Strategic Evolution toward Synthesis of the Isosteroidal Alkaloids Veratramine and Cyclopamine

Veratramine and cyclopamine are two structurally complex Veratrum alkaloids with significant biological activities, yet their efficient synthesis and the generation of diverse derivatives have remained challenging. Here, we describe a full account of our synthetic studies on these alkaloids. The first-generation 15-step route to veratramine featured a biomimetic rearrangement and a vinylogous Mannich reaction. After strategic refinement, we established a divergent, gram-scale, 13-step approach to both veratramine and cyclopamine from commercially available DHEA, relying on alkyne hydrocyanation, biomimetic skeletal rearrangement, and a reductive coupling/(bis-)cyclization sequence.