Synthetic Studies on Aplysiatoxin and Its Analogues

这项工作是为了开发一种合成applysiatoxin (I)的方法，applysiatoxin (I)是一种海洋天然产物，具有与TPA和telocidines非常相似的促肿瘤活性。我们也对未来从(I)合成新设计的明日启动子感兴趣。applysiatoxin (I)在C_1， C_<29>和C_<27>处有一个14元双内酯发色团，在C_<15>处有酚性部分，在C_1-C_<15>和C_<27>-C_<31>的无环部分有9个手性中心。我们对(1)的合成策略包括：1)反合成断开成3段A (C_8-C_<15>), B （C_2-C_7）和C，包括乙炔部分（C_1, C_<27>-C_<31>）；2)从(+)-酒石酸、(-)-酒石酸和(-)-苏氨酸开始，以光学纯形式合成所有片段；3) A段与B段偶联，接着A段与B段与乙炔部分C偶联；4)无环前体[a - b - c]段转化为(C_9, C_<27>)-二酸；5)采用Masamune等人开发的大内酯化法对c_9 -羟基和C_<27>-羧酸进行内酯化反应。最后的乳酸化仍未成功，目前正在进行中。

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.