Abstract
AbstractDevelopment of a unified total synthesis of madangamine alkaloids is described. The synthesis consists of three parts: (1) construction of the central ABC-ring, (2) installation of the skipped diene bearing a trisubstituted olefin, and (3) the synthesis of various D-rings from a tetracyclic ABCE-common intermediate. The ABC-tricyclic framework is successfully assembled by intramolecular allenylation. The most significant issue in this synthesis is the stereoselective installation of the skipped diene. This challenge is ultimately overcome by development of a stereodivergent approach using hydroboration of allenes and Migita-Kosugi-Stille coupling. The hydroboration is especially useful because the reaction of 1,1-disubstituted allenes with either 9-BBN or (Sia)2BH gives (E)- or (Z)-allylic alcohols, respectively. The key to the success of our unified total synthesis is macrocyclic alkylation to form a wide variety of D-rings from the tetracyclic ABCE-common intermediate. Our collective synthesis of madangamine alkaloids revealed structure–activity relationship of D-rings in their cytotoxicity against human cancer cell lines.
Publisher
Springer Nature Singapore