Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：The Society of Synthetic Organic Chemistry, Japan  

<p>Maitotoxin (MTX) is a ladder-shaped polyether produced by the dinoflagellate <i>Gambierdiscus toxicus</i>. MTX comprises of 32 cyclic ethers and 98 stereogenic centers with the molecular weight of 3422. The molecule can be divided in two parts, hydrophobic (northern hemisphere) and hydrophilic (southern hemisphere) regions. MTX elicits potent acute toxicity and Ca²⁺ influx activity. The unique giant structure and potent biological activity of MTX has attracted great deal of interest among synthetic chemists. During the course of our structure-activity relationship studies based on chemical synthesis of partial structure of MTX, we synthesized the C'D'E'F' and WXYZA'B'C' ring systems corresponding to partial structures of the hydrophobic region of MTX, and found that they inhibited MTX-induced Ca²⁺ influx with IC₅₀ values of 59µM and 30µM, respectively. With the expectation that a more extended partial structure would inhibit MTX-induced Ca²⁺ influx in a more potent manner, the WXYZA'B'C'D'E'F' ring corresponding to the hydrophobic region was synthesized. We have developed a convergent method for synthesizing ladder-shaped polyethers via α-cyano ethers, therefore we planned to synthesize the WXYZA'B'C'D'E'F' ring from the WXYZ ring and the C'D'E'F' ring systems via construction of the A'B' ring system. The C'D'E'F' ring was synthesized from the E' ring via successive construction of the D' and C' rings by using SmI₂ induced reductive cyclization, and Suzuki-Miyaura coupling to introduce a side chain, and Pd catalyzed cyclization to construct the F' ring. The WXYZ ring was synthesized from the W and Z rings via aldehyde-alkyne coupling, cyclodehydration, ring-expansion of a six-membered ring ketone to a seven-membered one, and methylation of an <i>O</i>, <i>S</i>-acetal. The WXYZ ring aldehyde and the C'D'E'F' ring diol was combined by acetal formation, and regioselective opening of the resulting seven-membered ring acetal afforded an α-cyano ether. Reduction of the nitrile followed by Grignard reaction afforded a diene, which was subjected to ring closing metathesis to furnish eight-membered cyclic ether. Oxidation of the secondary alcohol followed by base induced epimerization afforded an enone corresponding to the B' ring. Although reductive etherification of a methyl acetal to construct the A' ring was unsuccessful giving an undesired diastereomer at C117, that via radial reduction of an <i>O</i>, <i>S</i>-acetal resulted in the formation of the desired one. Introduction of the terminal olefin via Wittig reaction afforded the WXYZA'B'C'D'E'F' ring in 16 steps. The molecular weight of the synthesized compound is 1140, and the longest linear sequence from commercially available starting material is 53 steps with 104 total steps. Although a number of synthetic studies on partial structure of MTX have been reported, this is the first example of the synthesis of the WXYZA'B'C'D'E'F' ring segment of MTX. The NMR data for the synthetic compound are in good accordance with those for the natural product except for the W ring terminus due to the structure difference from MTX. Contrary to our expectation, the WXYZA'B'C'D'E'F' ring segment did not inhibit MTX-induced Ca²⁺ influx, presumably due to its poor solubility in aqueous media. These results provide potential clues to understanding the mode of action of MTX, and will aid in the design of biologically active molecules based on the partial structure of the natural product.</p>

DOI： 10.5059/yukigoseikyokaishi.81.35

Scopus

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： doi.org/10.5059/yukigoseikyokaishi.81.35

Web of Science

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： doi.org/10.1246/bcsj.20210397

Event date： 2024.5

Language：Japanese  

Country：Japan  

Event date： 2024.5

Language：Japanese  

Country：Japan  

Event date： 2024.5

Language：Japanese  

Country：Japan  

Event date： 2024.5

Language：Japanese  

Country：Japan  

Event date： 2024.5

Language：Japanese  

Country：Japan