P-39 シガトキシンの全合成(ポスター発表の部)

抄録

Ciguatoxin (1) is a principal toxin of ciguatera which is one of the most wide spread seafood poisonings. Our concept for the total synthesis toward Ciguatoxin (1) is based on acetylene dicobalthexacarbonyl complex-mediated ether-cyclizations. The reacton proceeds via a dicobalthexacarbonyl complex-stabilized cationic intermediate, which called Nicholas effect, subsequently undergoes endo cyclization to give a syn product thermodynamically. We have explored various decomplexation methods of the endo-acetylene cobalt complex. The retrosynthetic analysis toward ciguatoxin is revealed that the A, F, and G ring would be cyclized at the latest stage after the coupling between acetylene of left segment and aldehyde of right segment. Segment coupling between left segment 12 and right segment 13 afforded the acyclic acetylene 14. F-ring cyclization was successfully accomplished through intramolecular Nicholas reaction. The cyclic cobalt complex 16 was converted into corresponding ketone 17 via ligand exchange with dppm. Reductive etherification of the hydroxyketone provided BCDEFGHIJKLM-ring 19 in moderate yield. B-ring side chain was converted into acetylene in several steps. Sonogashira coupling with vinyliodide 25 to furnish the corresponding product enyne 37. Treatment of the acetylene cobalt complex of 37 with excess TMSOTf at -20℃ generated stable propargyl cation in dichloromethane solvent. Addition of THF solvent into this reaction mixture at -20℃ made a big progress by scavenging the excess Lewis acid in the reaction mixture to promote the equilibrium toward the cyclization product 38. Reductive decomplexation of the endo-cobalt complex 38 was accomplished under excess sodium hypophosphite to provide a cis olefin. Final deprotection of the four acyl groups with K_2CO_3 in a mixture of methanol and THF solvent afforded ciguatoxin (CTXIB, 1)