Progress towards the synthesis of aconitine: construction of the AE fragment and attempts to access the pentacyclic core

In this full article, we report our efforts towards the total synthesis of aconitine (1), a representative C-19-diterpenoid alkaloid that possesses perhaps one of the most architecturally intricate ring systems in nature. From (R)-(-)-carvone-derived 20, we first prepared chiral 2-methylenecyclohexane-1,3,5-triol derivative 19. A substrate-controlled intramolecular [3 + 2] cycloaddition of an in situ-generated nitrone intermediate 25 derived from 19 provides fully decorated A-ring building block 17. The first reported synthesis of fully functionalized aconitine AE fragment 16 is achieved from 17 by C11 hydroxylation, E-ring cyclization, and C5 one-carbon extension. Alkynylation of AE fragment 16 with CD fragment 15 gives radical cyclization precursors 14b and 14c. Efforts to achieve the challenging radical cyclization cascade of 14b and 14c under various conditions failed to produce the desired pentacyclic intermediate 12a in the route to aconitine (1).