Chemical Synthesis of the GHIJKLMNO Ring System of Maitotoxin K. C. Nicolaou,* Michael O. Frederick, Antonio C. B. Burtoloso, Ross M. Denton, Fatima Rivas, Kevin P. Cole, Robert J. Aversa, Romelo Gibe, Taiki Umezawa, and Takahiro Suzuki Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and Department of Chemistry and Biochemistry, UniVersity of California, San Diego, 9500 Gilman DriVe, La Jolla, California 92093 Received February 14, 2008; E-mail: kcn@scripps.edu Abstract: As the largest secondary metabolite to be discovered as of yet, the polyether marine neurotoxin maitotoxin constitutes a major structural and synthetic challenge. After its originally proposed structure (1) had been questioned on the basis of biosynthetic considerations, we provided computational and experimental support for structure 1. In an effort to provide stronger experimental evidence of the molecular architecture of maitotoxin, its GHIJKLMNO ring system 3 was synthesized. The 13 C NMR chemical shifts of synthetic 3 matched closely those corresponding to the same domain of the natural product providing strong evidence for the correctness of the originally proposed structure of maitotoxin (1). Introduction Maitotoxin is the largest secondary metabolite isolated 1 as yet from any living creature. Its legendary toxicity surpasses that of any known molecule, other than a few proteomic substances. As such, this impressive natural product elicited considerable attention from the scientific community. 1–5 Mai- totoxin was first detected in the gut of the surgeonfish Ctenocha- etus striatus, 1b,c and later in the dinoflagellate Gambierdiscus toxicus. 1d However, it would not be until 1988 that the substance was actually isolated from a broth of G. toxicus by Yasumoto and co-workers. 1e The gross structure of maitotoxin was proposed by Yasumoto and co-workers in 1993. 2b Its relative stereochemistry was defined by Kishi et al. in 1996, 3a with its absolute stereochemistry assigned by Tachibana et al. in the same year (1, Figure 1). 4e In 2006, the assigned structure of maitotoxin came under close scrutiny by Gallimore and Spencer on the basis of biosynthetic considerations, which suggested the opposite configuration at the two stereocenters of the JK junction (structure 1, C-51, C-52, Figure 1). 6 Following this challenge, and in order to test the Gallimore-Spencer hypoth- esis, we resorted to computational chemistry, which provided support for the originally proposed (1), rather than a revised, structure. 7 In a subsequent study, we synthesized the GHIJK ring system 2 (Figure 1) of maitotoxin and compared its 13 C chemical shifts with the corresponding 13 C chemical shifts of the natural product (1), an exercise that provided experimental evidence in support of the originally proposed structure (1) of maitotoxin. 8 In this article, we describe the chemical synthesis of the entire GHIJKLMNO ring domain 3 (Figure 1) of structure 1, and the comparison of the 13 C chemical shifts of this fragment to those reported for the same domain of the natural product, which provided further support for the originally proposed structure (1) of maitotoxin. Results and Discussion 1. Retrosynthetic Analysis. Having defined our target as structure 3, we proceeded to consider a strategy by which to (1) (a) Murata, M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293. (b) Yasumoto, T.; Bagnins, R.; Randal, J. E.; Banner, A. H. Bull. Jpn. Soc. Sci. Fish. 1976, 37, 724. (c) Yasumoto, T.; Bagnins, R.; Vernoux, J. P. Bull. Jpn. Soc. Sci. Fish. 1976, 42, 359. (d) Yasumoto, T.; Nakajima, I.; Bagnis, R.; Adachi, R. Bull. Jpn. Soc. Sci. Fish. 1977, 43, 1021. (e) Yokoyama, A.; Murata, M.; Oshima, Y.; Iwashita, T.; Yasumoto, T. J. Biochem. 1988, 104, 184. (2) (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. J. Am. Chem. 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