Concise Synthesis of 5α,6-Dihydroveragranine A and Veragranines A and B

(-)-Veragranines A and B are two steroidal alkaloids that exhibit potent analgesic activity. Herein, we report a 5-step biomimetic synthesis of 5α,6-dihydroveragranine A from hecogenin acetate, and the first divergent approach that allows access to veragranines A and B in 10~12 steps from deoxycholic acid. The synthesis of 5α,6-dihydroveragranine A features a cascade EF ring-opening/bromination/aldol condensation and C20 epimerization in a single step, and a Raney Ni/H2 enabled C26-azide reduction, imine formation and C16-Br hydrodebromination cascade in one pot. Based on our synthesis, an alternative biosynthetic proposal of veragranines was proposed. The synthesis of veragranines A and B features a well-designed photoredox-catalyzed decarboxylative Minisci reaction, which not only has good regioselective control but also results in the inversion of the stereochemistry at C20 through a radical process. Besides, the selection of an A/B cis-fused starting material enabled late-stage introduction of the Δ5(6) double bond, which simplified the process to introduce such a bond, and would be valuable for the synthesis of related natural products.