A unified total synthesis of stemoamide-type alkaloids is reported. Our synthetic approach features the chemoselective convergent assembly of five-membered building blocks via stemoamide as the common precursor to tetracyclic natural products. The synthesis consists of two successive coupling reactions of the three five-membered building blocks. The first coupling reaction is the vinylogous Michael addition/reduction sequence, which enables the gram-scale synthesis of stemoamide. The second coupling reaction is a chemoselective nucleophilic addition to stemoamide. While the lactone-selective nucleophilic addition to stemoamide affords saxorumamide and isosaxorumamide, the lactam-selective reductive nucleophilic addition leads to the formation of stemonine. Both chemoselective nucleophilic additions enable direct modification of stemoamide, resulting in highly concise and efficient total syntheses of the stemoamide-type alkaloids.

The collective synthesis of pentacyclic stemoamide-type alkaloids is recognized as a daunting task despite high demand for a comprehensive biological profiling of these natural products. In this Letter, we report a unified synthesis of seven pentacyclic alkaloids and two unnatural derivatives. The keys to success are (1) the chemoselective assembly of four five-membered building blocks, (2) the direct oxidation of pyrrolidine natural products to pyrrole derivatives, and (3) the stereodivergent construction of totally E- or Z-substituted butenolides.

Nucleophilic addition to amides has been recognized as a promising transformation for total synthesis of complex alkaloids. Amides can accept two different organometallic reagents through the nucleophilic addition, which enables it to serve as a stable surrogate of multi-substituted amines. However, the nucleophilic addition has been overlooked for a long time due to three main reasons: low electrophilicity of amide carbonyls, potential hydrolysis of the reaction intermediate and excess addition of an organometallic reagent. This mini review focuses on the recent progress of total synthesis of complex alkaloids based on the nucleophilic additions to N-alkoxyamides, tertiary amides and secondary amides.

Our research group has been exploring a lactam strategy for the concise total synthesis of complex alkaloids. In this article, we report full details of the unified total synthesis of stemoamide-type alkaloids by chemoselective assembly of five-membered rings based on the lactam strategy. First, the concise and gram-scale synthesis of tricyclic stemoamide was achieved by vinylogous Michael addition-reduction sequence of an unsaturated γ-lactam with an unsaturated γ-lactone, followed by N-alkylation to form the seven-membered ring. From stemoamide as a common intermediate, chemoselective nucleophilic addition of unsaturated lactone derivatives provides tetracyclic natural products. While stemonine is obtained by an Ir-catalyzed lactam-selective reductive Mannich reaction, saxorumamide and isosaxorumamide are produced through the lactone-selective nucleophilic addition of the lithiated 2-silyl furan. The developed conditions for the lactam-selective nucleophilic reactions are highly general, and were found to be applicable to the total synthesis of pentacyclic stemocochinin and isostemocochinin. The strategy enables the concise and unified total synthesis of tricyclic, tetracyclic and pentacyclic stemoamide-type alkaloids within 12 steps from a commercially available compound.