Maitotoxin (MTX), isolated from the dinoflagellate Gambierdiscus toxicus, is the most toxic and largest non-biopolymer known to date. The toxin possesses a powerful ability to elevate the intracellular Ca^<2+> level of a wide range of cell types. The gross chemical structure and stereochemistry on fused or directly connected ether rings were elucidated on the basis of extensive 2D/3D NMR measurements and negative FAB MS/MS experiments. However, the relative configurations on the acyclic residues (C1-C15, C35-C39, C63-C68, and C134-C142) remained to be determined. Herein we report the relative configurations on the C35-C39 and C63-C68 portions of MTX determined by comparison between stereochemically defined synthetic model compounds (1a-1d and 17) and MTX in their NMR spectra. In order to realize this strategy of stereochemical determination, it was required to assume, and consequently shown, that the preferred conformation of an appropriately designed fragment with the natural configuration in NMR solvents reflects that of the corresponding portion of MTX; the NMR characteristics of the fragment should therefore not be significantly different from those of the corresponding moiety of MTX. Since the stereochemical correlations between rings K/L, O/P, and V/W have already been revealed, the present results led to the complete stereochemical correlation spanning all the ether rings (A-F'; C15-C134) in MTX.
