the 14th Workshop Conference, Hoechst, Schloss Reisensburg, 18-22
September 1983; Bartmann, W., Trost, B. M., Eds.; Verlag Chemie:
Weinheim, 1984; pp 299-316. (b) Tietze, L. F. J. Heterocycl. Chem. 1990,
27, 47-69. (c) Tietze, L. F. Chem. ReV. 1996, 96, 115-136. (d) Tietze, L.
F.; Modi, A. Med. Res. ReV. 2000, 20, 304-322.
(22) Although in Scheme 1 we suggest that lactonization might be the final
step in the proposed biogenetic sequences, there is no reason that the lactone
could not be in place before the series of cyclizations (2 could be in the
â-keto-δ-lactone form prior to the condensation and cycloaddition steps).
(7) (a) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. Org.
Lett. 1999, 1, 645-648. (b) Vanderwal, C. D.; Vosburg, D. A.; Sorensen,
E. J. Org. Lett. 2001, 3, 4307-4310.
(8) Armstrong, A.; Goldberg, F. W.; Sandham, D. A. Tetrahedron Lett. 2001,
42, 4585-4587.
(9) Clarke, P. A.; Davie, R. L.; Peace, S. Tetrahedron Lett. 2002, 43, 2753-
2756.
(10) Suzuki, T.; Nakada, M. Tetrahedron Lett. 2002, 43, 3263-3267.
(11) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem. Soc. 2002,
124, 4552-4553.
(12) Evans, D. A.; Starr, J. T. Angew. Chem., Int. Ed. 2002, 41, 1787-1790.
(13) Yoshimura, S.; Sato, B.; Kinoshita, T.; Takase, S.; Terano, H. J. Antibiot.
2002, 55, C1.
(14) Our synthetic work was initially directed toward the originally disclosed
stereostructure (+)-1, and as such, most depictions of the natural product
and synthetic intermediates in this work are of this enantiomeric series.
(15) Dr. Seiji Yoshimura, Fujisawa Pharmaceutical Company, personal com-
munication.
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