Nucleophilic addition to N-alkoxyamides: Development and application to the total synthesis of gephyrotoxin

Nucleophilic addition to amide carbonyl groups is the simplest way to access multi-substituted amines found in biologically active natural alkaloids and pharmaceuticals. However, this promising transformation has received less attention due to their high stability. In this article, we describe our recent progress with N-alkoxyamides. Incorporation of an alkoxy group as a reactivity control element into the nitrogen atom of an amide successfully overcomes issues inherent to the nucleophilic addition. Especially, chemoselective version with the Schwartz reagent was useful, and enabled the concise total synthesis of (±)-gephyrotoxin.