Total Synthesis of Ussuriedine via a Late-Stage Stevens Rearrangement: Implications for Biosynthesis

Ussuriedine, an intricate heptacyclic steroidal alkaloid from the Veratrum family, features an unprecedented octahydro-3,6-methanoquinolizine framework. Its biosynthetic origins have not been established, and until now, no chemical synthesis has been reported. Here, we detail a de novo, convergent total synthesis of ussuriedine accomplished in 23 linear steps from ethyl vinyl ketone. The decalin (AB rings) and piperidine (F ring) fragments are coupled via reductive amination, establishing the connectivity required for an intramolecular [2 + 2 + 2] cyclotrimerization, which builds the aromatic D ring, thereby simultaneously constructing the C and E rings of the hexacyclic cevanine core. In the crucial final sequence, nitrogen quaternization followed by a [1,2]-Stevens rearrangement assembled the G ring, and selective oxidation of benzylic methine completed the natural product. The underlying chemical logic of the endgame, which connects the peripheral methyl and benzylic carbons, provides a mechanistic basis for a hypothesis on how nature might create ussuriedine's complex framework and underscores the power of chemical synthesis to inform natural product biosynthesis.