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 N-acyliminium cyclization of a propargylsilane, and formation of the (Z,Z)-skipped diene. Stereoselective synthesis of the (Z,Z)-skipped diene is especially challenging, and is accomplished by the combination of Z-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.
A unified total synthesis of madangamine alkaloids has been achieved. The common ABCE-tetracyclic intermediate was prepared through N-acyliminium ion cyclization, and subsequent formation of the (Z,Z)-skipped diene including Z-selective hydroboration. The late-stage installation of the various D-rings accomplished the collective total synthesis of madangamines A–E, which were used to elucidate the role of the D-rings in their cytotoxicities against various human cancer cell lines.
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