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Nucleophilic addition to amides has been recognized as a promising transformation for the total synthesis of polycyclic alkaloids. The reaction produces substituted amines from easily available amides while avoiding the unwanted high reactivities of amines and use of extra-protecting group manipulations. In this chapter, we introduce the development of two types of amide-selective nucleophilic addition reactions and their applications to total synthesis. The first topic is the total synthesis of gephyrotoxin based on the reductive allylation of an N-methoxylactam. The reaction takes place in the presence of a more electrophilic methyl ester by taking advantage of the N-methoxy group and the Schwartz reagent [Cp2ZrHCl]. The second topic is the unified total synthesis of stemoamide-type alkaloids by chemoselective assembly of five-membered rings. The most challenging step is an iridium-catalyzed reductive nucleophilic addition to a γ-lactam. A γ-lactone was installed to a γ-lactam carbonyl without affecting the γ-lactone found in tetracyclic protostemonamide, resulting in the total synthesis of pentacyclic protostemonines.

Development 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 stereodi-vergent 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, respec-tively. 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 interme-diate. Our collective synthesis of madangamine alkaloids revealed structure-activity relationship of D-rings in their cytotoxicity against human cancer cell lines.