Synthetic Studies on Aplysiatoxin and Its Analogues

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This work was undertaken to develop a method for the synthesis of Aplysiatoxin (I), a marine natural product exhibiting a tumor promoting activity very similar to that of the better known TPA and teleocidines. We have also interested in a synthesis of newly designed tomor promoters from (I) in future. Aplysiatoxin (I) includes a 14-membered bis-lactone chromophore at C_1, C_<29> and C_9, C_<27>, phenolic moiety at C_<15>, and 9 chiral centers on a acyclic parts of C_1-C_<15> and C_<27>-C_<31>.Our synthetic strategy toward (I) involves 1) retrosynthetic disconnection into three segments A (C_8-C_<15>), B (C_2-C_7), and C including acethyene moiety (C_1, C_<27>-C_<31>) ; 2) synthesis of all segments in optically pure form, starting from (+)-Tartaric acid, (-)-Tartaric Acid, and (-)-Threonine, respectively ; 3) coupling the segment A with B followed by A-B with acetylenic part C ; 4) a novel transformation of acyclic precursor shown as the segment [A-B-C] into (C_9, C_<27>)-seco acid; 5) lactonization of C_9-hydroxy group and C_<27>-carboxylic acid by using the macrolactonization method developed by Masamune and coworkers. The final lactonization is still unsuccessful and is now being conducted.