Advances in the Total Synthesis of Pharmacologically Important Fused Indolizidine Alkaloids: Securinine, Gephyrotoxin and Lepadiformine.

Indolizidine alkaloids represent a diverse group of naturally occurring compounds which are derived from various sources and possess a wide range of pharmacological activities. Fused indolizidine alkaloids represent a distinct subset of these compounds, where additional rings are fused with the indolizidine core. When combined with the specific stereochemistry typically required for their biological activity, the fused ring structure complicates the synthesis of this important class of compounds. Among the well-studied fused indolizidine alkaloids are securinine, gephyrotoxin, and lepadiformine, which have all exhibited potential in important therapeutic areas. Due to their complex structures, over the years numerous approaches have been proposed to synthesize these compounds. In this article, we review the progress made in synthetic routes for these key fused indolizidine alkaloids throughout history, providing a broad overview and the distinct advantages of the various strategies that could be employed in their synthesis.