ORGANIC
LETTERS
2008
Vol. 10, No. 22
5203-5206
Combinatorial Synthesis of the
1,5-Polyol System Based on Cross
Metathesis: Structure Revision of
Amphidinol 3
Tohru Oishi,* Mitsunori Kanemoto, Respati Swasono, Nobuaki Matsumori, and
Michio Murata*
Department of Chemistry, Graduate School of Science, Osaka UniVersity,
1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
oishi@chem.sci.osaka-u.ac.jp; murata@ch.wani.osaka-u.ac.jp
Received September 17, 2008
ABSTRACT
Combinatorial synthesis of a 1,5-polyol system corresponding to the C1-C14 unit of amphidinol 3 (AM3) and its diastereomers was achieved
via chemoselective cross metathesis as the key step. Comparison of 13C NMR data of the synthetic specimens with that of AM3 led to a
controversy regarding the originally proposed structure. From GC-MS analysis of the degradation product, the absolute configuration at C2
of AM3 has been revised to be R.
Marine dinoflagellates are a rich source of biologically and
structurally unique secondary metabolites.1 Amphidinols
(AMs) were isolated from the dinoflagellate Amphidinium
klebsii, which elicit potent antifungal and hemolytic activity.2
The biological activities can be accounted for by the
formation of ion-permeable pores in a sterol-dependent
manner.3 AMs comprise a hydrophobic polyene unit and a
hydrophilic part containing acyclic polyol and substituted
tetrahydropyran rings, in which structural diversity is mainly
focused on the polyol unit. Amphidinol 3 (AM3, 1, Figure
1) is the most potent antifungal among the AMs, and the
absolute configuration was elucidated by extensive NMR
analysis based on the JBCA method,4 modified Mosher
method,5 and HPLC analysis of the degradation products.6
The striking structural feature of AM3 has attracted consider-
able attention from the synthetic community, and a number
of synthetic studies have been reported by the Cossy,7
Roush,8 Rychnovsky,9 Paquette,10 and Marko´11 groups.
During the course of our mode-of-action studies of AMs,12
it was revealed that the structural difference of the polyol
domain and the terminal olefin moiety modulate the potency
(1) (a) Shimizu, Y. Chem. ReV. 1993, 93, 1685–1698. (b) Yasumoto,
T.; Murata, M. Chem. ReV. 1993, 93, 1897–1909.
(4) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana,
K. J. Org. Chem. 1999, 64, 866–876.
(2) Amphidinols: (a) Satake, M.; Murata, M.; Yasumoto, T.; Fujita, T.;
Naoki, H. J. Am. Chem. Soc. 1991, 113, 9859–9861. (b) Paul, G. K.;
Matsumori, N.; Murata, M.; Tachibana, K. Tetrahedron Lett. 1995, 36,
6279–6282. (c) Morsy, N.; Matsuoka, S.; Houdai, T.; Matsumori, N.;
Adachi, S.; Murata, M.; Iwashita, T.; Fujita, T. Tetrahedron 2005, 61, 8606–
8610. (d) Echigoya, R.; Rhodes, L.; Oshima, Y.; Satake, M. Harmful Algae
2005, 4, 383–389. (e) Morsy, N.; Houdai, T.; Matsuoka, S.; Matsumori,
N.; Adachi, S.; Oishi, T.; Murata, M.; Iwashita, T.; Fujita, T. Bioorg. Med.
Chem. 2006, 14, 6548–6554.
(5) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
(6) Murata, M.; Matsuoka, S.; Matsumori, N.; Paul, G. K.; Tachibana,
K. J. Am. Chem. Soc. 1999, 121, 870–871.
(7) (a) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451–1454. (b) Cossy,
J.; Tsuchiya, T.; Ferrie, L.; Reymond, S.; Kreuzer, T.; Colobert, F.; Jourdain,
P.; Marko, I. E. Synlett 2007, 2286–2288. (c) Colobert, F.; Kreuzer, T.;
Cossy, J.; Reymond, S.; Tsuchiya, T.; Ferrie, L.; Marko, I. E.; Jourdain, P.
Synlett 2007, 2351–2354.
(3) (a) Paul, G. K.; Matsumori, N.; Konoki, K.; Murata, M.; Tachibana,
K. J. Mar. Biotechnol. 1997, 5, 124–128. (b) Morsy, N.; Houdai, T.; Konoki,
K.; Matsumori, N.; Oishi, T.; Murata, M. Bioorg. Med. Chem. 2008, 16,
3084–3090.
(8) (a) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411–1414.
(b) Hicks, J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 5509–
5512. (c) Hicks, J. D.; Roush, W. R. Org. Lett. 2008, 10, 681–684.
10.1021/ol802168r CCC: $40.75
Published on Web 10/30/2008
2008 American Chemical Society