Maduropeptin, an extremely potent antitumor agent, was isolated from the groth filtrate of Acti nomadura madurae. It was identified as a 1: 1 complex of an acidic carrier apoprotein (32kDa) and 9-membered ring enediyne chromophore. The structure of intact chromophore has not been elucidated because it is too labile for isolation, and instead methanol adduct (1) was isolated from the methanol extract and was characterized except for the absolute stereochemistry. The chromophore (1) possesses a labile 9-membered diyne core, a macrolactam ansa-bridge and an aminosugar. We developed a new reductive olefination method from diol derivatives using SmI_2, and succeeded in synthesizing the aglycon (5). Installation of the 9-membered diyne ring is one of the most important steps in the synthesis of maduropeptin chromophore. We developed a new cyclization method using LiN(SiMe_2Ph)_2 and CeCl_3, which was superior to the previous combination, i.e., LiHMDS/CeCl_3. TBS group of cyclized 7 was removed and the alcohol (16) was converted to the azide. The TBDPS group was also removed and the alcohol (17) was oxidized to the corresponding carboxylic acid, which was converted to the pentafluorophenyl ester. Then, macrolactam (19) was formed spontaneously after Staudinger reaction. X-ray crystallographic analysis of 19 proved that the two triple bonds are greatly bent. To complete the synthesis of the aglycon (5), p-trifluoromethyl benzoate was chosen as the diol derivative. The corresponding dibenzoate (20) was exposed to the reduction conditions using SmI_2, so that the desired 4,13-Z-olefin (21) was solely produced. This regioselectivity would be controlled by the repulsion between the ansabridge and the C13-p-trifluoromethyl benzoate. Protected aglycon (22) was a mixture of two atropisomers, which were in equilibrium at room temperature. Finally, all protecting groups were removed and aglycon (5) was synthesized for the first time.
