Unified Total Synthesis of Madangamine Alkaloids

<p>The full details of a unified total synthesis of madangamine alkaloids are disclosed. Our central strategy is based on the construction of a common ABCE-tetracyclic system, followed by the late-stage installation of various D-rings. The common intermediate is assembled through <i>N</i>-acyliminium cyclization of a propargylsilane, and formation of the (<i>Z</i>,<i>Z</i>)-skipped diene. Stereoselective synthesis of the (<i>Z</i>,<i>Z</i>)-skipped diene is especially challenging, and is accomplished by the combination of <i>Z</i>-selective hydroboration of the 1,1-disubstituted allene and subsequent Migita-Kosugi-Stille coupling. Macrocyclic alkylation enables the late-stage variation of the D-rings on the common tetracyclic intermediate, resulting in the collective total syntheses of madangamines A–E. The synthetic madangamine alkaloids exhibited inhibitory activities against a variety of human cancer cell lines.</p>