Maitotoxin (MTX, 1) has been isolated as one of the responsible toxins for ciguatera, which is a form of food poisoning caused by ingestion of coral reef fish. Consequently, the toxin was found to originate from a dinoflagellate Gambierdiscus toxicus. While the planar structure with partial stereochemical assignments for MTX has been reported recently, the stereostructures of acyclic parts, C1-C14, C36-C38, C64-C67, and C135-C142, remains unknown. In this study, we report a synthesis of the tetracyclic fragment corresponding to C56-C75 of MTX and elucidation of the stereochemistry at C64 and C66, which could not be assigned by spectroscopic methods. Preliminary investigations by NOE, ^3JH,H data, and MM2-type calculations (Discover/InsightII) implied that the two hydroxy-bearing carbons had (64S^*, 66S^*) relative stereochemistry. Thus, we first aimed at the synthesis of this stereoisomer. Key steps in our synthesis involved acid-catalyzed 6-endo selective cyclization of epoxy alcohol to construct cis-fused 1,6-dioxadecalin system, and chelation-controlled Aldol condensation of the L/M and N/O ring fragments followed by 1,3-anti reduction of the resulting β-hydroxy ketone, to provide the tetracyclic fragment with (64S, 66S) stereochemistry. Its NMR data agreed extremely well with those of the corresponding part of MTX.
