ORGANIC
LETTERS
2009
Vol. 11, No. 1
237-239
Two-Directional Olefinic-Ester
Ring-Closing Metathesis using Reduced
Ti Alkylidenes. A Rapid Entry into
Polycyclic Ether Skeletons
Yuan Zhang and Jon D. Rainier*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East,
Salt Lake City, Utah 84112
Received November 4, 2008
ABSTRACT
The use of a reduced titanium ethylidene reagent in an efficient two-directional approach to polycyclic ether skeletons is described.
Although the majority of the polycyclic ether containing
natural products of the brevetoxin/ciguatoxin class bind and
activate voltage-gated sodium channels (VGSCs),1,2 others
either inhibit the binding of known VGSC agonists and/or
do not bind to VGSCs at all.3 This apparently disparate
behavior has led many to propose that polycyclic ethers might
be interesting tools to study ion channels.4
development of improved synthetic approaches that enable
the rapid construction of polyether skeletons from simple
starting materials.6 Outlined in this manuscript is our attempt
to address this through the use of a reduced titanium reagent
to effect two-directional olefinic-ester cyclizations.
Holding back their use in the context mentioned above
are the relatively small quantities of polyether natural
products that have traditionally been isolated from natural
sources or that are generated from synthesis programs.5 In
our opinion, a solution to this problem will come from the
In studies that were driven by our polycyclic ether
natural product total synthesis program,7 we recently
discovered that titanium ethylidene reagents were capable
of inducing olefinic ester cyclization and diene ring closing
metathesis reactions (eq 1).8 When compared to reagents
(1) Catterall, W. A.; Ceste´le, S.; Yarov-Yarovoy, V.; Yu, F. H.; Konoki,
K.; Scheuer, T. Toxicon 2007, 49, 124
(2) Gawley, R. E.; Rein, K. S.; Jeglitsch, G.; Adams, D. J.; Theodorakis,
E. A.; Tiebes, J.; Nicolaou, K. C.; Baden, D. G. Chem. Biol. 1995, 2, 533
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.
(3) (a) Inoue, M.; Hirama, M.; Satake, M.; Sugiyama, K.; Yasumoto,
T. Toxicon 2003, 41, 469. (b) LePage, K. T.; Rainier, J. D.; Johnson,
H. W. B.; Baden, D. G.; Murray, T. F. J. Pharm. Exp. Ther. 2007, 323,
174. (c) Cuypers, E.; Abdel-Mottaleb, Y.; Kopljar, I.; Rainier, J. D.; Raes,
A. L.; Snyders, D. J.; Tytgat, J. Toxicon 2008, 51, 974.
(6) (a) Marmsater, F. P.; West, F. G. Chem. Eur. J. 2002, 8 (19), 4346.
(b) Sasaki, M. Top. Heterocycl. Chem. 2006, 5, 149. (c) Nakata, T. Chem.
ReV. 2005, 105, 4314.
(4) Torikai, K.; Oishi, T.; Ujihara, S.; Matsumori, N.; Konoki, K.;
Murata, M.; Aimoto, S. J. Am. Chem. Soc. 2008, 130, 10217.
(5) (a) A 1100 L fermentation of G. toxicus was needed to isolate 1.2
mg of gambiero. Satake, M.; Murata, M.; Yasumoto, T. J. Am. Chem. Soc.
1993, 115, 361. (b) A total of 1100 kg of eel was needed to isolate 1.3 mg
of ciguatoxin. Tachibana, K.; Nukina, M.; Joh, Y.-G.; Scheuer, P. J. Biol.
Bull. 1987, 172, 122. (c) Our 44 step synthesis of gambierol generated 7.5
mg (see ref 7).
(7) (a) Johnson, H. W. B.; Majumder, U.; Rainier, J. D. Chem. Eur. J.
2006, 12, 1747. (b) Majumder, U.; Cox, J. M.; Johnson, H. W. B.; Rainier,
J. D. Chem. Eur. J. 2006, 12, 1736. (c) Johnson, H. W. B.; Majumder, U.;
Rainier, J. D. J. Am. Chem. Soc. 2005, 127, 848.
(8) Iyer, K.; Rainier, J. D. J. Am. Chem. Soc. 2007, 129, 12604.
(9) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem.
1994, 59, 2668.
10.1021/ol8025439 CCC: $40.75
Published on Web 12/01/2008
2009 American Chemical Society