Structure–activity relationship studies of maitotoxin (MTX), a marine natural product produced by an epiphytic dinoflagellate, were conducted using chemically synthesized model compounds corresponding to the partial structures of MTX. Both enantiomers of the LMNO ring system were synthesized via aldol reaction of the LM ring aldehyde and the NO ring ketone. These fragments were derived from a common cis-fused pyranopyran intermediate prepared through a sequence involving Nozaki–Hiyama–Kishi reaction, intramolecular oxa-Michael addition, and Pummerer rearrangement. The NOPQR(S) ring system, in which the original seven-membered S ring was substituted with a six-membered ring, was also synthesized through the coupling of the QR(S) ring alkyne and the NO ring aldehyde and the construction of the P ring via 1,4-reduction, dehydration, and hydroboration. The inhibitory activities of the synthetic specimens against MTX-induced Ca2+ influx were evaluated. The LMNO ring system and its enantiomer induced 36 and 18% inhibition, respectively, at 300 μM, whereas the NOPQR(S) ring system elicited no inhibitory activity.

Stereoselective synthesis of the C1–C29 part of amphidinol 3 (AM3) was achieved. The C1–C20 part was assembled from three building blocks via regioselective cross metathesis to form the C4–C5 double bond and addition of an alkenyllithium and a lithium acetylide to two Weinreb amides followed by asymmetric reduction to form the C9–C10 and C14–C15 bonds, respectively. The C21–C29 part was synthesized via successive cross metathesis and oxa-Michael addition sequence to construct the 1,3-diol system at C25 and C27 and Brown asymmetric crotylation to introduce the stereogenic centers at C23 and C24. Coupling of the C1–C20 and C21–C29 parts was achieved by Julia–Kocienski olefination and regio- and stereoselective dihydroxylation of the C20–C21 double bond in the presence of the C4–C5 and C8–C9 double bonds to afford the C1–C29 part of AM3.

Stereoselective synthesis of the C′D′E′F′ ring system of maitotoxin was achieved starting from the E′ ring through successive formation of the D′ and C′ rings based on SmI2-mediated reductive cyclization. Construction of the F′ ring was accomplished via Suzuki–Miyaura cross-coupling with a side chain fragment and Pd(II)-catalyzed cyclization of an allylic alcohol. The C′D′E′F′ ring system inhibited maitotoxin-induced Ca2+ influx in rat glioma C6 cells with an IC50 value of 59 μM.

Stereoselective synthesis of the C43–C67 part of amphidinol 3 (AM3) and its C51-epimer was achieved starting from a common intermediate corresponding to the tetrahydropyran moiety of AM3, via asymmetric oxidations and Julia–Kocienski olefination. By comparing NMR data of the synthetic specimens with those of AM3, the absolute configuration at C51 of AM3 was revised from R to S.

Amphidinol 3 (AM3), a membrane-active agent isolated from the dinoflagellate Amphidinium klebsii, consists of a long carbon chain containing 25 stereogenic centers. Although the absolute configuration of AM3 was determined by extensive NMR analysis and degradation of the natural product, the partial structure corresponding to the tetrahydropyran ring system was found to be antipodal to that of karlotoxin 2, a structurally related compound recently isolated from the dinoflagellate Karlodinium veneficum. By extensive degradation of the natural product and conversion of the resulting alcohol to an MTPA ester, the absolute configuration at C45 of AM3 was confirmed to be R, supporting the originally proposed structure.

Maitotoxin (MTX) is a ladder-shaped polyether produced by the epiphytic dinoflagellate Gambierdiscus toxicus. It is known to elicit potent toxicity against mammals and induce influx of Ca2+ into cells. An artificial ladder-shaped polyether possessing a 6/7/6/6/7/6/6 heptacyclic ring system, which was designed for elucidating interactions with transmembrane proteins, was found to be the most potent inhibitor against MTX-induced Ca2+ influx that has ever been reported.