ORGANIC
LETTERS
2001
Vol. 3, No. 17
2749-2752
Stereoselective Syntheses of the
C′D′E′F′-Ring System of Maitotoxin and
the FG-Ring System of Gambierol
Yasuharu Sakamoto, Goh Matsuo, Hiroko Matsukura, and Tadashi Nakata*
RIKEN (The Institute of Physical and Chemical Research), Wako,
Saitama 351-0198, Japan
Received June 27, 2001
ABSTRACT
The stereoselective syntheses of the C′D′E′F′-ring system of maitotoxin and the FG-ring system of gambierol were accomplished. The key
steps involve 6-endo-cyclization of methylepoxide, SmI2-induced reductive cyclization, 6-endo-cyclization of vinylepoxide, and formation of the
lactone ring.
Maitotoxin (MTX), isolated from the dinoflagellate Gam-
bierdiscus toxicus, is the most toxic and largest natural
product (MW 3422) known to date except for biopolymers
such as proteins or polysaccharides.1 MTX has been impli-
cated in ciguatera food poisoning and is involved in Ca2+-
dependent mechanisms over a wide range of cell types.2 The
full structure and partial relative configuration of MTX were
elucidated by Yasumoto et al.,3and then the relative config-
uration of the remaining parts and the absolute configuration
were determined by the Tachibana4 and Kishi5 groups,
independently. The unusual molecular structure of MTX
contains 32 fused ether rings, 28 hydroxyl groups, 21 methyl
groups, 2 sulfate esters, and 98 chiral centers (Figure 1). The
skeletal novelty, complexity, and biological activity of
MTX have attracted the attention of chemists and biologists
alike.
We have already reported the stereoselective synthesis of
the ST- and XY-ring systems,6 which have 6,7-membered
bicyclic ethers, based on our developed ring-expansion
reaction.7 We have also developed the SmI2-induced reduc-
tive cyclization to synthesize the trans-fused ether ring
systems stereoselectively8 and have recently reported an
efficient strategy for the stereoselective syntheses of 6,6- and
6,7-membered ether ring systems 1 having an angular methyl
(4) (a) Sasaki, M.; Nonomura, T.; Murata, M.; Tachibana, K. Tetrahedron
Lett. 1994, 35, 5023. (b) Sasaki, M.; Nonomura, T.; Murata, M.; Tachibana,
K. Tetrahedron Lett. 1995, 36, 9007. (c) Sasaki, M.; Matsumori, N.; Murata,
M.; Tachibana, K. Tetrahedron Lett. 1995, 36, 9011. (d) Matsumori, N.;
Nonomura, T.; Sasaki, M.; Murata, M.; Tachibana, K.; Satake, M.;
Yasumoto, T. Tetrahedron Lett. 1996, 37, 1269. (e) Sasaki, M.; Matsumori,
N.; Maruyama, T.; Nonomura, T.; Murata, M.; Tachibana, K.; Yasumoto,
T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1672. (f) Nonomura, T.; Sasaki,
M.; Matsumori, N.; Murata, M.; Tachibana, K.; Yasumoto, T. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1675.
(5) (a) Zheng, W.; DeMattei, J. A.; Wu, J.-P.; Duan, J. J.-W.; Cook, L.
R.; Oinuma, H.; Kishi, Y. J. Am. Chem. Soc. 1996, 118, 7946. (b) Cook,
L. R.; Oinuma, H.; Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1997,
119, 7928.
(6) (a) Nagasawa, K.; Hori, N.; Shiba, R.; Nakata, T. Heterocycles 1997,
44, 105. (b) Nakata, T.; Nomura, S.; Matsukura, H. Chem. Pharm. Bull.
1996, 44, 627.
(7) (a) Hori, N.; Nagasawa, K.; Shimizu, T.; Nakata, T. Tetrahedron
Lett. 1999, 40, 2145. (b) Nakata, T.; Nomura, S.; Matsukura, H. Tetrahedron
Lett. 1996, 37, 213.
(8) (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron
Lett. 1999, 40, 2811. (b) Hori, N.; Matsukura, H.; Nakata, T. Org. Lett.
1999, 1, 1099.
(1) Yokoyama, A.; Murata, M.; Oshima, Y.; Iwashita, T.; Yasumoto, T.
J. Biochem. 1988, 104, 184.
(2) (a) Takahashi, M.; Ohizumi, Y.; Yasumoto, T. J. Biol. Chem. 1982,
257, 7287. (b) Gusovsky, F.; Daly, J. W. Biochem. Pharmacol. 1990, 39,
1633.
(3) (a) Murata, M.; Iwashita, T.; Yokoyama, A.; Sasaki, M.; Yasumoto,
T. J. Am. Chem. Soc. 1992, 114, 6594. (b) Murata, M.; Naoki, H.; Iwashita,
T.; Matsunaga, S.; Sasaki, M.; Yokoyama, A.; Yasumoto, T. J. Am. Chem.
Soc. 1993, 115, 2060. (c) Murata, M.; Naoki, H.; Matsunaga, S.; Satake,
M.; Yasumoto, T. J. Am. Chem. Soc. 1994, 116, 7098. (d) Satake, M.; Ishida,
S.; Yasumoto, T.; Murata, M.; Utsumi, H.; Hinomoto, T. J. Am. Chem.
Soc. 1995, 117, 7019.
10.1021/ol016355k CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/21/2001