Total synthesis of the maduropeptin chromophore aglycon

Maduropeptin consists of a 1:1 complex of a carrier protein and a chromophore. The maduropeptin chromophore exhibits potent antitumor and antibacterial activities by means of a mechanism distinct from that of structurally related natural enediynes. The nine-membered enediyne forms after nucleophilic attack of the C14-amide nitrogen and then cycloaromatizes spontaneously to form the p -benzyne biradical, which can efficiently cleave double-stranded DNA by hydrogen abstraction. Thus, the chromophore represents a stable prodrug form of the highly reactive enediyne structure, In this paper, we report the first total synthesis of the aglycon 1 of the chromophore. The bicyclo[7.3.0]enediyne core with the exo -C4,13-Z -olefin and the 15-membered ansa-macrolactam with the non-biaryl atropisomerism are unique structural features that made this synthesis particularly challenging. The key reactions used in the described synthesis were cerium amide promoted nine-membered ring formation, one-pot macrolactam formation from the azide pentafluorophenyl ester, and SmI2-Mediated reductive 1,2-elimination to construct the C13-Z-olefin.