Total Synthesis of the Maduropeptin Chromophore Aglycon

Abstract

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 fro...